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Apoptosis in the Homeostasis of the Immune System and in Human Immune Mediated Diseases
Abstract and Figures
The immune system has evolved sophisticated mechanisms controlling the development of responses to dangerous antigens while avoiding unnecessary attacks to innocuous, commensal or self antigens. The risk of autoimmunity is continuously checked and balanced against the risk of succumbing to exogenous infectious agents. It is therefore of paramount importance to understand the molecular events linking the breakdown of tolerance and the development of immunodeficiency. Apoptotic mechanisms are used to regulate the development of thymocytes, the shaping of T cell repertoire, its selection and the coordinate events leading to immune responses in the periphery. Moreover, they are at the heart of the homeostatic controls restoring T cell numbers and establishing T cell memory. T lymphocytes shift continuously from survival to death signals to ensure immune responsiveness without incurring in autoimmune damage. In this review we shall consider some key facts on the relationship of lymphopenia to autoreactivity, the mechanisms controlling positive and negative selection in the thymus, the role of apoptosis in selected primary immunodeficiency states and in systemic and organ-specific autoimmunity, with examples from human diseases and their animal models.
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... In addition, other proteins (including pro-apoptotic and anti-apoptotic proteins) also play essential roles (Fleisher, 1997). Dysregulation of cell apoptosis has been observed in various disease states (including autoimmune diseases, neurodegenerative diseases, and cancer) (Giovannetti et al., 2008;Wong, 2011;Erekat, 2022). Necrosis is a type of non-programmed cell death that mainly occurs in acute injury, infection, and when apoptosis is inhibited, characterized by cell swelling and dissolution. ...
The death of cells can occur through various pathways, including apoptosis, necroptosis, mitophagy, pyroptosis, endoplasmic reticulum stress, oxidative stress, ferroptosis, cuproptosis, and disulfide-driven necrosis. Increasing evidence suggests that mitophagy and ferroptosis play crucial regulatory roles in the development of stroke. In recent years, the incidence of stroke has been gradually increasing, posing a significant threat to human health. Hemorrhagic stroke accounts for only 15% of all strokes, while ischemic stroke is the predominant type, representing 85% of all stroke cases. Ischemic stroke refers to a clinical syndrome characterized by local ischemic-hypoxic necrosis of brain tissue due to various cerebrovascular disorders, leading to rapid onset of corresponding neurological deficits. Currently, specific therapeutic approaches targeting the pathophysiological mechanisms of ischemic brain tissue injury mainly include intravenous thrombolysis and endovascular intervention. Despite some clinical efficacy, these approaches inevitably lead to ischemia-reperfusion injury. Therefore, exploration of treatment options for ischemic stroke remains a challenging task. In light of this background, advancements in targeted therapy for cerebrovascular diseases through mitophagy and ferroptosis offer a new direction for the treatment of such diseases. In this review, we summarize the progress of mitophagy and ferroptosis in regulating ischemia-reperfusion injury in stroke and emphasize their potential molecular mechanisms in the pathogenesis. Importantly, we systematically elucidate the role of medicinal plants and their active metabolites in targeting mitophagy and ferroptosis in ischemia-reperfusion injury in stroke, providing new insights and perspectives for the clinical development of therapeutic drugs for these diseases.
... However, ovariectomy has been used as an experimental animal model to simulate the physiological condition of menopause and both are associated with changes in body composition, loss of bones rigidity and increase the evidence of autoimmune disease. Estrogens and exactly estradiol 17B(E2) are able to regulate immune responses by cells development, cytokines or/and antibody production, apoptosis and proliferation [45] . Estrogen has also profound effects on B cell differentiation, function, activity [46] and survival by increasing expression of gens [47] . ...
The present experiment was investigated to study the complementary effect of vitamin C and Zinc supplementation on some parameters related to the immune system in intact and ovariectomized rabbits. Twenty female rabbits (7-8 weeks) have been used in this study. Ten of them had been subjected to ovariectomy and the other ten were left with intact ovaries. After recovery from the operation and acclimatization, the rabbits were divided into four equal groups as follow: Group one (G1): Intact rabbits received distilled water. Group two (G2): Intact rabbits received complementary vitamin C and Zinc with the dose (10.166 mg/kg/B.W) orally and daily. Group three (G3): Ovariectomized rabbits received distilled water. Group four (G4): Ovariectomized rabbits received complementary vitamin C and Zinc. The daily supplementation of complementary vitamin C and Zinc induces a significant increase in total leukocytes (14.06 and 11.08 × 10 3 /mm 3) in both intact and ovariectomized rabbits respectively. Moreover, the Arneth , s index reveals a significant higher percentage of neutrophils of four and five lobes in both supplemented groups. The total percentage of mature cells was (27.9% and 14.1%) for G2 and G4 respectively in comparison with (9.0% and 8.3%) for G1 and G3 respectively. There is a significant increase in eosinophil's and lymphocytes percentages in Ovariectomized rabbits only. However, the result also revealed a significant increase in total protein and total gamma concentration in both intact and ovariectomized rabbits that supplemented with complementary vitamin C and Zinc. In conclusion, the results from this experiment confirm and for the first time that the complementary vitamin C and Zinc supplementation to rabbits has an important protective role on the immune system in ovariectomized rabbits. This supplementation can overcome the deleterious effect of ovariectomy and ovarian hormones deficiency on bodies' immunity.
... Apoptosis plays a key role in maintaining homeostasis for the survival in multicellular organism, especially under pathophysiological stresses [1][2][3] . One typical example is the pathogenic infection-induced innate immune response, which is the first line of defense against infections and facilitates organism's survival via eliciting apoptosis that eliminates the infected cells to prevent pathogen replication and propagation [4][5][6][7] . ...
Caspase-mediated cleavage of PARP1 is a surrogate marker for apoptosis. However, the biological significance of PARP1 cleavage during apoptosis is still unclear. Here, using unbiased protein affinity purification, we show that truncated PARP1 (tPARP1) recognizes the RNA polymerase III (Pol III) complex in the cytosol. tPARP1 mono-ADP-ribosylates RNA Pol III in vitro and mediates ADP-ribosylation of RNA Pol III during poly(dA-dT)-stimulated apoptosis in cells. tPARP1-mediated activation of RNA Pol III facilitates IFN-β production and apoptosis. In contrast, suppression of PARP1 or expressing the non-cleavable form of PARP1 impairs these molecular events. Taken together, these studies reveal a novel biological role of tPARP1 during cytosolic DNA-induced apoptosis.
... Medical Immunology (Russia)/Meditsinskaya Immunologiya Медицинская Иммунология прессорной функции Treg является цитолизис посредством гранзима А. Известно, что Treg могут подавлять иммунный ответ, обуславливая апоптоз [16]. В этом случае механизмы апоптоза используются для регуляции развития тимоцитов, формирования репертуара T-клеток, их селекции и для координации событий, ведущих к периферическому иммунному ответу [11]. Treg могут управлять иммунным ответом при помощи перфорин/гранзимных путей. ...
The existing data on regulatory T cells (Tregs) in prostate cancer suggest that these cells may penetrate the prostate gland malignant tissue, suppressing antitumor immune response, thus promoting aggressive clinical course and low survival of the cancer patients. Evaluation of T cell subpopulations from the tumor microenvironment has shown that the number of CD4+Tregs is associated with inferior clinical prognosis. In particular, each additional CD4+Treg cell has been shown to cause a statistically significant increase in prostate cancer mortality by 12%, regardless of other clinical factors. There are several possible explanations for the increased infiltration of prostate cancer tissue with regulatory T cells. Firstly, malignant cells or tumor-associated macrophages are capable of secreting chemokine CCL22, which has an affinity for the CCR4 receptor expressed on Treg cells. Secondly, cytokines secreted by prostate tumors, such as TGF-β, may regulate the FoxP3 expression, thus expanding the Treg population. TGF-β, in turn, is a multifunctional cytokine that promotes survival and proliferation of transformed cells, including prostate epithelium, as evidenced by increased amounts in the patients with metastatic disease.
Introduction:
Fertility rates in developing countries have declined over the past decades, and the trend of delayed fatherhood is rising as societies develop. The reasons behind the decline in male fertility with advancing age remain mysterious, making it a compelling and crucial area for further research. However, the limited number of studies dedicated to unraveling this enigma poses a challenge. Thus, our objective is to illuminate some of the upregulated and downregulated mechanisms in the male testis during the aging process.
Areas covered:
Herein, we present a critical overview of the studies addressing the alterations of testicular proteome through the aging process, starting from sexually matured young males to end-of-life-expectancy aged males. The comparative studies of the proteomic testicular profile of men with and without spermatogenic impairment are also discussed and key proteins and pathways involved are highlighted.
Expert opinion:
The difficulty of making age-comparative studies, especially of advanced-age study subjects, makes this topic of study quite challenging. Another topic worth mentioning is the heterogeneous nature and vast cellular composition of testicular tissue, which makes proteome data interpretation tricky. The cell type sorting and comorbidities testing in the testicular tissue of the studied subjects would help mitigate these problems.
The immune system percolating throughout the body can impact the function of other organs by contributing to allergy or autoimmune disease. Thymic hypoplasia is one of the central features of this condition, and its main consequence is to restrict T-cell production. Children typically have low T cells with preserved antibody production, while adults more often have adequate T-cell counts, and a subset have impaired antibody production. Homeostatic proliferation is invoked by the body to try to correct the low T-cell counts, but it is associated with Th2 polarization, which contributes to atopic risk in this population. Low regulatory T cells are seen and may be part of the autoimmune predisposition. The effects are complex and often age dependent, consistent with other features of the syndrome. Careful monitoring is crucial for the management of the immunodeficiency.
Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human diseases like cancer, infections and ischaemia/reperfusion injury. Coordinated interactions between RIPK1, RIPK3 and MLKL lead to the formation of a dedicated death complex called the necrosome that triggers MLKL‐mediated membrane rupture and necroptotic cell death. Necroptotic cell death is tightly controlled by post‐translational modifications, among which especially phosphorylation has been characterised in great detail. Although selective ubiquitination is relatively well‐explored in the early initiation stages of necroptosis, the mechanisms and functional consequences of RIPK3 and MLKL ubiquitination for necrosome function and necroptosis are only starting to emerge. This review provides an overview on how site‐specific ubiquitination of RIPK3 and MLKL regulates, fine‐tunes and reverses the execution of necroptotic cell death.
Morbidity and mortality rates in invasive mycoses determine the need to improve methods for their timely diagnosis by assessment the patients’ immune status. Evaluation of individual immune status allows the clinician to predict the development and course of fungal infections. At the same time, identification of opportunistic mycosis in immunocompetent patients should require a search for some hidden immune deficiency. Determining the cause of such immune defects can help develop an effective strategy for both etiotropic and immune therapy of patients with invasive mycoses. Currently, the functions of regulatory T lymphocytes that support immunological tolerance in fungal infections remain to be incompletely studied. In this review, we present experimental works which suggest that the regulatory T lymphocytes are able to suppress immune responses to fungi by stimulating the immunosuppressive environment. It was shown that regulatory T lymphocytes use Toll-like receptor 2 to achieve immunosuppression in Candida infections. The balance between the number and function of regulatory T lymphocytes is essential for elimination of fungal pathogens and protection against post-infectious immunopathological conditions. It was found that the regulatory T lymphocytes provide protection at an early stage of Candida infection, since, due to IL-2 suppression, they enhance Th17 differentiation and clearance of fungi. Moreover, at the later stages of infection, the regulatory T lymphocytes have an inhibitory effect. The balance between Th17 and regulatory T lymphocytes in mucosal lining is considered the main factor for distinguishing between commensal carriage and Candida albicans infection. The study is presented which indicate that disseminated candidiasis associated with expansion of regulatory T lymphocytes stimulates a Th17-cell response that controls the course of the disease. The mechanisms that control regulatory T lymphocytes homeostasis are essential for providing effective protection against pathogens, as well as for controlling the immunopathological conditions associated with Candida infection. The review presents data that have established the role of TGF-β1 in increasing the viability of regulatory T lymphocytes, which is correlated with the pronounced immunomodulating role of these cells at the later phase of Candida infections of the mucous membrane. It has been also demonstrated that the pulmonary regulatory Tlymphocytes are induced during cryptococcal infection, which predominantly suppresses Th2 cells, thereby supporting its course. Expansion of the regulatory T lymphocytes upon administration of IL-2/antiIL-2 complex during cryptococcal infection led to a decrease in IgE production and a decrease in allergic airway inflammation. It should be noted that refinement of prognostic value of the regulatory T lymphocytes in human fungal infections may substantiate the basic principles of targeted immunotherapy.
Phagocytosis is a pivotal immunological process, and its discovery by Elia Metchnikoff in 1882 was a step toward the establishment of the innate immune system as a separate branch of immunology. Elia Metchnikoff received the Nobel Prize in physiology and medicine for this discovery in 1908. Since its discovery almost 140 years before, phagocytosis remains the hot topic of research in immunology. The phagocytosis research has seen a great advancement since its first discovery. Functionally, phagocytosis is a simple immunological process required to engulf and remove pathogens, dead cells and tumor cells to maintain the immune homeostasis. However, mechanistically, it is a very complex process involving different mechanisms, induced and regulated by several pattern recognition receptors, soluble pattern recognition molecules, scavenger receptors (SRs) and opsonins. These mechanisms involve the formation of phagosomes, their maturation into phagolysosomes causing pathogen destruction or antigen synthesis to present them to major histocompatibility complex molecules for activating an adaptive immune response. Any defect in this mechanism may predispose the host to certain infections and inflammatory diseases (autoinflammatory and autoimmune diseases) along with immunodeficiency. The article is designed to discuss its mechanistic complexity at each level, varying from phagocytosis induction to phagolysosome resolution.
Cytokines contribute to T cell homeostasis at all stages of T cell existence. However, the particular cytokine involved varies as T cells progress from a naïve through an activated to a memory state. In many cases the important cytokines are members of the interleukin 2 subfamily of the short-chain type I cytokines. A case is made for the idea that the evolutionary divergence of the short-chain family allowed for concurrent divergence in leukocytes.
The overrepresentation of particular HLA alleles in patients with celiac disease was first noted two decades ago. Several lines of evidence obtained during the last years strongly suggest that a particular HLA-DQ heterodimer, encoded by the DQA1*0501 and DQB1*0201 genes in cis or trans configuration, confers the primary disease susceptibility. This paper reviews the evidence behind this concept and discusses how this particular DQ molecule may be involved in the pathogenesis.
Cytokine deprivation from activated T cells leads to apoptosis associated with downregulation of the bcl-2 gene product. We show that a group of cytokines including IL-2, IL-4, IL-7 and IL-15, which can all signal through the γ-chain of the IL-2R (IL-2Rγ) prevent the apoptosis of IL-2-deprived activated T cells. This rescue involves the induction of the anti-apoptosis genes bcl-2 and bcl-xL but causes little change in expression of fax and bcl-xs which promote apoptosis. Furthermore, the prevention of apoptosis and induction of proliferation by the common γchain cytokines can be dissociated. These cytokines can thus regulate the persistence or removal of effector T cells by co-ordinating the balance between genes which promote and those which inhibit apoptosis, events which are probably mediated at least in part by signals through the common γ-chain. These data also implicate inappropriate T cell apoptosis resulting from a dysfunctional common 7-chain, as part of the pathophysiological defect in patients with X-linked Severe Combined Immunodeficiency (SCID).
Background: Endoscopic recurrence after surgery in Crohn's disease is frequent and unpredictable. Abnormal intestinal production of pro- (interleukin (IL)-1β, tumour necrosis factor α (TNF-α)) and anti- (IL-10) inflammatory cytokines has been associated with severe outcome in experimental models of colitis. Patients and methods: We evaluated if ileal TNF-α, IL-1β, or IL-10 mRNA levels measured at the time of surgery predict endoscopic recurrence, and if ileal IL-10 levels are associated with particular IL-10 promoter alleles. Ileal biopsies were obtained peroperatively from the healthy neoileum of patients undergoing a right ileocolectomy for Crohn's disease. Mucosal TNF-α, IL-1β, and IL-10 mRNA levels were quantified by competitive polymerase chain reaction. A cut off value was determined using a receiver operating curve. IL-10.G promoter haplotypes were analysed using a polymorphic dinucleotide repeat in the IL-10 promoter region. Results: Three months after surgery, 53% of patients had endoscopic recurrence while 47% remained free of disease. The risk of endoscopic recurrence correlated with ileal IL-10 mRNA concentrations (r2=0.81). Endoscopic recurrence occurred more frequently in patients classified as low IL-10 producers than in those that were high producers (80% v 40%) (p=0.02). Patients with at least one of the two alleles G7–8 or G10–13 produced, respectively, higher (p=0.006) and lower (p=0.029) ileal IL-10 mRNA. The distribution of IL-10.G microsatellite genotypes was similar in patients with or without endoscopic recurrence. Conclusion: Low ileal IL-10 mRNA concentration is a good marker of endoscopic recurrence in Crohn's disease but the distribution of IL-10.G haplotypes cannot predict the postoperative evolution of the disease.
Here we report the genomic cloning and characterization of the murine A1 genes, which belong to the bcl-2 gene family. Southern analysis indicated the existence of at least four A1 genes in the murine genome and four different A1 genes, designated A1-a, -b, -c and -d, were cloned from the murine genomic library. The A1-a, -b and -d genes consisted of two exons, whereas the A1-c gene contained 1 bp insertion in the coding region which may result in an aberrant and truncated protein by frame-shift. With the exception of A1-c, the coding regions among A1 genes are highly conserved at >97% at the nucleotide level and at .96% at the amino acid level. A1-a, -b and -d genes appeared to be expressed specifically in organs containing many neutrophils. In neutrophils, A1-a, -b and -d transcripts were detected at a comparable level. Our data suggest that the multiple A1 genes in mice were generated by gene duplication and each of them may function as antiapoptotic molecules in neutrophils.
An altered production of cytokines underlies inflammatory bowel disease (IBD) susceptibility. Various polymorphisms at the IL-10 and TNFalpha gene promoters control cytokine production levels. The influence of these polymorphisms on susceptibility to ulcerative colitis (UC) and Crohn's disease (CD) and their association with clinical features were analyzed.
Genetic polymorphisms of TNFalpha (-308 G/A) and IL-10 (-1082 G/A, -812 C/T, and -592 C/A) were determined using the LightCycler system with hybridization probes matched with one sequence variant. The study population included 99 UC patients, 146 CD patients, and 343 matched controls.
We did not find association between TNFalpha or IL-10 gene polymorphisms and UC or CD susceptibility, though a slight influence of -1082*G allele in UC appearance was observed. In a stratified analysis, a highly significant association between the -1082 AA IL-10 genotype and the steroid dependency was observed in IBD (p < 0.0001), contributing both UC (p = 0.004) and CD (p = 0.003) to this association. In contrast, TNFalpha genotypes did not influence steroid dependency in IBD. Further, the contribution of cytokine genotypes and of clinical features to the appearance of steroid-dependent status (dependent variable) was studied by multivariate analysis. The steroid-dependent phenotype correlated in UC with extensive disease (p = 0.010) and with the low producer -1082 AA IL-10 genotype (p = 0.002) and in CD with penetrating disease (p = 0.010), arthritis (p = 0.011), and the -1082 AA IL-10 genotype (p = 0.006).
The main conclusion is that carriage of the -1082 AA IL-10 genotype (low producer) is a relevant risk factor for developing steroid-dependent IBD.