Regulation generation: the suppressive functions of human regulatory T cells

Proper regulation of immune homeostasis is necessary to limit inflammation and prevent autoimmune and chronic inflammatory diseases. Many autoimmune diseases, such as psoriasis, are driven by vicious cycles of activated T cells that are unable to be suppressed by regulatory T cells. Effective suppression of auto-reactive T cells by regulatory T cells (Treg) is critical for the prevention of spontaneous autoimmune disease. Psoriatic Treg cells have been observed to a defect in their capacity to regulate, which clearly contributes to psoriasis pathogenesis. A challenge for translational research is the development of novel therapeutic interventions for autoimmune diseases that will result in durable remissions. Understanding the mechanism(s) of dysregulated T cell responses in autoimmune disease will allow for the development of future therapeutic strategies that may be employed to specifically target pathogenic, proinflammatory cells. Several reports have demonstrated a pathogenic role for Thl and Thl7 cells in psoriasis as well as other autoimmune diseases. Similarly, several laboratories have independently demonstrated functional defects in regulatory T cells isolated from patients with numerous divergent autoimmune diseases. One primary challenge of research in autoimmune diseases is therefore to restore the balance between chronic T cell activation and impairment of Treg suppressor mechanisms. To this end, it is critical to develop an understanding of the many suppressive mechanisms employed by Treg cells in hopes of developing more targeted therapeutic strategies for Treg-mediated autoimmune diseases.     

Selfie: Autoimmunity,boon or bane

The immune system provides protection to tissues damaged by infectious microrganisms or physical damage. In autoimmune diseases, the immune system recognizes and attacks its own tissues, i.e., self-destruction. Various agents such as genetic factors and environmental triggers are thought to play a major role in the development of autoimmune diseases. A common feature of all autoimmune diseases is the presence of autoantibodies and inflammation, including mononuclear phagocytes, autoreactive T lymphocytes, and autoantibody producing B cells (plasma cells). It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Autoimmune diseases can be classified as organ-specific or non-organ specific depending on whether the autoimmune response is directed against a particular tissue or against widespread antigens as in chronic inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Both SLE and RA are characterized by the presence of autoantibodies which play a major role in their etiopathogenesis. SLE is characterized by circulating antibodies and immune complex deposition that can trigger an inflammatory damage in organs. RA is a progressive inflammatory disease in which T cells, B cells, and pro-inflammatory cytokines play a key role in its pathophysiology.     

B cells and autoimmune liver diseases

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the three major autoimmune diseases affecting the liver. They are all characterized by the presence of a variety of autoantibodies, some of which are found in all three diseases, whereas others are restricted to one or two of them or are even specific for the particular disease. In this review we will first provide details of the serological features of these three autoimmune diseases that target the liver. In addition, we will highlight the possible pathogenic roles of autoreactive B cells, focusing on their immunological functions as autoantibody producing cells and as antigen-presenting cells for T cell priming. As well, we will describe the contribution of toll-like receptor (TLR) signaling to the activation of autoimmune B cells and the putative role of defects in regulatory T cell function in the development of autoimmune liver diseases.     

Unexpected Targets and Triggers of Autoimmunity

Recent findings indicate that the role of Th17 cells in the pathogenesis of tissue inflammation and autoimmunity has become rather complicated. While interleukin-17 (IL-17) producing CD4⁺ T cells are found frequently within the peripheral target tissue during the course of autoimmune disease, these cells may contribute to or protect from inflammation. Accumulating reports have revealed the existence of both pathogenic and non-pathogenic Th17 cells. These Th17 subsets produce the signature cytokines IL-17A and IL-17F yet have distinct and divergent roles in inducing autoimmune tissue inflammation. Comparative genomic sequence analyses between the pathogenic and non-pathogenic Th17 cells have exposed unexpected and extensive population heterogeneity within the Th17 subset. Here we review some of the unexpected factors that may drive pathogenic divergence. Understanding the functional consequences of Th17 cell diversity may allow for the selection of more precise targets for intervention in autoimmune and inflammatory diseases.     

Prostate autoimmunity: from experimental models to clinical counterparts

Different murine models of autoimmune prostatitis have been developed and characterized, proving the autoimmune origin of this pathology. Autoimmune prostatitis models have also provided a wealth of information on the mechanisms involved in disease development, shedding light on inciting autoantigens, regulatory and pathogenic T cells, and mediators of prostatic autoimmunity. Unfortunately, the clinical counterparts of experimental autoimmune prostatitis are still poorly defined. In this review, we will discuss evidence for the autoimmune origin of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and the chronic inflammatory nature of benign prostatic hyperplasia (BPH). The autoimmune pathogenesis of CP/CPPS and the chronic inflammation characteristic of BPH will be reviewed within the context of the recent demonstration that human prostate stromal cells from BPH tissue can act as antigen-presenting cells and are not only able to activate CD4⁺ T lymphocytes, but can also produce IL-12 and IL-23, which are key cytokines for the induction of pathogenic Th1 and Th17 cells.     

Regulation of neuroinflammation by B cells and plasma cells

The remarkable success of anti‐CD20 B cell depletion therapies in reducing the burden of multiple sclerosis (MS) disease has prompted significant interest in how B cells contribute to neuroinflammation. Most focus has been on identifying pathogenic CD20⁺ B cells. However, an increasing number of studies have also identified regulatory functions of B lineage cells, particularly the production of IL‐10, as being associated with disease remission in anti‐CD20–treated MS patients. Moreover, IL‐10–producing B cells have been linked to the attenuation of inflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. In addition to IL‐10–producing B cells, antibody‐producing plasma cells (PCs) have also been implicated in suppressing neuroinflammation. This review will examine regulatory roles for B cells and PCs in MS and EAE. In addition, we speculate on the involvement of regulatory PCs and the cytokine BAFF in the context of anti‐CD20 treatment. Lastly, we explore how the microbiota could influence anti‐inflammatory B cell behavior. A better understanding of the contributions of different B cell subsets to the regulation of neuroinflammation, and factors that impact the development, maintenance, and migration of such subsets, will be important for rationalizing next‐generation B cell–directed therapies for the treatment of MS.     

Human adipose-derived stromal/stem cells: A novel approach to inhibiting acute pancreatitis

Acute pancreatitis, a common necroinflammatory disease of the pancreas, remains an unsolved problem that is associated with significant morbidity and mortality. Intra-acinar cell activation of digestion enzymes triggers the events of acute pancreatitis and stimulates the production of inflammatory cytokines. Finally, inflammatory cytokines trigger inflammatory cascades that lead to systemic inflammatory response syndrome, multi-organ failure, or death. Therefore, proposing a novel strategy for acute pancreatitis would be greatly valuable. Research on adult stem cells has achieved a great deal of progress related to the repair and regeneration of tissues and organs. Human adipose-derived stromal/stem cells become a crucial model to study diseases and develop novel therapeutic applications, as these cells are plentiful, easier to obtain, and require less-invasive procedures. Accumulated data suggest human adipose-derived stromal/stem cells would be a valuable tool for cell-based therapy for inflammatory disease, autoimmune disease, tissue repair, and ischemic insults by controlling cell death, immune response, inflammation, and tissue regeneration. Thus, it is reasonable to hypothesize that human adipose-derived stromal/stem cells would be a novel approach to inhibiting inflammation and reducing acute pancreatitis.     

T cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self‐antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4⁺ T cells that secrete interleukin (IL)‐17, termed Th17, but also IL‐17‐secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL‐17‐producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8⁺ and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.     

The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease

The propagation and regulation of an immune response is driven by a network of effector and regulatory T (Treg) cells. The interplay of effector T and Treg cells determines the direction of the immune response towards inflammation or its resolution in an autoimmune disease setting. In autoimmune diseases, this interplay shifts the balance in favor of the development of autoreactive effector T cells, resulting in inflammatory pathology. The objective of an effective therapeutic approach for autoimmune disease is to restore this balance. In this review, we describe the characteristics and development of pathogenic T helper 1 (Th1) and Th17 cells and the beneficial Treg cells in autoimmune diseases and the crucial roles of the cytokine milieu in influencing the balance of these T-cell subsets. Given the importance of cytokines, we discuss current immunotherapeutic strategies using cytokine or cytokine receptor antibodies for the treatment of autoimmune diseases.     

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.     

Autoimmunity in dry eye disease – An updated review of evidence on effector and memory Th17 cells in disease pathogenicity

The classic Th1/Th2 dogma has been significantly reshaped since the subsequent introduction of several new T helper cell subsets, among which the most intensively investigated during the last decade is the Th17 lineage that demonstrates critical pathogenic roles in autoimmunity and chronic inflammation – including the highly prevalent dry eye disease. In this review, we summarize current concepts of Th17-mediated disruption of ocular surface immune homeostasis that leads to autoimmune inflammatory dry eye disease, by discussing the induction, activation, differentiation, migration, and function of effector Th17 cells in disease development, highlighting the phenotypic and functional plasticity of Th17 lineage throughout the disease initiation, perpetuation and sustention. Furthermore, we emphasize the most recent advance in Th17 memory formation and function in the chronic course of dry eye disease, a major area to be better understood for facilitating the development of effective treatments in a broader field of autoimmune diseases that usually present a chronic course with recurrent episodes of flare in the target tissues or organs.     

IL‐27: a double agent in the IL‐6 family

The cytokine interleukin (IL)‐6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL‐6 receives considerable attention in studies of innate and adaptive immunity, the IL‐6‐related family member IL‐27 is recognized increasingly for its effects on cellular proliferation, differentiation and leucocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells, where they direct the transition from innate to adaptive immunity. However, they are identified frequently as lymphokines that control responses in T cells and B cells. In this regard, IL‐27 often opposes the action of IL‐6. Here, we will review the role of IL‐6 and IL‐27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease.     

Macrophages with regulatory functions,a possible new therapeutic perspective in autoimmune diseases

Macrophages are pivotal cells involved in chronic inflammatory and autoimmune diseases. In fact, during these diseases, activated macrophages may play a critical role, promoting the inflammation as well as mediating the damage resolution. This dichotomy is referred to two end-stage phenotypes of macrophages, conventionally known as M1 and M2, playing a pro-inflammatory and anti-inflammatory role, respectively. The M1 macrophages are the mainly subset involved during inflammatory processes, producing pro-inflammatory mediators. Conversely, the M2 macrophages are proposed to contribute to the resolution phase of inflammation, when cells with pro-resolving property are recruited and activated. In fact, this subset of macrophages may activate regulatory T lymphocytes, which play a critical role in the maintenance of peripheral tolerance and preventing the occurrence of autoimmune diseases. On these bases, the polarization toward the M2 phenotype could play a therapeutic role for autoimmune diseases.In this Review we discussed the characteristic of M1 and M2 macrophages, focusing on the immunoregulatory role of M2 cells and their potential ability to control the inflammation and to promote the immunological tolerance.     

Enhanced killing activity of regulatory T cells ameliorates inflammation and autoimmunity

Regulatory T cells (Treg) are pivotal suppressor elements in immune homeostasis with potential therapeutic applications in inflammatory and autoimmune disorders. Using Treg as vehicles for targeted immunomodulation, a short-lived Fas-ligand (FasL) chimeric protein (killer Treg) was found efficient in preventing the progression of autoimmune insulitis in NOD mice, and amelioration of chronic colitis and graft versus host disease. The main mechanisms of disease suppression by killer Treg are: a) in the acute phase induction of apoptosis in effector cells at the site of inflammation decreases the pathogenic burden, and b) persistent increase in FoxP3⁺ Treg with variable CD25 co-expression induced by FasL sustains disease suppression over extended periods of time. Reduced sensitivity of Treg to receptor-mediated apoptosis under inflammatory conditions makes them optimal vehicles for targeted immunotherapy using apoptotic agents.     

Autoantigen-selected B cells are bystanders in spontaneous T cell-driven experimental autoimmune hepatitis

Autoreactive B cells are considered pathogenic drivers in many autoimmune diseases; however, it is not clear whether autoimmune B cells are invariably pathogenic or whether they can also arise as bystanders of T cell-driven autoimmune pathology. Here, we studied the B cell response in an autoantigen- and CD4⁺ T cell-driven model of autoimmune hepatitis (AIH), the Alb-iGP_Smarta mouse in which expression of a viral model antigen (GP) in hepatocytes and its recognition by GP-specific CD4⁺ T cells causes spontaneous AIH-like disease. T cell-driven AIH in Alb-iGP_Smarta mice was marked by autoantibodies and hepatic infiltration of plasma cells and B cells, particularly of isotype-switched memory B cells, indicating antigen-driven selection and activation. Immunosequencing of B cell receptor repertoires confirmed B cell expansion selectively in the liver, which was most likely driven by the hepatic GP model antigen, as indicated by branched networks of connected sequences and elevated levels of IgG antibodies to GP. However, intrahepatic B cells did not produce increased levels of cytokines and their depletion with anti-CD20 antibody did not alter the CD4⁺ T cell response in Alb-iGP_Smarta mice. Moreover, B cell depletion did not prevent spontaneous liver inflammation and AIH-like disease in Alb-iGP_Smarta mice. In conclusion, selection and isotype-switch of liver-infiltrating B cells was dependent on the presence of CD4⁺ T cells recognizing liver antigen. However, recognition of hepatic antigen by CD4⁺ T cells and CD4⁺ T cell-mediated hepatitis was not dependent on B cells. Thus, autoreactive B cells can be bystanders and need not be drivers of liver inflammation in AIH.     

Immunoregulatory role of B7-H1 in chronicity of inflammatory responses

Pathogenesis of most chronic human diseases, including chronic infections, autoimmune diseases and cancers, often involves a persistent, unresolved inflammatory response. The molecular mechanisms that determine the conversion of an acute inflammatory response into a chronic process had puzzled researchers for many years. Recent studies reveal that B7-H1 （CD274, PD-L1）, a newly identified co-stimulatory molecule, possesses dual functions of co-stimulation of naive T cells and inhibition of activated effector T cells. The aberrant cellular expression and deregulated function of B7-H1 have been reported during chronic viral and intracellular bacterial infection, as well as in many autoimmune diseases and cancers. Importantly, the deregulation of B7-H1＇s dual functions appears to be associated with a prolonged and incomplete immune response by luring naive T cells for activation and dampening activated effector T cells. Moreover, development of strategies targeting B7-H1 signals provides a new and promising approach to manipulate the devastating diseases associated with chronic inflammation. Thus, B7-H1 may play a critical immunoregulatory role in the chronicity of inflammatory responses. Cellular ＆ Molecular Immunology. 2006;3（3）：179-187.     

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.     

IL-17 and IL-17-producing cells and liver diseases,with focus on autoimmune liver diseases

The pro-inflammatory cytokine interleukin(IL)-17 and IL-17-producing cells are important players in the pathogenesis of many autoimmune / inflammatory diseases. More recently, they have been associated with liver diseases. This review first describes the general knowledge on IL-17 and IL-17 producing cells. The second part describes the in vitro and in vivo effects of IL-17 on liver cells and the contribution of IL-17 producing cells to liver diseases. IL-17 induces immune cell infiltration and liver damage driving to hepatic inflammation and fibrosis and contributes to autoimmune liver diseases. The circulating levels of IL-17 and the frequency of IL-17-producing cells are elevated in a variety of acute and chronic liver diseases. The last part focuses on the effects of IL-17 deletion or neutralization in various murine models. Some of these observed beneficial effects suggest that targeting the IL-17 axis could be a new therapeutic strategy to prevent chronicity and progression of various liver diseases.     

B cells in spontaneous autoimmune diseases of the central nervous system

B cells and their secreted products participate in the intricate network of pathogenic and regulatory immune responses. In human autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes, a role for B cells and antibodies is well established. However, in multiple sclerosis (MS), despite the presence of autoantibodies, B cells were less considered as a major participant of autoimmune processes, until recently. Several lines of evidence now indicate a more active role for B cells in disease pathogenesis. In this review, we discuss the diverse roles of B cells in autoimmune diseases with particular focus on multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE) as well as the recently generated spontaneous EAE mouse models.