Figure 5 - uploaded by Harvi Luthra
Content may be subject to copyright.
Clinical and histologic presentation of collagen arthritis in HLA-DQ8+,H-2Ab ~ mice. (A-C) The appearance of a normal rear paw from a bovine ClI-immunized HLA-DQ8 ,H-2Ab ~ mouse (A) contrasted with arthritic paws from an HLA-DQ8+,H-2Ab ~ animal (B) and a positive control BI0.T(6R.) mouse (C). (D-/) Cross-sections of the hind foot from an arthritis-resistant HLA-DQS-,H-2Ab ~ mouse (D and G) compared with an arthritic joint from HLA-DQS+,H-2Ab ~ (E and H) and B10.T (6R) animals (F and/). D and G illustrate normal synovial lining, while E, F, H, and I show regions of mononuclear cell infiltration of the synovium with pannus formation and cartilage and subchondral bone erosions. The magnifications of each section are noted in the lower right-hand corner. The areas of tissue illustrated in G, /4, and I are higher magnifications of the boxed areas in D, E, and F, respectively.
Source publication
Genetic studies have indicated that susceptibility to rheumatoid arthritis (RA) maps to the HLA-DR locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DR genes associated with RA, however, suggests that HLA-DQ molecules may also play a role in RA susceptibility. To examine the role of HL...
Contexts in source publication
Context 1
... susceptible to CIA. Among the 18 animals tested, 12 developed a noticeable arthritis in ~5 wk after immunization which progressed to severe ar- thritis and persisted until the termination of the experiment. In general, both HLA-DQ8+,H-2Ab ~ and B10.T(6R) ani- mals developed severe inflammation, swelling, and joint deformity in afflicted limbs (Fig. 5, B and C). Histologic ex- amination of arthritic hind limbs showed that the nature of the inflammatory infiltrate was similar in both strains; a marked synovitis consisting of synovial cell hyperplasia, in- filtration of mononuclear cells, and erosion of articular car- tilage and subchondral bone was observed (Fig. 5, E and H versus F ...
Context 2
... deformity in afflicted limbs (Fig. 5, B and C). Histologic ex- amination of arthritic hind limbs showed that the nature of the inflammatory infiltrate was similar in both strains; a marked synovitis consisting of synovial cell hyperplasia, in- filtration of mononuclear cells, and erosion of articular car- tilage and subchondral bone was observed (Fig. 5, E and H versus F and /). Transgene-negative HLA-DQ8-,H-2Ab ~ littermates showed no signs of clinical arthritis and histo- logic evidence of synovial inflammation was not detected (Fig. 5, A, D, and G). Serum analysis revealed that both ar- thritic and nonarthritic HLA-DQ8+,H-2Ab ~ and B10.T(6R) mice possessed the bovine CII~pecific ...
Context 3
... synovitis consisting of synovial cell hyperplasia, in- filtration of mononuclear cells, and erosion of articular car- tilage and subchondral bone was observed (Fig. 5, E and H versus F and /). Transgene-negative HLA-DQ8-,H-2Ab ~ littermates showed no signs of clinical arthritis and histo- logic evidence of synovial inflammation was not detected (Fig. 5, A, D, and G). Serum analysis revealed that both ar- thritic and nonarthritic HLA-DQ8+,H-2Ab ~ and B10.T(6R) mice possessed the bovine CII~pecific IgG antibody that was cross-reactive against mouse CII. Also, no significant correlation in the level of CII antibody and the develop- ment or severity of CIA was detected in either the HLA- ...
Citations
... HLA-II-expressing humanized mouse models are well-established and frequently used as clinical translation models for studying mechanisms underlying dysregulated host immune responses to infections [10,20,21], streptococcal and staphylococcal superantigen responses, dermatitis, collagen-induced arthritis [22][23][24], food allergens [25], dust allergens [26], progression of demyelination and neurological deficits in Theiler's murine encephalomyelitis virus infection [27], and brain pathology in experimental autoimmune encephalomyelitis [28,29]. Building upon our previous work [30], and given the potential for the differential presentation of immune responses and outcomes by DR and DQ alleles, in the present study, we utilized the HLA-DQ8 (DQA1*0301/DQB1*0302) mice (DQ8) to investigate the skin-brain axis and effects of clindamycin (CLN) following subcutaneous GAS infection. ...
The broad range of clinical manifestations and life-threatening infections caused by the Gram-positive bacterium, Streptococcus pyogenes or Group A Streptococcus (GAS), remains a significant concern to public health, with a subset of individuals developing neurological complications. Here, we examined the concurrent neuroimmune effects of subcutaneous GAS infections in an HLA-Class II (HLA) transgenic mouse model of subcutaneous GAS infection. To investigate changes in the skin–brain axis, HLA-DQ8 (DQA1*0301/DQB1*0302) mice (DQ8) were randomly divided into three groups: uninfected controls (No Inf), GAS infected and untreated (No Tx), and GAS infected with a resolution by clindamycin (CLN) treatment (CLN Tx) (10 mg/kg/5 days) and were monitored for 16 days post-infection. While the skin GAS burden was significantly reduced by CLN, the cortical and hippocampal GAS burden in the male DQ8 mice was not significantly reduced with CLN. Immunoreactivity to anti-GAS antibody revealed the presence of GAS bacteria in the vicinity of the neuronal nucleus in the neocortex of both No Tx and CLN Tx male DQ8 mice. GAS infection-mediated cortical cytokine changes were modest; however, compared to No Inf or No Tx groups, a significant increase in IL-2, IL-13, IL-22, and IL-10 levels was observed in CLN Tx females despite the lack of GAS burden. Western blot analysis of cortical and hippocampal homogenates showed significantly higher ionized calcium-binding adaptor-1 (Iba-1, microglia marker) protein levels in No Tx females and males and CLN Tx males compared to the No Inf group. Immunohistochemical analysis showed that Iba-1 immunoreactivity in the hippocampal CA3 and CA1 subregions was significantly higher in the CLN Tx males compared to the No Tx group. Our data support the possibility that the subcutaneous GAS infection communicates to the brain and is characterized by intraneuronal GAS sequestration, brain cytokine changes, Iba-1 protein levels, and concurrent CA3 and CA1 subregion-specific microgliosis, even without bacteremia.
... HLA-DQ8 mice were first described over 20 years ago, and were originally developed to study rheumatoid arthritis, an autoimmune disease linked to HLA risk genes (Nabozny, Baisch, Cheng, et al., 1996;Taneja & David, 2010). These mice lack all mouse MHC class II molecules (H2-Aβ°), but express the human HLA-DQ8 α and β genes, and are designated as DQ8.Aβ 0 or HLA-DQ8. ...
Celiac disease (CeD) is a common immune-mediated disease triggered by the ingestion of gluten in genetically predisposed individuals. CeD is unique in that the trigger (gluten), necessary genes (HLA-DQ2 and DQ8), and the autoantigen (tissue transglutaminase) have been identified, allowing additional environmental co-factors, like the intestinal microbiota, to be studied through relevant in vivo models. Murine models for CeD have come a long way in the past decade and there are now in vitro and in vivo tools available that mimic certain aspects of clinical disease. These models, many of which express the CeD risk genes, have recently been used to study the mechanisms through which the microbiota play a role in CeD pathogenesis through a gnotobiotic approach. Historically, the generation of gnotobiology technology in mid-20th century allowed for the study of immunity and physiology under a complete absence of microbes (axenic) or known colonized status (gnotobiotic). This enabled understanding of mechanisms by which certain bacteria contribute to health and disease. With this perspective, here, we will discuss the various murine models currently being used to study CeD. We will then describe how utilizing axenic and gnotobiotic CeD models has increased our understanding of how microbes influence relevant steps of CeD pathogenesis, and explain key methodology involved in axenic and gnotobiotic modeling.
... and HLA-DQA1*03.01 genes) (15,16). The RIP-hB7.1 transgene was inserted in a HIV-derived recombinant lentiviral vector (LV-RIP-hB7.1; ...
... Most hPPI peptides that were previously defined as recognized by human CD8 + T cells (11,26) were recognized by T cells obtained from diabetic YES-RIP-hB7.1 mice ( Figure 4A). Responses were detected against hPPI 2-11 (p ≤ 0.03), hPPI 6-14 (p ≤ 0.001), hPPI [15][16][17][18][19][20][21][22][23][24] (p ≤ 0.02), and hPPI [33][34][35][36][37][38][39][40][41][42] (p ≤ 0.013). No responses were observed against any of these hPPI peptides in control YES mice and in non-diabetic YES-RIP-hB7.1 mice. ...
... No responses were observed against any of these hPPI peptides in control YES mice and in non-diabetic YES-RIP-hB7.1 mice. When considering responses that were over the mean ± 3SD of responses seen in control YES mice, significant responses were observed against hPPI 6-14 (9/26, p ≤ 0.016), hPPI [15][16][17][18][19][20][21][22][23][24] ( (15.4%), and hPPI 101-109 (15.4%), although they did not reach statistical significance in the whole population of diabetic mice analyzed ( Table S3). As a whole, 93.75% YES-RIP-hB7.1 diabetic mice showed a response to at least one of the HLA-A*02:01-restricted hPPI peptides studied (defined as > mean ± 3SD of the response of YES mice against each given peptide, Table S3). ...
To circumvent the limitations of available preclinical models for the study of type 1 diabetes (T1D), we developed a new humanized model, the YES-RIP-hB7.1 mouse. This mouse is deficient of murine major histocompatibility complex class I and class II, the murine insulin genes, and expresses as transgenes the HLA-A*02:01 allele, the diabetes high-susceptibility HLA-DQ8A and B alleles, the human insulin gene, and the human co-stimulatory molecule B7.1 in insulin-secreting cells. It develops spontaneous T1D along with CD4⁺ and CD8⁺ T-cell responses to human preproinsulin epitopes. Most of the responses identified in these mice were validated in T1D patients. This model is amenable to characterization of hPPI-specific epitopes involved in T1D and to the identification of factors that may trigger autoimmune response to insulin-secreting cells in human T1D. It will allow evaluating peptide-based immunotherapy that may directly apply to T1D in human and complete preclinical model availability to address the issue of clinical heterogeneity of human disease.
... Briefly, cosmids H11A (30-kb DNA) and Â10A (38-kb DNA fragment), which contain the DQA*0301 and DQB*0302 genes, respectively, were microinjected into (CBA/J. B10.M) F2 embryos, as previously described (35). Transgene-positive founders were identified by Southern blot analysis of tail DNA and subsequently mated to B10.M mice. ...
Multiple sclerosis (MS) is an autoimmune disease of the CNS in which the interaction between genetic and environmental factors plays an important role in disease pathogenesis. Although environmental factors account for 70% of disease risk, the exact environmental factors associated with MS are unknown. Recently, gut microbiota has emerged as a potential missing environmental factor linked with the pathobiology of MS. Yet, how genetic factors, such as HLA class II gene(s), interact with gut microbiota and influence MS is unclear. In the current study, we investigated whether HLA class II genes that regulate experimental autoimmune encephalomyelitis (EAE) and MS susceptibility also influence gut microbiota. Previously, we have shown that HLA-DR3 transgenic mice lacking endogenous mouse class II genes (AE-KO) were susceptible to myelin proteolipid protein (91-110)-induced EAE, an animal model of MS, whereas AE-KO.HLA-DQ8 transgenic mice were resistant. Surprisingly, HLA-DR3.DQ8 double transgenic mice showed higher disease prevalence and severity compared with HLA-DR3 mice. Gut microbiota analysis showed that HLA-DR3, HLA-DQ8, and HLA-DR3.DQ8 double transgenic mice microbiota are compositionally different from AE-KO mice. Within HLA class II transgenic mice, the microbiota of HLA-DQ8 mice were more similar to HLA-DR3.DQ8 than HLA-DR3. As the presence of DQ8 on an HLA-DR3 background increases disease severity, our data suggests that HLA-DQ8-specific microbiota may contribute to disease severity in HLA-DR3.DQ8 mice. Altogether, our study provides evidence that the HLA-DR and -DQ genes linked to specific gut microbiota contribute to EAE susceptibility or resistance in a transgenic animal model of MS.
... On the other hand, the endogenous murine MHC class II molecule (Ab o or AE o ) was deleted in most HLA class II transgenic mice in order to promote the expression of the introduced HLA class II molecules on T cells, which is a feature similar to that observed in humans ). The developers hypothesized that the expression of the human class II molecule, in the absence of mouse class II gene products, leads to the preferential development of a population of human class II-restricted T cells (Nabozny et al. 1996). However, it should be noted that there are disadvantages associated with MHC class II manipulation. ...
Various types of transgenic mice carrying either class I or II human leukocyte antigen (HLA) molecules are readily available, and reports describing their use in a variety of studies have been published for more than 30 years. Examples of their use include the discovery of HLA-specific antigens against viral infection as well as the reproduction of HLA-mediated autoimmune diseases for the development of therapeutic strategies. Recently, HLA transgenic mice have been used to reproduce HLA-mediated idiosyncratic drug toxicity (IDT), a rare and unpredictable adverse drug reaction that can result in death. For example, abacavir-induced IDT has successfully been reproduced in HLA-B*57:01 transgenic mice. Several reports using HLA transgenic mice for IDT have proven the utility of this concept for the evaluation of IDT using various HLA allele combinations and drugs. It has become apparent that such models may be a valuable tool to investigate the mechanisms underlying HLA-mediated IDT. This review summarizes the latest findings in the area of HLA transgenic mouse models and discusses the current challenges that must be overcome to maximize the potential of this unique animal model.
... It has been reported HLA-DQ molecules play a provocative role in joint destruction susceptibility of RA [26]. HLA-DQA and HLA-DQB locus are important for susceptibility of arthritis in rat models [27] and HLA-DQ8 is a highly susceptible gene in transgenic mice [28]. Whereas HLA-DR shows permissive or protective roles in mice models [29]. ...
It has been reported Human Leukocyte Antigen (HLA) gene polymorphism is a risk factor for the development of Behçet’s disease (BD). In this study, the association of HLA class II subtypes HLA-DP, DQ, DR, and T cell subsets in BD patients with arthritis was evaluated. Frequencies of HLA-DP, DQ, DR positive cells, and T cell subsets in peripheral blood leukocytes (PBL) were measured by flow cytometric analysis in BD, and compared to rheumatoid arthritis as disease controls and healthy controls. Frequencies of HLA-DQ were significantly decreased in whole PBL and granulocytes of BD active patients as compared to healthy controls. In monocytes populations, proportions of HLA-DR positive cells were significantly increased in BD active patients as compared to healthy controls. Proportions of CD4+CCR7+ and CD8+CCR7+ cells were significantly higher in BD active patients than in BD inactive in whole PBL. Frequencies of CD4+CD62L- and CD8+CD62L- cells in lymphocytes were significantly decreased in active BD than those in inactive BD. There were also correlations between disease activity markers and T cell subsets. Our results revealed HLA-DP, DQ, and DR expressing cell frequencies and several T cell subsets were significantly correlated with BD arthritis symptoms.
... We generated mice lacking endogenous class II molecules and expressing the RA-associated HLA-DQ8 gene. 13,14 Immunization of DQ8 mice with CII leads to a robust antigen-specific cellular and humoral response and mice develop severe CIA with histopathological changes as observed in humans. 14 Mice expressing DRB1*0401 and DRB1*0402 transgene but lacking endogenous class II molecules have been generated. ...
... We generated mice lacking endogenous class II molecules and expressing the RA-associated HLA-DQ8 gene. 13,14 Immunization of DQ8 mice with CII leads to a robust antigen-specific cellular and humoral response and mice develop severe CIA with histopathological changes as observed in humans. 14 Mice expressing DRB1*0401 and DRB1*0402 transgene but lacking endogenous class II molecules have been generated. ...
OBJECTIVE:
Although the etiology of rheumatoid arthritis (RA) is unknown, recent studies have led to the concept that gut dysbiosis may be involved in onset. In this study, we aimed to determine if human gut commensals modulate the immune response and gut epithelial integrity in DQ8 mice.
METHODS:
DQ8 mice were orally gavaged with RA-associated (Eggerthella lenta or Collinsella aerofaciens) and non-associated (Prevotella histicola or Bifidobacterium sp.) on alternate days for 1 week in naïve mice. Some mice were immunized with type II collagen and oral gavage continued for 6 weeks and followed for arthritis. Epithelial integrity was done by FITC-Dextran assay. In addition, cytokines were measured in sera by ELISA and various immune cells were quantified using flow cytometry.
RESULTS:
Gut permeability was increased by the RA-associated bacteria and was sex and age-dependent. In vivo and in vitro observations showed that the RA-non-associated bacteria outgrow the RA-associated bacteria when gavaged or cultured together. Mice gavaged with the RA-non-associated bacteria produced lower levels of pro-inflammatory MCP-1 and MCP-3 and had lower numbers of Inflammatory monocytes CD11c+Ly6c+, when compared to controls. E. lenta treated naïve mice produce Th17 cytokines.
CONCLUSIONS:
Our studies suggest that gut commensals influence immune response in and away from the gut by changing the gut permeability and immunity. Dysbiosis helps the growth of RA-associated bacteria and reduces the beneficial bacteria.
... In humans, HLA-DQB1 * 03 occurs in linkage with the RA risk locus HLA-DRB1 * 04 and has been suggested to affect the clinical expression of RA (176)(177)(178). Immunization with heterologous CII induced autoreactive T and B cell response and severe inflammatory arthritis in 70% of DQ8 Tg animals (179), while of mice expressing a protective DQ6 Tg, only 14% presented mild arthritis and 60% of Tg mice with mixed DQ8/DQ6 haplotype developed moderate CIA in response to CII (180). DQ8 Tg mice with deleted CD4 did not develop arthritis, while CD8 deficient DQ8 Tg mice developed severe CIA along with increased autoantibody levels, suggesting that CD4+ T cells, but not CD8+ T cells are indispensable for initiation of CIA (181). ...
Rodent models of rheumatoid arthritis (RA) have been used over decades to study the immunopathogenesis of the disease and to explore intervention strategies. Nevertheless, mouse models of RA reach their limit when it comes to testing of new therapeutic approaches such as cell-based therapies. Differences between the human and the murine immune system make it difficult to draw reliable conclusions about the success of immunotherapies. To overcome this issue, humanized mouse models have been established that mimic components of the human immune system in mice. Two main strategies have been pursued for humanization: the introduction of human transgenes such as human leukocyte antigen molecules or specific T cell receptors, and the generation of mouse/human chimera by transferring human cells or tissues into immunodeficient mice. Recently, both approaches have been combined to achieve more sophisticated humanized models of autoimmune diseases. This review discusses limitations of conventional mouse models of RA-like disease and provides a closer look into studies in humanized mice exploring their usefulness and necessity as preclinical models for testing of cell-based therapies in autoimmune diseases such as RA.
... These mice express the human form of RA-susceptible MHC, HLA-DR4 and/or HLA-DQ8. This allows the researchers to study arthritis in mice but correlate the pathology to humans due to the human genetic background [2,33,42]. the activation and secretion of pro-inflammatory cytokines by myeloid cells; the T-B cell collaboration leading to autoantibody production by plasma cells; and the osteoimmune cross-talk leading to osteoclast differentiation. These intricate pathways regulate autoimmune inflammation of the synovial joint as shown by arrows (leading to activation/induction) and blunt ends (leading to suppression/inhibition). ...
... Several researchers also use the proteoglycan-induced arthritis (PGIA) model in BALB/c mice, which is a T cell-dependent and autoantibody/B cell-driven disease [41]. Humanized mice are also used to study arthritis [2,33,42]. These mice express the human form of RA-susceptible MHC, HLA-DR4 and/or HLA-DQ8. ...
... These mice express the human form of RA-susceptible MHC, HLA-DR4 and/or HLA-DQ8. This allows the researchers to study arthritis in mice but correlate the pathology to humans due to the human genetic background [2,33,42]. ...
Rheumatoid arthritis (RA) is a chronic, debilitating illness characterized by painful swelling of the joints, inflammation of the synovial lining of the joints, and damage to cartilage and bone. Several anti-inflammatory and disease-modifying drugs are available for RA therapy. However, the prolonged use of these drugs is associated with severe side effects. Furthermore, these drugs are effective only in a proportion of RA patients. Hence, there is a need to search for new therapeutic agents that are effective yet safe. Interestingly, a variety of herbs and other natural products offer a vast resource for such anti-arthritic agents. We discuss here the basic features of RA pathogenesis; the commonly used animal models of RA; the mainstream drugs used for RA; the use of well-characterized natural products possessing anti-arthritic activity; the application of nanoparticles for efficient delivery of such products; and the interplay between dietary products and the host microbiome for maintenance of health and disease induction. We believe that with several advances in the past decade in the characterization and functional studies of natural products, the stage is set for widespread clinical testing and/or use of these products for the treatment of RA and other diseases.
