B cells as a therapeutic target in autoimmune disease (original) (raw)
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B-Cell Depletion and Repopulation in Autoimmune Diseases
Clinical Reviews in Allergy & Immunology, 2008
Although T-lymphocytes have long been regarded as the prime effector of autoimmune diseases, numerous studies have since highlighted a key role for Blymphocytes. For example, disturbances in the distribution of circulating B-cell subsets were reported in primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Consequently, this was the rationale to treat such patients for B-cell depletion with anti-CD20 monoclonal antibody (rituximab). The aim of this review is to describe and analyze the B-cell subset distribution at baseline and after rituximab therapy in patients with SLE, rheumatoid arthritis, and pSS. Finally, we will compare factors that may interfere with anti-CD20-mediated B-cell depletion in these autoimmune diseases.
B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis
Rheumatology
Selective B-cell depletion with anti-CD20 therapy is a promising novel treatment option for patients with refractory autoimmune disease. The anti-CD20 antibody, rituximab, is the first therapeutic monoclonal antibody to have been approved by the European Medical Agency (EMEA) and the US Food and Drug Administration (FDA) for the treatment of relapsed, low-grade, follicular non-Hodgkin's lymphoma. Rituximab is now being studied in a range of autoimmune diseases, most notably rheumatoid arthritis, but also chronic immune thrombocytopenic purpura and systemic lupus erythematosus. Current data obtained from studies of rituximab single-agent therapy for autoimmune disease show good tolerability and sustained improvement in disease symptoms, although the precise mechanisms of action in autoimmunity remain to be fully clarified. Future research is likely to be focused on the optimization of responses with rituximab-based therapy. However, early observations suggest that this approach is likely to yield significant clinical benefits in a wide range of organ-specific and systemic autoimmune diseases.
B cell-targeted therapies in autoimmunity: rationale and progress
F1000 biology reports, 2009
B cells are recognized as main actors in the autoimmune process. Autoreactive B cells can arise in the bone marrow or in the periphery and, if not properly inhibited or eliminated, can lead to autoimmune diseases through several mechanisms: autoantibody production and immune complex formation, cytokine and chemokine synthesis, antigen presentation, T cell activation, and ectopic lymphogenesis. The availability of agents capable of depleting B cells (that is, anti-CD20 and anti-CD22 monoclonal antibodies) or targeting B cell survival factors (atacicept and belimumab) opens new perspectives in the treatment of diseases such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis.
Recent Progress in the Understanding of B-Cell Functions in Autoimmunity
Scandinavian Journal of Immunology, 2001
Our early concepts of the normal role of B cells in immunity focused on their ability to produce antibodies (Ab) and in the case of autoimmune diseases autoAbs, some of which were pathogenic. Over the past 10 years, it has became apparent that B cells display a variety of characteristics, other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating T-cell subsets and dendritic cell (DC) function through cytokine production, and in activation of T cells. Receptors editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Transgenic animal models have now shown that B cells are necessary for many autoimmune diseases although their Ab products are not required in some cases. Negative signalling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domaincontaining protein tyrosine phosphatase-1 has also been documented. In fact, we have now reached a new era whereby the B cell has returned as an important contributor to autoimmune disorders, so that the race is on to characterize signalling regulation via the B-cell receptor and coreceptors. Identification of such molecules and their potential defects should lead to effective ways of controlling the immune response and in particular preventing the development of autoimmune states. The classical view of B cells in the biology of immune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing Ab turns out to be rather naõ Ève. Indeed, studies over the last few years indicate that this view is far from complete, and suggest that B lymphocytes have extraordinarily diverse functions within the immune system. Furthermore, it is becoming increasingly clear that the pathogenesis of autoimmune diseases cannot solely be accounted for by T cells, and intrinsic abnormalities of B cells have been described in such conditions. In this brief review we highlight some recent observations in the context of B lymphocyte in pathophysiology, and focus on their revival as pivotal players the pathophysiology in autoimmune diseases. Yet, it remains difficult to provide a model of how important B cells are in immunity and autoimmunity.
B cells as effectors and regulators of autoimmunity
Autoimmunity, 2012
A classic understanding of the interplay between B and T cell components of the immune system that drive autoimmunity, where B cells provide an effector function, is represented by systemic lupus erythematosus (SLE), an autoimmune condition characterised by the production of auto-antibodies. In SLE, CD4 þ T cells provide cognate help to self-reactive B cells, which in turn produce pathogenic auto-antibodies (1). Thus, B cells act as effectors by producing auto-antibody aided by T cell help such that B and T cell interactions are unidirectional. However, this paradigm of B and T cell interactions is challenged by new clinical data demonstrating that B cell depletion is effective for T cell mediated autoimmune diseases including type I diabetes mellitus (T1D) (2), rheumatoid arthritis , and multiple sclerosis (4). These clinical data indicate a model whereby B cells can influence the developing autoimmune T cell response, and therefore act as effectors, in ways that extend beyond the production of autoantibody (5). In this review by largely focusing on type I diabetes we will develop a hypothesis that bi-directional B and T interactions control the course of autoimmunity.
B-lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders
Biochemical Society Transactions, 2001
B-lymphocyte depletion therapy is being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not been a major problem. T h e mechanism of action is unclear, but appears to be consistent with the lowering of autoantibody levels, where relevant antibodies are quantifiable. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-lymphocyte subsets may be a rate-limiting step in pathogenesis.
BioMed research international, 2014
Autoimmunity remains a complex physiologic deviation, enabled and perpetuated by a variety of interplayers and pathways. Simplistic approaches, targeting either isolated end-effectors of more centrally placed interactors of these mechanisms, are continuously tried in an effort to comprehend and halt cascades with potential disabling and deleterious effects in the affected individuals. This review focuses on theoretical and clinically proved effects of rituximab-induced CD20+ B cell depletion on different systemic autoimmune diseases and extrapolates on pathogenetic mechanisms that may account for different interindividual or interdisease responses.
B lymphocytes on the front line of autoimmunity
Autoimmunity Reviews, 2006
The paradigm that B cell response to self antigens (Ag) is promoted by antibodies (Ab) has become unsatisfactory. Studies over the last decade have indeed revealed that B cells serve extraordinarily diverse functions within the immune system other than Ab production. They normally play a role in the development in the regulation, as well as the activation of lymphoid architecture, regulating dentritic cells and T cell subsets function through cytokine production. Receptor editing is also essential in B cells and aids in preventing autoimmunity. Both abnormalities in the distribution of B cells subsets and clinical benefit response to B cell depletion in autoimmune states illustrate their importance. Transgenic animal models have demonstrated that sensitivity of B cells to Ag receptor cross-linking correlates to autoimmunity: negative signaling by CD5 and CD22 in maintaining tolerance through recruitment of phosphatase has thus been documented. In short, a new area has been reached, whereby B lymphocytes return as a significant contributor to autoimmune disorders. D
B cell depletion therapy in systemic rheumatic diseases: Different strokes for different folks?
Clinical Immunology, 2006
Autoantibodies have, until recently, been the overriding focus of investigators of autoantibody-associated diseases. Increasing attention is now being paid to B cells, which not only are the producers of autoantibodies but also contribute to autoimmune disease via autoantibody-independent mechanisms. Therapeutic measures that target B cells for depletion are gaining in popularity. In this review, we will focus on two distinct approaches of depleting B cells; one employing a direct-kill approach by engagement of B cell surface CD20 with an anti-CD20 monoclonal antibody (rituximab), and the other employing an indirect starvation approach by neutralization of B lymphocyte stimulator (BLyS), a potent B cell survival factor. Among the systemic immune-based rheumatic disorders, we will focus on rheumatoid arthritis and systemic lupus erythematosus, two disorders for which therapeutic B cell targeting is being intensely investigated.