B Cells in Health and Disease

B cells play a key role in regulating the immune system by producing antibodies, acting as antigen-presenting cells, providing support to other mononuclear cells, and contributing directly to inflammatory pathways. Accumulating evidence points to disruption of these tightly regulated processes in the pathogenesis of autoimmune disorders. Although the exact mechanisms involved remain to be elucidated, a fundamental feature of many autoimmune disorders is a loss of B-cell tolerance and the inappropriate production of autoantibodies. Dysfunctional immune responses resulting from genetic mutations that cause intrinsic B-cell abnormalities and induction of autoimmunity in the T-cell compartment by B cells that have broken tolerance may also contribute to these disorders. These findings provide the rationale for B-cell depletion as a potential therapeutic strategy in autoimmune disorders and other disease states characterized by inappropriate immune responses. Preliminary results with the CD20-targeted monoclonal antibody rituximab indicate that rituximab can improve symptoms in a number of autoimmune and neurologic disorders (including rheumatoid arthritis, systemic lupus erythematosus, and paraneoplastic neurologic syndromes). Additional studies are warranted to further characterize the role of B cells in autoimmune diseases and the therapeutic utility of B-cell depletion. B cells play a key role in regulating the immune system by producing antibodies, acting as antigen-presenting cells, providing support to other mononuclear cells, and contributing directly to inflammatory pathways. Accumulating evidence points to disruption of these tightly regulated processes in the pathogenesis of autoimmune disorders. Although the exact mechanisms involved remain to be elucidated, a fundamental feature of many autoimmune disorders is a loss of B-cell tolerance and the inappropriate production of autoantibodies. Dysfunctional immune responses resulting from genetic mutations that cause intrinsic B-cell abnormalities and induction of autoimmunity in the T-cell compartment by B cells that have broken tolerance may also contribute to these disorders. These findings provide the rationale for B-cell depletion as a potential therapeutic strategy in autoimmune disorders and other disease states characterized by inappropriate immune responses. Preliminary results with the CD20-targeted monoclonal antibody rituximab indicate that rituximab can improve symptoms in a number of autoimmune and neurologic disorders (including rheumatoid arthritis, systemic lupus erythematosus, and paraneoplastic neurologic syndromes). Additional studies are warranted to further characterize the role of B cells in autoimmune diseases and the therapeutic utility of B-cell depletion. A fully functional immune system is essential for self-preservation and good health. Healthy immune responses have several key defining attributes, including specificity in recognition of foreign bodies or antigen and mobilization of an appropriate response. A healthy immune system has a highly discriminative ability to recognize “self” from “nonself,” is able to respond vigorously on initial encounter to a pathogenic antigen, and uses memory to increase the speed of subsequent responses to antigens that have been encountered previously. The system must also be self-limiting for normal immune responses. Immune responses are orchestrated by a complex, continually evolving cooperative network of mobile cells and their products.1Delves PJ Roitt IM The immune system: first of two parts.N Engl J Med. 2000; 343: 37-49Crossref PubMed Scopus (658) Google Scholar, 2Delves PJ Roitt IM The immune system: second of two parts.N Engl J Med. 2000; 343: 108-117Crossref PubMed Scopus (355) Google Scholar The high degree of complexity and inter-dependency among the many components of the immune system is such that it is possible for dysfunction to occur as a result of either an identifiable insult or an unknown trigger. Consequently, not all immune responses are protective; some can result in inflammatory processes, tissue destruction, and the development of autoimmune disease.3Davidson A Diamond B Autoimmune diseases.N Engl J Med. 2001; 345: 340-350Crossref PubMed Scopus (868) Google Scholar Our understanding of the mechanisms involved in normal immune responses has increased substantially during the past 2 decades. One of the most important insights to emerge has been an increased appreciation of the roles that B cells play in regulating the immune system in the preservation of health. In addition to producing antibodies, critical immunoregulatory roles for B cells have been described, including direct effects on the behavior of other cells in the immune system4Hodgkin PD Basten A B cell activation, tolerance and antigen-presenting function.Curr Opin Immunol. 1995; 7: 121-129Crossref PubMed Scopus (60) Google Scholar or indirect effects through antigen presentation and the production of cytokines.5Lund FE Garvy BA Randall TD Harris DP Regulatory roles for cytokine-producing B cells in infection and autoimmune disease.Curr Dir Autoimmun. 2005; 8: 25-54Crossref PubMed Google Scholar, 6Chan OT Hannum LG Haberman AM Madaio MP Shlomchik MJ A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus.J Exp Med. 1999; 189: 1639-1648Crossref PubMed Scopus (599) Google Scholar, 7Martin F Chan AC Pathogenic roles of B cells in human autoimmunity; insights from the clinic.Immunity. 2004; 20: 517-527Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar Furthermore, data from animal models demonstrate that autoimmune B cells can drive responses when none should occur, resulting in disease. Elucidation of the pathways of B-cell activation raises the possibility of targeting B cells in the treatment of autoimmune disorders such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), and autoimmune neurologic disorders.8Carter RH B cell signalling as therapeutic target.Ann Rheum Dis. 2004; 63: ii65-ii66Crossref PubMed Scopus (3) Google Scholar, 9Carter RH B cells: new ways to inhibit their function in rheumatoid arthritis.Curr Rheumatol Rep. 2004; 6: 357-363Crossref PubMed Scopus (1) Google Scholar, 10Smolen JS Steiner G Therapeutic strategies for rheumatoid arthritis.Nat Rev Drug Discov. 2003; 2: 473-488Crossref PubMed Scopus (683) Google Scholar This review examines the characteristics of B cells, including their proliferation and differentiation, and their functions in maintaining overall health. Possible mechanisms by which disordered B-cell functions can contribute to autoimmune responses and disease are discussed. Finally, the case for investigating B cells as a therapeutic target in autoimmune disease and evidence of the therapeutic benefits of B-cell depletion in autoimmune disorders are summarized. Lymphocytes and antigen-presenting cells (APCs) constitute the adaptive immune system that responds to specific immune challenges, such as foreign microorganisms, and also have the potential for autoimmunity.11Goldsby RA Kindt TJ Osborne BA Kuby Immunology. 4th ed. W. H. Freeman and Co, New York, NY2000Google Scholar, 12Parslow TG The immune response.in: Parslow TG Stites DP Terr AI Imboden JB Medical Immunology. 10th ed. McGraw-Hill, New York, NY2001: 66-71Google Scholar B lymphocytes are derived from the bone marrow, and they mature through sequential, programmed steps (Figure 1). Hematopoietic stem cells in the bone marrow mature into pro-B cells, pre-B cells, and then immature B cells. These cells enter the blood as transitional B cells and migrate to secondarylymphoid organs. The cells that survive past this stage become naive B cells in the periphery. Some peripheral B cells appear poised to mount a rapid but low-affinity antibody response to typical bacterial antigens, such as cell wall components. Other B cells, particularly after exposure to protein antigens, require T-cell help, generally in a structure called the germinal center, where B cells that express higher-affinity antibodies are selected and expand. Both the rapid antibody response and the T-cell-dependent pathways are regulated by APCs of different lineages. The B-cell products of the germinal center may differentiate into memory B cells or via plasmablasts into antibody-producing plasma cells. Plasma cells produce and secrete soluble antibody that is reactive with the activating antigen, whereas memory B cells carry membrane-bound antibody and are poised to mount a rapid and heightened response to subsequent antigen exposure.11Goldsby RA Kindt TJ Osborne BA Kuby Immunology. 4th ed. W. H. Freeman and Co, New York, NY2000Google Scholar Terminally differentiated plasma cells may survive and produce antibody in the bone marrow for years. However, the relationship among plasmablasts, memory B cells, and long-lived plasma cells remains obscure. Clonal selection of B cells occurs during differentiation, with each clone expressing a specific antibody molecule in a membrane form (although there are exceptions). Clonal selection underpins immunobiologic memory and allows expansion of the relevant clone when reexposure to a specific antigen occurs. To cope with the challenge of a potentially limitless number of antigens, a correspondingly large number of clones are required to maintain health. This is achievable because the genes in lymphocytes that code for antigen receptor proteins can combine in a vast number of arrangements.11Goldsby RA Kindt TJ Osborne BA Kuby Immunology. 4th ed. W. H. Freeman and Co, New York, NY2000Google Scholar Additional antibody diversification occurs via somatic mutation of antibody during clonal expansion in the periphery, which appears to occur at a high frequency.14McKean D Huppi K Bell M Staudt L Gerhard W Weigert M Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin.Proc Natl Acad Sci U S A. 1984; 81: 3180-3184Crossref PubMed Scopus (405) Google Scholar, 15Brard F Shannon M Prak EL Litwin S Weigert M Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice.J Exp Med. 1999; 190: 691-704Crossref PubMed Scopus (109) Google Scholar However, these processes also generate self-reactive molecules, creating a potential problem. The immune system has evolved such that the binding of antigen, whether self or foreign, to the membrane form of immunoglobulin (which serves as the antigen recognition receptor for the B cell) is insufficient to induce the B cell to produce antibody. Rather, the B cell must receive additional activation signals, such as binding of cytokines, ligation of costimulatory receptors on the B cell by counter receptors on activated T cells, or binding of receptors on B cells (eg, Toll-like receptors), that recognize molecular motifs specific to certain types of pathogens. Only then will the B cell differentiate into an antibody-producing cell. Some experimental support exists for the concept that the ability to discriminate between “self” and “nonself” involves learning to respond aggressively when there are signals that suggest the presence of invasive pathogens and having effective regulatory mechanisms for suppressing inflammatory responses when such signals are absent.16Matzinger P The danger model: a renewed sense of self.Science. 2002; 296: 301-305Crossref PubMed Scopus (3337) Google Scholar In this context, autoimmunity could result from intrinsic B-cell abnormalities that bypass the need for extrinsic activation signals and/or from intrinsically normal B cells responding to inappropriate activation signals generated by the innate system. In addition to producing antibodies, B cells can act as efficient APCs to stimulate T cells4Hodgkin PD Basten A B cell activation, tolerance and antigen-presenting function.Curr Opin Immunol. 1995; 7: 121-129Crossref PubMed Scopus (60) Google Scholar, 17Lanzavecchia A Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes.Annu Rev Immunol. 1990; 8: 773-793Crossref PubMed Scopus (524) Google Scholar and to allow optimal development of memory in the CD4+ T-cell population.18Linton PJ Harbertson J Bradley LM A critical role for B cells in the development of memory CD4 cells.J Immunol. 2000; 165: 5558-5565PubMed Google Scholar Compared with nonspecific uptake associated with professional APCs, selective uptake of antigen by antigen-specific B cells is markedly superior, with up to 1000-fold or greater efficiency.17Lanzavecchia A Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes.Annu Rev Immunol. 1990; 8: 773-793Crossref PubMed Scopus (524) Google Scholar, 19Silverman GJ Carson DA Roles of B cells in rheumatoid arthritis.Arthritis Res Ther. 2003; 5: S1-S6Crossref PubMed Google Scholar Whereas other APCs take up antigen as a sampling of the extracellular environment through pinocytosis or through internalization of receptors for immune complexes, B cells capture and internalize only the antigen recognized by the membrane form of immunoglobulin that serves as the specific antigen receptor for each B cell. The internalized antigen is broken down into peptides in lysozomes, some of which bind to major histocompatibility complex class II molecules. The peptide/major histocompatibility complex class II molecules are then transported to the surface of the B cell for presentation to CD4+ helper T cells. As a result, the repertoire of B cells can determine which antigen is presented to T cells, particularly when the antigen concentration is low. Furthermore, B cells produce cytokines, notably interleukin (IL) 4, IL-6, IL-10, and tumor necrosis factor α, which have regulatory effects on antigen-presenting dendritic cells or support the survival of other mononuclear cells.5Lund FE Garvy BA Randall TD Harris DP Regulatory roles for cytokine-producing B cells in infection and autoimmune disease.Curr Dir Autoimmun. 2005; 8: 25-54Crossref PubMed Google Scholar In animal models, polarizing cytokines (IL-4, IL-10, and interferon-γ) produced by B cells are known to regulate the differentiation of T cells,20Harris DP Haynes L Sayles PC et al.Reciprocal regulation of polarized cytokine production by effector B and T cells.Nat Immunol. 2000; 1: 475-482Crossref PubMed Scopus (676) Google Scholar suggesting that the production of cytokines by B cells may also regulate immune responses to infectious pathogens. B cells can both generate and respond to chemotactic factors responsible for leukocyte migration and therefore have a major contributory role in mediating inflammatory cell infiltration processes. Additionally, B cells can synthesize membrane-associated molecules that help and support adjacent T cells.19Silverman GJ Carson DA Roles of B cells in rheumatoid arthritis.Arthritis Res Ther. 2003; 5: S1-S6Crossref PubMed Google Scholar, 21Mebius RE van Tuijl S Weissman IL Randall TD Transfer of primitive stem/progenitor bone marrow cells from LTα-/- donors to wild-type hosts: implications for the generation of architectural events in lymphoid B cell domains.J Immunol. 1998; 161: 3836-3843PubMed Google Scholar Collectively, these properties show that B cells are important players in combating infection by producing antibodies, serving as APCs, providing help and support to other mononuclear cells, and contributing directly to inflammatory processes (Figure 2). When all these activities are appropriately coordinated and tightly regulated, the immune response is kept well honed and poised to respond. However, dysfunction may occur in B-cell-mediated regulatory functions, resulting in or contributing to various autoimmune diseases. Given the complexity of the immune system, the development of an individual B cell is unlikely to follow a predictable and well-executed series of decision points whereby an antigen-reactive cell is expanded to a clone that produces a single antibody.22Nemazee D Weigert M Revising B cell receptors.J Exp Med. 2000; 191: 1813-1817Crossref PubMed Scopus (230) Google Scholar A more realistic perspective is that their development depends on a series of error-prone, random rearrangement events and mutations whereby specificity for the original antigen is maintained (or not) by selective pressures.22Nemazee D Weigert M Revising B cell receptors.J Exp Med. 2000; 191: 1813-1817Crossref PubMed Scopus (230) Google Scholar The development of self-reactive B cells is unavoidable given the random nature of clonal diversification; indeed, at least half of the antibodies expressed by immature human B cells are self-reactive.23Wardemann H Yurasov S Schaefer A Young JW Meffre E Nussenzweig MC Predominant autoantibody production by early human B cell precursors.Science. 2003; 301: 1374-1377Crossref PubMed Scopus (1510) Google Scholar Furthermore, some germline (ie, unmutated) immunoglobulin genes encode antibodies that are broadly reactive to a range of molecules, including self-antigens.24Chen X Martin F Forbush KA Perlmutter RM Kearney JF Evidence for selection of a population of multi-reactive B cells into the splenic marginal zone.Int Immunol. 1997; 9: 27-41Crossref PubMed Scopus (146) Google Scholar These antibodies may provide an initial form of “native” immunity to certain pathogens, such as bacteria. The presence of these self-reactive B cells in the periphery may also broaden the repertoire of antibodies available for expansion, mutation, and further selection in the periphery in response to pathogens. The process of somatic mutation in germinal centers, which increases diversity in the periphery, may also introduce mutations that result in newly created autoreactive antibodies. Thus, production of B cells that express antibodies with some capacity to bind to self-antigens may be the price of survival. Tolerance, the silencing of inappropriate production of self-reactive antibodies that arise during B-cell development, requires a crucial balance between ensuring the capacity for appropriate, diverse immune responses to pathogens and injuring the health of an individual through autoreactivity. Selection against self-reactive antibodies occurs at multiple checkpoints during B-cell development, including in the bone marrow at the immature B-cell stage and in the periphery at the transition between new emigrant and mature B cells.23Wardemann H Yurasov S Schaefer A Young JW Meffre E Nussenzweig MC Predominant autoantibody production by early human B cell precursors.Science. 2003; 301: 1374-1377Crossref PubMed Scopus (1510) Google Scholar At least 3 mechanisms, including clonal deletion, receptor editing, and anergy, are thought to lead to tolerance during B-cell development. Clonal deletion, the negative selection and elimination of B cells that express autoantibodies that bind self-antigens strongly, has beenshown to mediate tolerance of B cells during the pre-B-cell to B-cell transition on exposure to self-antigen.25Nemazee D Buerki K Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras.Proc Natl Acad Sci U S A. 1989; 86: 8039-8043Crossref PubMed Scopus (216) Google Scholar, 26King LB Norvell A Monroe JG Antigen receptor-induced signal transduction imbalances associated with the negative selection of immature B cells.J Immunol. 1999; 162: 2655-2662PubMed Google Scholar Receptor editing is the process whereby self-reactive B cells may escape elimination by replacing their antigen receptors. This involves genetic rearrangements induced by encounter with self-antigens, changing antigen receptor specificities from “self” to “nonself.”27Radic MZ Erikson J Litwin S Weigert M B lymphocytes may escape tolerance by revising their antigen receptors.J Exp Med. 1993; 177: 1165-1173Crossref PubMed Scopus (355) Google Scholar, 28Gay D Saunders T Camper S Weigert M Receptor editing: an approach by autoreactive B cells to escape tolerance.J Exp Med. 1993; 177: 999-1008Crossref PubMed Scopus (765) Google Scholar In some cases in which B cells have attempted to replace an autoreactive antigen receptor, the B cell may express both the replacement antigen receptor and the autoreactive antigen receptor, as has been observed in animal models.29Li Y Li H Weigert M Autoreactive B cells in the marginal zone that express dual receptors.J Exp Med. 2002; 195: 181-188Crossref PubMed Scopus (222) Google Scholar Binding of antigen to the new replacement receptor can induce the B cell to produce both the antibody specific to the antigen and the self-reactive antibody, circumventing the regulatory process. The physiologic importance of this observation is not yet clear, but it provides another potential mechanism for autoantibody production. Another mechanism, anergy, which involves functional inactivation of self-reactive B cells, may be a discrete entity or may represent a form of delayed deletion.4Hodgkin PD Basten A B cell activation, tolerance and antigen-presenting function.Curr Opin Immunol. 1995; 7: 121-129Crossref PubMed Scopus (60) Google Scholar, 30Fulcher DA Basten A Reduced life span of anergic self-reactive B cells in a double-transgenic model.J Exp Med. 1994; 179: 125-134Crossref PubMed Scopus (216) Google Scholar Anergic mechanisms in autoreactive cells can result in specific phenotypic and functional changes, such as down-regulation of membrane receptor, failure to respond to normal immune stimuli, and shortened cell survival. A fundamental feature of autoimmune diseases is the loss of B-cell tolerance in the periphery and the inappropriate production of autoantibodies. Given the large number of autoantibodies that are produced under physiologic conditions, it seems probable that even minor changes in the regulation of autoantibodies could result in increased likelihood of autoimmunity.23Wardemann H Yurasov S Schaefer A Young JW Meffre E Nussenzweig MC Predominant autoantibody production by early human B cell precursors.Science. 2003; 301: 1374-1377Crossref PubMed Scopus (1510) Google Scholar Although most strongly self-reactive antibodies are counterselected at the immature B-cell stage,23Wardemann H Yurasov S Schaefer A Young JW Meffre E Nussenzweig MC Predominant autoantibody production by early human B cell precursors.Science. 2003; 301: 1374-1377Crossref PubMed Scopus (1510) Google Scholar central tolerance is not complete under physiologic conditions. For example, self-reactive B cells can be found in the periphery in healthy humans and animals,31Shlomchik MJ Craft JE Mamula MJ From T to B and back again: positive feedback in systemic autoimmune disease.Nat Rev Immunol. 2001; 1: 147-153Crossref PubMed Scopus (471) Google Scholar although they are generally inactive, and autoreactive antibodies remain undetectable in the serum. These clonally silent B cells could escape cell death and be induced to proliferate and secrete self-reactive antibodies in otherwise healthy individuals in the setting of a random event, such as a virus that induces especially strong activation signals (eg, cytokines), or they may be activated in disease states via inappropriate stimuli, such as binding of pathogen recognition receptors (eg, Toll-like receptors) by chromatin-containing immune complexes.15Brard F Shannon M Prak EL Litwin S Weigert M Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice.J Exp Med. 1999; 190: 691-704Crossref PubMed Scopus (109) Google Scholar, 32Marshak-Rothstein A Busconi L Rifkin IR Viglianti GA The stimulation of Toll-like receptors by nuclear antigens: a link between apoptosis and autoimmunity.Rheum Dis Clin North Am. 2004; 30 (ix.): 559-574Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 33Rifkin IR Leadbetter EA Beaudette BC et al.Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells.J Immunol. 2000; 165: 1626-1633PubMed Google Scholar Moreover, if the new antigen-binding site on an autoantibody interacts with a self-antigen to generate positive cell survival signals, by stimulating or mimicking T-cell cytokine activity, the B cell may survive and proliferate. In this way, autoantibodies may drive their own production.34Edwards JC Cambridge G Abrahams VM Do self-perpetuating B lymphocytes drive human autoimmune disease?.Immunology. 1999; 97: 188-196Crossref PubMed Scopus (167) Google Scholar Autoimmunity may also result from overaggressiveness of the immune system to invasive pathogens, possibly due to mutations in genes that increase responsiveness.35Nath SK Kilpatrick J Harley JB Genetics of human systemic lupus erythematosus: the emerging picture.Curr Opin Immunol. 2004; 16: 794-800Crossref PubMed Scopus (142) Google Scholar Other models suggest that B cells that become autoimmune have genetic abnormalities that result in loss of tolerance. For example, genetic abnormalities that create intrinsic B-cell abnormalities can cause SLE-like diseases in animals.36Sobel ES Katagiri T Katagiri K Morris SC Cohen PL Eisenberg RA An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity.J Exp Med. 1991; 173: 1441-1449Crossref PubMed Scopus (198) Google Scholar Furthermore, some genetic predispositions identified in humans seem likely to have a direct effect on B cells and could contribute to an increased risk of autoimmune disease.37Su K Li X Edberg JC Wu J Ferguson P Kimberly RP A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcγRIIb alters receptor expression and associates with autoimmunity, II: differential binding of GATA4 and Yin-Yang1 transcription factors and correlated receptor expression and function.J Immunol. 2004; 172: 7192-7199Crossref PubMed Scopus (93) Google Scholar, 38Li X Wu J Carter RH et al.A novel polymorphism in the Fcγ receptor IIB (CD32B) transmembrane region alters receptor signaling.Arthritis Rheum. 2003; 48: 3242-3252Crossref PubMed Scopus (156) Google Scholar The process of receptor revision may also introduce changes in B-cell antigen specificity. Receptor revision involves secondary rearrangement of immunoglobulin genes of B cells in the periphery, thereby changing antigen specificity.39Wilson PC Wilson K Liu YJ Banchereau J Pascual V Capra JD Receptor revision of immunoglobulin heavy chain variable region genes in normal human B lymphocytes.J Exp Med. 2000; 191: 1881-1894Crossref PubMed Scopus (136) Google Scholar, 40de Wildt RM Hoet RM van Venrooij WJ Tomlinson IM Winter G Analysis of heavy and light chain pairings indicates that receptor editing shapes the human antibody repertoire.J Mol Biol. 1999; 285: 895-901Crossref PubMed Scopus (180) Google Scholar It tends to occur after, or concurrent with, somatic mutation and generates high-affinity antibodies.39Wilson PC Wilson K Liu YJ Banchereau J Pascual V Capra JD Receptor revision of immunoglobulin heavy chain variable region genes in normal human B lymphocytes.J Exp Med. 2000; 191: 1881-1894Crossref PubMed Scopus (136) Google Scholar, 40de Wildt RM Hoet RM van Venrooij WJ Tomlinson IM Winter G Analysis of heavy and light chain pairings indicates that receptor editing shapes the human antibody repertoire.J Mol Biol. 1999; 285: 895-901Crossref PubMed Scopus (180) Google Scholar, 41Ohmori H Kanayama N Mechanisms leading to autoantibody production: link between inflammation and autoimmunity.Curr Drug Targets Inflamm Allergy. 2003; 2: 232-241Crossref PubMed Scopus (19) Google Scholar Receptor revision is likely to generate new, possibly self-reactive receptors in mature B cells, thereby complicating immune tolerance.22Nemazee D Weigert M Revising B cell receptors.J Exp Med. 2000; 191: 1813-1817Crossref PubMed Scopus (230) Google Scholar The presence of autoreactive B cells in the periphery in humans has been demonstrated by multiple investigators.42Pugh-Bernard AE Silverman GJ Cappione AJ et al.Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance.J Clin Invest. 2001; 108: 1061-1070Crossref PubMed Scopus (234) Google Scholar, 43Zheng NY Wilson K Wang X et al.Human immunoglobulin selection associated with class switch and possible tolerogenic origins for C delta class-switched B cells.J Clin Invest. 2004; 113: 1188-1201PubMed Google Scholar, 44Yurasov S Wardemann H Hammersen J et al.Defective B cell tolerance checkpoints in systematic lupus erythematosus.J Exp Med. 2005; 201: 703-711Crossref PubMed Scopus (527) Google Scholar These autoreactive B cells normally appear primarily in the immature and naive subsets of B cells and appear restricted from entering the memory or switch populations. However, both the negative selection of autoreactive B cells in the transition from the immature to the naive mature subset and the restriction of autoreactive B cells in switching may be defective in SLE and RA.44Yurasov S Wardemann H Hammersen J et al.Defective B cell tolerance checkpoints in systematic lupus erythematosus.J Exp Med. 2005; 201: 703-711Crossref PubMed Scopus (527) Google Scholar, 45Samuels J Ng YS Coupillaud C Paget D Meffre E Impaired early B cell tolerance in patients with rheumatoid arthritis.J Exp Med. 2005; 201: 1659-1667Crossref PubMed Scopus (250) Google Scholar These changes allow the production of high-affinity, switched autoantibodies in human autoimmune disease. Accumulating evidence indicates that B cells have more essential functions in regulating immune responses than previously realized, particularly with respect to their interaction with and activation of T cells. Thus, exaggeration or dysregulation of any of these activities could potentially contribute to the development and maintenance of disease.46Dorner T Burmester GR The role of B cells in rheumatoid art