BAFF: a local and systemic target in autoimmune diseases

BAFF (B lymphocyte activating factor of the tumour necrosis factor family) is a vital homeostatic cytokine for B cells that helps regulate both innate and adaptive immune responses. Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFF‐R, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation‐inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G. In contrast, neither BAFF nor APRIL is required for the survival or reactivation of memory B cells or B1 cells. BAFF also helps DC maturation and interleukin (IL)‐6 release and is required for proper formation of a follicular dendritic cell (FDC) network within germinal centres, although not for B cell affinity maturation. The clinical efficacy of BAFF blockade in animal models of autoimmunity may be caused both by the decline in the number of inflammatory cells and by the inhibition of DC maturation within target organs. Blockade of BAFF and its homologue APRIL are being explored for human use; several Phase I and II clinical trials of BAFF inhibitors for autoimmunity have been completed and Phase III trials are in progress.     

Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene modulation: A comprehensive review

Autoimmune diseases are clinical syndromes that result from pathogenic inflammatory responses driven by inadequate immune activation by T- and B-cells. Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Recently, with the advancement of understanding of the immunological and molecular basis of autoimmune diseases, gene modulation has become a potential approach for the tailored treatment of autoimmune disorders. Gene modulation can be applied to regulate the levels of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines by inhibiting these cytokine expressions using short interfering ribonucleic acid (siRNA) or by inhibiting cytokine signaling using small molecules. In addition, gene modulation delivering anti-inflammatory cytokines or cytokine antagonists showed effectiveness in regulating autoimmunity. In this review, we summarize the potential target genes for gene or immunomodulation in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human. Emerging approaches to investigate cytokine regulation through gene modulation may be a potential approach for the tailored immunomodulation of some autoimmune diseases near in the future.     

Interplay Between Effector Th17 and Regulatory T Cells

Introduction  Over two decades ago, T helper cells were classified into its functional subsets. Soon after the classical observation of Mosmann et al., immunologists agreed to accept the Th1/Th2 paradigm of the T helper subsets. Each subset is not only characterized by its specific cytokines pattern and effector functions but also by their properties to counter regulate each other’s functions. This classification helped to understand the complex principles of T helper cell biology and allowed us to comprehend different immune reactions in context of Th1 and Th2 subsets. Discussion  Although Th1 subsets thought to be the crucial player for most of the organ-specific autoimmune diseases like multiple sclerosis and type-1 diabetes but the loss of Th1 dominant cytokine, IFN-γ did not prevent the development of autoimmunity which raised the possibility of involvement of other Th subsets, different from Th1 cells in the induction of autoimmunity. Conclusion  Recently, a new subset of Th cells that predominantly produce IL-17 and induce autoimmunity has been discovered, and it is believed that this subset may be the major cell type involved in orchestrating tissue inflammation and autoimmunity. Recent data propose that the differentiation factors of Th17 cells reveal a link with induction of Foxp3⁺ regulatory T cells. Here, we review the interplay between Th17 and Foxp3⁺ T-reg cells and Tr1 cells during autoimmune inflammatory reaction.     

Emerging role of air pollution in autoimmune diseases

Autoimmune diseases (ADs) are a broad spectrum of disorders featured by the body's immune responses being directed against its own tissues, resulting in prolonged inflammation and subsequent tissue damage. Recently, the exposure to ambient air pollution has been implicated in the occurrence and development of ADs. Mechanisms linking air pollution exposures and ADs mainly include systemic inflammation, increased oxidative stress, epigenetic modifications induced by exposures and immune response caused by airway damage. The lung may be an autoimmunity initiation site in autoimmune diseases (ADs). Air pollutants can bind to the Aryl hydrocarbon receptor (AHR) to regulate Th17 and Treg cells. Oxidative stress and inducible bronchus associated lymphoid tissue caused by the pollutants can influence T, B cells, resulting in the production of proinflammatory cytokines. These cytokines stimulate B cell and dendritic cells, resulting in a lot of antibodies and self-reactive T lymphocytes. Moreover, air pollutants may induce epigenetic changes to contribute to ADs. In this review, we will concern the associations between air pollution and immune–inflammatory responses, as well as mechanisms linking air pollution exposure and autoimmunity. In addition, we focus on the potential roles of air pollution in major autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes mellitus (T1DM).     

Translational Mini‐Review Series on B Cell‐Directed Therapies: B cell‐directed therapy for autoimmune diseases

B cells play an important role in the pathogenesis of both systemic and organ‐specific autoimmune diseases. Autoreactive B cells not only produce autoantibodies, but are also specialized to present specific autoantigens efficiently to T cells. Furthermore, these B cells can secrete proinflammatory cytokines and can amplify the vicious cycle of self‐destruction. Thus, B cell‐directed therapies are potentially an important approach for treating autoimmune diseases. On the other hand, like T cells, there are subsets of B cells that produce anti‐inflammatory cytokines and are immunosuppressive. These regulatory B cell subsets can protect against and ameliorate autoimmune diseases. Thus targeting B cells therapeutically will require this balance to be considered. Here we summarize the roles of pathogenic and regulatory B cells and current applications of B cell‐directed therapy in autoimmune diseases. Considerations for future development of B cell‐directed therapy for autoimmune diseases have also been discussed.     

Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases

B-cell depletion therapy has beneficial effects in autoimmune diseases. This is only partly explained by an elimination of autoantibodies. How does B-cell depletion improve disease? Here, we review preclinical studies showing that B cells can propagate autoimmune disorders through cytokine production. We also highlight clinical observations indicating the relevance of these B-cell functions in human autoimmunity. Abnormalities in B-cell cytokine production have been observed in rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. In the first two diseases, B-cell depletion erases these abnormalities, and improves disease progression, suggesting a causative role for defective B-cell cytokine expression in disease pathogenesis. However, in the last two disorders, the pathogenic role of B cells and the effect of B-cell depletion on cytokine-producing B cells remain to be clarified. A better characterization of cytokine-expressing human B-cell subsets, and their modulation by B cell-targeted therapies might help understanding both the successes and failures of current B cell-targeted approaches. This may even lead to the development of novel strategies to deplete or amplify selectively pathogenic or protective subsets, respectively, which might be more effective than global depletion of the B-cell compartment.     

The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases

The importance of transforming growth factor-beta-1 (TGF-beta1) in immunoregulation and tolerance has been increasingly recognized. It is now proposed that there are populations of regulatory T cells (T-reg), some designated T-helper type 3 (Th3), that exert their action primarily by secreting this cytokine. Here, we emphasize the following concepts: (1) TGF-beta1 has multiple suppressive actions on T cells, B cells, macrophages, and other cells, and increased TGF-beta1 production correlates with protection and/or recovery from autoimmune diseases; (2) TGF-beta1 and CTLA-4 are molecules that work together to terminate immune responses; (3) Th0, Th1 and Th2 clones can all secrete TGF-beta1 upon cross-linking of CTLA-4 (the functional significance of this in autoimmune diseases has not been reported, but TGF-beta1-producing regulatory T-cell clones can produce type 1 inflammatory cytokines); (4) TGF-beta1 may play a role in the passage from effector to memory T cells; (5) TGF-beta1 acts with some other inhibitory molecules to maintain a state of tolerance, which is most evident in immunologically privileged sites, but may also be important in other organs; (6) TGF-beta1 is produced by many cell types, is always present in the plasma (in its latent form) and permeates all organs, binding to matrix components and creating a reservoir of this immunosuppressive molecule; and (7) TGF-beta1 downregulates adhesion molecules and inhibits adhesion of leukocytes to endothelial cells. We propose that rather than being passive targets of autoimmunity, tissues and organs actively suppress autoreactive lymphocytes. We review the beneficial effects of administering TGF-beta1 in several autoimmune diseases, and show that it can be effectively administered by a somatic gene therapy approach, which results in depressed inflammatory cytokine production and increased endogenous regulatory cytokine production.     

Targeting B cells and plasma cells in autoimmune diseases: From established treatments to novel therapeutic approaches

Autoimmune diseases are characterized by the recognition of self-antigens by the immune system, which leads to inflammation and tissue damage. B cells are directly and indirectly involved in the pathophysiology of autoimmunity, both via antigen-presentation to T cells and production of proinflammatory cytokines and/or autoantibodies. Consequently, B lineage cells have been identified as therapeutic targets in autoimmune diseases. B cell depleting strategies have proven beneficial in the treatment of rheumatoid arthritis (RA), systemic lupus erythematous (SLE), ANCA-associated vasculitis (AAV), multiple sclerosis (MS), and a wide range of other immune-mediated inflammatory diseases (IMIDs). However, not all patients respond to treatment or may not reach (drug-free) remission. Moreover, B cell depleting therapies do not always target all B cell subsets, such as short-lived and long-lived plasma cells. These cells play an active role in autoimmunity and in certain diseases their depletion would be beneficial to achieve disease remission. In the current review article, we provide an overview of novel strategies to target B lineage cells in autoimmune diseases, with the focus on rheumatic diseases. Both advanced therapies that have recently become available and more experimental treatments that may reach the clinic in the near future are discussed.     

Insulinoma‐released exosomes activate autoreactive marginal zone‐like B cells that expand endogenously in prediabetic NOD mice

Exosomes (EXOs) are nano‐sized secreted microvesicles that can function as potent endogenous carriers of adjuvant and antigens. To examine a possible role in autoimmunity for EXOs, we studied EXO‐induced immune responses in nonobese diabetic (NOD) mice, an autoimmune‐prone strain with tissue‐specific targeting at insulin‐secreting beta cells. EXOs released by insulinoma cells can activate various antigen‐presenting cells to secrete several proinflammatory cytokines and chemokines. A subset of B cells responded to EXO stimulation in culture by proliferation, and expressed surface markers representing marginal zone B cells, which was independent of T helper cells. Importantly, splenic B cells from prediabetic NOD mice, but not diabetic‐resistant mice, exhibited increased reactivity to EXOs, which was correlated with a high level of serum EXOs. We found that MyD88‐mediated innate TLR signals were essential for the B‐cell response; transgenic B cells expressing surface immunoglobulin specific for insulin reacted to EXO stimulation, and addition of a calcineurin inhibitor FK506 abrogated the EXO‐induced B‐cell response, suggesting that both innate and antigen‐specific signals may be involved. Thus, EXOs may contribute to the development of autoimmunity and type 1 diabetes in NOD mice, partially via activating autoreactive marginal zone‐like B cells.     

Syndromes mononucléosiques et pathologies hématologiques liés au virus d'Epstein-Barr

The Epstein-Barr virus (EBV), which preferentially infects B cells, persists in the infected subject as a latent asymptomatic infection. In adolescents, infectious mononucleosis is the symptomatic manifestation of primary EBV infection. The viral latency in the memory B-cells, the reservoir cells in peripheral blood in individuals is controlled by CD4 and CD8 positive T-cells. Immunodeficient patients are at high risk of developing EBV driven B-cell lymphomas as the consequence of the expression of oncogenic latency proteins LMP1 and EBNA2. These proteins expressed in infected B cells identify latency III or proliferation program in virus transformed B-cell, leading to lymphoid proliferation. In addition to immunodeficiency-related lymphomas, the most frequent lymphoid malignancies associated with EBV are the endemic Burkitt lymphoma, Hodgkin lymphoma and nasal type T-cell lymphoma.     

Transforming growth factor beta (TGF-beta) and autoimmunity

TGF-beta1 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-beta receptor type II in T cells have enabled the study of cell lineage specific effects of TGF-beta providing clues to the potential etiology of autoimmunity. These studies suggest that TGF-beta 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.     

B cell autonomous TLR signaling and autoimmunity

B cells play a central role in the pathogenesis of multiple autoimmune diseases and the recognition of the importance of B cells in these disorders has grown dramatically in association with the remarkable success of B cell depletion as a treatment for autoimmunity. The precise mechanisms that promote alterations in B cell tolerance remain incompletely defined. There is increasing evidence, however, that TLRs play a major role in these events. Stimulation of B cells via the TLR pathway not only leads to an increase in antibody production but also promotes additional changes including cytokine production and up-regulation of activation markers increasing the effectiveness of B cells as APCs. Understanding the role of TLRs in systemic autoimmunity will not only provide insight into the disease pathogenesis but may also lead to the development of novel therapies. This article gives an overview of TLR signaling in B cells and the possible involvement of such signals in autoimmune diseases.     

Lymphokines in Autoimmunity—A Critical Review

The pathogenesis of autoimmunity remains an enigma; however, growing evidence points to a possible involvement of lymphokines both in the initiation phase and especially in the effector stage of many autoimmune diseases. Although no single experimental approach can accurately mimic the highly complex interplay of genetic, hormonal, and immune factors inherent in the development of autoimmunity, several lines of evidence strongly suggest a major role for lymphokines, in particular interferons (IFN), tumor necrosis factor (TNF), and interleukins 1 and 2 (IL-1, IL-2). These include the pleiotropic biologic activities of lymphokines which often synergize and interact, and can mediate several prominent clinical and laboratory manifestations of autoimmunity. Patients undergoing therapy with IFN or IL-2 may develop varied autoimmune syndromes, often an exacerbation of previously latent autoimmunity. Likewise, the administration of IFN to experimental animals can cause or accelerate autoimmune disease and, more importantly, specific lymphokine blockade was shown to be protective. Moreover, in the animal models of autoimmunity and in many patients with autoimmune diseases, increased lymphokine levels can be demonstrated either in the circulation or locally, often correlating with disease activity. Finally, aberrant MHC class II expression on nonlymphoid cells can be identified in the target organs of most autoimmune diseases and extensive data suggest that it can present autoantigen, activate autoreactive T cells, and initiate a cascade of self-propagating autoimmunity. Thus, a local release of IFN-γ, the major inducer of MHC class II, may be pivotal to the development of organ-specific autoimmunity. The central role of cytokines in lymphocyte traffic into inflammatory sites as well as a growing understanding of lymphokine production patterns by different T cell subsets important in autoimmunity lends further support for this hypothesis, at the same time revealing that certain lymphokines may have a protective inhibitory effect on autoimmunity (e.g., IL-4, TGF-β). In conclusion, varied data strongly suggest that several lymphokines, produced mainly locally and interacting with each other, have an important role in the pathogenesis of autoimmunity. Although the initiating events and complex interactions remain largely unclear, recent advances are encouraging, and may lead to specific manipulations of lymphokines in the future treatment of autoimmune diseases.     

Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases

I hypothesize that human chronic autoimmune diseases are based on infection of autoreactive B lymphocytes by Epstein-Barr virus (EBV), in the following proposed scenario. During primary infection, autoreactive B cells are infected by EBV, proliferate and become latently infected memory B cells, which are resistant to the apoptosis that occurs during normal B-cell homeostasis because they express virus-encoded anti-apoptotic molecules. Genetic susceptibility to the effects of B-cell infection by EBV leads to an increased number of latently infected autoreactive memory B cells, which lodge in organs where their target antigen is expressed, and act there as antigen-presenting cells. When CD4(+) T cells that recognize antigens within the target organ are activated in lymphoid organs by cross-reactivity with infectious agents, they migrate to the target organ but fail to undergo activation-induced apoptosis because they receive a co-stimulatory survival signal from the infected B cells. The autoreactive T cells proliferate and produce cytokines, which recruit other inflammatory cells, with resultant target organ damage and chronic autoimmune disease.     

The role of B cell metabolism in autoimmune diseases

B cells are major players in immune responses being the source of protective antibodies and antigen presenting cells. When self-tolerance fails, auto reactive B cells produce autoantibodies and pro-inflammatory cytokines leading to the development of autoimmune diseases. Many recent studies have assessed importance of metabolic pathways in B cells, demonstrating their role in controlling autoimmunity and maintaining immune homeostasis. Alterations in B cell functions in autoimmune diseases are closely associated with abnormal metabolic shifts, allowing auto reactive B cells to escape tolerogenic checkpoints. Understanding the metabolic changes in B cells, opens up new possibilities for targeting metabolic pathways and manipulating metabolic avenues as a therapeutic strategy for the treatment of autoimmune diseases.     

TH2 cells in systemic autoimmunity: insights from allogeneic diseases and chemically-induced autoimmunity.

Systemic autoimmune diseases can be induced experimentally in rodents by graft-versus-host or host-versus-graft reactions and by chemicals such as HgCl2, gold salts and D-penicillamine. These models share several features, such as productions of anti-nuclear antibodies, immune glomerulonephritis, MHC class II hyperexpression on B cells, hyper-IgE, increased IL-4 activity and impairment of IL-2 production. This profile of cytokines suggests a central role for TH2-type cells in their pathogenesis. Here, Michel Goldman and colleagues review the data supporting this hypothesis and discuss the possible molecular bases for T-cell activation in chemically-induced systemic autoimmunity.     

IL-23的研究进展

IL 2 3是新近发现的一种细胞因子 ,主要来源于活化的单核巨噬细胞和B细胞。它具有多种生物学功能 ,能促进T细胞尤其是CD4 T细胞增殖 ,促进T细胞、抗原提呈细胞产生IFN γ与IL 12 ,对树突状细胞的共刺激功能起调节作用 ,具有抗肿瘤和抗转移活性 ,而且与自身免疫和炎症反应疾病密切相关。