ACHAIKI IATRIKI | 2022; 41(4):203–210
Review
Stamatis-Nick Liossis, Foteini Angelopoulou
Department of Rheumatology, University of Patras Medical School and Patras University Hospital, Patras, Greece
Received: 09 Apr 2022; Accepted: 03 Jun 2022
Corresponding author: Stamatis-Nick Liossis Department of Internal Medicine, Division of Rheumatology, University of Patras Medical School, 26504, Rion, Patras, Greece, Tel.: +30 2613 603 693, Fax: +30 2610-993 98, E-mail: snliossis@med.upatras.gr
Key words: B lymphocytes, Autoimmune diseases, Systemic sclerosis, Rheumatoid arthritis, Systemic lupus erythematosus.
Abstract
B lymphocytes are the effector cells of humoral immunity. Their multifaceted role spans from antibody and cytokine production to antigen presentation and T cell activation. Disturbances in their developmental pathways can have detrimental consequences as demonstrated by the complex molecular and clinical phenotypes of several autoimmune diseases. In recent years, the antibody-independent role of B cells in conditions classically thought of as T cell mediated has been supported by the successful implementation of B cell depletion therapies. Herein, we review the role of B cells in three autoimmune diseases: Systemic Lupus Erythematosus, Rheumatoid Arthritis and Systemic Sclerosis.
B CELL DEVELOPMENT AND MATURATION
The first indication of the existence of a cell population charged with antibody production was given by von Behring and Kitasato in 1890 when they remarked that circulating “antitoxins” where important for tetanus and diphtheria immunity [1]. It was nearly 80 years later that Max Cooper and Robert Good using a chicken animal model proved that cells derived from the bursa of Fabricius (the chicken equivalent of bone marrow) were responsible for antibody production while a different population of cells derived from the thymus mediated delayed-type hypersensitivity responses [2]. Since then, B lymphocytes have been the object of exciting research.
There are three well-characterized subpopulations of B cells. B1 cells that are produced in the fetal liver, have a distinct developmental process, self-renewing ability and are responsible for the majority of natural antibody production [3-5]. They have innate-like features and home mainly in the pleural and peritoneal cavity. B2 cells that are derived from multipotent hemopoietic stem cells in the bone marrow and subsequently migrate to secondary lymphoid organs (lymph nodes) where they mature and become activated via interaction with antigens. In 2002 a new B cell population was described, characterized as regulatory B cells, capable of producing the anti-inflammatory IL-10 [6]. This subset was able to suppress inflammatory responses in experimental murine models of collagen-induced arthritis and autoimmune encephalitis [7,8]. A critical step in B cell development is the B cell receptor generation. This is achieved by a complex process involving continuous gene segment rearrangement of the Ig heavy and light chain loci. B cells have the ability during their development to rearrange the V, D and J gene segments in the heavy chain locus and V, J gene segments in the light chain locus [9-11]. This mechanism is utilized in class switching and affinity maturation of B cell receptors. Antigen receptor gene rearrangement ensures diversity in the receptor repertoire of B cells and therefore sufficient immunity against a variety of different pathogens, such as viruses, bacteria etc. It is also one of the mechanisms employed to avert self-reactive cells. Taking into account the wide variety of the produced antigenic receptors that guarantee an adequate immune response, it is only logical and statistically probable that a portion of them would recognize self-antigens. In order to avert self-reactivity a network of sophisticated mechanisms is employed for the silencing of self-reactive B cells. Self-reactive B cells can be silenced either during their development in the bone marrow (central tolerance), or during their maturation and activation in peripheral lymphoid organs (peripheral tolerance). Central tolerance is ensured by three mechanisms: Clonal deletion, clonal anergy and receptor editing. The strong recognition of a self-antigen present at a high concentration in the bone marrow induces either cellular death by apoptosis (clonal deletion) or a light chain recombination resulting in a new, possibly not self-reactive receptor (receptor editing). The inability to exert effector functions (clonal anergy) is induced by BCR activation without concurrent co-stimulatory receptor activation. About 20% of moderately auto-reactive B cells still manage to migrate to the periphery, where they become anergic or undergo cellular death (apoptosis) [12,13]. When immune tolerance is breached, interaction with the correspondent self-antigens initiates an inflammatory response and its consequences, destruction of healthy tissues and organs. B cells are the driving force in five pathological processes involved in autoimmunity: autoantibody production, processing and presentation of autoantigens to autoreactive T-cells, inflammatory cytokine production and development of ectopic tertiary lymphoid structures.
In this paper we aim to summarize the direct and indirect role of B cells in three autoimmune disorders: systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis.
SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic Lupus Erythematosus (SLE) is considered as the model for systemic autoimmunity. It is a multifactorial disease associated with significant morbidity and mortality and up today presents a therapeutic challenge for the practicing physician. It primarily affects women of child-bearing age, of Hispanic and African American ancestry, and its clinical presentation can be highly heterogenous, affecting multiple systems [14]. Despite its varying phenotype and multiple hypothesized pathophysiological pathways involved, intrinsic B cell dysregulation appears to be a common denominator in both human and animal models.
The extensive repertoire of (auto) antibodies against a multitude of self-antigens is a hallmark of the condition, with antinuclear antibodies being an almost universal characteristic [15-17]. Of note, anti-dsDNA and anti-Sm antibodies to this day remain part of the ACR criteria for SLE diagnosis [18]. A portion of these autoantibodies exert a well-established pathogenetic role and are directly linked to specific clinical manifestations and phenotypes of the disease.
Autoantibodies against antigens of red blood cells may cause autoimmune hemolytic anemia [19,20]. Certain anti-DNA antibodies cross react with NMDA receptors in the central nervous system and are able to breach the blood-brain barrier causing neuronal cell death in murine models [21]. In SLE patients, anti-NMDA-R antibodies have been associated with neurocognitive defects [22]. When anti-Ro antibodies are present in the sera of pregnant SLE patients, they can cause congenital heart block in approximately 2% of neonates [23]. Antibodies against phospholipids and β2-glycoprotein are associated with thrombotic events and recurrent miscarriages, a clinical entity known as antiphospholipid syndrome [24].
Autoantibodies also yield their noxious capacity via the formation and deposition of immune complexes. One of the most severe and life-threatening manifestations of SLE, lupus nephritis, could be instigated by the deposition of immune complexes and subsequent inflammatory cascade and tissue injury [25-27]. While evidence to fully delineate the multifaceted role of B cells in human SLE is circumstantial and occasionally contradictory, animal model studies provide considerably more consistent results. Murine models particularly have been crucial in underscoring the antibody-independent functions of B cells in autoimmunity. MRL/lpr mice are a model for systemic autoimmunity with a clinical phenotype resembling SLE and similar antibody profile, with anti-ds DNA antibodies. In 1994, Schlomchik et al proved that when made B cell deficient, these mice did not exhibit any sign of autoimmune glomerulonephritis or vasculitis, and as expected, lacked autoantibodies. Additionally, T cell activation was remarkably diminished, highlighting the necessity of B cell-T cell interaction for optimal cellular immune responses [28].
Chan et al later used the same murine model to demonstrate that when B cells were genetically engineered to express surface Ig but not secret soluble immunoglobulins, disease expression was not attenuated, with the mice developing severe nephritis and vasculitis, providing further proof that antibody-independent B cell functions contribute to disease expression [29]. In an attempt to further elucidate the mechanisms behind the breach of immune tolerance, characterization of the surface molecular phenotype of B lymphocytes became of great interest, thus providing invaluable information about peripheral blood composition of B cell subsets. Firstly, there seems to be an expansion of plasma and memory B cell compartments, while peripheral naive B cells are consistently reduced [30-33]. Circulating plasma cell levels have also been strongly associated with disease activity and anti-dsDNA antibody titers [34]. Of note, the FcγRIIb inhibitory receptor is underexpressed in SLE memory B cells, leading to a lower threshold of reactivation and ensuing differentiation into antibody secreting cells [35].
Regulatory B cells have also been found functionally impaired, unable to suppress T helper cell proliferation in SLE. While murine models suggest reduced levels of IL-10 as the resulting malfunction of regulatory B cell impairment [36,37], human studies indicate that IL-10 enhances rather than suppresses disease expression, thus creating yet another conundrum [38-40].
A recently discovered subset of B cells, referred to as Age Related B cells (ABCs) has been the focus of great interest. ABCs were initially thought of as an antigen-experienced, exhausted phenotype associated with normal senescence and inflammation such as autoimmunity and infections [41-44]. Exhaustive studies have further classified the nature of these cells, depending on surface marker expression and transcriptional signatures. Specifically, CD11hiTbet+ B cells, a population expanded in SLE but not healthy elders, shares many of ABCs key features, such as their antigen presentation capacity and their ability to differentiate into antibody secreting cells [45,46]. Interestingly, the expansion of this population has also been associated with increased disease activity scores and antinuclear antibody titers [45]. Further studies are required to illuminate their cryptic role, origin and developmental pathways.
The immunopathogenic role of B-cell derived cytokines has also been extensively studied in lupus, offering useful insights into the complex pathways leading to the breach of self-tolerance. Aberrant IL-6 production by lupus B cells drives their terminal differentiation into antibody secreting cells and induces further IL-6 production, creating a positive feedback loop [47]. Supporting this finding, IL-6 receptor blockade significantly suppresses auto-antibody secretion in human lupus B cells, while lupus-prone mice treated with anti-IL-6 monoclonal antibodies display substantially mitigated kidney disease and antibody production [48]. IL-4, IL-21, IFN-γ, TGF-β and lymphotoxin α produced by B cells also exert pathogenic roles in the propagation of inflammation and tissue injury [49,50].
The pivotal role of B cell dysregulation in the cellular and molecular events leading to the eventual presentation of lupus is showcased by the central role of B depletion therapies in our therapeutic armamentarium in recent years. Despite the failure of large clinical trials to exhibit therapeutic effect [51], Rituximab, an anti-CD20 monoclonal antibody is, to this day, successfully used in life-threatening presentations and refractory disease. Further investigation into the aberrant developmental pathways and infringement on self-tolerance checkpoints of B cells is required in order to guide individualized treatment and minimize adverse events.
SYSTEMIC SCLEROSIS
Systemic sclerosis (SSc) is an heterogenous systemic autoimmune disease characterized by the excessive production and deposition of extracellular matrix in the skin and visceral organs such as the oesophagus, lower gastrointestinal track, heart and lungs, resulting in phenotypic variation [52]. Autoantibodies is a central feature of the disease, with antinuclear antibodies being present in >90% of patients [53]. Hypergammaglobulinemia and polyclonal B cell hyperactivity have also been well documented laboratory characteristics of SSc patients [54]. A direct link between autoimmunity and fibrosis, however, is yet to be discovered. Autoantibodies associated with SSc include anti-topoisomerase I abs, anti -RNA polymerase abs, anticentromere antibodies or anti-Th/To Ab [55,56]. However, autoantibodies have not been directly linked to fibrosis. This finding is supported by the two most accurate mouse models for SSc at our disposal, the tight skin (TSK/+) mouse and the Bleomycin (BLM) treated mouse. The tight skin mouse is the product of a tandem mutation in the fibrillin-1 gene resulting in a fibrotic phenotype resembling SSc, with subcutaneous inflammatory infiltration and fibrosis and lung emphysema [57].
Bleomycin is an antibiotic used widely as a chemotherapeutic agent that, when injected subcutaneously in mice, causes lung fibrosis, dermal inflammatory infiltration and fibrosis as well as autoantibody production [58]. A recently described feature of SSc is the expansion of naive B cell populations while memory B cells as well as plasmablasts/ plasma cell precursor populations are diminished due to enhanced apoptosis. However, despite their reduced number, SSc memory B lymphocytes were found chronically activated in vivo, with an increased capacity to produce autoantibodies [59].
B regulatory cells, a subpopulation that produces the anti-inflammatory IL-10, were also shrinked, and serum IL-10 levels reduced compared to healthy controls [60]. Another well described phenotypic change in peripheral SSc B cells is the over expression and increased phosphorylation of the positive signal modulator CD19 [61,62]. CD19 is a transmembrane protein widely expressed in all stages of B cell development that can decrease the threshold for BCR activation [63]. When CD19 expression was studied in TSK/+ mice it was found unaltered compared to wild type mice. However, CD19 phosphorylation was indeed increased and CD19 mediated intracellular signaling was enhanced early in B cell activation leading to the conclusion that TSK/+ mice B cells are indeed chronically activated [64,65]. Additionally, CD19 loss in TSK/+ completely abrogated hypergammaglobulinemia and autoantibody production, while it ameliorated skin fibrosis [64]. Additionally, CD22, a negative regulatory molecule that increases the threshold for B cell activation preventing aberrant immune responses, is under-expressed in SSc B cells [65].
Cytokine production, another important capacity, also appears to be impaired in systemic sclerosis, with overwhelming evidence supporting the overproduction of pro-inflammatory, profibrogenic cytokines such as IL-6 and TGF-b. Increase of the pro-inflammatory IL-6 in the sera of patients with systemic sclerosis, compared to healthy controls has also been well documented and is associated with the extend of dermal fibrosis [66,67]. Finally, direct B cell-fibroblast interaction has also been described. It has been proven by in vitro experiments, that direct B cell-fibroblast contact is needed for the stimulation of fibroblasts and the excess production of collagen. Lastly, the effectiveness of B cell depletion therapies in the treatment of systemic sclerosis, especially lung involvement, is a testament to the true extent of B cell involvement in SSc pathogenesis [68].
RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetric inflammatory polyarthritis leading to progressive bone and cartilage erosion, that can often be accompanied by extra-articular manifestations, such as subcutaneous rheumatoid nodules, sicca syndrome, peripheral neuropathy and pulmonary interstitial fibrosis. Its pathogenesis is complex and driven by many simultaneous pathological processes [69]. Many immune cells such as T lymphocytes, macrophages and B cells are involved in the synovial inflammatory process.
B cells were first implicated in the pathogenesis of RA as the producers of the autoantibodies RF and anti-CCP, that have served as excellent diagnostic and predictive biomarkers [70]. Rheumatoid factor is an autoantibody against the Fc portion of IgG and anti-CCPs are directed against peptides and proteins that have been post-translationally modified by a process called citrullination. Citrullination is the conversion of arginine into citrulline by a cluster of enzymes called arginine deiminases [71]. Although RF is not exclusive to RA and can present in other autoimmune diseases, infections as well as approximately 10% of healthy individuals, high titers of RF have been associated with clinically and radiographically more severe disease, functional impairment and extra-articular manifestations [72]. A wide variety of other autoantibodies have since been associated with RA including but not limited to antibodies against type II collagen, immunoglobulin-binding protein, rheumatoid arthritis- associated autoantigen hnRNP-A2 (RA33), glucose-6- phosphate isomerase (GPI), and calp statin [73-76]. Despite the fact that their contribution to synovial inflammation has been elegantly demonstrated in animal models, such as the collagen-induced arthritis murine model and the K/B-N model, it still remains unclear in human disease [77].
As we have already mentioned, B cells serve as excellent antigen-presenting cells, especially in low-concentration antigens. Specifically in RA, RF+ B cells take up RF-containing immunocomplexes via their antigenic receptors and proceed to process and present antigens to T helper cells, thus orchestrating a stronger and more effective adaptive immune response [78]. B cells are also thought to be crucial for synovial lymphoneogenesis. Ectopic follicle-like synovial structures rich in B cells, T cells, macrophages and FDCs with a follicle-like architecture and germinal centers have been found in approximately 25% of RA patients. Takemura et al studied synovial biopsies from RA patients undergoing joint replacement surgery [79]. They were able to distinguish three distinct patterns: diffuse infiltration of B cells, T cells, dendritic cells and macrophages lacking structure, B- and T-cell infiltrates resembling secondary follicles with germinal centers and B-, T- cell aggregates lacking germinal centers. Furthermore, they found actively proliferating B cells and follicular dendritic cell networks only in the aggregates containing germinal centers. Similarly, Humby et al also found three histological patterns a lympho-myeloid pattern with a B cell predominance, a diffuse myeloid-lineage infiltration pattern with low B cell counts and a pauci-immune with a prevalent stromal cell presence [80]. In addition to the aforementioned autoantibody production, antigen presentation and contribution to lymph neogenesis, B cells also produce cytokines that propagate the inflammatory process such IL-6, IL-10 and lymphotoxin β, providing a positive reinforcement circuit for optimal T-cell/macrophage activation [81]. Although, their role is not fully elucidated, the successful treatment of RA with B cell depletion therapies is a strong indicator that B cells are one of the driving forces behind the aberrant synovial immune response.
CONCLUSION
B cells were brought to the spotlight as the producer cells of antibodies. Their role however, proved to be substantially more intricate. That is masterfully demonstrated by the catastrophic results of the disruption of their homeostasis (Table 1). Their functional repertoire spans from antigen presentation and T cell activation to pro- and anti-inflammatory cytokine production. Their study continues to yield exciting new results. B lymphocyte dysregulation has been discovered in classically considered T cell mediated autoimmune diseases, something that is highlighted by the successful implementation of B cell depletion therapies.
Conflict of interest disclosure
None to declare
Declaration of funding sources
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Author Contributions
FA performed the literature search, extracted data from the retrieved articles, analyzed the data and participated in manuscript drafting; SNL conceived the idea and designed the study, extracted data from the retrieved articles, analyzed the data and participated in manuscript drafting. Both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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