The role of B cells and their interactions with stromal cells in the context of inflammatory autoimmune diseases

Interactions between B cells and stromal cells have essential functions in immune cell development and responses. During chronic inflammation, the pro-inflammatory microenvironment leads to changes in stromal cells, which acquire a pathogenic phenotype specific to each organ and disease. B cells are recruited to the site of inflammation and interact with these pathogenic stromal cells contributing to the disease’s severity. In addition to producing autoantibodies, B cells contribute to the pathogenesis of autoimmune inflammatory diseases by serving as professional antigen-presenting cells, producing cytokines, and through additional mechanisms. This review describes the role of B cells and their interactions with stromal cells in chronic inflammation, with a focus on human disease, using three selected autoimmune inflammatory diseases: rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. Understanding B cells roles and their interaction with stromal cells will help develop new therapeutic options for the treatment of 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.     

Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation

B cells possess a variety of immune functions that are involved in normal and abnormal immune responses, including autoimmune disorders. Through murine models of intestinal inflammation, we here demonstrate a B cell subset that is induced in gut-associated lymphoid tissues and is characterized by CD1d upregulation. This B cell subset appears under a chronic inflammatory environment, produces IL-10, and suppresses progression of intestinal inflammation by downregulating inflammatory cascades associated with IL-1 upregulation and STAT3 activation rather than by altering polarized T helper responses. This study indicates that B cells, by producing cytokines such as IL-10, can act as regulatory cells in immunologically mediated inflammatory reactions.     

Multiple sclerosis

Summary: Multiple sclerosis (MS) is a complex genetic disease associated with inflammation in the central nervous system (CNS) white matter and is thought to be mediated by autoimmune processes. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. The association of the disease with major histocompatibility complex genes, the inflammatory white matter infiltrates, similarities with animal models, and the observation that MS can be treated with immunomodulatory and immunosuppressive therapies support the hypothesis that autoimmunity plays a major role in the disease pathology. This review discusses the immunopathology of MS with particular focus given to regulatory T cells and the role of B cells and antibodies, immunomodulatory therapeutics, and finally new directions in MS research, particularly new methods to define the molecular pathology of human disease with high‐throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understandings and therapies for this disease.     

The immune response to Prevotella bacteria in chronic inflammatory disease

The microbiota plays a central role in human health and disease by shaping immune development, immune responses and metabolism, and by protecting from invading pathogens. Technical advances that allow comprehensive characterization of microbial communities by genetic sequencing have sparked the hunt for disease‐modulating bacteria. Emerging studies in humans have linked the increased abundance of Prevotella species at mucosal sites to localized and systemic disease, including periodontitis, bacterial vaginosis, rheumatoid arthritis, metabolic disorders and low‐grade systemic inflammation. Intriguingly, Prevotella abundance is reduced within the lung microbiota of patients with asthma and chronic obstructive pulmonary disease. Increased Prevotella abundance is associated with augmented T helper type 17 (Th17) ‐mediated mucosal inflammation, which is in line with the marked capacity of Prevotella in driving Th17 immune responses in vitro. Studies indicate that Prevotella predominantly activate Toll‐like receptor 2, leading to production of Th17‐polarizing cytokines by antigen‐presenting cells, including interleukin‐23 (IL‐23) and IL‐1. Furthermore, Prevotella stimulate epithelial cells to produce IL‐8, IL‐6 and CCL20, which can promote mucosal Th17 immune responses and neutrophil recruitment. Prevotella‐mediated mucosal inflammation leads to systemic dissemination of inflammatory mediators, bacteria and bacterial products, which in turn may affect systemic disease outcomes. Studies in mice support a causal role of Prevotella as colonization experiments promote clinical and inflammatory features of human disease. When compared with strict commensal bacteria, Prevotella exhibit increased inflammatory properties, as demonstrated by augmented release of inflammatory mediators from immune cells and various stromal cells. These findings indicate that some Prevotella strains may be clinically important pathobionts that can participate in human disease by promoting chronic inflammation.     

Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm.

The concept that airway inflammation leads to airway disease has led to a widening search for the types of cellular and molecular interactions responsible for linking the initial stimulus to the final abnormality in airway function. It has not yet been possible to integrate all of this information into a single model for the development of airway inflammation and remodeling, but a useful framework has been based on the behavior of the adaptive immune system. In that paradigm, an exaggeration of T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli leads to airway inflammatory disease, especially asthma. In this review, we summarize alternative evidence that the innate immune system, typified by actions of airway epithelial cells and macrophages, may also be specially programmed for antiviral defense and abnormally programmed in inflammatory disease. Furthermore, this abnormality may be inducible by paramyxoviral infection and, in the proper genetic background, may persist indefinitely. Taken together, we propose a new model that highlights specific interactions between epithelial, viral, and allergic components and so better explains the basis for airway immunity, inflammation, and remodeling in response to viral infection and the development of long-term disease phenotypes typical of asthma and other hypersecretory airway diseases.     

77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence for a genetic link

Autoimmune hepatitis is a chronic immune-mediated disease characterized by a loss of tolerance against liver resident antigens. The genetic background of autoimmune hepatitis is considered to be polygenic. Here we analyzed the genetic association of the tyrosine phosphatase CD45 and autoimmune hepatitis. CD45 plays an important role in normal antigen receptor mediated signaling in T and B cells. A point mutation at nucleotide position 77 of the CD45 gene results in abnormal CD45 splicing. In this study a significantly higher frequency of the 77 C/G genotype was observed in 190 autoimmune hepatitis patients when compared to 210 healthy blood donors. Our data identify CD45 as a gene associated with AIH, and further substantiates the hypothesis that CD45 represents a modifier gene of human autoimmunity.     

Genetics of immune‐mediated inflammatory diseases

Immune‐mediated inflammatory diseases (IMIDs) are characterized by dysregulation of the normal immune response, which leads to inflammation. Together, they account for a high disease burden in the population, given that they are usually chronic conditions with associated co‐morbidities. Examples include systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease and type 1 diabetes. Since the advent of genome‐wide association studies, evidence of considerable genetic overlap in the loci predisposing to a wide range of IMIDs has emerged. Understanding the genetic risk and extent of genetic overlap between IMIDs may help to determine which genes control which aspects of the different diseases; it may identify potential novel therapeutic targets for a number of these conditions, and/or it may facilitate repurposing existing therapies developed originally for different conditions. The findings show that autoantibody‐mediated autoimmune diseases cluster more closely with each other than autoantibody‐negative diseases such as psoriasis, psoriatic arthritis, Crohn's disease and ankylosing spondylitis which, instead, form a seronegative genetic cluster. The genetic clustering largely mirrors the known response to existing biological therapies, but apparent anomalies in treatment response are discussed.     

The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation

Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called ‘efferocytosis’. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released ‘damage associated molecular patterns’ (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections.     

The common genetic hypothesis of autoimmune/inflammatory disease

Individual inflammatory and autoimmune diseases are discrete clinical entities. The clinical presentation of any specific inflammatory disease is the culmination of complex interactions between genetics, primary and secondary immune effector mechanisms, and environmental triggers. Although often different in clinical presentation, common cellular and molecular immune pathways have been shown to be intimately involved in the destruction of different target tissues in different disease states, which ultimately defines specific diseases. At the genetic level, comparative genomic analysis of autoimmune and inflammatory disorders suggests shared genetic components for these clinically related diseases. This leads to a common genetic hypothesis which states that, unlike classical mendelian genetic disorders, common autoimmune and inflammatory disorders arise from combinatorial interactions of common non-disease specific loci, disease specific loci, and specific environmental triggers.     

The Th1/Th2 balance in autoimmunity

The study of autoimmune disease in the context of T-helper type 1 (Th1) and T-helper type 2 (Th2) CD4⁺ T-cell responses demonstrates that the relative contribution of either T-cell type to the development of a particular autoimmune response can influence whether or not this response leads to clinical disease. Moreover, this influence can be quite different depending on whether the particular disease process is cell mediated or antibody mediated. Recent studies have demonstrated that the development of Th1 and Th2 responses may be significantly influenced by the costimulatory molecules recognized by responding CD4 T cells, and by other undefined factors in the genetic background. It has also been demonstrated that autoreactive Th2 CD4⁺ cells can regulate the activity of disease-causing Th1 CD4⁺ T cells in vivo. Control of autoimmune disease may thus be achieved by procedures that regulate the relative contribution of Th1/Th2 CD4 T cells to an autoimmune response.     

Cutting Edge Issues in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease characterized by the destruction of medium- to large-sized bile ducts and intense concentric fibrosis. Complications from PSC include bacterial cholangitis, cirrhosis, and cholangiocarcinoma and a therapy that might alter the natural history of the disease remains lacking. Our understanding of the pathogenesis of PSC also remains rudimentary but the strong association between PSC and inflammatory bowel disease suggest causal links between the diseases. The male predominance in PSC, lack of a defined, pathogenic auto-antigen, and the potential role of the innate immune system suggest that PSC may be due to dysregulation of immunity rather than a classic autoimmune disease. However, PSC shares several genetic susceptibility loci with other autoimmune diseases including the human leukocyte antigen DRB01*03 haplotype. The precise immune response of PSC is largely unknown but likely involves activation of the innate immune system by bacterial components delivered to the liver via the portal vein. Induction of adhesion molecules and chemokines leads to the recruitment of intestinal lymphocytes. Bile duct injury results from the sustained inflammation and production of inflammatory cytokines. Biliary strictures may cause further damage as a result of bile stasis and recurrent secondary bacterial cholangitis. Progress in our basic understanding of PSC is desperately needed in order to rationally design new therapeutic approaches to this disease.     

Current multiple sclerosis treatments have improved our understanding of MS autoimmune pathogenesis

Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults. When MS is not treated, it leads to irreversible and severe disability. The etiology of MS and its pathogenesis are not fully understood. The recent discovery that MS‐associated genetic variants code for molecules related to the function of specific immune cell subsets is consistent with the concept of MS as a prototypic, T‐cell‐mediated autoimmune disease targeting the CNS. While the therapeutic efficacy of the currently available immunomodulatory therapies further strengthen this concept, differences observed in responses to MS treatment as well as additional clinical and imaging observations have also shown that the autoimmune pathogenesis underlying MS is much more complex than previously thought. There is therefore an unmet need for continued detailed phenotypic and functional analysis of disease‐relevant adaptive immune cells and tissues directly derived from MS patients to unravel the immune etiology of MS in its entire complexity. In this review, we will discuss the currently available MS treatment options and approved drugs, including how they have contributed to the understanding of the immune pathology of this autoimmune disease.     

Protective and Detrimental Roles for Regulatory T Cells in a Viral Model for Multiple Sclerosis

Multiple sclerosis (MS) has been proposed to be an immune‐mediated disease in the central nervous system (CNS) that can be triggered by virus infections. In Theiler's murine encephalomyelitis virus (TMEV) infection, during the first week (acute stage), mice develop polioencephalomyelitis. After 3 weeks (chronic stage), mice develop immune‐mediated demyelination with virus persistence, which has been used as a viral model for MS. Regulatory T cells (Tregs) can suppress inflammation, and have been suggested to be protective in immune‐mediated diseases, including MS. However, in virus‐induced inflammatory demyelination, although Tregs can suppress inflammation, preventing immune‐mediated pathology, Tregs may also suppress antiviral immune responses, leading to more active viral replication and/or persistence. To determine the role and potential translational usage of Tregs in MS, we treated TMEV‐infected mice with ex vivo generated induced Tregs (iTregs) on day 0 (early) or during the chronic stage (therapeutic). Early treatment worsened clinical signs during acute disease. The exacerbation of acute disease was associated with increased virus titers and decreased immune cell recruitment in the CNS. Therapeutic iTreg treatment reduced inflammatory demyelination during chronic disease. Immunologically, iTreg treatment increased interleukin‐10 production from B cells, CD4⁺ T cells and dendritic cells, which may contribute to the decreased CNS inflammation.     

Clinical and immunological parameters of Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic autoimmune disease that primarily affects the exocrine glands, resulting in their functional impairment. In SS, lymphocytic infiltration of salivary and lacrimal glands, and deposition of several types of autoantibodies, mainly anti-SS-A (anti-Ro) and anti-SS-B (anti-La), lead to chronic inflammation, with xerostomia and keratoconjunctivitis sicca. In its primary form (pSS), SS does not involve additional connective tissue diseases, whereas in its secondary and more common form (sSS), SS presents in association with other rheumatic autoimmune diseases, mainly rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). As in most autoimmune diseases, environmental, hormonal and genetic factors are implicated in SS pathogenesis. In SS T cells predominate in mild lesions, whereas B cells predominate in advanced lesions. Th1, Th2, Th17, follicular helper T (Tfh) cells and regulatory cells (Tregs/Bregs), with their characteristic cytokine profiles, have been implicated in the pathogenesis of SS. It has been suggested that Th1 and Th17 cells initiate SS and, as the disease progresses, Th2 and Tfh cells predominate. It is assumed that, as in all autoimmune and inflammatory conditions, tolerance defects contribute to SS pathogenesis. It is intriguing that in SS it remains unclear which types of regulatory cells are functional and whether they ameliorate or worsen the disease. In this review we present a comprehensive update on SS with emphasis on immune system involvement, and suggest new insights into SS immunopathogenesis.     

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.     

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.     

Asthma as a paradigm for autoimmune disease

Allergy and autoimmunity result from dysregulation of the immune system. Until recently, it was generally accepted that the mechanisms that govern these disease processes are quite disparate; however, new discoveries suggest possible common pathogenetic effector pathways. This review illustrates the concomitant presentation of these conditions and the potential relationship or common mechanisms in some cases, by looking at the key elements that regulate the immune response in both asthma and autoimmune conditions: mast cells, antibodies, T cells, cytokines, and genetic determinants. The parallel appearance of asthma and autoimmune conditions in the same patients may reveal that such aberrations of the immune system have a common pathophysiologic mechanism. Mast cells, which play a key role in asthma, and the wealth of inflammatory mediators they express, make it likely that they have profound effects on many autoimmune processes. Activation of protein kinases by inflammatory cytokines and environmental stresses may contribute to both allergic and autoimmune diseases. The presence of autoantibodies in some allergic diseases suggests an autoimmune basis for these conditions. Because of the central role T cells play in immune reactivity, the T cell receptor loci have long been considered important candidates for a common disease susceptibility within the immune system such as asthma, atopy, and autoimmunity. Immunomodulation is the key to successful treatment of asthma and autoimmune conditions.     

A genetic basis for shared autoimmunity in mouse models

Development of autoimmune disease is the result of activation of the immune system that subsequently leads to tissue destruction. Although the clinical outcome significantly differs between autoimmune diseases, some pathogenic pathways could be shared. During the recent years, intense efforts to find the genetic factors behind development of the complex and polygenic autoimmune diseases have been undertaken. The difficulties in addressing what genetic factors predispose for autoimmunity in humans underline the importance of animal models in the understanding of the general mechanisms behind the initiation of disease. Interestingly, it has been observed in studies of experimental models of autoimmune diseases, that many of the genetic linkages to disease development are located in the same genetic regions and potentially could be controlled by the same gene. Furthermore, comparison of the mouse/rat genetic regions with regions of association to human inflammatory diseases, also demonstrates some homologous loci between species. Some mouse strains can develop disease in more than one model for autoimmunity. This not only argues for some general mechanisms, but it also supports mechanisms related to the specific tissues attacked in the various autoimmune diseases. Here, we will discuss some aspects of shared autoimmunity in mouse models from a genetic point of view.