Breakdown Of Immune Tolerance Research Articles

Adult-onset type 1 diabetes patients display decreased IGRP-specific Tr1 cells in blood

The breakdown of immune tolerance against islet antigens causes type 1 diabetes (T1D). The antigens associated with adult-onset T1D (AT1D) remain largely undefined. It is possible that AT1D patients display a unique type of CD4+ T cells specific for a certain islet antigen. Here we analyzed the cytokine production profiles of CD4+ helper T (Th) cells that are specific for three islet antigens; GAD65, preproinsulin, and IGRP in patients with AT1D, juvenile-onset T1D (JT1D), and age-, gender- and human leukocyte antigen (HLA)-matched control adults. While IGRP-specific Th cells in AT1D patients were dominantly Th1 cells, IGRP-specific Th cells in control adults and JT1D patients were dominantly Th2 and T regulatory type 1 (Tr1) cells. Notably, the frequency of IGRP-specific Tr1 cells was significantly lower in AT1D patients than in control adults and JT1D patients. In conclusion, our study suggests that IGRP-specific Th cells play a unique pathogenic role in AT1D.

T cells in the control of organ-specific autoimmunity.

Immune tolerance is critical to the avoidance of unwarranted immune responses against self antigens. Multiple, non-redundant checkpoints are in place to prevent such potentially deleterious autoimmune responses while preserving immunity integral to the fight against foreign pathogens. Nevertheless, a large and growing segment of the population is developing autoimmune diseases. Deciphering cellular and molecular pathways of immune tolerance is an important goal, with the expectation that understanding these pathways will lead to new clinical advances in the treatment of these devastating diseases. The vast majority of autoimmune diseases develop as a consequence of complex mechanisms that depend on genetic, epigenetic, molecular, cellular, and environmental elements and result in alterations in many different checkpoints of tolerance and ultimately in the breakdown of immune tolerance. The manifestations of this breakdown are harmful inflammatory responses in peripheral tissues driven by innate immunity and self antigen-specific pathogenic T and B cells. T cells play a central role in the regulation and initiation of these responses. In this Review we summarize our current understanding of the mechanisms involved in these fundamental checkpoints, the pathways that are defective in autoimmune diseases, and the therapeutic strategies being developed with the goal of restoring immune tolerance.

The immunological clock: the role of cryptochrome in regulatory T cell function (IRM15P.602)

Abstract Circadian rhythms are defined as 24 hour oscillations in physiological and behavioral processes. Clinical data suggests circadian involvement in the predisposition and progression of immune-related morbidities such as cancer and autoimmune disease. Recent studies have demonstrated the direct role of core molecular clock components in maintaining the immune system. A subset of CD4+ T cells known as regulatory T cells (Treg) are critical for preserving balance in the immune system and have been shown to be able to prevent a broad range of autoimmune disease. By studying the role of core circadian genes in Treg cells the connection between the circadian clock and autoimmune disease may be further elucidated. We have identified a core circadian clock gene, cryptochrome (Cry), to have a role in Treg cell function both in vitro and in vivo. The deficiency of Cry in Treg cells results in a breakdown in immune tolerance, which results in severe pathological autoimmunity in mice. This is characterized by immune cell infiltration into peripheral tissues as well as increased numbers of cytokine producing CD4 and CD8 T cells. It was also seen that ectopic expression of Cry in Treg cells results in increased suppression of T cell proliferation in vitro. Thus, we have demonstrated a direct role of Cry expression in the function of Treg cells.

Immunohistochemical expression of Claudin-1 in Hashimoto's thyroiditis and Graves' disease patients

Autoimmune thyroid diseases, including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are complex diseases in which a combination of genetic susceptibility and environmental encounters leads to breakdown of immune tolerance. Epidemiological and histological data indicate that thyroid cancer (TC) frequently occurs in the context of HT (Guarino et al. 2010), and that the association between HT and TC is antibody specific (Azizi et al. 2014). Several authors reported overexpression of claudin-1, protein of tight junctions, in invasive tumor cells, including TC, and it seems to be an early step in carcinogenesis for at least some cancer types.

Characterization of B cells in muscle-specific kinase antibody myasthenia gravis.

Objective:To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG).Methods:In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell–activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures.Results:As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naïve, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease.Conclusions:We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody–positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG.

Integrative analysis of mRNA and miRNA array data reveals the suppression of retinoic acid pathway in regulatory T cells of Graves' disease.

It is well known that regulatory T cells (Tregs) are abnormal in Graves' disease (GD) and play crucial roles in the breakdown of immune tolerance and GD development. However, there are controversies about whether the quantity and/or function of Tregs is aberrant in GD. The molecular mechanism of Tregs abnormality and its effects on GD development was still unclear, until now. MiRNAs play important roles in the function and development of the immune system including Tregs. To reveal the Tregs abnormality and its molecular mechanism in GD, we systematically studied the quantity and immunosuppressive function as well as the differential expression profiles of miRNA and mRNA of Tregs in newly diagnosed patients with GD using TaqMan miRNA array and mRNA microarray. Our results showed that the quantity and immunosuppressive function of Tregs in initial patients with GD was significantly decreased. More importantly, the retinoic acid (RA) pathway was markedly suppressed and its agonist, all-trans retinoic acid, could notably improve the quantity and immunosuppressive function of Tregs from patients with GD in vitro. In addition, many other pathways including protein ubiquitination and circadian rhythm were also significantly regulated in Tregs of GD. This integrative study first revealed the expression profiles of mRNA/miRNA in Tregs of initial GD and RA pathway might play important roles in GD development. Our results implied that all-trans RA, which had been used for a long time in the clinical setting, had potential value in the treatment of GD and was worthy of additional study.

Psoriasis is not an autoimmune disease?

The concept that psoriasis is an autoimmune disease needs to be questioned. The autoimmune label has been based on molecular mimicry between streptococcal and keratin proteins and the existence of homologous peptides between these proteins. However, it is only peripheral blood CD8, and not CD4, T lymphocytes that respond to the homologous peptides. This ignores the fact that it is CD4 T cells which are necessary to initiate psoriasis. Recent studies on skin bacterial microbiota have found a variety of bacteria in both normal skin and psoriatic lesions. In biopsy specimens, the most common phylum was Firmicutes and the most common genus streptococcus in both psoriasis and normal skin. The innate immune system is activated in psoriasis, and recent genetic findings have shown the majority of susceptibility loci are associated with innate immunity. There is a known clinical relationship between both Crohn's disease (CD) and periodontitis, and psoriasis, and patients with psoriasis share mutations in some innate immunity genes with individuals with CD. It is now accepted that CD is due to a breakdown of immune tolerance (dysbiosis) to bacteria in the intestine. These findings suggest that psoriasis is initiated by an abnormal response to bacteria in the skin due to genetic factors.

Co-delivery of autoantigen and b7 pathway modulators suppresses experimental autoimmune encephalomyelitis.

Autoimmune diseases such as multiple sclerosis (MS) are characterized by the breakdown of immune tolerance to autoantigens. Targeting surface receptors on immune cells offers a unique strategy for reprogramming immune responses in autoimmune diseases. The B7 signaling pathway was targeted using adaptations of soluble antigen array (SAgA) technology achieved by covalently linking B7-binding peptides and disease causing autoantigen (proteolipid peptide (PLP)) to hyaluronic acid (HA). We hypothesized that co-delivery of a B7-binding peptide and autoantigen would suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Three independent B7-targeted SAgAs were created containing peptides to either inhibit or potentially stimulate the B7 signaling pathway. Surprisingly, all SAgAs were found to suppress EAE disease symptoms. Altered cytokine expression was observed in primary splenocytes isolated from SAgA-treated mice, indicating that SAgAs with different B7-binding peptides may suppress EAE through different immunological mechanisms. This antigen-specific immunotherapy using SAgAs can successfully suppress EAE through co-delivery of autoantigen and peptides targeting with the B7 signaling pathway.

A Highly Sensitive Live Cell Based Assay for Detection of Antibodies Against N-methyl-d-aspartate Receptors

breakdown of immune tolerance; a phenomenon associated with the development of Multiple Sclerosis (MS). B lymphocytes are key players in the pathogenesis of MS and, while B lymphocytes are traditionally regarded as promoters of the immune response via antibody secretion and cytokine production, recent studies have confirmed an important role for these lymphocytes in the negative regulation of immunity. Within this scenario, BTLA, a novel inhibitory receptor that ligates B7 familymember proteins, was identified. Similar to CTLA-4 and PD-1, BTLA is expressed on activated B and T cells alone. Binding of BTLA to B7-H4 (B7S1, B7x), its putative ligand, inhibits TCRinitiated cytokine production and cell cycle progression, suggesting a role for BTLA in peripheral tolerance; its possible involvement in MS is nevertheless still unknown. Recently a novel subset of regulatory B lymphocytes (Breg) known as B10 cells, which regulate immune responses through the production of the anti-inflammatory cytokine interleukin-10 (IL-10), was identified. Objectives: To define the possible role of B cells in the pathogenesis of MS. Methods: We analysed by flow-cytometry the surface expression of BTLA, as well as IL-10 and TGF beta production, in un-stimulated or in myelin oligodendrocyte glycoprotein (MOG)-stimulated CD19+ B lymphocytes of MS patients with a clinical and MRI diagnosis of either relapsing-remitting (RRMS), chronic progressive (CPMS), or benign MS (BEMS); results were compared to those obtained in age and sex matched healthy controls (HC). Results: Whereas no differences were seen in un-stimulated cells, MOG-stimulated, BTLA-expressing CD19+ cells were augmented in BEMS and HC compared to all the other patients (p b 0.01); IL-10and TGFbeta-producing CD19+ Breg were augmented as well in MOG-stimulated cells of BEMS and HC compared to RRMS and CPMS groups. Conclusions: Data herein indicate that a quantitative and qualitative impairment of Breg accompanies the breakdown of immune tolerance associated with MS. Because a significant increase of Bregs and of BTLA-expressing CD19+ cells was seen in BMS, a regulatory role in preventing disease progression could be envisioned for these cells. These results could help the design of novel diagnostic and therapeutic approaches to MS. Monitoring BTLA expression could be a novel prognostic tool in MS patients. Grant by the Italian Ministry of Health: Ricerca Corrente 2013–14.

A role for regulatory B cells in preventing the progression of Multiple Sclerosis

Background: Alterations in immune regulation could result in the breakdown of immune tolerance; a phenomenon associated with the development of Multiple Sclerosis (MS). B lymphocytes are key players in the pathogenesis of MS and, while B lymphocytes are traditionally regarded as promoters of the immune response via antibody secretion and cytokine production, recent studies have confirmed an important role for these lymphocytes in the negative regulation of immunity. Within this scenario, BTLA, a novel inhibitory receptor that ligates B7 family member proteins, was identified.

Understanding the roles of activation threshold and infections in the dynamics of autoimmune disease

Onset and development of autoimmunity have been attributed to a number of factors, including genetic predisposition, age and different environmental factors. In this paper we discuss mathematical models of autoimmunity with an emphasis on two particular aspects of immune dynamics: breakdown of immune tolerance in response to an infection with a pathogen, and interactions between T cells with different activation thresholds. We illustrate how the explicit account of T cells with different activation thresholds provides a viable model of immune dynamics able to reproduce several types of immune behaviour, including normal clearance of infection, emergence of a chronic state, and development of a recurrent infection with autoimmunity. We discuss a number of open research problems that can be addressed within the same modelling framework.

OP0104 Low-Dose Interleukin-2 Therapy Caused Selective Expansion of Regulatory T Cells Together with RAPID Reduction of Disease Activity in A Patient with Severe Refractory Sle

BackgroundSLE is characterized by the breakdown of immune tolerance towards nuclear autoantigens. Aberrant activation of autoreactive T and B cells leads to uncontrolled inflammation and production of autoantibodies ultimately resulting...

Programmed death-1 pathway in cancer and autoimmunity.

Programmed death-1 (PD-1) is a co-receptor that is expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. A major functional role of the PD-1 signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune diseases. Elimination of the PD-1 pathway can therefore result in the breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanisms. Therefore, blockade of the PD-1 pathway has become an attractive target in cancer therapy. Recent clinical trials have shown that anti-PD-1 agents have profound effects on solid tumor regression. Current approaches include six agents that are either PD-1 and PD-L1 targeted neutralizing antibodies or fusion proteins. More than forty clinical trials are underway to better define the role of PD-1 blockade in variety of tumor types. In this review we will highlight the basic biology of the PD-1 system and discuss its potential roles in both autoimmunity and cancer. We propose that future research on PD-1 may lead to the translation of fundamental regulatory pathways into the development of practical new approaches for the treatment of autoimmune diseases and cancer.

Alterations in immune cell subsets and their cytokine secretion profile in childhood idiopathic thrombocytopenic purpura (ITP).

Immune thrombocytopenic purpura (ITP) is acquired autoimmune disease in children characterized by the breakdown of immune tolerance. This work is designed to explore the contribution of different lymphocyte subsets in acute and chronic ITP children. Imbalance in the T helper type 1 (Th1)/Th2 cytokine secretion profile was investigated. The frequency of T (CD3(+), CD4(+), CD8(+)) and B (CD19(+)) lymphocytes, natural killer (NK) (CD16(+) 56(+)) and regulatory T (T(reg)) [CD4(+) CD25(+high) forkhead box protein 3 (FoxP3)(+) ] cells was investigated by flow cytometry in 35 ITP children (15 acute and 20 chronic) and 10 healthy controls. Plasma levels of Th1 cytokines [interferon (IFN-γ) and tumour necrosis factor (TNF-α)] and Th2 [interleukin (IL)-4, IL-6 and IL-10)] cytokines were measured using enzyme-linked immunosorbent assay (ELISA). The percentage of Treg (P < 0·001) and natural killer (NK) (P < 0·001) cells were significantly decreased in ITP patients compared to healthy controls. A negative correlation was reported between the percentage of T(reg) cells and development of acute (r = -0·737; P < 0·01) and chronic (r = -0·515; P < 0·01) disease. All evaluated cytokines (IFN-γ, TNF-α, IL-4, IL-6 and IL-10) were elevated significantly in ITP patients (P < 0·001, P < 0·05, P < 0·05, P < 0·05 and P < 0·001, respectively) compared to controls. In conclusion, our data shed some light on the fundamental role of immune cells and their related cytokines in ITP patients. The loss of tolerance in ITP may contribute to the dysfunction of T(regs). Understanding the role of T cell subsets will permit a better control of autoimmunity through manipulation of their cytokine network.

Critical role of DNA methylation in the pathogenesis of systemic lupus erythematosus: new advances and future challenges

Systemic lupus erythematosus (SLE) is a systemic multi-organ autoimmune disease with different immunological characteristics and clinical manifestations characterized by an autoantibody response to nuclear and cytoplasmic antigens; the etiology of this disease remains largely unknown. Most recent genome-wide association studies demonstrate that genetics significantly predispose to SLE onset, but the incomplete disease concordance rates between monozygotic twins indicates a role for other complementary factors in SLE pathogenesis. Recently, much evidence strongly supports other molecular mechanisms involved in the regulation of gene expression ultimately causing autoimmune disease, and several studies, both in clinical settings and experimental models, have demonstrated that epigenetic modifications may hold the key to a better understanding of SLE initiation and development. DNA methylation changes the structure of chromatin, being typically able to modulate the fine interactions between promoter-transcription factors and encoding genes within the transcription machinery. Alteration in DNA methylation has been confirmed as a major epigenetic mechanism that may potentially cause a breakdown of immune tolerance and perpetuation of SLE. Based on recent findings, DNA methylation treatments already being used in oncology may soon prove beneficial to patients with SLE. We herein discuss what we currently know, and what we expect in the future.

The Link Between Periodontal Disease and Rheumatoid Arthritis: An Updated Review

Porphyromonas gingivalis is a leading pathogen in chronic periodontitis, a disease process involving progressive destruction of the tissues that support the teeth. Recently, the organism has been reported to produce a unique bacterial enzyme, P. gingivalis peptidyl-arginine deiminase (PPAD), which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function; hence, PPAD may be involved in deregulation of the host’s signalling network and immune evasion. Further, accumulating evidence suggests a role for autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contribute to the breakdown of immune tolerance to citrullinated epitopes, chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and the initiation of RA. In this review, we discuss evidence that PPAD may represent a mechanistic link between periodontitis and RA, diseases that are known to be significantly associated at the epidemiological level.

T-helper and regulatory T-cell cytokines in the peripheral blood of patients with active alopecia areata

Alteration in T-lymphocyte function and cytokines secreted by T-cell subsets has been proposed in the immunopathogenesis of alopecia areata (AA). The role of T-helper and regulatory T-cell cytokines in the pathogenesis of active AA has not been established. To assess the role of hallmark cytokines of T-helper cells (Th1, Th2 and Th17) and regulatory T cells (Tregs) in the pathogenesis of AA, and its clinical correlation. Fifty-one patients with AA and 45 age- and sex-matched healthy control subjects were included in the study. Serum interleukin (IL)-2, interferon (IFN)-γ, IL-10, IL-13, IL-17A and transforming growth factor (TGF)-β1 were measured by enzyme-linked immunosorbent assay in both groups. Correlation of serum cytokine levels with age, sex, disease subtype and duration, number of patches on the scalp, associated autoimmune disorders and atopy was studied. The serum cytokine levels of IL-2, IFN-γ, IL-13 and IL-17A were significantly increased, and serum TGF-β1 levels were significantly decreased (P < 0·05) in patients with AA compared with controls. Serum IL-2 levels were significantly different among AA subgroups (P < 0·05). IL-2 levels were positively correlated with the total disease duration and the number of patches on the scalp. The increased levels of serum IL-2, IFN-γ, IL-13 and IL-17A suggested altered T-helper cell function, and reduced serum TGF-β1 levels suggested a defect in Treg function. Therefore, enhanced T-cell-mediated immunity and breakdown of immune tolerance due to deficiency in Tregs may facilitate the occurrence of AA.

Patients With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Have Defective Treg Cell Function Exacerbated by the Presence of a Suppression‐Resistant Effector Cell Population

The development of pathogenic antineutrophil cytoplasmic antibodies (ANCAs) can result in systemic small vessel vasculitis. However, the breakdown in immune tolerance that results in the induction and persistence of ANCAs is not well understood. We undertook this study to test our hypothesis that abnormal T cell regulation is central to disease pathogenesis in patients with ANCA-associated vasculitis (AAV). Peripheral blood samples were obtained from 62 patients with AAV and 19 healthy controls for flow cytometric analysis of CD4+ T cell populations. Functional T cell studies were performed with fluorescence-activated cell sorted CD4+ T cell populations stimulated with anti-CD3/anti-CD28. We demonstrated two separate abnormalities in T cell regulation in patients with AAV. First, we showed that the Treg cell frequency was increased in the peripheral blood of patients with active disease, but Treg cells from patients with AAV had decreased suppressive function. Treg cells from patients with active disease disproportionately used a FoxP3 isoform lacking exon 2, which might alter Treg cell function. Second, we identified a CD4+ T cell population with increased frequency that was resistant to Treg cell suppression, produced proinflammatory cytokines, and was antigen experienced. AAV is associated with disruption of the suppressive Treg cell network and with increased frequency of a distinct proinflammatory effector T cell subset that comprises the majority of peripheral CD4+ T cells.

Is chronic plaque psoriasis triggered by microbiota in the skin?

There is a known association between psoriasis and Crohn disease (CD). Patients with CD are five times more likely to develop psoriasis, and, conversely, patients with psoriasis are more likely to develop CD. Many gastroenterologists now accept that CD results from a breakdown of immune tolerance to the microbiota of the intestine in genetically susceptible individuals. The microbiota of the skin have recently been investigated in psoriasis. Firmicutes was the most common phylum, and Streptococcus the most common genus identified. Beta-haemolytic streptococci have been implicated in both guttate and chronic plaque psoriasis. Furthermore, the innate immune system has been shown to be activated in psoriasis, and many of the genes associated with the disease are concerned with the signalling pathways of the innate immune system, notably interleukin-23 and nuclear factor κB. Patients with psoriasis also have an increased incidence of periodontitis, a disease thought to be due to an abnormal response to normal oral commensals. Based on the similarities between CD and psoriasis, we propose that psoriasis is due to a breakdown of immune tolerance to the microbiota of the skin. In support of this hypothesis we provide evidence for microbiota in the skin, activation of the innate immune system, and genetic abnormalities involving the innate immune system.

Human Parvovirus B19 Induced Apoptotic Bodies Contain Altered Self-Antigens that are Phagocytosed by Antigen Presenting Cells

Human parvovirus B19 (B19V) from the erythrovirus genus is known to be a pathogenic virus in humans. Prevalence of B19V infection has been reported worldwide in all seasons, with a high incidence in the spring. B19V is responsible for erythema infectiosum (fifth disease) commonly seen in children. Its other clinical presentations include arthralgia, arthritis, transient aplastic crisis, chronic anemia, congenital anemia, and hydrops fetalis. In addition, B19V infection has been reported to trigger autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. However, the mechanisms of B19V participation in autoimmunity are not fully understood. B19V induced chronic disease and persistent infection suggests B19V can serve as a model for viral host interactions and the role of viruses in the pathogenesis of autoimmune diseases. Here we investigate the involvement of B19V in the breakdown of immune tolerance. Previously, we demonstrated that the non-structural protein 1 (NS 1) of B19V induces apoptosis in non-permissive cells lines and that this protein can cleave host DNA as well as form NS1-DNA adducts. Here we provide evidence that through programmed cell death, apoptotic bodies (ApoBods) are generated by B19V NS1 expression in a non-permissive cell line. Characterization of purified ApoBods identified potential self-antigens within them. In particular, signature self-antigens such as Smith, ApoH, DNA, histone H4 and phosphatidylserine associated with autoimmunity were present in these ApoBods. In addition, when purified ApoBods were introduced to differentiated macrophages, recognition, engulfment and uptake occurred. This suggests that B19V can produce a source of self-antigens for immune cell processing. The results support our hypothesis that B19V NS1-DNA adducts, and nucleosomal and lysosomal antigens present in ApoBods created in non-permissive cell lines, are a source of self-antigens.