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Molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when similarities between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign-derived antigen in a susceptible individual. However, molecular mimicry is unlikely to be the only underlying mechanism for autoimmune responses; other factors such as breach in central tolerance, non-specific bystander activation, or persistent antigenic stimuli (amongst others) may also contribute to the development of autoimmune diseases. Host genetics, exposure to microbiota and environmental chemicals are additional links to our understanding of molecular mimicry. Our current knowledge of the detailed mechanisms of molecular mimicry is limited by the issues of prolonged periods of latency before the appearance of disease, the lack of enough statistical power in epidemiological studies, the limitations of the potential role of genetics in human studies, the relevance of inbred murine models to the diverse human population and especially the limited technology to systematically dissect the human T-cell repertoire and B-cell responses. Nevertheless, studies on the role of autoreactive T-cells that are generated secondary to molecular mimicry, the diversity of the T-cell receptor repertoires of auto-reactive T-cells, the role of exposure to cryptic antigens, the generation of autoimmune B-cell responses, the interaction of microbiota and chemical adjuvants with the host immune systems all provide clues in advancing our understanding of the molecular mechanisms involved in the evolving concept of molecular mimicry and also may potentially aid in the prevention and treatment of autoimmune diseases., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

CXC Chemokine Receptor 3 (CXCR3) is functionally pleiotropic and not only plays an important role in chemotaxis, but also participates in T cell differentiation and may play a critical role in inducing and maintaining immune tolerance. These observations are particularly critical for autoimmune cholangitis in which CXCR3 positive T cells are found around the portal areas of both humans and mouse models of primary biliary cholangitis (PBC). Herein, we investigated the role of CXCR3 in the pathogenesis of autoimmune cholangitis. We have taken advantage of a unique CXCR3 knockout dnTGFβRII mouse to focus on the role of CXCR3, both by direct observation of its influence on the natural course of disease, as well as through adoptive transfer studies into Rag-/- mice. We report herein that not only do CXCR3 deficient mice develop an exacerbation of autoimmune cholangitis associated with an expanded effector memory T cell number, but also selective adoptive transfer of CXCR3 deficient CD8 + T cells induces autoimmune cholangitis. In addition, gene microarray analysis of CXCR3 deficient CD8 + T cells reveal an intense pro-inflammatory profile. Our data suggests that the altered gene profiles induced by CXCR3 deficiency promotes autoimmune cholangitis through pathogenic CD8 + T cells. These data have significance for human PBC and other autoimmune liver diseases in which therapeutic intervention might be directed to chemokines and/or their receptors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Autoantibodies appear in the sera of rhesus macaques following SIV infection. The present study was conducted to examine the role of viral load, antiviral chemotherapy and stage of disease on the titers of such autoantibodies and the spectrum of autoantigens that become the target of such autoimmune responses. In addition, the role of regulatory T cells (Tregs) was also examined. Results of these studies showed that the highest autoantibody titers were noted in animals with lower relative plasma viral loads with a wider spectrum of autoantigens that are the target of such responses as compared with lower autoantibody titers in animals with relatively higher plasma viral loads and a narrower spectrum of autoantigens. Short-term antiviral chemotherapy did not influence the titers of autoantibodies. While there was a gradual decrease in the frequency and absolute number of Tregs, the levels of Tregs was inversely correlated with viral load and lower autoantibody titers. The mechanisms for these differences remain unknown and suggest complex relationships exist between levels of immunosuppression, autoimmune response, homeostatic proliferation and the spectrum of autoantigens that become the target of such autoimmune responses.

CD4+CD25high regulatory T cells (Tregs) play a critical role in self-tolerance, as seen in murine autoimmunity. Studies on Tregs in human autoimmunity have focused primarily on peripheral blood samples. A study targeting diseased tissue should identify direct relationships between Tregs and autoimmunity. Peripheral blood samples were collected from 91 patients with primary biliary cirrhosis (PBC), 28 immediate relatives, and 41 healthy controls, and Treg frequencies were determined as a percentage of CD4+CD25high T cells in CD4+TCR-alphabeta+ T cells. A tissue-targeted determination of frequency and distribution of FoxP3+ Tregs was also performed on 90 different liver tissue specimens exhibiting PBC (n = 52), chronic hepatitis C (CHC) (n = 30), and autoimmune hepatitis (AIH) (n = 8). Treg suppression studies were performed on 50 PBC patients and 27 controls. Patients with PBC demonstrated a relative reduction of Tregs compared with controls (P < .0002). Interestingly, a deficiency in CD4+CD25+ Tregs was also found in the daughters and sisters of PBC patients compared with controls (P < .0007). However, functional studies did not reveal a global PBC Treg defect. The level of FoxP3-expressing Tregs was markedly lower in affected PBC portal tracts compared with CHC and AIH (P < .001). In addition, the CD8+T cell/FoxP3+ Treg ratio was significantly higher in livers of late-stage PBC compared with those of CHC (P < .001) and early-stage AIH (P < .001). In conclusion, these data provide support for a genetic modulation of Treg frequency and illustrate the role Tregs play in the loss of tolerance in PBC.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease with profound changes in different compartments of the immune system, including those involved in innate, and adaptive immunity. New data from epidemiological studies of PBC have reinforced the thesis that the cause for this relatively uncommon disease is likely to be a combination of both environmental factors and a susceptible genetic predisposition. Recent findings of abnormalities of the innate immune system in PBC suggest that they may serve as links between the environmental factors and the early events in PBC development. Viral and bacterial infections as well as xenobiotics are some of the potential environmental factors that have been implicated in this complex process. Identification of the etiological factors for PBC will point to new preventive or therapeutic treatments.

The goal of this communication is to summarize the following-the types of autoimmune responses that have been characterized in human HIV-1 infection; the potential mechanisms that were initially thought to be the basis for such autoimmune responses; the prevalence and incidence of conventional autoimmune diseases with HIV-1 infection; the spectrum of autoimmune disorders following the institution of HAART and its associated mechanisms; the role of such autoimmunity in SIV-infected nonhuman primates; and the molecular basis for autoimmune responses, such as the role of exosomes in lentiviral disease.

Autoimmune antibodies and autoimmune responses have been characterized in both human HIV infection and the rhesus macaque (RM) non-human primate model of SIV infection and reasoned to contribute to the pathogenesis of AIDS. Many theories for the induction and maintenance of such responses have been entertained including molecular mimicry between HIV proteins and self molecules, CD4+ T cell loss accompanied by loss of normal immune regulation that dictate self-non-self-reactivity, defective negative/positive selection of T cells to name a few. The precise mechanisms that lead to such immune dysfunction is difficult to study in humans. Our lab has been studying such autoimmune responses in both SIV-infected RM and sooty mangabeys (SM), a species from Africa that are naturally infected with SIV but do not display any detectable signs of immune deficiency or autoimmunity. We submit that this model is an important model since it allows for narrowing down those mechanisms and pathways that are a result of lentiviral infection per se from those that specifically cause disease including autoimmunity. During the course of these studies, we have ruled out a role for plasma and cellular viral loads, anti-viral humoral responses and a variety of cell signaling pathways. We have identified select pathways that appear to play roles in the pathogenesis of lentiviral infection and disease. These include pathways involved in innocent bystander killing by apoptosis of CD4+ T cells, role for differential regulation of the cell cycle, and a role for distinct host proteins that get incorporated by the virions as they are assembled and either bud out of CD4+ T cells or exit the cells in the form of multi-vesicular endosomal particles from monocytes/macrophages from SIV-infected disease susceptible RM and disease-resistant SM. We present our current working model and hypotheses that are designed to elucidate differences that are responsible for such distinct outcomes of lentiviral infection, autoimmunity and disease. We believe that such findings have important implications for the design of vaccines against human HIV infection.

Background & Aims: Although considerable effort has been directed toward the mapping of peptide epitopes by autoantibodies, the role of nonprotein molecules has been less well studied. The immunodominant autoantigen in primary biliary cirrhosis (PBC), E2 components of pyruvate dehydrogenase complexes (PDC-E2), has a lipoate molecule bonded to the domain to which autoantibodies are directed., Methods: We examined sera from patients with PBC (n = 105), primary sclerosing cholangitis (n = 70), and rheumatoid arthritis (n = 28) as well as healthy volunteers (n = 43) for reactivity against lipoic acid. The lipoic acid hapten specificity of the reactive antibodies in PBC sera was determined following incubation of aliquots of the sera with human serum albumin (HSA), lipoylated HSA (HSA-LA), PDC-E2, lipoylated PDC-E2, polyethylene glycol (PEG), lipoylated PEG, free lipoic acid, and synthetic molecular mimics of lipoic acid., Results: Anti-lipoic acid specific antibodies were detected in 81% (79 of 97) of antimitochondrial antibody (AMA)-positive patients with PBC but not in controls. Two previously unreported specificities in AMA-positive sera that recognize free lipoic acid and a carrier-conjugated form of lipoic acid were also identified., Conclusions: We hypothesize that conjugated form(s) of native or xenobiotic lipoic acid mimics contribute to the initiation and perpetuation of autoimmunity by at first breaking self-tolerance and participating in subsequent determinant spreading. The variability in the immunoreactive carrier/lipoate conjugates provides an experimental framework on which potential mechanisms for the breakdown of self-tolerance following exposure to xenobiotics can be investigated. The data have implications for patients taking lipoic acid as a dietary supplement.

Background: Increased incidence and prevalence of peripartum cardiomyopathy (PPCM) have been documented in the Hospital Albert Schweitzer (HAS) District of Haiti. Although the basis for this increased incidence of PPCM remains unclear, there is growing evidence for an underlying autoimmune process. One potential risk factor for increased autoreactivity is a micronutrient deficiency. In Africa, low plasma selenium (Se) level has been reported as a possible risk factor for PPCM. This report details results of initial studies to test the hypothesis that plasma levels of Se and/or other micronutrients may be related to PPCM risk in this population., Methods: Under the direction of the Institutional Review Board (HAS Ethics Committee) and with informed consent, levels of Se and other micronutrients were measured in plasma samples obtained from PPCM mothers and parity-matched control mothers from the HAS District of Haiti., Results: Mean plasma Se level in 18 PPCM patients was 110 ng/ml (range 67-145) compared to mean plasma Se level in 34 control mothers of 121 ng/ml (range 98-172) (P=0.1748). These levels are substantially greater than those reported for pediatric patients with Keshan cardiomyopathy, which can be prevented by Se prophylaxis. No deficiency or significant difference was found in any other micronutrient tested (Vitamin A (retinol), Vitamin B(12), Vitamin C, Vitamin E, and B-Carotene) for these PPCM and control mothers., Conclusion: Although there are several possible mechanisms by which Se could play a role in the pathobiology of PPCM, there is no evidence that Se deficiency is a cause of PPCM or a risk factor for the development of PPCM in this district of Haiti. The results of this investigation indicate that future studies of PPCM in this population should focus on other potential etiologic and risk factors.

The interferon (IFN) signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity. We have generated a unique murine model named ARE-Del, with chronic overexpression of IFNγ, by altering IFNγ metabolism. Importantly, these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis, including high titers of autoantibodies and portal inflammation. We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis. To study this hypothesis, ARE-Del+/- mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied. JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage, associated with a significant reduction in splenic and hepatic CD4+ T cells and CD8+ T cells. Functionally, ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγ and TNF from splenic CD4+ T cells. Additionally, ruxolitinib treatment also decreased the frequencies of germinal center B (GC B) cells and T follicular helper (Tfh) cells and led to lower serological AMA levels. Of note, liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment. Mechanistically, ruxolitinib inhibited the secretion of IL-6, TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro, indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway. Our data highlight the significance, both immunologically and clinically, of the JAK/STAT signaling pathway in autoimmune cholangitis.

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.

A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multilineage immune responses to mitochondrial self-antigens in primary biliary cholangitis, the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC-E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti-PDC-E2 autoantibodies cross-react with the chemical xenobiotics 2-octynoic acid and 6,8-bis (acetylthio) octanoic acid and further that there is a high frequency of PDC-E2-specific peripheral plasmablasts. Herein we generated 104 recombinant monoclonal antibodies (mAbs) based on paired heavy-chain and light-chain variable regions of individual plasmablasts derived from primary biliary cholangitis patients. We identified 32 mAbs reactive with native PDC-E2, including 20 specific for PDC-E2 and 12 cross-reactive with both PDC-E2 and 2-octynoic acid and 6,8-bis (acetylthio) octanoic acid. A lower frequency of replacement somatic hypermutations, indicating a lower level of affinity maturation, was observed in the complementarity-determining regions of the cross-reactive mAbs in comparison to mAbs exclusively recognizing PDC-E2 or those for irrelevant antigens. In particular, when the highly mutated heavy-chain gene of a cross-reactive mAb was reverted to the germline sequence, the PDC-E2 reactivity was reduced dramatically, whereas the xenobiotic reactivity was retained. Importantly, cross-reactive mAbs also recognized lipoic acid, a mitochondrial fatty acid that is covalently bound to PDC-E2.ConclusionOur data reflect that chemically modified lipoic acid or lipoic acid itself, through molecular mimicry, is the initial target that leads to the development of primary biliary cholangitis. (Hepatology 2017;66:885-895).

Primary biliary cirrhosis (PBC) is characterized by an intense biliary inflammatory CD4(+) and CD8(+) T cell response. Very limited information on autoantigen-specific cytotoxic T lymphocyte (CTL) responses is available compared with autoreactive CD4(+) T cell responses. Using peripheral blood mononuclear cells (PBMCs) from PBC, we identified an HLA-A2-restricted CTL epitope of the E2 component of pyruvate dehydrogenase (PDC-E2), the immunodominant mitochondrial autoantigen. This peptide, amino acids 159-167 of PDC-E2, induces specific MHC class I-restricted CD8(+) CTL lines from 10/12 HLA-A2(+) PBC patients, but not controls, after in vitro stimulation with antigen-pulsed dendritic cells (DCs). PDC-E2-specific CTLs could also be generated by pulsing DCs with full-length recombinant PDC-E2 protein. Furthermore, using soluble PDC-E2 complexed with either PDC-E2-specific human monoclonal antibody or affinity-purified autoantibodies against PDC-E2, the generation of PDC-E2-specific CTLs, occurred at 100-fold and 10-fold less concentration, respectively, compared with soluble antigen alone. Collectively, these data demonstrate that autoantibody, helper, and CTL epitopes all contain a shared peptide sequence. The finding that autoantigen-immune complexes can not only cross-present but also that presentation of the autoantigen is of a higher relative efficiency, for the first time defines a unique role for autoantibodies in the pathogenesis of an autoimmune disease.

Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in which mice immunized with 2-octynoic acid coupled to BSA (2OA-BSA), a compound identified by quantitative structure activity relationships (QSAR) of human AMA binding, develop an intense inflammatory cholangitis with striking similarities to humans with PBC. In particular, we have constructed several unique gene-deleted mice, including mice deleted of IL-12p40, IL-12p35, IFN-γ, IL-23p19, IL-17A, IL-17F and IL-22, immunized these animals with 2OA-BSA and followed the natural history of immunopathology to identify key pathways that might provide clues for successful therapy. Our data indicate that whereas both IL-12/Th1 and IL-23/Th17 are involved in cholangitis, it is the IL-12/Th1 signaling pathway that elicits pathology. In fact, deletion of IFN-γ prevents disease and suppresses autoantibodies. Importantly, deletion of the Th17 cytokines IL-17A and IL-22, but not IL-17F, reduces biliary damage; IL-17A-knockout mice have reduced levels of anti-mitochondrial antibody. We further demonstrate that the production of IFN-γ is significantly decreased in the liver of IL-23p19−/−, IL-17A−/− and IL-22−/− mice compared with controls. However, the ability of T cells to produce IFN-γ was not affected in Th17 cytokine-deficient mice. Our data indicate that a deficient Th17 pathway suppresses the accumulation of IFN-γ producing cells in liver during the early phase of cholangitis. In conclusion, whereas IFN-γ has a pivotal role in the early events involved in the pathogenesis of autoimmune cholangitis induced by 2OA-BSA, the IL-23/Th17 pathway potentiates the effects of IL-12/IFN-γ-mediated immunopathology. [ABSTRACT FROM AUTHOR]

An increasing number of severe neurological complications associated with Zika virus (ZIKV), chiefly Guillain-Barré syndrome (GBS) and primary microcephaly, have led the World Health Organization to declare a global health emergency. Molecular mimicry between glycolipids and surface molecules of infectious agents explain most of the cases of GBS preceded by infection, while a direct toxicity of ZIKV on neural cells has been raised as the main mechanism by which ZIKV induces microcephaly. Gangliosides are crucial in brain development, and their expression correlates with neurogenesis, synaptogenesis, synaptic transmission, and cell proliferation. Targeting the autoimmune response to gangliosides may represent an underexploited opportunity to examine the increased incidence of neurological complications related to ZIKV infection. [ABSTRACT FROM AUTHOR]

Abstract: This special edition of the Journal of Autoimmunity is dedicated to celebrate the enormous contributions of Dr. Noel Rose, a physician-scientist, someone that can be readily anointed as a gifted scientist who laid down the foundation and fundamental concepts of human autoimmunity. Dr. Rose performed a series of landmark studies that extend back more than 50 years and whose work is the cornerstone of the commonly used term “from the bench to the bedside.” The studies included not only characterization of a normal immune response but, more importantly, defining the nature of not only the antigen, but also the aberrant response that results in organ, tissue specific reactions and immunopathology. These pioneering studies contributed to the biochemical nature of antigens, dissection of the immune repertoire, the recognition of the importance of genetics and environment, and the distinctions between a normal and an autoimmune response. Hence, this volume has been coined “Navigating the Passage Between Charybdis and Scylla: Recognizing the Achievements of Noel Rose.” [Copyright &y& Elsevier]

The purpose of this review is to provide an overview of the spectrum of autoimmune responses that we have so far characterized in the simian immunodeficiency virus (SIV)-infected disease susceptible rhesus macaques, the potential role of the lymphopenic state for the generation of the autoimmune response and the important new finding that such autoimmune response in fact can serve to provide both clinical benefit and clinical disease depending on the stage of the disease and the nature of the host proteins that are recognized during this process. [ABSTRACT FROM AUTHOR]

The absence of suitable mouse models has represented a major drawback in our understanding of early events leading to the development of primary biliary cirrhosis (PBC). The recent report of not one, but three mouse models, each with distinctive features resembling PBC, represents a major advance in PBC research and generates novel experimental perspectives. The dnTGFβRII mouse, the IL-2Rα–/– mouse and the NOD.c3c4 mouse are all characterized by different genetic backgrounds and modifications, nonetheless all develop characteristic lymphocytic biliary infiltrates and specific antimitochondrial antibody response. Each model reflects characteristics of PBC in association with unique phenotypic differences. These three distinct models will allow a better understanding of the specific genetics involved in breaking of tolerance and progression of disease, in association with the possible definition of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed. [ABSTRACT FROM AUTHOR]

Abstract: The crucial role of regulatory cells in self-tolerance and autoimmunity has been clearly established in numerous types of regulatory cells, the majority of which are CD4+ T cells. Much focus has been placed on thymically derived CD4+CD25+ regulatory T cells, given that the depletion of this subset in murine models results in the spontaneous development of autoimmune diseases. These naturally occurring regulatory T cells are found to be functionally mature in the thymus, and exert suppression in a contact-dependent manner. Another important category of immunosuppressive cells consists of conditionally induced regulatory T cells such as Tr1, Th3, and various other CD4+ lymphocytes. Understanding the development and regulatory functions of immunoregulatory cells may elucidate the etiology for loss of self-tolerance. This review will summarize the characteristics, developmental pathways, and functions of regulatory T cells, as well as their role in human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, Myasthenia Gravis, Kawasaki disease, autoimmune polyglandular syndrome type II, type 1 diabetes, autoimmune lymphoproliferative syndrome, and systemic lupus erythematosus. [Copyright &y& Elsevier]

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serologic hallmark of PBC is the presence of antibodies to mictochondria, especially to the E2 component of the pyruvate dehydrogenase complex. The mechanisms by which (and if) such antibodies produce liver tissue injury are unknown. However, the presence of these antibodies has allowed detailed immunological definition of the antigenic epitopes, the nature of reactive autoantibodies and the characterization of T-cell responses. Several mechanisms may now be proposed regarding the immune-mediated bile duct damage in PBC, including the possible role of T-cell-mediated cytotoxicity and intracellular interaction between the IgA class of antimitochondrial antibodies and mitochondrial autoantigens. There are major questions which remain unanswered, including, of course, etiology, but also the reasons for female predominance, the absence of PBC in children, the relative inffectiveness of immunosuppressive drugs, and the specific role of mitochondrial antigens. The data so far provide suggestive evidence that PBC is a mucosal disease; this thesis provides a basis for discussion of etiology via the enterohepatic circulation of toxins and/or infection. [ABSTRACT FROM AUTHOR]

Background and Aims Materials and Methods Results Conclusions There is increased interest in utilizing dietary interventions to alter the progression of autoimmune diseases. These efforts are driven by associations of gut microbiota/metabolites with levels of short‐chain fatty acids (SCFAs). Propionate is a key SCFA that is commonly used as a food preservative and is endogenously generated by bacterial fermentation of non‐digestible carbohydrates in the gut. A thesis has suggested that a diet rich in propionate and other SCFAs can successfully modulate autoimmunity. Herein, we investigated the effect of long‐term administration of propionylated high‐amylose resistant starches (HAMSP) on the course of murine primary biliary cholangitis.Groups of female ARE‐Del mice were fed an HAMSP diet either before or after disease onset. A detailed immunobiological analysis was performed involving autoantibodies and rigorous T‐cell phenotyping, including enumeration of T‐cell subsets in the spleen, liver, intestinal intraepithelial lymphocytes and lamina propria by flow cytometry. Histopathological scores were used to assess the frequency and severity of liver inflammation and damage to hepatocytes and bile ducts.Our results demonstrate that a long‐term propionate‐yielding diet re‐populated the T‐cell pool with decreased naïve and central memory T‐cell subsets and an increase in the effector memory T cells in mice. Similarly, long‐term HAMSP intake reduced CD4+CD8+ double‐positive T cells in intraepithelial lymphocytes and the intestinal lamina propria. Critically, HAMSP consumption led to moderate‐to‐severe hepatocellular steatosis in ARE‐Del mice, independent of the stage of autoimmune cholangitis.Our data suggest that administration of HAMSP induces both regulatory and effector T cells. Furthermore, HAMSP administration resulted in hepatocellular steatosis. Given the interest in dietary modulation of autoimmunity and because propionate is widely used as a food preservative, these data have significant implications. This study also provides new insights into the immunological and pathological effects of chronic propionate exposure. [ABSTRACT FROM AUTHOR]

Abstract: Homeostasis of the immune system is achieved through refined regulation and communication between immunologically relevant receptor and their cognate ligands amongst mononuclear cells during ontogeny and day to day immune responses. An aberrance in not only the kinetics of receptor expression but also the relative diversity of expression alter these events. More importantly, improper modulation of ligand binding affinity can be a triggering event that results in autoimmunity. As one of the most common post-translational modifications, tyrosine sulfation possesses the ability to regulate mononuclear cell function at various stages of the immune response. For example, removal of sulfated tyrosine residues consistently decreases the binding affinity of the ligand to its corresponding receptor as exemplified by studies of several tyrosine sulfated proteins such as PSGL-1, CD44v5, CCR5, and CXCR4, all known to play a role in a variety of autoimmune diseases. This review defines possible roles that tyrosine sulfated proteins may play in the pathogenesis of autoimmune diseases. [Copyright &y& Elsevier]

Abstract: The role of adaptive as well as innate immune responses in the pathology of primary biliary cirrhosis (PBC) has been a major subject of investigation. Primary biliary cirrhosis is an autoimmune liver disease involving the destruction of small bile ducts, which eventually leads to liver cirrhosis. Adaptive immune responses involving autoantibody production by B cells and autoreactive T cells have been labeled as the most probable mediators of tissue destruction. Autoantibody production against mitochondrial antigens is used as a key diagnostic marker in PBC, being present in 90–95% of patient sera. Besides blood, these antimitochondrial antibodies are found in liver, bile, saliva, and urine of patients and target mitochondrial autoantigens that are well conserved between species. One possible mechanism of antibody-mediated tissue destruction is via the transcytosis of immunoglobulin A antimitochondrial antibodies through biliary epithelium. Another mechanism may involve the recognition by antimitochondrial antibodies of the mitochondrial autoantigens abnormally expressed on patient biliary epithelium. The second component of the adaptive immune response in PBC involves T cells, which comprise a large fraction of infiltrating leukocytes in diseased livers. Autoreactive CD4+ and CD8+ T cells recognizing mitochondrial antigens targeted by antimitochondrial antibodies have been isolated with specificity for epitopes that overlap with those of B cells. Cytokines production of such infiltrates indicates the involvement of both TH1 and TH2 responses in the diseased tissue. Besides adaptive responses, innate immunity effector mechanisms involving eosinophils, macrophages, and B cells hyperresponsive to bacterial DNA CpG motifs has been implicated in the pathology of PBC. Despite research efforts, the etiology of PBC still remains elusive, although theories involving the participation of genetic factors, molecular mimicry due to microorganisms, and a role for modification of native autoantigens by xenobiotics have been proposed. [Copyright &y& Elsevier]

Abstract: Dominant-negative TGF-β receptor II (dnTGF-βRII) mice spontaneously develop an autoimmune cholangitis resembling human primary biliary cirrhosis (PBC). Interestingly, the dominant-negative TGF-β receptor is expressed by both CD4+ and CD8+ T cells and leads to greatly reduced (but not absent) TGF-β signaling resulting in T cell intrinsic cell mediated autoimmunity. However, the mechanisms of the T cell dysregulation remain unclear. Recently it has been shown that TGF-β signaling is intimately involved with miRNA biogenesis and control. Herein we show that lack of T cell TGF-β signaling leads to down regulation of T cell miRNAs but up-regulation of the key inflammatory miRNA 21. Furthermore, the expression of miR-21 from hepatic effector CD8+ T cells is significantly higher than in the same subsets isolated from spleen and mesenteric lymph nodes of the dnTGF-βRII mice. Previous studies indicate that miR-21 increases the synthesis of IFN-γ and IL-17A by T cells and suppresses apoptosis via programmed cell death protein 4 (PDCD4). Data presented herein demonstrate that transfecting w.t. B6 T cell subsets with miR-21 resulted in up-regulation of the inflammatory cytokines TNF-α and IFN-γ, thus partly replicating the dnTGF-βRII T cell phenotype. In conclusion, these data suggest miR-21 plays a critical role in the production of pro-inflammatory cytokines in dnTGF-βRII mice, which could be a contributing factor for the development of the organ-specific autoimmune cholangitis and colitis in this murine model of human PBC. [Copyright &y& Elsevier]

Abstract: TGF-β1 deficient mice develop multifocal inflammatory autoimmune disease and serve as a valuable animal model of autoimmunity. Transgenic expression of a dominant negative form of TGF-β receptor type II in T cells have enabled the study of cell lineage specific effects of TGF-β providing clues to the potential etiology of autoimmunity. These studies suggest that TGF-β deficiency may induce autoimmune disease by influencing a number of immunological phenomena including lymphocyte activation and differentiation, cell adhesion molecule expression, regulatory T cell function, the expression of MHC molecules and cytokines, and cell apoptosis. The spectrum of effects appears to be significant in mucosal immunity and may contribute to the pathogenesis of inflammatory bowel disease. [Copyright &y& Elsevier]

Abstract: The NOD mouse has been an important model of type 1 diabetes and autoimmune diseases for over 20 years. Experimental and genetic manipulations of the NOD mouse have demonstrated a broad susceptibility to multiple autoimmune syndromes. This predisposition to autoimmunity is due to defects in both central and peripheral tolerance. The defect of central tolerance is likely secondary to improper negative selection mediated by the unique MHC Class II molecule, I-Ag7 as well as intrinsic T cell signaling defects. The genetic basis for impaired peripheral tolerance is controlled by over 20 susceptibility loci termed insulin-dependent diabetes (idd) loci. The maintenance of peripheral tolerance is impaired by alterations in T cell signaling and apoptosis. In addition, insufficient co-stimulation from accessory cells, and defective regulatory T cells, may promote the production of autoreactive T cells. [Copyright &y& Elsevier]

Reductions in populations of both Pre-B cell (Hardy fractions D) and Pro-B cells (Hardy fractions B-C) have been described in association with murine lupus. Recent studies of B cell populations, based on evaluation of B cell differentiation markers, now allow the enumeration and enrichment of other stage specific precursor cells. In this study we report detailed analysis of the ontogeny of B cell lineage subsets in New Zealand black (NZB) and control strains of mice. Our data suggest that B cell development in NZB mice is partially arrested at the fraction A Pre-Pro B cell stage. This arrest at the Pre-Pro B cell stage is secondary to prolonged lifespan and greater resistance to spontaneous apoptosis. In addition, expression of the gene encoding the critical B cell development transcription factor BSAP is reduced in the Pre-Pro B cell stage in NZB mice. This impairment may influence subsequent B cell development to later stages, and thereby accounts for the down-regulation of the B cell receptor component Igα (mb-1). Furthermore, levels of expression of the Rug2 , λ5 and Igβ (B29) genes are also reduced in Pre-Pro B cells of NZB mice. The decreased frequency of precursor B cells in the Pre-Pro B cell population occurs at the most primitive stage of B cell differentiation. [ABSTRACT FROM AUTHOR]

New Zealand Black (NZB) mice are a well-known animal model of human autoimmune disease. Although the mechanism for development of autoimmunity is unclear, NZB mice are well known for severe thymic microarchitecture abnormalities. It is thought that thymic dendritic cells (DC) may play a role in thymic education and contribute to the autoimmune process. To address this issue and, in particular, that qualitative and/or quantitative differences exist in thymic DC, we took advantage of a novel restriction analysis system that allow definition of differences in the expression of tyrosine kinases using highly enriched populations of thymic DC from NZB compared to BALB/c and C57BL/6 mice. The method chosen, restriction analysis of gene expression, allowed the determination of protein tyrosine kinase transcription profiles. We report herein that NZB mice have a significant upregulation of C-met compared to the control strains. The abnormality of the C-met transcription was confined to thymic DC. We believe that its abnormal expression reflects the resistance of thymic cells to apoptosis, which will ultimately lead to defects and/or abnormal signaling by the interaction of thymic DC and thymocytes. Further studies involving such interactions are under way. [ABSTRACT FROM AUTHOR]