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Neurobehavioral alteration in autoimmune mice
Abstract
Inbred MRL, NZB and BXSB strains of mice spontaneously develop a systemic, lupus-like autoimmune disease. The progress of autoimmunity is accompanied with a cascade of behavioral changes, most consistently observed in tasks reflective of emotional reactivity and the two-way avoidance learning task. Given the possibility that behavioral alterations may reflect a detrimental consequence of autoimmune-inflammatory processes and/or an adaptive response to chronic malaise, they are tentatively labeled as autoimmunity-associated behavioral syndrome (AABS). It is hypothesized that neuroactive immune factors (pro-inflammatory cytokines, brain-reactive antibodies) together with endocrine mediators (corticotropin-releasing factor, glucocorticoids) participate in the etiology of AABS. Since AABS develops natively, and has a considerable face and predictive validity, and since the principal pathway to autoimmunity is known, AABS may be a useful model for the study of CNS involvement in human autoimmune diseases and by extension, for testing autoimmune hypotheses of several mental disorders (major depression, schizophrenia, Alzheimer's disease, autism and AIDS-related dementia).
... In addition, we discuss experimental data pointing to viable pathogenic mechanisms that underlie CNS involvement in SLE. Excellent reviews about other aspects of this and other murine models of lupus can be found elsewhere [3,11,[21][22][23][24][25][26][27][28][29][30][31][32][33][34]. ...
... MRL/lpr) differs from the congenic (control) MRL/+ strain by a defect in membrane apoptoticsignaling Fas protein, which is due to a retrotransposon in the Fas gene [50,51]. In addition to the typical signs of peripheral SLE, including autoantibodies, skin disease, arthritis, lymphadenopathy, and nephritis, MRL/lpr mice develop a constellation of behavioral outcomes referred to as "autoimmunity-associated behavioral syndrome" [24], particularly in the behavioral domains of emotional reactivity, motivated behavior, and cognitive function [14,20,22,24,33,. ...
... MRL/lpr) differs from the congenic (control) MRL/+ strain by a defect in membrane apoptoticsignaling Fas protein, which is due to a retrotransposon in the Fas gene [50,51]. In addition to the typical signs of peripheral SLE, including autoantibodies, skin disease, arthritis, lymphadenopathy, and nephritis, MRL/lpr mice develop a constellation of behavioral outcomes referred to as "autoimmunity-associated behavioral syndrome" [24], particularly in the behavioral domains of emotional reactivity, motivated behavior, and cognitive function [14,20,22,24,33,. ...
To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.
... Lupus-prone mice such as NZB, NZBWF1 and MLR/lpr exhibit significantly increased anxiety profiles on EPM test and have been used as a model for understanding the etio pathogenesis of anxiety disorders in SLE patients [8,9]. Genome-wide scan and linkage study revealed that the region harboring IFN-α genes on chromosome 4 in NZB mice is linked to the anxiety-like behavior on EPM test in NZB/NZW (New Zealand White) F1 mice [10]. ...
... The finding suggests that type I-IFN signaling is not required for the increased anxiety profile developed in these autoimmune mice. Nonetheless, previous studies reported that lupus-prone mice develop behavior changes in parallel with the autoimmune process, suggesting that behavioral dysfunctions are the consequence of autoimmune disease [8,9]. ...
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that is accompanied by neuropsychiatric manifestations such as anxiety. Despite undefined etio-pathogenesis for SLE, emerging evidence supports the importance of type I interferon (IFN) in the pathogenesis of autoimmune formation and renal damage both in SLE patients and lupus mice. Linkage mapping identified a quantitative trait locus (QTL) for elevated plus-maze (EPM) performance on the segment of chromosome 4 in lupus-prone New Zealand black (NZB) mice where the type I IFN-α genes are harbored. To determine possible roles of type I IFNs for anxiety-like behaviors in NZB mice, we evaluated the anxiety profile by EPM test in NZB mice with deficiency of type I-IFN receptor (IFNARKO). Consistent with previous observation, disruption of the type I-IFN signaling resulted in a dramatic attenuation in glomerulonephritis, splenomegaly and plasma anti-nuclear antibodies (ANA) in NZB mice. However, blockade of type I-IFN signaling had no effect on performance in the EPM by NZB/IFNARKO mice in comparison to wild type controls. The results support a pathogenic role for type I -IFN in autoimmune development and kidney inflammation. Nonetheless, type I-IFN signaling is not responsible for increased anxiety profile developed in these autoimmune mice.
... Besides systemic autoimmunity and inflammation, a large percentage of these animals develop various brain abnormalities and a constellation of behavioral deficits. The lack of an adequate (genetically similar) control group and a high incidence of inherited brain anomalies in NZB and BXSB strains (Sherman et al., 1987(Sherman et al., , 1990a, however, precludes a direct linkage between immunopathogenic mechanisms on one side, and brain damage and aberrant behavior on the other (Lal et al., 1988;Forster et al., 1988a, b;Schrott et al., 1993Schrott et al., , 1992Schrott and Crnic, 1996a (Sakic et al., 1997b;Szechtman et al., 1997;Ballok, 2007). The MRL/lpr and the congenic MRL/Mp mice are comparable in many respects (appearance, size, and reproductive age), except in the onset of systemic autoimmune disease. ...
... Due to the presence of the lymphoproliferative (lpr) gene on chromosome 19 and a subsequent deficit in apoptotic Fas receptor expression (Singer et al., 1994) MRL/lpr mice develop an accelerated form of the chronic lupus-like condition (Theofilopoulos, 1992). This murine form of SLE is accompanied by a constellation of behavioral deficits, operationally labeled "autoimmunity-associated behavioral syndrome" (Sakic et al., 1997b). At the onset of serological manifestations the deficits are most consistently noted in tasks reflective of emotional reactivity and affective behavior , while at advanced stages of lupus-like disease learning/memory deficits may emerge (Sakic et al., 1992;Hess et al., 1993). ...
This chapter summarizes current knowledge on the relationship between systemic autoimmune/inflammatory processes, brain pathology,
and mental (dys) function. Several lines of evidence are presented, as well as the molecular mechanisms instrumental in the
initiation and maintenance of complex pathogenic circuits. Although the emphasis is on systemic lupus erythematosus and its
associated neuropsychiatric manifestations, other disorders relevant to the immunological theory of mental disorders are also
reviewed. Together with relevant immunopathology, the associated permissive conditions (e.g., breached blood-brain barrier)
are discussed in the context of an upregulation in brain-reactive autoantibodies, neuroactive cytokines, complement components,
and immune complexes. The gaps in our present knowledge and future directions are outlined at the end of the chapter.
... To test the possibility that extracellular purinergic signaling plays a role in the spontaneous emergence of autoimmune/inflammatory disease, neuronal atrophy, and behavioral deficits in MRL-lpr animals, the P2X purinoceptor antagonist (Humphrey et al., 1995), suramin, was employed in the present study. An imbalanced neuroimmuno-endocrine network is also proposed to play a key role in the etiology of brain damage in lupus-like disease (Sakic et al., 1997a;Ballok, 2007), but whether central neurons can be initially damaged by an autoimmune-driven upregulation in corticosterone production (Shanks et al., 1999;Lechner et al., 2000) has not previously been examined in MRL mice. Therefore, the overall expectation was that chronic treatment with suramin would suppress the onset of peripheral disease, thereby preventing behavioral impairments, as well as early signs of neurodegeneration in NP-SLE mice. ...
... The so-called "autoimmunity-associated behavioral syndrome" in MRL-lpr mice resembles, in many aspects, sickness behavior of infected animals (Sakic et al., 1997a). Sickness behavior appears to be the expression of a central motivational state that reorganizes the organism's priorities to cope with infectious pathogens (Hart, 1990). ...
Neurologic and psychiatric (NP) manifestations are severe complications of systemic lupus erythematosus (SLE). As commonly seen in patients, spontaneous disease onset in the MRL/MpJ-Faslpr/J (MRL-lpr) mouse model of NP–SLE is accompanied by increased autoantibodies, pro-inflammatory cytokines and behavioral dysfunction which precede neuroinflammation and structural brain lesions. The role of purinergic receptors in the regulation of immunity and behavior remains largely unexplored in the field of neuropsychiatry. To examine the possibility that purinoception is involved in the development of affective behaviors, the P2X purinoceptor antagonist, suramin, was administered to lupus-prone mice from 5 to 14 weeks of age. In addition to food and water measures, novel object and sucrose preference tests were performed to assess neophobic anxiety- and anhedonic-like behaviors. Enzyme-linked immunosorbant assays for anti-nuclear antibodies (ANA) and pro-inflammatory cytokines were employed in immunopathological analyses. Changes in dendritic morphology in the hippocampal CA1 region were examined by a Golgi impregnation method. Suramin significantly lowered serum ANA and prevented behavioral deficits, but did not prevent neuronal atrophy in MRL-lpr animals. In a new batch of asymptomatic mice, systemic administration of corticosterone was found to induce aberrations in CA1 dendrites, comparable to the “stress” of chronic disease. The precise mechanism(s) through which purine receptor inhibition exerted beneficial effects is not known. The present data supports the hypothesis that activation of the peripheral immune system induces nociceptive-related behavioral symptomatology which is attenuated by the analgesic effects of suramin. Hypercortisolemia may also initiate neuronal damage, and metabolic perturbations may underlie neuro-immuno-endocrine imbalances in MRL-lpr mice.
... A signi®cant decrease of NPY and VIP levels were measured in 5-and 8- month-old NZB and NZB/W F1 mice while an enhancement of SP and CGRP was observed at 8 months in autoimmune mice when compared with NZW (*P , 0:05, **P , 0:01, ANOVA Kruskal±Wallis' post-hoc test). compared with the NZW mice [19] and that these differences are related to the development of the disease [18]. One possible mechanism for the activity and avoidance de®cits is an altered emotionality and/or increased anxiety in response to adverse stimuli, which could both interfere with task acquisition and memory consolidation [19]. ...
... It has been reported that in the early months of age the NZB/W F1 mice do not display neuronal impairment , while they later present de®cits in cognitive functions [20] [25], essentially memory and learning. Likewise the autoimmune NZB parental strain is also characterized by learning and memory de®cits although the patterns of impairment are differently expressed [18]. Considerable evidence exists to indicate that NPY is involved in cognitive functions and in anxiety-like behaviour [4] [26]. ...
It has been reported that more than 50% of lupus patients show various forms of neurological deficits including impaired cognitive functions and psychiatric disorders. Using an animal model of lupus we investigated the production of neuropeptides in the brain of NZB/W F1 female hybrid mice and its parental strain NZB and NZW. Our results indicate that the alteration in learning and memory described in lupus mice are paralleled by a decrease in calcitonin gene-related peptide, substance P and neuropeptide Y (NPY) levels in the hippocampus and a significant decrease of NPY in the cortex. These findings are interesting in the light of previously reported results suggesting that these neuropeptides can play an important role in cognitive functions. We also observed a decrease of NPY and vasoactive intestinal polypeptide levels in the hypothalamus of lupus prone mice and these changes may be related to the disregulation of the hypothalamus-pituitary-adrenal axis observed in lupus prone mice.
... Given that no animal model provides a complete representation of human condition, each strain has distinct features that make it more or less adequate for examining certain aspects of lupus-like disease. Considering MRL mice do not show inherited brain abnormalities (Sherman et al., 1987), this strain has been useful in examining the interrelationships between systemic autoimmunity, neuropathology, and aberrant behavior (Ballok, 2007;Gulinello and Putterman, 2011;Sakic et al., 1997). Namely, research involving the MRL model led to the discovery of autoimmunity-associated neuronal degeneration and CSF cytotoxicity (Maric et al., 2001;Sakic et al., 1997), which either preceded, or paralleled the first clinical reports (DeGiorgio et al., 2001;Trysberg et al., 2003). ...
... Considering MRL mice do not show inherited brain abnormalities (Sherman et al., 1987), this strain has been useful in examining the interrelationships between systemic autoimmunity, neuropathology, and aberrant behavior (Ballok, 2007;Gulinello and Putterman, 2011;Sakic et al., 1997). Namely, research involving the MRL model led to the discovery of autoimmunity-associated neuronal degeneration and CSF cytotoxicity (Maric et al., 2001;Sakic et al., 1997), which either preceded, or paralleled the first clinical reports (DeGiorgio et al., 2001;Trysberg et al., 2003). As shown in early studies, profound neuronal damage associated with autoimmunity is frequently observed in lupus-prone MRL/lpr mice. ...
Brain morphology and function are susceptible to various psysiological influences, including changes in the immune system. Inflammation and autoimmunity are two principal immunological responses that can compromise the function of multiple organs and tissues, including the central nervous system. The present article reviews clinical and experimental evidence pointing to structural brain damage induced by chronic autoimmune and/or inflammatory processes. Largely due to the vast complexity of neuroendocrine and immune systems, most of the principal pathogenic circuits are far from elucidated. In addition to summarizing the current knowledge, this article aims to highlight the importance of interdisciplinary research and combined efforts of physicians and scientists in revealing the intricate links between immunity and mental health.
... These mice exhibited an increased mortality rate at 5 months, and males and females MRL/lpr mice were both affected unlike the NZB/W F1 mice. There exist a bias in the neuropsychiatric component of SLE toward the female mice [19]. In contrast to NZ strains, they develop a broader spectrum of auto-antibodies, including anti-dsDNA, ANA, anti-Ro, anti-Sm, sn-RNP, anti-La and ribosomal, erythrocyte, rheumatoid factor, and cryoglobulins, as well as more diverse organ involvement, including arthritis, sialadenitis, cerebritis, skin rash, vasculitis and ocular diseases [20][21][22]. ...
Laboratory animal models are beneficial when they recapitulate all or just some of the clinical and immunological manifestations of the disease. Various animals such as cats, rats, dogs, hamsters, guinea pigs, rabbits, horses, minks, pigs, and primates have been described lupus-like phenotype. However, a mouse has remained the preferable animal for scientific investigations as a result of their reduced lifespan, easy reproduction, markedly low costs, public acceptance, ease of genetic management, and the probability to stay under standardized conditions. It is highly challenging to establish a mouse model with all features of lupus because of the difficulty and the heterogeneity of the clinical features in systemic lupus erythematous (SLE). Additionally, due to the multiple differences between the mouse and human immune system, the direct translation usually fails. Each mouse model has specific characteristics and shares many subsets of aspects with the disease observed in humans, which gives researchers a tool to select their particular needs. Over 50 years, many mice models have been developed and used to dissect the pathogenesis of lupus, also to test novel drugs and therapies. In general, mice models that contribute considerably in SLE understanding can be divided into four groups: Spontaneous models, induced models, genetically modified models, along with humanizing mouse models that are the link between the mouse and human immune system. In this updated review, we will present what has been learned from different lupus mice models and how these models have contributed to a better understanding of lupus pathogenesis and treatment.
... Although a research focus on central mechanisms underlying OCD and behavioral sensitization is a very reasonable strategy, a plausible contribution of peripheral mechanisms should not be discounted, given the findings of peripheral immune factors altering behavior (Sakic et al., 1997;Kapadia and Sakic, 2011) and the possibility of gut-brain signaling modulating behavioral performance (Sekirov et al., 2010;Bercik et al., 2011;Collins et al., 2013;Bharwani et al., 2016;Foster, 2016;Stilling et al., 2016;Dinan and Cryan, 2017a). Moreover, there are suggestions for a role of peripheral mechanisms in quinpirole sensitization (Coscina et al., 1998;France, 2009, 2010) and OCD (Swedo et al., 1998;da Rocha et al., 2008;Rees, 2014;Turna et al., 2016). ...
Long-term treatment of rats with the D2/D3 dopamine agonist quinpirole induces compulsive checking (proposed as animal model of obsessive-compulsive disorder) and locomotor sensitization. The mechanisms by which long-term use of quinpirole produces those behavioral transformations are not known. Here we examined whether changes in gut microbiota play a role in these behavioral phenomena ηP, by monitoring the development of compulsive checking and locomotor sensitization at the same time as measuring the response of gut microbiota to chronic quinpirole injections. Two groups of rats received nine injections of saline (n=16) or quinpirole (n=15; 0.25 mg/kg), at weekly intervals for the first 5 weeks and then two injections per week until the end of treatment. After each injection, rats were placed on a large open field for 55 min, and their behavior was video recorded for subsequent analysis. Fecal matter was collected after each trial and frozen for bacterial community profiling of the 16 S rRNA gene, using paired-end reads of the V3 region. The results indicated that the induction of locomotor sensitization and compulsive checking was accompanied by changes in several communities of bacteria belonging to the order Clostridiales (class Clostridia, phylum Firmicutes), and predominantly in Lachnospiraceae and Ruminococcaceae families of bacteria. It is suggested that changes in these microbes may serve to support the energy use requirements of compulsive checking and obsessive-compulsive disorder.
... Whereas these earlier studies focused on cellular effects, our results suggest that BRA-rich CSF promotes an assortment of impairments in metabolic demands, emotional reactivity, olfactory function, and motivated behaviors. In this regard, the functional profile of animals receiving autoimmune CSF mimics several aspects of the so-called "autoimmunity-associated behavioral syndrome" that lupus-prone MRL-lpr mice develop [93,108]. Characteristic behavioral deficits in this substrain include confined exploration in the vicinity of their "home-base" [96,98], reduced responsiveness to palatable stimulation [9,91], response perseveration in spatial learning tasks [10,46,96], excessive immobility when forced to swim [98], and altered olfactory function [57,60]. ...
Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is often accompanied by brain atrophy and diverse neuropsychiatric manifestations of unknown origin. More recently, it was observed that cerebrospinal fluid (CSF) from patients and lupus-prone mice can be neurotoxic and that acute administration of specific brain-reactive autoantibodies (BRAs) can induce deficits in isolated behavioral tasks. Given the chronic and complex nature of CNS SLE, the current study examines broad behavioral performance and neuronal Ca2+ signaling in mice receiving a sustained infusion of cerebrospinal fluid (CSF) from CNS SLE patients and putative BRAs (anti-NR2A, anti-ribosomal P, and anti-α-tubulin). A 2-week intracerebroventricular (i.c.v.) infusion of CSF altered home-cage behavior and induced olfactory dysfunction, excessive immobility in the forced swim test, and perseveration in a learning task. Conversely, sustained administration of purified BRAs produced relatively mild, both inhibitory and stimulatory effects on olfaction, spatial learning/memory, and home-cage behavior. In vitro studies revealed that administration of some CSF samples induces a rapid influx of extracellular Ca2+ into murine neurons, an effect that could be partially mimicked with the commercial anti-NR2A antibody and blocked with selective N-methyl-D-aspartate (NMDA) receptor antagonists. The current findings confirm that the CSF from CNS SLE patients can be neuroactive and support the hypothesis that intrathecal BRAs induce synergistically diverse effects on all domains of behavior. In addition, anti-NMDA receptor antibodies may alter Ca2+ homeostasis of central neurons, thus accounting for excitotoxicity and contributing to the heterogeneity of psychiatric manifestations in CNS SLE and other autoantibody-related brain disorders.
... Due to a spontaneous Fas lpr mutation on chromosome 19 (Watanabe-Fukunaga et al. 1992a;Watanabe-Fukunaga et al. 1992b), the MRL/MpJ-Fas lpr/lpr (MRL/lpr) substrain develops an accelerated form of systemic autoimmune disease by three months of age (Dixon et al. 1978), with the clinical and behavioral manifestations reminiscent of CNS SLE (Gulinello and Putterman 2011;Jeltsch-David and Muller 2014). In comparison to age-matched MRL/MpJ-Fas +/+ (MRL +/+) controls that develop autoimmune manifestations later in life, MRL/lpr mice display increased anxiety-like behavior, impaired motivation and Bcognitiveî nflexibility, jointly termed Bautoimmunity-associated behavioral syndrome^ (Sakic et al. 1997b). Diseased MRL/lpr mice characteristically confine their exploration to the perimeter of an open field (Sakic et al. 1992;Sakic et al. 1994), are slower to approach and investigate novel objects (Sakic et al. 1994), display impaired inter-male aggression (Sakic et al. 1998a), and spend less time exploring unfamiliar conspecifics (Kapadia et al. 2012). ...
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is frequently accompanied by diverse neuropsychiatric manifestations. An increased frequency of olfactory deficits has been recently reported as another marker of CNS involvement in SLE patients. Similarly, we observed that spontaneous development of lupus-like disease in MRL/lpr mice is accompanied by altered olfaction-related behaviors. However, it remained unclear whether the behavioral deficits are due to systemic autoimmunity, or the distinct genetic make-up. To address this question, we presently examine whether prolonged treatment with the immunosuppressive drug cyclophosphamide (CY) restores odor-guided behaviors in MRL/lpr mice. Over 12 weekends, MRL/lpr and control MRL +/+ males were given ad lib access to a sweetened CY solution or a vehicle. Their responsiveness to different scents was assessed at ages corresponding to mild, modest, and severe disease. Odor-guided exploratory behavior was further examined in the novel object test at 21 weeks of age, shortly before terminal assessment of immunopathology. In comparison to control groups, MRL/lpr mice exposed to CY exhibited normal spleen size and antibody levels, as well as increased responsiveness to an attractant and a novel object. However, CY treatment also exacerbated their aberrant response to a repellent, suggesting a dual mode of action on brain olfactory systems. The present results reveal that generalized immunosuppression modulates odor-guided behaviors in lupus-prone animals. Although key pathogenic mechanisms are not clear, the findings strengthen the construct validity of the MRL model by supporting the hypothesis that onset of systemic autoimmunity alters the activity of olfactory circuits.
... In the case of animal models of maternal immune activation, there is a cascade of inflammatory responses that are dependent on the pathogenic agent and can potentiate immune responses in offspring in a strain-dependent manner (111). It is hypothesized that pro-inflammatory cytokines, brain-reactive antibodies, and endocrine mediators, such as corticotropin-releasing factor and glucocorticoids participate in the etiology of autoimmunity-associated behavioral syndrome (164). Also, neonatal rat infection with Borna disease virus results in abnormalities of early development and increase in locomotor activity; stereotypies and brain expression of mRNA for IL-1α, IL1-β, IL-6, TNF-α, and TNF-β (165). ...
... In the case of animal models of maternal immune activation, there is a cascade of inflammatory responses that are dependent on the pathogenic agent and can potentiate immune responses in offspring in a strain-dependent manner (111). It is hypothesized that pro-inflammatory cytokines, brain-reactive antibodies, and endocrine mediators, such as corticotropin-releasing factor and glucocorticoids participate in the etiology of autoimmunity-associated behavioral syndrome (164). Also, neonatal rat infection with Borna disease virus results in abnormalities of early development and increase in locomotor activity; stereotypies and brain expression of mRNA for IL-1α, IL1-β, IL-6, TNF-α, and TNF-β (165). ...
Autism spectrum disorder (ASD) involves a complex interplay of both genetic and environmental risk factors, with immune alterations and synaptic connection deficiency in early life. In the past decade, studies of ASD have substantially increased, in both humans and animal models. Immunological imbalance (including autoimmunity) has been proposed as a major etiological component in ASD, taking into account increased levels of pro-inflammatory cytokines observed in postmortem brain from patients, as well as autoantibody production. Also, epidemiological studies have established a correlation of ASD with family history of autoimmune diseases; associations with major histocompatibility complex haplotypes and abnormal levels of immunological markers in the blood. Moreover, the use of animal models to study ASD is providing increasing information on the relationship between the immune system and the pathophysiology of ASD. Herein, we will discuss the accumulating literature for ASD, giving special attention to the relevant aspects of factors that may be related to the neuroimmune interface in the development of ASD, including changes in neuroplasticity.
... Moreover, autoantibodies have been noted to evoke depressive-like behaviour following their introduction into healthy mice [13,14,37,41]. Substantial reductions in circulating serum autoantibodies following immunosuppressive therapy and subsequent improved performance on various behavioural tests in mice have also provided compelling evidence to support a direct role for autoantibodies in the development of depressive-like behavioural deficits [33,34,36]. In one such study, reduced dendritic spine density significantly correlated with increased serum levels of anti-nuclear antibodies (ANA) and behavioural dysfunction [35]. ...
Autoantibodies have been implicated in the etiologic pathway of depressive disorders. Here, we determine the association between the presence of a panel of autoantibodies at baseline and change in depression symptom score over 5-year follow-up in a cohort of healthy elderly Australians.
Serum samples from 2049 randomly selected subjects enrolled in the Hunter Community Study (HCS) aged 55-85 years were assayed for a range of autoimmune markers (anti-nuclear autoantibodies, extractable nuclear antigen autoantibodies, anti-neutrophil cytoplasmic autoantibodies, thyroid peroxidase autoantibodies, tissue transglutaminase autoantibodies, anti-cardiolipin autoantibodies, rheumatoid factor and cyclic citrullinated peptide autoantibodies) at baseline. Depression symptom score was assessed using the Centre for Epidemiological Study (CES-D) scale at baseline and 5 years later.
Autoantibody prevalence varied amongst our sample with ANA being the most prevalent; positive in 16% and borderline in 36% of study population. No evidence for a relationship was found between change in CES-D score over time and any autoimmune marker. Statins and high cholesterol were significantly associated with change in CES-D score over time in univariate analysis; however, these were probably confounded since they failed to remain significant following multivariable analysis.
Autoantibodies were not associated with change in CES-D score over time. These findings point to an absence of autoimmune mechanisms in the general population or in moderate cases of depression.
Copyright © 2015. Published by Elsevier Masson SAS.
... Female mice exhibit higher serum IgG levels as well as increased ANA titers at 2-3 months of age, although this does not result in differences in overall systemic pathology or mortality (Andrews et al., 1978). More significantly, a bias towards female mice is seen in the neuropsychiatric component of SLE (Sakić et al., 1997). ...
Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.
... As many patients with SLE, evidence suggests that MRL-lpr mice show changes in emotional function and cognition [82,96] in parallel with, but sometimes also before, abnormalities in the immune system. Mainly, anxiety and depressive-like behaviors have been observed [97]. This finding has raised the possibility that the characterization of behavioral modifications in autoimmune mice may help clarifying the link between autoimmunity and cognition. ...
Mouse models of autoimmunity, such as (NZB × NZW)F1, MRL/MpJ-Faslpr (MRL-lpr) and BXSB mice, spontaneously develop systemic lupus erythematosus (SLE)-like syndromes with heterogeneity and complexity that characterize human SLE. Despite their inherent limitations, such models have highly contributed to our current understanding of the pathogenesis of SLE as they provide powerful tools to approach the human disease at the genetic, cellular, molecular and environmental levels. They also allow novel treatment strategies to be evaluated in a complex integrated system, a favorable context knowing that very few murine models exist that adequately mimic human autoimmune diseases. As we move forward with more efficient medications to treat lupus patients, certain forms of the disease emerge that require to be better understood at the mechanistic level. This is the case of neuropsychiatric (NP) events that affect 50-60% at SLE onset or within the first year after SLE diagnosis. Intense research performed at deciphering NP features in lupus mouse models has been undertaken. It is central to develop the first lead molecules aimed at specifically treating NPSLE. Here we discuss how mouse models, and most particularly MRL-lpr female mice, can be used for studying pathogenesis of NPSLE in an animal setting, what are the NP symptoms that develop, and how they compare with human SLE, and, with a critical view, what are the neurobehavioral tests that are pertinent for evaluating the degree of altered functions and the progresses resulting from potentially active therapeutics.
... A number of studies show a link between ASD and a family history of autoimmune diseases or those families with altered inflammatory cytokines or other immune problems [76,78] . The autoimmune hypothesis and development of the mental disorders has long existed [79] . ...
Autism spectrum disorders (ASD) comprise a group of neurodevelopmental abnormalities that begin in early childhood and are characterized by impairment of social communication and behavioral problems including restricted interests and repetitive behaviors. Several genes have been implicated in the pathogenesis of ASD, most of them are involved in neuronal synaptogenesis. A number of environmental factors and associated conditions such as gastrointestinal (GI) abnormalities and immune imbalance have been linked to the pathophysiology of ASD. According to the March 2012 report released by United States Centers for Disease Control and Prevention, the prevalence of ASD has sharply increased during the recent years and one out of 88 children suffers now from ASD symptoms. Although there is a strong genetic base for the disease, several associated factors could have a direct link to the pathogenesis of ASD or act as modifiers of the genes thus aggravating the initial problem. Many children suffering from ASD have GI problems such as abdominal pain, chronic diarrhea, constipation, vomiting, gastroesophageal reflux, and intestinal infections. A number of studies focusing on the intestinal mucosa, its permeability, abnormal gut development, leaky gut, and other GI problem raised many questions but studies were somehow inconclusive and an expert panel of American Academy of Pediatrics has strongly recommended further investigation in these areas. GI tract has a direct connection with the immune system and an imbalanced immune response is usually seen in ASD children. Maternal infection or autoimmune diseases have been suspected. Activation of the immune system during early development may have deleterious effect on various organs including the nervous system. In this review we revisited briefly the GI and immune system abnormalities and neuropeptide imbalance and their role in the pathophysiology of ASD and discussed some future research directions.
... While MRL/lpr mice exhibit high serum levels of autoantibodies and pro-inflammatory cytokines within the first two months of life, congenic MRL +/+ mice develop similar symptoms much later (17). Alterations in exploration, spatial learning, and emotional reactivity represent key features of the "autoimmunity-associated behavioral syndrome" (AABS) in the MRL/lpr substrain (18). Impaired performance in several paradigms have suggested that altered emotional reactivity and spatial learning are consequences of an accelerated form of SLE-like disease (12;13;19-21). ...
Neuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N-methyl-D-aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we presently examine the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE-like disease.
A broad behavioral battery and 7-Tesla MRI were used to examine whether prolonged treatment with MEM (~25 mg/kg b.w. in drinking water) prevents CNS involvement in this spontaneous model of SLE.
Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain-specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL +/+ mice and had a negative effect on body mass gain. Similarly, MRI revealed comparable increases in the volume of periventricular structures in MEM-treated groups.
Sustained exposure to MEM affects body growth, brain morphology, and behavior primarily by pharmacological, and not autoimmunity-dependant mechanisms. Substrain-specific improvement in exploratory behavior of MEM-treated MRL/lpr mice may indicate that the NMDA system is merely a constituent of a complex pathogenenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE-like syndrome.
... The inbred MRL/MpJ-Fas lpr /J (MRL-lpr) substrain spontaneously develops autoimmune disease and has been extensively utilized as a model of SLE (Theofilopoulos, 1992). In addition to spontaneous lupus-like manifestations, these mice develop a constellation of behavioral deficits, jointly labeled autoimmunity-associated behavioral syndrome, or AABS 1 (Sakic et al., 1997). Their brain pathology is characterized by ventricular enlargement (Denenberg et al., 1992), neuronal atrophy (Sakic et al., 1998 ), and infiltration of leukocytes into the choroid plexus (Alexander et al., 1983; Ma et al., 2006) and surrounding brain parenchyma (Farrell et al., 1997; Zameer and Hoffman, 2004 ). ...
Neuropsychiatric (NP) manifestations and brain pathology are poorly understood and potentially fatal concomitants of systemic lupus erythematosus (SLE). For many years, autoantibodies to brain tissue (i.e., brain-reactive antibodies, BRA) were proposed as a key factor in pathogenesis of CNS manifestations. Recent evidence suggests that intrathecal BRA, rather than serum autoantibodies, are a better predictor of disturbed brain morphology and function. We presently test this hypothesis by examining the relationship among BRA in cerebrospinal fluid (CSF), behavioral deficits, and brain pathology in a well-established animal model of CNS lupus. We showed earlier that significant diversity in disease manifestations within genetically homogenous MRL-lpr mice allows for constructive and informative correlational analysis. Therefore, levels of CSF antibodies were presently correlated with behavioral, neuropathological and immune measures in a cohort of diseased MRL-lpr males (N = 40). ELISA, Western Blotting, standardized behavioral battery, digital planimetry, HE staining, and immunohistochemistry were employed in overall data collection. The IgG antibodies from CSF were binding to different regions of brain parenchyma, with dentate gyrus, amygdale, and subventricular zones showing enhanced immunoreactivity. High levels of CSF antibodies correlated with increased immobility in the forced-swim test and density of HE+ cells in the paraventricular nucleus. Peripheral measures of autoimmunity were associated with other deficits in behavior and neuropathology. This correlation pattern suggests that etiology of brain damage in lupus-prone mice is multifactorial. Intrathecal BRA may be important in altering motivated responses and activity of major neuroendocrine axes at the onset of SLE-like disease.
... MRL/lpr) differs from the congenic (control ) MRL/+ strain by a defect in membrane apoptoticsignaling Fas protein, which is due to a retrotransposon in the Fas gene [50, 51]. In addition to the typical signs of peripheral SLE, including autoantibodies, skin disease, arthritis, lymphadenopathy, and nephritis, MRL/lpr mice develop a constellation of behavioral outcomes referred to as " autoimmunity-associated behavioral syndrome " [24] , particularly in the behavioral domains of emotional reactivity, motivated behavior, and cognitive function [14, 20, 22, 24, 33, 52–75]. ...
To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.
... Therefore, this study examined the role of downstream complement proteins, C5a/C5aR in the well established lupus rodent model, MRL/MpJ-Tnfrsf6 lpr (MRL/lpr) (Brey et al., 1997). MRL/lpr mice are felt to accurately reflect that which occurs in human SLE, including the neuropsychiatric manifestations (Sakic et al., 1997; Ballok et al., 2003). MRL/lpr mice differ from the congenic MRL/MpJ (MRL+/+) strain by the nearly complete absence of the proapoptotic membrane Fas protein, due to a retroviral insertion in the Tnfrsf6 gene (Adachi et al., 1993; WatanabeFukunaga et al., 1992). ...
To investigate the role of C5a generated on complement activation in brain, the lupus model, MRL/lpr mice were treated with C5a receptor(R) antagonist (ant). Neutrophil infiltration, ICAM, TNF-alpha and iNOS mRNA expression, neuronal apoptosis and the expression of p-JNK, pSTAT1 and p-Erk were reduced and p-Akt increased on C5aR inhibition in MRL/lpr brains. MRL/lpr serum caused increased apoptosis in neurons showing that lupus had a direct effect on these cells. C5aRant pretreatment prevented the lupus serum induced loss of neuronal cells. Our findings demonstrate for the first time that C5a/C5aR signaling plays an important role in the pathogenesis of CNS lupus.
... There is also a substrain of MRL/MpJ, MRL-Fas lpr , which is homozygous for the lymphoproliferation spontaneous mutation (Fas lpr ) and develops a lupus-like autoimmune disease starting at about three months of age (Hewicker 1990). As compared to MRL-Fas lpr mice, MRL/MpJ mice displayed less anxiety and depressive-like behaviors (Gao et al., 2009;Sakic, Szechtman, & Denburg, 1997). However, the MRL/MpJ mice were not compared with any strains ordinarily used in psychopharmacology investigations. ...
Adult hippocampal neurogenesis has been implicated in the pathophysiology of depression and in the therapeutic effects of antidepressant drugs. Current immunohistochemical methods that study neurogenesis are time consuming and labor intensive. Therefore, a significantly more rapid flow cytometric method was characterized to measure neurogenesis in the adult mouse brain. The sensitivity of mice to the effects of antidepressant treatments is dependent on genetic background. Thus, studies were conducted comparing the responsiveness of 2 inbred mouse strains, MRL/MpJ and C57BL/6J, to the acute and chronic effects of antidepressants on neurochemistry and behavior. Acutely, MRL/MpJ mice displayed more robust behavioral and neurochemical responses to pharmacologically distinct antidepressants than C57BL/6J mice. Chronic administration of the antidepressant drugs fluoxetine and desipramine produced robust elevations in hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) protein levels in MRL/MpJ mice. C57BL/6J mice treated similarly with antidepressant drugs were mainly unresponsive on these measures. Mice were tested in the novelty-induced hypophagia (NIH) paradigm to examine a behavioral response associated with chronic, but not acute, antidepressant treatment. Only MRL/MpJ mice were behaviorally responsive to chronic antidepressant administration in the NIH paradigm. The positive effects of chronic antidepressants on hippocampal cell proliferation and BDNF paralleled the ability of these drugs to produce changes in NIH behavior. These studies highlight the advantages of using flow cytometry to study hippocampal neurogenesis and identify the MRL/MpJ mouse as a strain with superior response to antidepressant drug treatments that may lead to a better understanding of the genetics behind antidepressant efficacy and sensitivity.
... The latter is accompanied by deposition of immune complexes, complement activation (23), and induction of proinflammatory cytokines (24) that have been implicated in the pathogenesis of SLE. Behavioral changes were reported in lupus models and were found to correlate with hippocampus aberrations (25)(26)(27)(28). ...
Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is manifested by neurologic deficits and psychiatric disorders. The aim of this study was to examine SLE-associated CNS pathology in lupus-prone (NZBxNZW)F1 (NZB/NZW) mice, and to evaluate the ameliorating effects of treatment with a tolerogenic peptide, hCDR1 (human first complementarity-determining region), on these manifestations.
Histopathologic analyses of brains from lupus-prone NZB/NZW mice treated with vehicle, hCDR1, or a control scrambled peptide were performed. The messenger RNA expression of SLE-associated cytokines and apoptosis-related molecules from the hippocampi was determined. Anxiety-like behavior was assessed by open-field tests and dark/light transfer tests, and memory deficit was assessed using a novel object recognition test.
Infiltration was evident in the hippocampi of the lupus-afflicted mice, and the presence of CD3+ T cells as well as IgG and complement C3 complex deposition was observed. Furthermore, elevated levels of gliosis and loss of neuronal nuclei immunoreactivity were also observed in the hippocampi of the mice with lupus. Treatment with hCDR1 ameliorated the histopathologic changes. Treatment with hCDR1 down-regulated the high expression of interleukin-1beta (IL-1beta), IL-6, IL-10, interferon-gamma, transforming growth factor beta, and the proapoptotic molecule caspase 8 in the hippocampi of the mice with lupus, and up-regulated expression of the antiapoptotic bcl-xL gene. Diseased mice exhibited increased anxiety-like behavior and memory deficit. Treatment with hCDR1 improved these parameters, as assessed by behavior tests.
Treatment with hCDR1 ameliorated CNS pathology and improved the tested cognitive and mood-related behavior of the mice with lupus. Thus, hCDR1 is a novel candidate for the treatment of CNS lupus.
Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune/inflammatory disease. The heterogeneity and complexity of clinical presentation has made it challenging to study or treat this syndrome. The (NZW×BXSB) F1 lupus-prone male mouse model of this disease is potentially useful to study mechanism and treatment modalities, but there is a lack of information about this model’s characterization and disease progression. Therefore, the aim was to examine this lupus model’s physical/clinical disease presentation and its immunological status.
Materials and methods
Clinical and physical status were observed in 8- and 16-week-old male and female (± 1 week) (NZW/LacJ x BXSB/MpJ) F1 mice (n = 8 per group). Young males (8 ± 1 week) without disease and female (16 ± 1 week) mice served as controls. Physical changes, quantitative values of autoantibodies, and blood cell parameters were determined. Necropsy and post-mortem histopathology were also performed.
Results
With aging (≥ 12 weeks), significant increases in severe abdominal distension/swelling, inability to walk, paleness of paws and significant weight increase were observed compared to controls (p < 0.05). The necropsy examination showed abdominal distension associated with serous effusion and histological examination identified severe edema and multi-organ abnormalities (spleen, lymph nodes, and kidney). Significant increases in anti-double-stranded DNA antibody (anti-dsDNA) was seen in old/sick compared to female (p = 0.0002) or young male (p = 0.0036) mice. Old mice developed immune thrombocytopenia compared to female (p = 0.0056) and young male (p = 0.0007) mice. Anti-platelet was detectable in old, sick mice. The mortality rate increased with aging; more than 35% of male mice died during this study between the ages of 13-18 weeks.
Conclusion
We found that the (NZW/LacJ x BXSB/MpJ) F1 male mice spontaneously exhibit, over varying lengths of time, extremely severe and fatal clinical disease symptoms. This model may be too severe to be helpful in investigating SLE and testing potential treatment modalities.
The rapidly growing field of immunopsychiatry combines expertise and insights from immunology, psychiatry and neuroscience to understand the role of inflammation and other immune processes in causing and treating mental illness. This represents a major shift in mental health science, traditionally focused on psychological and neuronal mechanisms of depression, psychosis and dementia. This book provides the first comprehensive overview of recent, inter-disciplinary research linking disordered function of the immune system to the brain and mental illness. It offers a broad and deep perspective on the implications of immune system involvement in psychiatric disorders, including a balanced focus on basic science and clinical applications. Chapters cover the scientific evidence linking immune processes to major mental illnesses such as schizophrenia, depression, anxiety and dementia. An invaluable guide for graduate students, doctors in training, scientific researchers and others interested in the link between the immune system and mental health.
The previous chapter introduced the ImmunoEmotional Regulatory System (IMMERS). Also, there was a brief discussion about psychological states/psychiatric disorders that so far have been linked to the IMMERS. The present chapter considers another aspect of the IMMERS in which physiological states/physical diseases can be fit to the IMMERS.KeywordsAllergic rhinitisAsthmaAutoimmune diseasesCancerCardiovascular diseasesEmotion regulationEmotion dysregulationHemodialysisHuman immunodeficiency virusImmunoemotional regulatory systemInfectionInflammatory bowel diseasemetabolic syndromeNeurological diseasesPhysical diseasesPhysiological statesSkin diseasesSleep disordersStrokeTraumaVaccination
The link between systemic autoimmunity, brain pathology, and aberrant behavior is still a largely unexplored field of biomedical science. Accumulating evidence points to causal relationships between immune factors, neurodegeneration, and neuropsychiatric manifestations. By documenting autoimmunity-associated neuronal degeneration and cytotoxicity of the cerebrospinal fluid from disease-affected subjects, the murine MRL model had shown high validity in revealing principal pathogenic circuits. In addition, unlike any other autoimmune strain, MRL mice produce antibodies commonly found in patients suffering from lupus and other autoimmune disorders. This review highlights importance of the MRL model as a useful preparation in understanding the links between immune system and brain function.
Systemic Lupus Erythematosus (SLE) is a complex autoimmune inflammatory disease causing a diverse clinical spectrum of organ damage such as kidney and liver failure. The control of the immunological deregulation and repair of the vascular integrity to prevent organ damage are keys for treatment. Available chemotherapy options are toxic and are not efficient in controlling inflammation and vasculitis.
Mesenchymal Stem Cells (MSCs) have been shown to have potent immune-regulatory properties. Exogenously introduced human MSCs do not cause adverse effects, providing a remarkable safety and feasibility profile in clinical trials. The wide variabilities in the outcomes of clinical studies increased the desire of the scientists to review the designs and outcomes of preclinical animal studies. Using SLE mouse models that have specific immunological abnormalities may help us design better MSC human clinical trials. This chapter reviews the previous studies performed on animal models of SLE using syngeneic, allogeneic, or xenogeneic MSCs.
Introduction:Neuropathic pain is defined by the IASP as pain initiated or caused by a primary lesion or dysfunction of the nervous system [1]. Although this definition has been useful to establish a difference between neuropathic pain and nociceptive pain, it lacks diagnostic specificity. Recently, a new precise definition of neuropathic pain has been proposed to meet these shortcomings and to be used for clinical and research purposes (Table 12.1) [2]. Neuropathic pain after spinal cord injury (SCI) is a type of central neuropathic pain and is a frequent complication of spinal injury which is often refractory. People with spinal cord injury consistently rate pain as one of the most difficult problems to manage, despite the other problems (bowel and bladder function, sexual functioning). Studies investigating the prevalence of neuropathic pain in patients with SCI estimate that chronic pain manifests in approximately two-thirds of patients while one-third of these patients experience severe pain. Spinal cord injury-related pain significantly interferes with daily functioning and ability to participate in life activities [3]. When pain is not treated sufficiently, it leads to physical and psychological disorders decreasing the quality of life and life satisfaction. The long-term prognosis for pain relief following SCI is often poor. Patients reporting neuropathic pain are likely to continue experiencing severe pain at 3-5 years following their injury [4]. Predictive factors for onset of (chronic) neuropathic pain following SCI are old age at the time of the injury, the early onset of pain in the weeks following the initial injury (initial intense pain, continuous pain), associated pathologies (ulcers, infection), and gunshot wound being the cause of the trauma. Level of injury, complete or incomplete SCI, and gender have no impact on the onset of neuropathic pain [5].
Introduction: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Autoimmunity and degeneration are two intertwined processes that lead to the progressive demyelination and eventual death of CNS neurons [1]. The three most common forms of MS, based on clinical course, are relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS). Relapsing-remitting MS is the most common form, and is characterized by episodic relapses - the clinical manifestation of a symptomatic lesion in the CNS. Approximately 85% of RRMS evolve into SPMS, which is marked by an absence of relapses and a steady worsening of disability. Primary progressive MS is defined by the absence of relapses, with progressive disability accruing from the onset of disease. Regardless of disease type, the subsequent CNS dysfunction manifests in a multitude of clinical symptoms, including weakness, spasticity, numbness, paresthesias, vision impairment, ataxia, tremor, cognitive impairment, fatigue, mood disorders, bowel and bladder dysfunction, sexual dysfunction, and several types of pain. Of the multitude of symptoms that people with MS experience, roughly one third rank pain as the most serious [2-4]. Pain is associated with sleep disorders, mood disorders, and poor health-related quality of life scores [3,5-8]. Effective treatments to manage central pain in MS are also lacking and are currently limited to those known to work for peripheral pain syndromes. To date, there have been few randomized controlled trials to guide specific treatments for MS-associated pain.
Neurological involvement is one of the most devastating complications of the disease, systemic lupus erythematosus (SLE). To understand the effect of the drugs, cyclophosphamide (CY) and prednisolone (PD) on CNS manifestations, the New Zealand Black/White (NZB/W) lupus mice, were given a cocktail of both drugs by intraperitoneal injections daily from 22 to 44 weeks of age. The treatment prolonged survival (10% of the treated 20 NZB/W mice died compared to 50% of the 30 NZB/W mice, with no mortality in the control NZW mice). Real-time PCR analysis showed a three- to fifteen-fold increase in the expression of GFAP, vimentin and syndecan4 in the cerebral cortex of 44 week NZB/W mice. These alterations were prevented by CY and PD treatment. Immunostaining revealed increased GFAP expression in NZB/W mice compared to congenic, nondiseased NZW mice, which was prevented by treatment. In addition, concomitant changes were observed in the expression of extracellular matrix proteins, collagen IV and fibronectin. To determine the impact of these alterations on the neurological manifestations of SLE, behavior was studied in these mice. The NZB/W mice were spontaneously less active in the open field and exhibited a decrease in distance traveled (58% of control, p<0.01) and ambulatory measurements (52% of control, p<0.01). They took more time (8.8+1.2min) to escape from the maze compared to the control NZW mice (2.6+0.8min). Even more striking was that the behavioral deficits were alleviated in these mice by CY and PD treatment. These results support the hypothesis that increased astrogliosis and altered extracellular matrix proteins may be two of the critical factors that mediate lupus brain disease.
Hepatitis-B vaccine (HBVv) can prevent HBV-infection and associated liver diseases. However, concerns regarding its safety, particularly among patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the aluminum adjuvant in HBVv was related to immune mediated adverse events. Therefore, we examined the effects of immunization with HBVv or alum on SLE-like disease in a murine model.
NZBWF1 mice were immunized with HBVv (Engerix), or aluminum hydroxide (alum) or phosphate buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze and the forced swimming tests) and brain histology.
Immunization with HBVv induced acceleration of kidney disease manifested by high anti-dsDNA antibodies (p < 0.01), early onset of proteinuria (p < 0.05), histological damage and deposition of HBs antigen in the kidney. Mice immunized with HBVv and/or alum had decreased cells counts mainly of the red cell lineage (p < 0.001), memory deficits (p < 0.01), and increased activated microglia in different areas of the brain compare with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with alum.
In conclusion, herein we report that immunization with the HBVv aggravated kidney disease in an animal model of SLE. Immunization with either HBVv or alum affected blood counts, neurocognitive functions and brain gliosis. Our data support the concept that different component of vaccines may be linked with immune and autoimmune mediated adverse events.
SUMMARY Multiple sclerosis (MS) is a chronic disease of the CNS characterized by inflammation, demyelination and axonal injury. In addition to the well-recognized features of the disease such as weakness, fatigue and paralysis, patients with MS may also experience a number of other comorbid disorders. Chronic pain, anxiety and depression affect a large percentage of MS patients. While a number of animal models are available to study the pathophysiology of MS, it is only recently that these models have been used to ask questions about other comorbid conditions associated with the disease. We will now summarize some of the major findings in this area. Although these animal models have been in use for many decades, it is clear that they are still capable of addressing novel and clinically relevant questions about the disease.
An early onset of systemic, lupus-like disease in MRL-lpr mice is accompanied by deterioration in their behavioral performance and atrophy of pyramidal neurons in the parietal cortex and the hippocampal CA1 area. Using the immunosuppressive drug cyclophosphamide (CY) to attenuate the disease, we have tested the hypothesis that the autoimmune/inflammatory process is responsible for changes in brain morphology. A modified Golgi impregnation method revealed that, in comparison to saline-treated controls, immunosuppressive treatment with CY (100 mg/kg/week i.p. over 8 weeks) increased dendritic branching and spine numerical density in the CA1 region of MRL-lpr mice and MRL +/+ mice, which develop less severe manifestations of the disease. More interestingly, CY selectively prevented the atrophy and aberrant morphology of pyramidal neurons in the parietal cortex of MRL-lpr mice. The neuropathological measures (in particular reduced dendritic spine density) significantly correlated with increased serum levels of antinuclear antibodies and splenomegaly. The present results support the hypothesis that chronic autoimmune disease induces functionally important changes in neuronal morphology, and provide an empirical basis for understanding the behavioral dysfunction in systemic lupus erythematosus and autoimmune phenomena reported in some forms of mental illness.
Neuropsychiatric (NP) manifestations and brain atrophy are common, etiologically unexplained complications of the systemic autoimmune disease lupus erythematosus (SLE). Similar to patients with NP SLE, behavioral deficits and neurodegeneration occur in aged, lupus-prone MRL/lpr mice. In order to gain a better understanding of the time course and nature of CNS involvement, we compare the neuro-immuno-endocrine profiles of two lupus-prone MRL/lpr stocks, which differ in disease onset and severity. Mice from stock 485 (characterized by early lupus-like manifestations) display blunted responsiveness to palatable solutions and impaired nocturnal activity as early as 7 weeks of age. They also have increased IgG levels in cerebrospinal fluid (CSF) before high serum autoantibody levels and splenomegaly are detected. Moreover, when compared to age-matched 6825 controls, 485 mice exhibit elevated serum corticosterone, enlarged left adrenal gland, and enhanced haematoxylin/eosin staining in the hypothalamic paraventricular nucleus. Swimming speed and novel object exploration become impaired only when more severe peripheral manifestations are documented in 17 week-old 485 mice. The obtained results suggest that performance deficits during the prodromal phase of NP SLE-like disease are associated with autoantibodies in CSF and asymmetric activation of the hypothalamus-pituitary-adrenal axis. Subsequent deterioration in behavioral performance evolves alongside systemic autoimmunity and inflammation. Although a leaky blood-CSF barrier is a possible explanation, one may hypothesize that, similar to neonatal lupus, maternal antibodies to brain antigens cross blood-placental barrier during embryogenesis and induce early endocrine and behavioral deficits in offspring.
The link between systemic autoimmunity, brain pathology, and aberrant behavior is still largely unexplored field of biomedical science. Accumulating evidence points to causal relationships between immune factors, neurodegeneration, and neuropsychiatric manifestations. By documenting autoimmunity-associated neuronal degeneration and cytotoxicity of the cerebrospinal fluid from disease-affected subjects, the murine MRL model had shown high validity in revealing principal pathogenic circuits. In addition, unlike any other autoimmune strain, MRL mice produce antibodies commonly found in patients suffering from lupus and other autoimmune disorders. This review highlights importance of the MRL model as an indispensible preparation in understanding the links between immune system and brain function.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that damages several bodily systems, including the CNS. Brain atrophy and diverse neuropsychiatric manifestations are common and serious complications of SLE. Recently, it has been reported that many patients with CNS involvement also present with olfactory deficits of unknown etiology. Similar to CNS SLE, spontaneous development of lupus-like disease in MRL/lpr mice is accompanied by neurodegeneration in periventricular regions and a constellation of behavioral deficits dependent on olfaction. To test the possibility that olfactory dysfunction also occurs in autoimmune mice, we presently examine odor-guided behaviors using a battery of paradigms. Indeed, lupus-prone males spent less time exploring unfamiliar conspecifics and demonstrated age-dependant performance deficits when exposed to low concentrations of attractant and repellant odors. The emergence of olfactory changes was associated with a skewed distribution of DCX(+) cells in the proximal portion of the rostral migratory stream (RMS). The present results are consistent with the hypothesis that the onset of a SLE-like condition affects periventricular regions, including the RMS, as evidenced by disrupted migration of neuronal precursor cells toward the olfactory bulb. If so, ensuing hyposmia and/or olfactory memory deficit may contribute to altered performance in other behavioral tasks and reflect a prodrome of brain damage induced by chronic autoimmune disease.
Immunological privilege of the central nervous system (CNS) has often been viewed as the summation of mechanisms that are protective of, but extrinsic to, the CNS. Their primary role has then been seen as isolating the CNS from the organism as a whole. Experiments in recent years indicate that the CNS itself may have an innate immune system comprised of astrocytes and microglia capable of regulating the initiation and progression of immune responses. Thus, immunological privilege should be considered as an intrinsic property of the CNS that could involve direct CNS:immune cell interactions. Malfunctions of these intrinsic mechanisms could play significant roles augmenting or even initiating CNS-directed autoimmunity and inflammation. J. Neurosci. Res. 55:1–8, 1999. © 1999 Wiley-Liss, Inc.
Nervous system or “neuropsychiatric” (NP) involvement in SLE has been recognized sincethe first descriptions by Kaposi (1925), but estimates of its prevalence have varied widely. In the absence of major NP events (eg., stroke, psychosis), the nervous system was presumed to be unaffected. Owing to the multiple “minor” NP symptoms endorsed by SLE patients, including cognitive and mood problems, neuropsychological assessment was introduced into the study of NP-SLE in the 1980s to systematically study brain function in patients both with and without overt NP manifestations. In human SLE, there are now multiple studies documenting a high prevalence of cognitive dysfunction. Mechanisms that lead to abnormal cognition in SLE, however, are not yet fully understood. A prevailing notion has been that autoantibodies which target neuronal or cross-reactive lymphocytic antigens directly cause brain damage and result in cognitive impairment; proof of this direct pathogenic role is lacking, although positive clinical correlations have been found. The potential biological impartance of phospholipid antibodies (a marker of a hypercoagulable state) in the development and prediction of cognitive decline in specific domains, has provided a clue to one mechanism (thrombosis) to be targeted therapeutically. Another relevant and informative approach to pathogenesis derives from studies in lupus-prone MRL/lpr mice, who develop an autoimmune-associated behavioural syndrome (AABS), characterized by significant abnormalities in both “emotional” and “cognitive” tasks; some of these abnormal behaviours can be induced by the cytokine, IL-6, and/or be positively associated with lymphoid infiltrates in the brain. In humans, we have shown: the positive effects of immunosuppressive therapies on cognitive function and concomitant reversal of abnormalities on brain imaging by positron emission tomography (PET), and of single patient drug/placebo trials of low dose corticosteroids; the contributions of generalized disease activity, mood problems, pain and fatigue to cognitive dysfunction; the types of cognitive dysfunction that have been documented or proposed to be associated with specific autoantibodies or pro-inflammatory cytokines; and, the course of cognitive dysfunction over time, including risk factors. Future understanding of the complexity of neuroimmune interactions could utilise information obtained from both human and animal models of NP-SLE.
Fatigue is a debilitating condition suffered by many as the result of chronic disease, yet relatively little is known about its biological basis or how to effectively manage its effects. This study sought to evaluate chronic fatigue by using lupus-prone mice and testing them at three different time periods. Lupus-prone mice were chosen because fatigue affects over half of patients with Systemic Lupus Erythematosus. Eleven MLR⁺/(+) (genetic controls) and twelve MLR/MpJ-Fas /J (MRL/lpr; lupus-prone) mice were tested three times: once at 12, 16 and 20 weeks of age. All mice were subjected to a variety of behavioral tests including: forced swim, post-swim grooming, running wheel, and sucrose consumption; five of the MLR⁺/(+) and five of the MLR/lpr mice were also tested on a fixed ratio-25 operant conditioning task. MRL/lpr mice showed more peripheral symptoms of lupus than controls, particularly lymphadenopathy and proteinuria. Lupus mice spent more time floating during the forced swim test and traveled less distance in the running wheel at each testing period. There were no differences between groups in post-swim grooming or in number of reinforcers earned in the operant conditioning task indicating the behavioral changes were not likely due simply to muscle weakness or motivation. Correlations between performance in the running wheel, forced swim test and sucrose consumption were conducted and distance traveled in the running wheel was consistently negatively correlated with time spent floating. Based on these data, we conclude that the lupus-prone mice were experiencing chronic fatigue and that running wheel activity and floating during a forced swim test can be used to evaluate fatigue, although these data cannot rule out the possibility that both fatigue and a depressive-like state were mediating these effects.
Multiple sclerosis (MS) and the animal model, experimental autoimmune encephalomyelitis (EAE), are both accompanied by motor and non-motor symptoms. Pathological changes in the activities of key neurotransmitters likely underlie many of these symptoms. We have previously described disturbances in the levels of 5-hydroxytryptamine (5-HT/serotonin), noradrenaline (NE) and γ-aminobutyric acid (GABA) in a mouse model of EAE. The potential therapeutic effect of a drug that targets these three neurotransmitters, the antidepressant and anti-panic drug phenelzine (PLZ), was assessed in mice with MOG(35-55) induced EAE. The neurotransmitter content of EAE and control tissue after PLZ administration was first evaluated by HPLC. The ability of PLZ treatment to modulate EAE disease course and clinical signs was then assessed. Daily PLZ treatment, starting seven days after disease induction, delayed EAE onset, reduced disease severity in the chronic phase and was associated with substantial improvements in exploratory behavior and a novel measure of sickness and/or depression. Upon completion of the experiment, PLZ's effects on histopathological markers of the disease were examined. No differences were observed in T cell infiltration, microglia/macrophage reactivity, demyelination or axonal injury in PLZ-treated spinal cords. However, EAE mice treated with PLZ showed a normalization of 5-HT levels in the ventral horn of the spinal cord that might account for the improvements in behavioral outcomes. These results demonstrate the therapeutic potential of MAO inhibitors such as PLZ in MS. Additionally, the behavioral changes observed in EAE mice indicate that alterations in non-motor or 'affective' measures may be valuable to consider in addition to traditional measures of gross locomotor function.
The association between anti-triosephosphate isomerase (TPI) antibodies and MRL/MpJ-Fas(lpr) (MRL/lpr) mice was examined. We found that serum anti-TPI antibody levels in MRL/lpr mice, measured by enzyme-linked immunosorbent assay, were significantly higher than that of age-matched Balb/c mice and NZB/WF1 mice. Anti-TPI antibodies were detected in serum and cerebrospinal fluid in MRL/lpr mice by Western blotting. Inoculation of anti-TPI monoclonal antibody-producing hybridoma into the brain of Balb/c mice resulted in immunoglobulin deposition in the regions near the ventricles, hippocampus, and choroid plexus. Anti-TPI antibodies may play a role in the etiology of brain damage and behavioral deficits in MRL/lpr mice.
It has been postulated that brain inflammatory processes associated with autoimmune diseases may be causative factors in emotional disorders. Accordingly, we examined emotional behaviors in autoimmune-prone cytokine B-cell-activating factor (BAFF) transgenic mice, a model of systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome.
Male BAFF transgenic mice were examined on a series of standard laboratory assays of emotionality. Mice were also tested for brain inflammation, stress-induced c-Fos expression, hippocampal progenitor cell proliferation, and hippocampal neurogenesis-dependent and neurogenesis-independent long-term potentiation (LTP).
Our study revealed that older BAFF transgenic mice exhibit an anxiety-like phenotype associated with brain inflammation. Furthermore, anxious mice display an abnormal neuronal activation within the limbic system in response to mild anxiogenic stimuli. Proliferation of newly formed neurons in the subgranular zone of adult hippocampus was significantly decreased in anxious BAFF transgenic mice that also showed impaired neurogenesis-dependent and neurogenesis-independent dentate gyrus LTP.
Our results suggest that anxiety associated with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome can be linked to brain inflammation, impaired neurogenesis, and hippocampal plasticity. BAFF transgenic mice can be used in future studies to test compounds of therapeutic value for the treatment of mood disorders associated with autoimmune diseases.
To date, neurotransmitter and immune abnormalities in autism are the only consistently documented findings other than neurobehavioral symptoms. Reciprocal communication between two major adaptive systems of human organism, the CNS and the immune system, is sustained via multiple pathways and is mediated by neurotransmitters, hormones, cytokines, chemokines, and corresponding cell receptors. Evidence for a dialogue between them has emerged as a universal concept of the neuroimmune regulation of homeostasis. In the paper we propose several plausible scenarios of how defects in either system may affect neuroimmune communications and lead to the pathology, as well as immunodiagnostic panels for recognition of immunopathological changes in people with autism in the Republic of Macedonia.
The human autoimmune disorder systemic lupus erythematosus (SLE) is often accompanied by psychiatric manifestations including anxiety. In this study, the performance of SLE-prone NZB × NZW F1 (B/W) hybrid mice was compared with nonautoimmune NZW control mice on 3 anxiety tasks: the elevated plus maze, the open-field drink test, and the novel-object task. B/W mice displayed decreased activity as well as an anxiety profile in all 3 tasks, which was characterized by avoidance of open and exposed places even when the motivation to explore these areas was high. Cytokines are overexpressed in autoimmune disease, and NZW controls injected with the cytokine interferon-α displayed an anxiety profile in the plus maze. Thus, cytokines may play a role in the genesis of the behavioral manifestations of autoimmune disease.
1.1. This paper reviews recent findings on cellular and humoral immunity and inflammatory markers in depression.2.2. It is shown that major depression may be accompanied by systemic immune activation or an inflammatory response with involvement of phagocytic (monocytes, neutrophils) cells, T cell activation, B cell proliferation, an “acute” phase response with increased plasma levels of positive and decreased levels of negative acute phase proteins, higher autoantibody (antinuclear, antiphospholipid) titers, increased prostaglandin secretion, disorders in exopeptidase enzymes, such as dipeptidyl peptidase IV, and increased production of interleukin (IL)-1β and IL-6 by peripheral blood mononuclear cells.3.3. It is hypothesized that increased monocytic production of interleukins (Il-1β and Il-6) in severe depression may constitute key phenomena underlying the various aspects of the immune and “acute” phase response, while contributing to hypothalamic-pituitary-adrenalaxis hyperactivity, disorders in serotonin metabolism, and to the vegetative symptoms (i.e. the sickness behavior) of severe depression.
Systemic lupus erythematosus (SLE) patients are at risk for developing a host of neuropsychiatric disorders that can affect any level of the nervous system. These can include defects in the highest cerebral functions of reasoning, memory, and reality testing, defects in motor function and its regulation, involvement of the spinal cord and nerves, and even abnormalities at the neuromuscular junction. No single pathogenic mechanism can account for this variety of clinical manifestations. The neuropsychiatric events appear to be caused by a combination of the two major autoimmune processes that are responsible for damage to other organ systems in SLE cell membrane-reactive autoantibodies and immune complex-mediated vascular damage.
The cytokine interleukin-6 (IL-6) is produced by a variety of cells, including macrophages, T-cells, and B-cells. Recent studies have confirmed a neuroendocrine role for IL-6 in the regulation of anterior pituitary (AP) hormone release. Because the neurointermediate pituitary lobe (NIL) may modulate AP hormone release, we investigated the production of IL-6 by NIL cells in vitro. NIL tissue removed from pituitary glands of male Long-Evans rats was enzymatically and mechanically dispersed, and the cells were subsequently cultured in 96-well tissue culture plates for 4-6 days in 10% serum-containing RPMI-1640. Test incubations were performed in serum-free RPMI-1640, and IL-6 concentrations were determined using the 7TD1 cell bioassay. Preliminary studies revealed a cell-dependent release of IL-6: increasing the number of NIL cells per well from 6.25 to 50 x 10(3) revealed detectable basal release of IL-6 between 25-50 x 10(3) cells/well. The endotoxin lipopolysaccharide (LPS; 100 ng/ml) and IL-1 beta (100 n...
This chapter focuses on some behavioral adaptations in autoimmune disease-susceptible mice. Cyclophosphamide, a potent immunosuppressive drug, has noxious gastrointestinal properties. Normal, healthy animals avoid consumption of solutions containing cyclophosphamide (CY), and they avoid distinctively flavored solutions that are associated with injections of the drug. When dissolved in chocolate milk, a highly preferred drinking solution for the mouse, animals show a dose-related decrease in consumption of the CY-laced solution. Nevertheless, at concentrations that will be consumed, lupus-prone mice with manifest symptoms of autoimmune disease drink more CY-laced chocolate milk than healthy, congenic control mice. Mice with active symptoms of disease drink sufficient amounts of the CHOC/CY solution to reverse their pre-experimental lymphadenopathy and reduce their elevated autoantibody titers. The immunologically derived changes that are immediately responsible for the death of the animals may not, in the time available, respond to the therapeutic effects of the low doses of CY that are consumed by these lupus-prone animals.
This chapter presents behavioral sequelae of autoimmune disease. Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS), principally affecting oligodendrocytes and the myelin they elaborate. Changes both in cellular and humoral immunity accompany the disease process. Exacerbations in MS have been associated with transient lowering of T8+ lymphocyte subpopulations in peripheral blood. Functional immunologic suppression is impaired in progressive MS and may be associated with a decrease in circulating suppressor/inducer (CD4+ 2H4+) T cells. The key idea in the foregoing is that autoimmune phenomena are associated with altered behavior. It may be that the set of immunologic events, namely, cytokine secretion, altered cellular functioning, antiidiotypic interactions, and brain reactive autoantibody, which is peculiar to autoimmune disease, may affect brain functioning in a way different from the norm. The effects of the autoimmune response on brain functioning may not only have an effect on those specific neuroimmunologic circuits affecting the immune system but may also have effects on CNS functioning unrelated to immune system homeostasis and behavior.
This chapter focuses on the presence of important psychoneuroimmunological factors in the etiology of neurobehavioral pathology associated with aging and Alzheimer's disease. The neuroimmunopathological effector mechanisms that could be involved have been identified and characterized in studies of other neurological diseases, and various sites and mechanisms for interactions between the central nervous system and peripheral immune system have also been revealed. Brain-reactive antibodies are found in the sera and cerebrospinal fluid of patients with Alzheimer's disease, and some of the antibody populations have specificities matching the neurological targets known to undergo deterioration in Alzheimer's disease. The identification of brain-reactive antibodies in association with Alzheimer's disease has suggested both novel diagnostics and potentially successful therapeutic approaches. Aging mice show formation of both diverse and specific brain-reactive antibodies, and immune transfer studies have implicated age-related changes in immune function as important factors in the appearance of these antibodies. The same immune factors may be involved in age-related changes in brain functions related to capacity for avoidance acquisition of the age-related acquisition deficits following transfer of immunity from aged to young mice.
Review of the experimental and theoretical analysis of avoidance behaviors can provide fascinating insights into the development of the psychology of learning in America. This is because problems in the analysis of avoidance behaviors often stimulated the development of new experimental designs and new theoretical concepts which in turn had substantial impact upon how we interpreted all other learning phenomena. Most simply, the phenomenon of avoidance learning was always--and continues to be--a source of difficulties. The difficulties are of three types: (a) paradigmatic, (b) methodological, and (c) theoretical. We shall consider each in turn.
Recent studies of immune system dysfunction suggest that, in some patients, autism may be a neuroimmunological disorder. When one considers these findings along with new neuropathological descriptions in autism, they bear similarities to other postinfectious and neurological immune disorders, such as Sydenham's chorea and the autoimmune component of amyotrophic lateral sclerosis. The various immunologic abnormalities described in autism mirror its clinical heterogeneity and may eventually explain several common pathways for its pathogenesis. We hypothesize that this may involve an autoimmune attack on excitatory cell systems which are regionally and temporally specific in the developing brain.
It has been suggested that "phylogenetically prepared fear reactions" may be useful behavioral assays of the effects of anxiolytic agents. In the present experiments, rats' natural proclivity to stay near the perimeters of a novel environment (i.e., thigmotaxis) was suppressed by anxiolytic agents (diazepam 1-5 mg/kg; chlordiazepoxide 1-10 mg/kg; pentobarbital 1-10 mg/kg), with a relative potency that was similar to their relative potency in the treatment of human anxiety. Furthermore, when effects on general activity were factored out using analysis of covariance, the test also showed some degree of drug-class specificity, since neither d-amphetamine, morphine, nor chlorpromazine produced this anti-thigmotaxic effect. These results support an earlier report that thigmotaxis may be a useful test for anxiolytic activity in rats.
The release of soluble factors, also known as cytokines, by macrophages and lymphocytes during infectious diseases is one of the earliest events that contributes to the host defence and outcome of infection. From these cytokines, interleukin-1 (IL-1) in concert with interleukin-6 (IL-6) and tumor necrosis factor (TNF) are considered as prominent factors that initially may coordinate and regulate this defence reaction, which is commonly referred to as the acute-phase response. As a part of the complex spectrum of the action of these cytokines, they have the apparent ability to affect the brain leading to changes in thermoregulation, appetite, sleep-wake cycle, and the activity of the neuroendocrine system as exemplified by the activation of the hypothalamo-pituitary-adrenal system. This chapter discusses a variety of aspects of the bilateral interaction of cytokines and glucocorticoids. It discusses the possibility that the immunoendocrine feedback loop, which is termed as the immune-hypothalamo-pituitary-adrenal axis, may be an integral part of the regulation of immune-tolerance to self-antigens.
Recent research has shown that alterations of the immune system are associated with several psychiatric disorders. Patients with schizophrenia or major depression show a number of changes including those of cellular immunity, cytokine production, and levels of cytokines, soluble cytokine receptors and acute-phase proteins that indicate an immune activation, Findings from studies of cerebrospinal fluid (CSF) also point to an activation of the immune system, at least in a subgroup of patients with schizophrenia. The relationship between clinical characteristics and immune parameters in schizophrenia suggests that immune activation plays a role in the pathogenesis of the disorder in at least one-third of schizophrenic patients. Cytokines interact with some catecholamines, and a hypersecretion of certain cytokines, such as interleukin (IL)-2 and IL-6, is hypothesised to contribute to schizophrenia and depression, possibly via an influence on the catecholaminergic system. Immune mediators can activate astrocytes and microglia, and probably also neurons, to secrete cytokines. The strong connection between cytokines and catecholamines is underlined by the finding that noradrenaline (norepinephrine) stimulates the release of IL-1 and IL-6 from astrocytes. Via these mechanisms, an immune process in the CNS seems to maintain itself by a feedback process. An increased permeability of the blood-brain barrier can reinforce the immune-activating process in the CNS. Furthermore, pharmacoimmunological investigations of antipsychotics and antidepressants point to an inhibiting influence of these agents on several cytokines. Further research is required to fully elucidate the immune process and the role of cytokines in the CNS. This may allow the development of drugs that will selectively influence certain cytokines. The development of immuno-inhibiting drugs or drugs that prevent the activation of cytokines may have implications for the drug treatment of psychiatric disorders.
The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.
MRL/1 and BXSB male mice have a systemic lupus erythematosus (SLE)-like disease similar to but more acute than that occurring in NZB X W mice. The common elements of lymphoid hyperplasia, B-cell hyperactivity, autoantibodies, circulating immune complex (IC), complement consumption, IC glomerulonephritis with gp70 deposition, and thymic atrophy were found in all three kinds of SLE mice. On the basis of these common elements, SLE seen in these mice can be considered a single disease in the same sense that human SLE is one disease. The differences in the SLE expressed in the different mice are no greater than those found in an unselected series of humans with SLE. However, the significant quantitative and qualitative variations in abnormal immunologic expression suggest that different constellations of factors, genetic and/or pathophysiologic, may operate in the three murine strains and that each constellation is capable of leading, via its particular abnormal immunologic consequences, to the activation of common immunopathologic effector mechanisms that cause quite similar SLE-like syndromes. From an experimental point of view, the availability of several inbred murine strains of commonplace histocompatibility types that express an SLE-like syndrome makes possible innumerable manipulations which should help to elucidate the nature and cause(s) of this disorder.
The development of autoimmune disease in the MRL/MpJ-lpr inbred mouse strain depends upon the maturation of a subset of T lymphocytes that may cause sustained activation of immunological effector cells such as B cells and macrophages. We tested the hypothesis that abnormal effector cell activation reflects constitutive overexpression of a T cell cytokine. We found that a newly defined T cell cytokine, Eta-1, is expressed at very high levels in T cells from MRL/l mice but not normal mouse strains and in a CD4-8- 45R+ T cell clone. The Eta-1 gene encodes a secreted protein that binds specifically to macrophages, possibly via a cell adhesion receptor, resulting in alterations in the mobility and activation state of this cell type (Patarca, R., G. J. Freeman, R. P. Singh, et al. 1989. J. Exp. Med. 170:145; Singh, R. P., R. Patarca, J. Schwartz, P. Singh, and H. Cantor. 1990. J. Exp. Med. 171:1931). In addition, recent studies have indicated that Eta-1 can enhance secretion of IgM and IgG by mixtures of macrophages and B cells (Patarca, R., M. A. Lampe, M. V. Iregai, and H. Cantor, manuscript in preparation). Dysregulation of Eta-1 expression begins at the onset of autoimmune disease and continues throughout the course of this disorder. Maximal levels of Eta-1 expression and the development of severe autoimmune disease reflect the combined contribution of the lpr gene and MRL background genes.
In a prior study we found excellent Lashley III maze learning in BXSB mice and poor learning in NZB mice, despite the fact that both strains are autoimmune and develop cortical ectopias. This prompted us to examine NZB Lashley maze performance in detail, including comparisons to other strains and attempts to improve performance by giving additional trials with or without additional intramaze visual cues. In conventional Lashley testing (10 trials), RF mice (non-autoimmune and nonectopic) and BXSBs performed well in the Lashley maze. They had high learning indices and few errors. NZB mice performed poorly, with low learning indices and many errors. Even with additional trials or additional trials plus intramaze cues, NZB performance remained poor. The number of backward and forward errors stayed high; learning indices were low. Since both BXSB and NZB mice develop autoimmune disorders and cortical ectopias, it is unlikely that differential Lashley performance is the result of the presence of these phenomena. NZB mice are known to have alterations in their hippocampal morphology, and this is a possible mediator of the Lashley deficit.
We have reported previously that anterior pituitary cells released interleukin-6 (IL-6) and that this release was stimulated by lipopolysaccharide (LPS), phorbol myristate acetate (PMA), or agents that increased intracellular cAMP concentrations. We now report that IL-1 stimulates IL-6 release from anterior pituitary cells in vitro. IL-lα and IL-1β (0.04–25 ng/ml) significantly increased IL-6 release 3- to 4-fold in a concentration-related manner during 6-h incubations; however, there was no change in extracellular or intracellular cAMP concentrations. IL-lα and IL-1β (10 ng/ml), vasoactive intestinal peptide (VIP, 500 nM), prostaglandin E2 (PGE2,1 μM), and LPS (1 ng/ml) stimulated IL-6 release to a similar degree. In the presence of VIP and PGE2, IL-lα and IL-1β increased IL-6 release without any apparent further change in extracellular or intracellular cAMP. Conversely, LPS did not increase cAMP concentrations, and IL-1 did not significantly increase IL-6 release in the presence of LPS. The preexposure ...
The MRL-lpr/lpr and MRL-++ mice were studied for the expression of cytokines in the spleen, lymph node., thymus, kidney and brain through the reverse transcription-polymerase chain reaction (RT-PCR). The frequencies of IL-4 and TNF-a expression in the thymus and spleen were significantly higher in MRL-lpr/lpr mice than in MRL-++ mice from the age of 17 to 32 weeks. More importantly, IL-4 transcript was demonstrated in the early rather than in the terminal stage of the lupus disease. At the 20th week, MRL-lpr/lpr mice with active disease exhibited higher concentrations of IL-1α, IL-6 and TNF-a in serum than MRL-++ mice. Interestingly, in MRL-lpr/lpr but not MRL-++ mice, the IL-6 concentration in culture supernatants of the thymic cells was significantly higher than that of the splenic or lymph node cells. On the other hand, IL-6 and IL-l/? were expressed in the brain and kidney of MRL-lpr/lpr mice but not of MRL-++ mice. Cultured MRL-lpr/lpr mesangial cells could also express IL-6 but to a lesser extent. These results suggest that the abnormal splenic and thymic IL-4 and TNF-α expression may predispose the development of autoimmune reactions. The expression of IL-1ß and IL-6 in the brain and kidney may be implicated in the damage of these two organs in MRL-lpr/lpr mice.
A mAb against murine IL-6 receptor (IL-6R), KMH7, was obtained by immunization of hamster with recombinant soluble murine IL-6R. Flow cytometry analysis of IL-6R distribution on lymphocytes in BALB/c showed that IL-6R was expressed on peripheral lymph node (LN) T cells of either CD4+ or CD8+ phenotype, and Peyer's patch IgA+ B cells, but not on splenic B cells and thymocytes. A similar distribution was observed in 5 week old MRL/Ipr and 16-week-old MRL/n mice. In contrast, in 16 week old MRL/Ipr mice of both sexes, IL-6R was expressed on splenic IgM+ cells. Peripheral LN CD4+ T cells in 16 week old female MRL/Ipr mice did not express IL-6R. Thymocytes in any population with a phenotype of CD4+ or CD8+, double negative, and double positive were not stained with KMH7 in both BALB/c and MRL/Ipr mice. In both strains, IL-6R was induced in CD4+ or CD8+ thymocytes after 2 days of culture, suggesting that CD4+ thymocytes in MRL/Ipr have a potential to express IL-6R. Our results suggest that overexpression of IL-6R on B cells and absence of IL-6R on peripheral CD4+ cells are concurrent with, or may contribute to, B cell hyperreactivity and T cell abnormality in this strain.
Developmental ectopias (nests of neurons) in the molecular layer of the cerebral neocortex and associated dysplasias of underlying layers have been seen in two strains of mice (New Zealand Black and BXSB) that spontaneously develop autoimmune disorders. The ectopias are usually unilateral and males are more often affected than females. The emerging situation is comparable to that of male dyslexics who in addition to their language problems show similar developmental brain anomalies. These anomalies are through to have their origin during the last stages of neuronal migration. We believe that maternal autoantibodies passing through the placenta and blood-brain barrier may damage the important structural components of the cerebral cortex affecting the final positions of migrating neurons. The autoimmune mice are a useful experimental animal model for understanding the development of neuropathology in dyslexics.
An immunoregulatory feedback circuit exists between the CNS and the immune system comparable to other feedback systems that maintain homeostasis in mammals. Moreover, the brain “enjoys” certain privileges and autonomies. The privileges include a redistribution of blood flow, which provides additional blood to the brain under conditions of anoxia, and a redistribution of nutrients so that the brain preferentially receives an additional supply under conditions of starvation. The so-called immunologic privilege of the brain serves to shield it from systemic immune reactions that may be damaging to neural structures. An example of an autonomy is the independent endocrine capacity of the CNS; but does it also possess an independent immune capacity? Studies on neuron-binding immunoglobulins (lgs) have revealed that some of these lgs are directed against antigens shared between neural structures and tissues outside the CNS, such as the Thy-1 antigen of thymic lymphocytes. Other lgs appear to be specific for neural antigens. This suggests that the blood-brain-barrier (BBB) may protect neural structures from cross-reacting with extraneural antibodies. But the BBB would also provide a barrier to the systemic immune system when aberrant antigens are generated within the CNS. Observations such as these have given rise to the hypothesis that antibodies to neural antigens might be generated within the CNS. Evidence is provided here from studies on monkeys, as well as a review of relevant literature, that the CNS contains structures that can provide an independent immune capacity. These include perivascular and glial cells and elements of the choroid plexus. Some of these structures also display markers similar to those displayed by immunocytes. It is proposed here that neuronophagia and the resultant loss of neurons with age may be due to immune reactions confined to the CNS. It is also proposed that certain CNS phenomena associated with Alzheimerapos;s disease may be due to parallel age-related autoimmune reactions not causally related to AD.
Cerebrospinal fluid (CSF) from patients with a variety of central nervous system (CNS) disorders was assayed for cytokines, prostaglandins, and autoantibodies. CSF interleukin-6 (IL-6) in patients with CNS infection (374.24 ± 92.61 pg/mL) and neuropsychiatric systemic lupus erythematosus (NP-SLE) (71.40 ± 5.89 pg/mL) were significantly higher than in patients with CNS inflammation (33.92 ± 29.36 pg/mL) or controls (non-inflammatory CNS diseases) (4.35 ± 3.00 pg/mL). Interleukin-1β, interferon α, and tumor necrosis factor α were undetectable in these samples: CSF prostaglandin E2 (PGE2) also exhibited similar patterns as IL-6. CSF immunoglobulin G (IgG) in patients with NP-SLE (8.84 ± 1.80 mg/dL) was much higher than in patients with CNS infection (4.65 ± 3.09 mg/dL), CNS inflammation (2.54 ± 1.24 mg/dL), or controls (2.11 ± 1.03 mg/dL). CSF autoantibodies against calf thymus antigens were present in patients with NP-SLE but not in patients with CNS infection as demonstrated by immunoblot. These results suggest that high IL-6 and PGE2 in CSF favors the diagnosis of CNS infection, while modestly elevated IL-6, high IgG, and autoantibodies against calf thymus antigens in CSF are the features of NP-SLE.
Intravenously administered interleukin-6 (IL-6), a monokine produced by activated monocytes and folliculostellate cells of the pituitary gland, has been recently reported to elevate plasma ACTH level and to stimulate PRL, GH and LH release from cultured pituitary cells. To determine the site(s) of action of IL-6 in the control of pituitary hormone release, we injected human recombinant IL-6 into the third brain ventricle (3V) of freely moving, conscious male rats. Both 0.05 and 0.25 pmol doses of IL-6 were ineffective to change plasma ACTH in comparison to the values in controls. The maximal IL-6 dose tested of 1.25 pmol increased plasma ACTH within 15 min and the response lasted over 180 min. Plasma TSH levels were significantly lowered by a dose of 0.25 pmol IL-6, but neither the lower dose of 0.05 pmol nor the higher dose of 1.25 pmol altered plasma TSH levels throughout the 180 min of the experiment. Plasma PRL and GH levels were not changed by any IL-6 dose tested. In ovariectomized rats plasma LH and FSH levels were also unaltered by IL-6. The effects of IL-6 on plasma ACTH and TSH were only partially paralleled by increased rectal temperature which suggests that hypothalamic temperature regulating centers were independent of these actions. To evaluate a possible direct effect on the pituitary, IL-6 was incubated in vitro with hemipituitaries under an atmosphere of 95% O2/5% CO2. After 1 h of incubation IL-6 failed to cause any change in the secretion of pituitary hormones throughout a concentration range of 10–15–10–9M. Increased ACTH and GH secretion into the incubation medium was found only with 10–13M IL-6 after a 2-hour incubation, whereas there was no effect on PRL, TSH, LH and FSH release. The results support a possible role for IL-6 at both hypothalamic and/or pituitary levels to stimulate ACTH and GH and to decrease TSH release.Copyright © 1991 S. Karger AG, Basel
There is sufficient evidence now available to warrant redefining conditioning and problem-solving in rather special ways so that learning will be seen to consist of two basic processes, associationism and hedonism. A completely monistic explanation seems to be impossible. We should probably refer not to "
the learning process," but to
two such processes. This is not, however, a renewal of the "vicious convenience" of using both the laws of effect and exercise, since these latter two principles were ordinarily applied to the same learning process. In the current formulation, which was made fairly explicit by Skinner a decade ago, conditioning—the acquisition of secondary drives—is related to the autonomic nervous system, problem-solving—the reduction of primary or secondary drives—to the central nervous system. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The characteristics of soluble interleukin-6 receptor (sIL-6R) in murine sera were examined. To investigate a relationship between serum sIL-6R level and autoimmune diseases, quantitative analysis of serum sIL-6R in MRL/lpr mice was performed by an enzyme-linked immunosorbent assay. The serum sIL-6R level in MRL/lpr mice of both sexes was below the detection limit (< 1.0 ng/ml) at 8 weeks of age, but it increased in accordance with age and reached 42 ± 9.3 ng/ml in female and 31 ± 13 ng/ml in male mice at 30 weeks of age. In MRL/+ mice, although an age-associated increase in serum sIL-6R level was observed, it was much less extensive than that in MRL/lpr mice. Elevated serum sIL-6R level at the age of 30 weeks was observed in female and male (NZB × NZW)F1 mice (32 ± 10 ng/ml and 17 ± 5.0 ng/ml, respectively), and male BXSB/Mpj Yaa mice (42 ± 18 ng/ml), suggesting that elevated serum sIL-6R in aged mice is one of the characteristics of autoimmune-prone mice. Quantitative analysis of serum IL-6 in MRL/lpr revealed that the serum sIL-6R level correlated well with the serum IL-6 level. We also showed that sIL-6R in the sera from MRL/lpr mice could mediate the IL-6 functions through the IL-6 signal-transducing receptor component gpl30, suggesting that elevated production of sIL-6R may partly contribute to development of autoimmune disease in MRL/lpr mice.
This review focuses on the significance of brain-reactive antibodies (BRA) to ageassociated cognitive decline and Alzheimerapos;s disease, drawing on evidence available from both human and animal studies. Human studies suggest a relationship between BRA formation, age, and Alzheimerapos;s disease. Experiments with mice indicate that BRA formation and age-related learning deficits are accelerated following adoptive transfer of immunity from aged to young mice. Furthermore, mice selected for autoimmunity and early formation of BRA also show accelerated, age-related learning deficits. It is concluded that a further analysis of the nature of BRA and their targets within the nervous system could reveal important immunological influences in cognitive dysfunctions related to aging and Alzheimerapos;s disease. It is suggested that treatments that delay or prevent age-related immunological dysfunctions be evaluated for their ability to retard age-associated cognitive decline.
Two recently described murine strains, MRL/1 and BXSB, develop a lupus-like syndrome resulting in a 50% mortality by the fifth month of age. Comparison of the immunopathological and virological characteristics of these mice with those of the NZB/NZW F1 mouse reveals several pathogenetic common denominators but no obvious common etiologic factors. In all three kinds of mice, the lupus-like syndrome consists of a fatal immune complex type glomerulonephritis and complete or near complete thymic cortical atrophy plus lymphoid hyperplasia that varies in degree among the three kinds of mice. The nephritic glomeruli contain a concentration of antinuclear antibodies plus varying amounts of stainable gp70. This syndrome is consistently correlated with abnormally elevated serum IgG levels, antinuclear antibodies, anti ds-and ssDNA antibodies, and circulating immune complexes, as well as depressed serum hemolytic complement. Features that differ among the three kinds of mice include: H2 type, anti-lymphocyte antibody, cryoglobulins, T-B cell ratios, sex incidence of disease, vasculitis, and on cornaviral flora. The serum gp70 levels in the three mice also differ considerably, but all are within the range of gp70 levels found in some immunologically normal strains.
The clearance of erythrocytes sensitized with IgG was studied in (MRL-lpr) and (MRL-+/+) mice, which spontaneously develop autoimmune disease. In both strains, an age-dependent decline in clearance of IgG-sensitized erythrocytes was found. Impaired clearance occurred at an earlier age in MRL-lpr mice than in MRL-+/+ mice, correlating with the relative severity of autoimmune disease in these strains. Androgen treatment improved clearance in MRL-+/+ mice but not in MRL-lpr mice, even though autoantibody levels, renal function, and survival were improved. These results suggest that the beneficial effects of androgen on autoimmune disease are not due solely to improved clearance of immune complexes. Castration followed by estrogen administration did not influence immune clearance or autoimmune disease in MRL-lpr mice. These results indicate that impaired immune clearance is a common feature in several autoimmune mouse strains. However, the effects of sex hormones on immune clearance and autoimmune disease may be dissociated in some strains.
MRL/1 mice spontaneously develop a hindlimb arthropathy, as well as a number of immunologic abnormalities, including circulating rheumatoid factors. Although previous studies have suggested that this arthropathy is primarily an inflammatory process, we performed a comprehensive histomorphologic study which indicated that inflammation is a late manifestation of MRL/1 arthritis. The pathologic changes that occur in the joints of these mice can be divided into 3 stages. The first stage develops between the ages of 7 and 13 weeks and consists of synovial cell proliferation in the joint recesses. The second stage is characterized by continued proliferation of synovial cells which take on an appearance similar to that of transformed mesenchymal cells. The earliest destructive changes occur in the second stage and include marginal erosions, followed soon after by progressive destruction of articular and meniscal cartilage. The final stage is characterized by a diminution of synovial cell proliferation, extensive cartilage destruction, formation of scar tissue and fibrocartilage, and a very moderate infiltration of the synovial stroma by mononuclear and polymorphonuclear inflammatory cells. Throughout the disease progression there is a striking dissociation between inflammatory cell infiltration or exudation and tissue destruction. The histomorphologic similarities between human rheumatoid synovitis and the arthritis of MRL/1 mice, as well as the presence of rheumatoid factors, make this mouse strain an excellent model for studying human rheumatoid arthritis.
New Zealand Black (NZB) mice have severe autoimmune disease and approximately 40% have cortical ectopias in layer I of sensorimotor cortex. Because the ectopias are similar to those found in dyslexics, NZB mice have been used as an animal model for developmental learning disorders. In addition, these mice have been used as a model of learning deficits associated with autoimmune disease. To determine whether early intervention would affect learning processes in NZB mice, they were reared after weaning in standard cages or enriched environments. They were given a battery of behavioral tests to measure learning, laterality, and activity, after which they were sacrificed and their brains examined for cortical ectopias. The tests sorted into two behavioral sets. Ectopia-associated behaviors included black-white discrimination learning and the Morris spatial maze. As a group, the mice performed well on these tasks. Ectopic mice had poorer performance than non-ectopics on these measures, and environmental enrichment countered the effects of the ectopias. Autoimmune-associated behavior involved two-way avoidance learning in a shuttlebox. Mice were uniformely poor on this task, ectopias did not affect behavior, and environmental enrichment was without benefit. Evidence from this and other studies shows that poor shuttlebox performance is related to the presence of autoimmune disease. Thus, autoimmune disease and cortical ectopias each appear to affect a separate set of behavioral processes. Environmental enrichment is most effective for behavioral impairments mediated via cortical ectopias, but is much less effective, if at all, if autoimmunity is the primary mediator of the impairments.
Fifty consecutive psychiatric consultations on 48 patients over an 18-month period in an arthritis hospital are analyzed. The range of psychiatric disorders and their relationship to characteristics of the patient population, such as age, sex, and medical diagnosis, are described. Approximately 2% of patients admitted to the hospital during this period elicited psychiatric consultation. This rate is one-third of the consultation rate of an acute medical and surgical hospital serviced by the same consultants. The relative distribution of psychiatric diagnoses—depression 59%, personality disorders and drug abuse 15%, psychosis 10%, conversion reaction 10%, and “other” 6%—was similar to that encountered in an acute general hospital setting. Although depression was the most prevalent psychiatric problem, it was severe enough to elicit consultation only in 1% of the total hospitalized population; its severity did not correlate directly with the severity of rheumatoid arthritis, the most common medical diagnosis encountered. Neither a particular medical illness nor sex accounted for a disproportionate share of the psychiatric consultations.
In a previous study, in which fertilized DBA ova were transferred into an autoimmune female, and NZB ova were transferred into a non-autoimmune female, we found that (1) the maternal environment affected the degree of autoimmunity, (2) the incidence of cortical ectopias was not affected by the maternal environment (3) DBA and NZB females had greater paw asymmetry if reared in an autoimmune uterus, and (4) avoidance learning scores were inversely related to degree of autoimmunity. In the present experiment, reciprocal crosses of DBA and BXSB mice were studied to confirm and extend the original findings. DB mice (DBA female × BXSB male) had greater immune activity than the BD animals, had poorer avoidance learning, but were better on black-white discrimination learning and the Lashley III maze. The BD mice had greater paw asymmetry. Only one of 38 animals had a cortical ectopia. The results lead to the following conclusions: (1) there is an inverse relationship between amount of immune activity and active avoidance learning; (2) some uterine factor in autoimmune mice causes females to have greater paw asymmetry; (3) cortical ectopias are under genetic control; and (4) the lesser immune activity of the BD mice suggests that they developed a suppressor system following early exposure to autoimmunity in the uterine/maternal environment.
Routine cell stains disclose abnormal, usually single, nests of ectopic neurons in neocortical layer I of New Zealand Black (NZB) and BXSB autoimmune mice. We have suggested that these anomalies represent only the most visible part of more widespread cortical disorganization. In an attempt to determine the true magnitude of cellular and fiber disruption associated with the presence of ectopias, we stained cortical sections containing ectopias in layer I from NZB and BXSB mice with an antibody directed against the 68 kDa subunit of neurofilament protein. The neurofilament-stained sections revealed substantial disruption of the cortical layers underlying the ectopic neurons. This resulted primarily from the existence of dense, radially oriented fiber bundles spanning the thickness of the cortex underlying the ectopias. In some instances these fiber bundles could be seen to join the corpus callosum. Even in a small ectopia, where standard stains show no associated cortical dysplasia, dense neurofilament staining was present in layers II and III. It was concluded that the brains of autoimmune mice have severe developmental cortical disorganization, which could account for the behavioral differences displayed by these animals.
Twenty to forty percent of New Zealand Black mice, a strain that develops severe autoimmune disease and learning deficits, exhibit focal unilateral collections of ectopic neurons and glia in layer I of the neocortex with underlying laminar dysplasia. This type of anomaly traditionally has been considered to represent disordered neuronal migration. In an attempt to further characterize these abnormalities, we compared counts of immunohistochemically-stained VIP-neurons in cortical regions containing ectopias and in adjacent cortex to homologous regions of the opposite hemisphere. There was an overall increase in the number of these neurons in the hemisphere containing the ectopias, which resulted from an increase in the number of VIP neurons both in the column of cortex within and underlying the ectopias and in the medially adjoining columns. We concluded that the presence of ectopias in the cerebral cortex not only represent abnormal migration, but also an increase in the number of at least one subset of neurons.
NZB and BXSB mice were given a battery of behavioral tests including paw preference, water escape, Lashley III maze, and discrimination learning. Their brains were then evaluated for cortical ectopias. The incidence of ectopias was 40.5% in NZBs and 48.5% in BXSBs. In the NZB strain left-pawed ectopic mice (both male and female) had the fastest swimming time in the water escape test, while right-pawed ectopics were the slowest. The same findings were obtained for left- and right-pawed ectopic BXSB males, but not for the females. However, on discrimination learning the BXSB males had the exact opposite pattern: right-pawed ectopics were the best learners while left-pawed ectopics were the worst. Male BXSBs and both male and female NZBs were manifesting autoimmune disease at the time of testing, while female BXSBs were not, suggesting that autoimmunity is a necessary background condition for the differential expression of ectopias and paw preference upon learning processes. The finding that the left-pawed ectopic BXSB mice, who were the poorest learners in the non-spatial discrimination learning test, learned best in the spatial water escape test in agreement with the Geschwind hypothesis that pathological events during brain development may, in some instances, produce superiority of function.
NZB and BXSB mice develop autoimmune disease and learn poorly on avoidance tasks. In addition, many of these mice have ectopic collections of neurons, which occur prenatally, in layer I of the cerebral neocortex. The purpose of these experiments was to evaluate the contribution of the uterine/maternal environment upon these variables by transferring fertilized ova to an autoimmune or a non-autoimmune maternal host. In Experiment 1 fertilized DBA ova were transferred into the uteri of BXSB maternal recipients. Later, these animals and conventionally reared DBAs were tested for paw preference, swimming rotation, water escape learning, and shuttlebox avoidance learning. Blood was taken for measurement of immune parameters, and their brains were examined for cortical ectopias. As compared to conventional DBAs, the ova transfer mice had greater amounts of anti-dsDNA autoantibodies, poorer avoidance learning, and poorer water escape learning; in addition, the females had greater paw asymmetry. There was only 1 ectopia in the 81 ova transfer animals, and none in the 78 control mice. In Experiment 2 fertilized NZB ova were transferred into the uteri of non-autoimmune hybrid females and the same procedures were followed as in Experiment 1. Ova transfer mice had lesser amounts of anti-dsDNA autoantibodies, better avoidance learning scores, and females had less paw asymmetry; in addition, within the ova transfer group males were clockwise swimmers whereas females swam counterclockwise. There were 4 ectopics out of 17 ova transfer mice (23.5%), which did not differ from the 40.5% of the control group. In both experiments the uterine environment did not affect the occurrence of ectopias.(ABSTRACT TRUNCATED AT 250 WORDS)
Mouse strains with or without disorders were examined in order to further assess the incidence of brain anomalities in immune-disordered strains. The brain was examined in Nissl-stained serial sections under a light microscope for the presence of abnormalities, with specific attention to ectopic collections of neurons in layer I of the neocortex, as reported in the autoimmune New Zealand Black (NZB) and BXSB strains. The present study was designed to survey additional strains with immune disorders (Snell dwarf, C57BL/6J-nu/nu, BALB/cByJ- nu/nu, and SJL) and 7 control strains without immune disorders. In addition, we attempted to replicate past findings in the higly affected BXSB strain and the MRL/1 strain, which develops autoimmune disease, but has a low incidence of brain abnormalities. The largest number of brain abnormalities (20–40%) were seen in the C57BL/6J- nu/nu, Snell dwarf and BXSB strains. The anomalies in the C57BL/6J- nu/nu and BXSB mice consisted of ectopic neurons in layer I of the neocortex, whereas the Snell dwarf mice had either neuron-free areas in the cortex, or rippling of cortical layers II-IV, and one case had agenesis of the corpus callosum. Between 4% and 8% of the mice from the SJL, MRL/1, and MRL +/+ strains had either neuron-free areas in the cortex or ectopic neurons in layer I. The BALB/cByJ- nu/nu and control strains did not have any cortical abnormalities. Future studies will be designed to determine whether immune-based alterations to the developing brain are responsible for the brain anomalies present in immune-disordered strains.
Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.
A spontaneously occurring antibody cytotoxic to dissociated cells of the neonate mouse cerebellum was found in the sera of some New Zealand (NZ) mice. No significant activity was found in the sera of six non-autoimmune mouse strains. The degree of cytotoxicity was similar towards both allogeneic and syngeneic cells. Absorption of the cytotoxic sera with brain and kidney homogenates removed the reactivity, while liver removed less reactivity. Absorptions with thymocytes and several other tissue homogenates and cells had no effect on the cytotoxicity levels, nor was there a correlation between the levels of thymocytotoxicity and cerebellar cell cytotoxicity. The antibody cytotoxic for cerebellar cells could not be demonstrated in the cerebrospinal fluid (CSF) of any mice examined, including a mouse with high serum cytotoxic levels. Gel filtration of reactive sera indicated that the antibody is of the IgM class.
The presence of an antibody in New Zealand Black (NZB) mice to dissociated cerebellar cells from 6–10 day-old BDF1 mice was detected by indirect immunofluorescence. The sera from NZB mice displayed a significantly higher binding to cerebellar cells by this technique than did the sera from two non-autoimmune strains (BDF1 and CAF1). The NZB sera showed a positive correlation between an index of cytotoxicity to cerebellar cells and the percentage of cerebellar cells showing serum immunoglobulin (Ig) binding. The NZB sera also showed a significant positive correlation between IgM binding and cytotoxicity to cerebellar cells. No relationship was seen between IgG1 and IgG2 fluorescence and the index of cytotoxicity. In addition, in none of the mice was there a positive correlation between levels of thymocytotoxicity and binding by any of the tested classes of immunoglobulin to dissociated cerebellar cells.Further characterization of the antibody using Sephadex G-200 fractionation of NZB sera showed Ig binding to cerebellar cells for peaks I (void volume) and II of the three major peaks. Pooled normal mouse sera showed elevated Ig fluorescence in only the second peak. In all cases, the heightened fluorescence was determined to be IgM when the appropriate fluoresceinated antisera was used. The data suggest the presence, in some NZB mice, of an IgM antibody reactive with componets of the central nervous system.