Advertisement
Mayo Clinic Proceedings Home

B Cells in Health and Disease

  • Author Footnotes
    * Dr Carter receives consulting fees from Genentech/Biogen Idec.
    Robert H. Carter
    Correspondence
    Individual reprints of this article are not available. Address correspondence to Robert H. Carter, MD, Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, 409 LHRB, Birmingham, AL 35294-0007
    Footnotes
    * Dr Carter receives consulting fees from Genentech/Biogen Idec.
    Affiliations
    Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham
    Search for articles by this author
  • Author Footnotes
    * Dr Carter receives consulting fees from Genentech/Biogen Idec.
      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.
      APC (antigen-presenting cell), IL (interleukin), RA (rheumatoid arthritis), SLE (systemic lupus erythematosus)
      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.
      • Delves PJ
      • Roitt IM
      The immune system: first of two parts.
      • Delves PJ
      • Roitt IM
      The immune system: second of two parts.
      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.
      • Davidson A
      • Diamond B
      Autoimmune diseases.
      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 system
      • Hodgkin PD
      • Basten A
      B cell activation, tolerance and antigen-presenting function.
      or indirect effects through antigen presentation and the production of cytokines.
      • Lund FE
      • Garvy BA
      • Randall TD
      • Harris DP
      Regulatory roles for cytokine-producing B cells in infection and autoimmune disease.
      • Chan 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.
      • Martin F
      • Chan AC
      Pathogenic roles of B cells in human autoimmunity; insights from the clinic.
      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.
      • Carter RH
      B cell signalling as therapeutic target.
      • Carter RH
      B cells: new ways to inhibit their function in rheumatoid arthritis.
      • Smolen JS
      • Steiner G
      Therapeutic strategies for rheumatoid arthritis.
      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.

      THE IMMUNE SYSTEM AND B CELLS: FORM AND FUNCTION

      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.
      • Goldsby RA
      • Kindt TJ
      • Osborne BA
      • Parslow TG
      The immune response.
      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.
      • Goldsby RA
      • Kindt TJ
      • Osborne BA
      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.
      Figure thumbnail gr1
      FIGURE 1B-cell differentiation. D = diversity region; IGHV = immunoglobulin heavy chain variable region; IGKV = immunoglobulin κ light chain variable region; IGLV = immunoglobulin λ light chain variable region; J = joining region. Adapted from IMGT, the international ImMunoGeneTics information system, with permission.
      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.
      • Goldsby RA
      • Kindt TJ
      • Osborne BA
      Additional antibody diversification occurs via somatic mutation of antibody during clonal expansion in the periphery, which appears to occur at a high frequency.
      • McKean 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.
      • Brard 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.
      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.
      • Matzinger P
      The danger model: a renewed sense of self.
      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.

      B-CELL IMMUNOLOGIC FUNCTIONS: INDEPENDENT OF ANTIBODY PRODUCTION

      In addition to producing antibodies, B cells can act as efficient APCs to stimulate T cells
      • Hodgkin PD
      • Basten A
      B cell activation, tolerance and antigen-presenting function.
      • Lanzavecchia A
      Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes.
      and to allow optimal development of memory in the CD4+ T-cell population.
      • Linton PJ
      • Harbertson J
      • Bradley LM
      A critical role for B cells in the development of memory CD4 cells.
      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.
      • Lanzavecchia A
      Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes.
      • Silverman GJ
      • Carson DA
      Roles of B cells in rheumatoid arthritis.
      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.
      • Lund FE
      • Garvy BA
      • Randall TD
      • Harris DP
      Regulatory roles for cytokine-producing B cells in infection and autoimmune disease.
      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,
      • Harris DP
      • Haynes L
      • Sayles PC
      • et al.
      Reciprocal regulation of polarized cytokine production by effector B and T cells.
      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.
      • Silverman GJ
      • Carson DA
      Roles of B cells in rheumatoid arthritis.
      • Mebius 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.
      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.
      Figure thumbnail gr2
      FIGURE 2Autoreactive B cells in health and disease. Normal regulatory mechanisms induce tolerance to autoreactive B cells in a healthy, functioning immune system. Loss of tolerance can lead to the inappropriate production of autoantibodies and/or enhancement of other autoreactive processes, ultimately leading to tissue damage. BLyS = B-lymphocyte stimulator; IFNα = interferon-α; IL-10 = interleukin 10; LTβ = lymphotoxin-β; TNF = tumor necrosis factor.

      B CELLS AND DISEASE STATES

      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.
      • Nemazee D
      • Weigert M
      Revising B cell receptors.
      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.
      • Nemazee D
      • Weigert M
      Revising B cell receptors.
      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.
      • Wardemann H
      • Yurasov S
      • Schaefer A
      • Young JW
      • Meffre E
      • Nussenzweig MC
      Predominant autoantibody production by early human B cell precursors.
      Furthermore, some germline (ie, unmutated) immunoglobulin genes encode antibodies that are broadly reactive to a range of molecules, including self-antigens.
      • Chen 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.
      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.
      • Wardemann H
      • Yurasov S
      • Schaefer A
      • Young JW
      • Meffre E
      • Nussenzweig MC
      Predominant autoantibody production by early human B cell precursors.
      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.
      • Nemazee D
      • Buerki K
      Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras.
      • King LB
      • Norvell A
      • Monroe JG
      Antigen receptor-induced signal transduction imbalances associated with the negative selection of immature B cells.
      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.”
      • Radic MZ
      • Erikson J
      • Litwin S
      • Weigert M
      B lymphocytes may escape tolerance by revising their antigen receptors.
      • Gay D
      • Saunders T
      • Camper S
      • Weigert M
      Receptor editing: an approach by autoreactive B cells to escape tolerance.
      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.
      • Li Y
      • Li H
      • Weigert M
      Autoreactive B cells in the marginal zone that express dual receptors.
      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.
      • Hodgkin PD
      • Basten A
      B cell activation, tolerance and antigen-presenting function.
      • Fulcher DA
      • Basten A
      Reduced life span of anergic self-reactive B cells in a double-transgenic model.
      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.
      • Wardemann H
      • Yurasov S
      • Schaefer A
      • Young JW
      • Meffre E
      • Nussenzweig MC
      Predominant autoantibody production by early human B cell precursors.
      Although most strongly self-reactive antibodies are counterselected at the immature B-cell stage,
      • Wardemann H
      • Yurasov S
      • Schaefer A
      • Young JW
      • Meffre E
      • Nussenzweig MC
      Predominant autoantibody production by early human B cell precursors.
      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,
      • Shlomchik MJ
      • Craft JE
      • Mamula MJ
      From T to B and back again: positive feedback in systemic autoimmune disease.
      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.
      • Brard 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.
      • Marshak-Rothstein A
      • Busconi L
      • Rifkin IR
      • Viglianti GA
      The stimulation of Toll-like receptors by nuclear antigens: a link between apoptosis and autoimmunity.
      • Rifkin IR
      • Leadbetter EA
      • Beaudette BC
      • et al.
      Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells.
      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.
      • Edwards JC
      • Cambridge G
      • Abrahams VM
      Do self-perpetuating B lymphocytes drive human autoimmune disease?.
      Autoimmunity may also result from overaggressiveness of the immune system to invasive pathogens, possibly due to mutations in genes that increase responsiveness.
      • Nath SK
      • Kilpatrick J
      • Harley JB
      Genetics of human systemic lupus erythematosus: the emerging picture.
      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.
      • Sobel 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.
      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.
      • Su 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.
      • Li X
      • Wu J
      • Carter RH
      • et al.
      A novel polymorphism in the Fcγ receptor IIB (CD32B) transmembrane region alters receptor signaling.
      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.
      • Wilson 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.
      • de 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.
      It tends to occur after, or concurrent with, somatic mutation and generates high-affinity antibodies.
      • Wilson 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.
      • de 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.
      • Ohmori H
      • Kanayama N
      Mechanisms leading to autoantibody production: link between inflammation and autoimmunity.
      Receptor revision is likely to generate new, possibly self-reactive receptors in mature B cells, thereby complicating immune tolerance.
      • Nemazee D
      • Weigert M
      Revising B cell receptors.
      The presence of autoreactive B cells in the periphery in humans has been demonstrated by multiple investigators.
      • Pugh-Bernard AE
      • Silverman GJ
      • Cappione AJ
      • et al.
      Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance.
      • Zheng 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.
      • Yurasov S
      • Wardemann H
      • Hammersen J
      • et al.
      Defective B cell tolerance checkpoints in systematic lupus erythematosus.
      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.
      • Yurasov S
      • Wardemann H
      • Hammersen J
      • et al.
      Defective B cell tolerance checkpoints in systematic lupus erythematosus.
      • Samuels J
      • Ng YS
      • Coupillaud C
      • Paget D
      • Meffre E
      Impaired early B cell tolerance in patients with rheumatoid arthritis.
      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.
      • Dorner T
      • Burmester GR
      The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets.
      Importantly, presentation of antigen by self-reactive B cells that have broken tolerance can activate T cells that had been anergic to the self-antigen, as shown in an animal model of SLE.
      • Shlomchik MJ
      • Craft JE
      • Mamula MJ
      From T to B and back again: positive feedback in systemic autoimmune disease.
      • Mamula MJ
      • Fatenejad S
      • Craft J
      B cells process and present lupus autoantigens that initiate autoimmune T cell responses.
      Thus, autoantigen presentation by B cells may induce activation of T cells that otherwise would remain unresponsive to a particular self-antigen. This effect of B cells may play a role in epitope spreading, in which the T-cell compartment progressively becomes reactive to more sites on a given self antigen over time. Thus, loss of tolerance in the B-cell compartment can induce autoimmunity in the T-cell compartment. This appears to be the case in RA, in which the inflammatory cascade of events is traditionally considered primarily mediated by activated T cells.
      • Panayi GS
      The immunopathogenesis of rheumatoid arthritis.
      T-cell activation has been shown to be critically dependent on B cells in RA in humans, whereas other APCs cannot maintain T-cell activation.
      • Takemura S
      • Klimiuk PA
      • Braun A
      • Goronzy JJ
      • Weyand CM
      T cell activation in rheumatoid synovium is B cell dependent.
      • Roosnek E
      • Lanzavecchia A
      Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells.
      There is evidence for enhanced B-cell activation in RA, including isolation of B cells that have undergone receptor revision from ectopic germinal centers in inflamed tissues in patients with RA.
      • Ohmori H
      • Kanayama N
      Mechanisms leading to autoantibody production: link between inflammation and autoimmunity.
      • Kim HJ
      • Krenn V
      • Steinhauser G
      • Berek C
      Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis.
      The activated B cells may be driving loss of tolerance in T cells in RA. However, recent animal models clearly make the point that certain antibodies are able to induce arthritis directly.
      • Matsumoto I
      • Maccioni M
      • Lee DM
      • et al.
      How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease.
      • Monach PA
      • Benoist C
      • Mathis D
      The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease.
      The relative contribution of production of autoantibodies and of other functions of B cells, including activation of T cells and cytokine production, to the pathogenesis of RA will be an important focus of research in the immediate future.

      B CELLS AS A THERAPEUTIC TARGET IN AUTOIMMUNE DISEASE

      As discussed, B cells are essential for maintaining health, particularly in their responsibility for routine surveillance for foreign pathogens throughout the body. However, their known roles in the pathogenesis of autoimmune disorders, predominantly those characterized by chronic inflammation, identify B cells as an important therapeutic target. The use of monoclonal antibody treatment to target and selectively deplete B cells is well established in the treatment of B-cell malignancies,
      • Plosker GL
      • Figgitt DP
      Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.
      • Kosmas C
      • Stamatopoulos K
      • Stavroyianni N
      • Tsavaris N
      • Papadaki T
      Anti-CD20-based therapy of B cell lymphoma: state of the art.
      and a similar approach is now being investigated in the treatment of autoimmune disorders. This type of treatment may be able to reduce autoantibody production and also inhibit the ability of B cells to act as APCs, thereby affecting the contribution of T cells to disease.
      The monoclonal antibody rituximab, which is directed against the CD20 B-cell surface antigen, produces rapid, sustained, and selective depletion of circulating B cells.
      • Maloney DG
      • Liles TM
      • Czerwinski DK
      • et al.
      Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.
      Rituximab is believed to deplete B cells by induction of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.
      • Reff ME
      • Carner K
      • Chambers KS
      • et al.
      Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.
      • Maloney DG
      • Smith B
      • Rose A
      Rituximab: mechanism of action and resistance.
      The effects of rituximab on B cells are transient, such that after treatment, B cells return to baseline levels within 6 to 12 months.
      • McLaughlin P
      • Grillo-López AJ
      • Link BK
      • et al.
      Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.
      During this time, most circulating B cells have an immature phenotype, with a slow recovery of memory (CD27+) B cells. The characterization of the recovering B cells and their variability among treated individuals are subjects of ongoing study. Treatment with rituximab in B-cell malignancies is generally well tolerated and does not appear to be associated with increased susceptibility to infections.
      • Plosker GL
      • Figgitt DP
      Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.
      At least with single courses of treatments, the primary adverse effects have been infusion reactions. These can include both tumor lysis syndromes in malignancies and responses to the infusion itself.
      Selective B-cell depletion therapy with rituximab, as monotherapy or in combination with other agents, has been evaluated in several open-label, preliminary studies in several autoimmune diseases. Most data on the effects of rituximab on autoimmune diseases are available from studies in patients with RA, including results from one randomized, double-blind, controlled trial.
      • Edwards JC
      • Szczepanski L
      • Szechinski J
      • et al.
      Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.
      • De Vita S
      • Zaja F
      • Sacco S
      • De Candia A
      • Fanin R
      • Ferraccioli G
      Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells.
      • Kramm H
      • Hansen KE
      • Gowing E
      • Bridges A
      Successful therapy of rheumatoid arthritis with rituximab: renewed interest in the role of B cells in the pathogenesis of rheumatoid arthritis.
      • Leandro MJ
      • Edwards JC
      • Cambridge G
      Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion.
      Rituximab improved disease symptoms of RA and was well tolerated in these studies. Case reports or prospective open-label studies have also reported the efficacy of rituximab in SLE and lupus nephritis,
      • Leandro MJ
      • Cambridge G
      • Edwards JC
      • Ehrenstein MR
      • Isenberg DA
      B-cell depletion in the treatment of patients with systematic lupus erythematosus: a longitudinal analysis of 24 patients.
      • Looney RJ
      • Anolik JH
      • Campbell D
      • et al.
      B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab.
      • Sfikakis PP
      • Boletis JN
      • Lionaki S
      • et al.
      Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial.

      Albert D, Khan S, Stansberry J, et al. A phase I trial of rituximab (anti-CD20) for treatment of systematic lupus erythematosus. In: Program and abstracts of the American College of Rheumatology/Association of Rheumatology Health Professionals 68th Annual Meeting; October 16-21, 2004; San Antonio, Tex. Abstract 1125.

      idiopathic thrombocytopenic purpura,
      • Stasi R
      • Stipa E
      • Forte V
      • Meo P
      • Amadori S
      Variable patterns of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura [letter].
      antineutrophil cytoplasmic antibody-associated vasculitis,
      • Keogh KA
      • Wylam ME
      • Stone JH
      • Specks U
      Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis.
      transplant rejection,
      • Becker YT
      • Becker BN
      • Pirsch JD
      • Sollinger HW
      Rituximab as treatment for refractory kidney transplant rejection.
      and neurologic disorders such as dermatomyositis,
      • Levine TD
      Rituximab in the treatment of dermatomyositis: an open-label pilot study.
      paraneoplastic neurologic syndromes,
      • Smitt PS
      • Gratama JW
      • Shamsili S
      • Hooijkaas H
      • van't Veer M
      Rituximab induced depletion of circulating B cells in anti-Hu and anti-Yo associated paraneoplastic neurological syndromes.
      • Pranzatelli MR
      • Travelstead AL
      • Tate ED
      • et al.
      B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes.
      IgM antibody-related polyneuropathies,
      • Levine TD
      • Pestronk A
      IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using rituximab.
      • Pestronk A
      • Florence J
      • Miller T
      • Choksi R
      • Al-Lozi MT
      • Levine TD
      Treatment of IgM antibody associated polyneuropathies using rituximab.
      and demyelinating diseases
      • Cree BA
      • Lamb S
      • Morgan K
      • Chen A
      • Waubant E
      • Genain C
      An open label study of the effects of rituximab in neuromyelitis optica.
      (the efficacy of rituximab in autoimmune diseases other than RA has been reviewed by Looney
      • Looney RJ
      B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis.
      ). Results from these studies are encouraging, with significant sustained improvements in clinical assessments reported. Rituximab was also well tolerated in patients with these autoimmune disorders. An association between a positive clinical response and reduction in autoantibody levels after B-cell depletion with rituximab has been observed in RA
      • Cambridge G
      • Leandro MJ
      • Edwards JC
      • et al.
      Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis.
      and IgM antibody-related polyneuropathies.
      • Levine TD
      • Pestronk A
      IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using rituximab.
      More controlled clinical trials using rituximab are needed to confirm the benefits observed in the preliminary trials. However, findings to date suggest that B-cell activation is not simply a bystander effect of the inflammatory process; rather, results indicate that B cells play an important role in the pathogenesis of these diseases. Interestingly, little change in total serum IgG occurs for at least a year after a single course of treatment, even though at least some autoantibodies are reduced. Since CD20 is not expressed on fully differentiated plasma cells, this suggests that at least certain autoantibodies are derived from newly generated antibody-secreting cells, whereas total serum IgG is largely produced by long-lived plasma cells. In addition, animal models suggest that different subsets of B cells are depleted at different rates after treatment with anti-CD20. For example, marginal zone B cells persist longer than follicular B cells.
      • Gong Q
      • Ou Q
      • Ye S
      • et al.
      Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.
      This may become more important when repeated treatment is considered. The persistence of some percentage of marginal zone B cells, in combination with maintenance of serum IgG, may provide protection from infections, particularly pneumococcus, which might be lost with repeated B-cell depletion. As other therapeutic approaches targeting B cells are developed, such as blockade of B-lymphocyte stimulator or antibodies to other B-cell surface molecules, differences in effects on both early and late stages of B-cell differentiation may provide subtle but potentially important differences in their clinical effects.

      CONCLUSIONS

      B cells are essential for efficient immune responses and the maintenance of health. However, accumulating evidence points to the involvement of B cells in the pathophysiology of several autoimmune disorders, suggesting their potential as a relevant target for therapeutic intervention. Preliminary clinical evidence suggests that selective B-cell depletion is associated with clinical improvements in patients with autoimmune disease. Thus, B-cell depletion may prove to be a valuable alternative treatment modality for patients with autoimmune disease in which B cells are known (or suspected) to contribute to the disease. An important goal is to understand how B-cell depletion therapy alters the diverse mechanisms by which B cells contribute to autoimmunity. Additional studies are warranted to further characterize the role of B cells in autoimmune diseases and the therapeutic utility of B-cell depletion or other modalities that target B cells, such as those that alter B-cell activation.

      REFERENCES

        • Delves PJ
        • Roitt IM
        The immune system: first of two parts.
        N Engl J Med. 2000; 343: 37-49
        • Delves PJ
        • Roitt IM
        The immune system: second of two parts.
        N Engl J Med. 2000; 343: 108-117
        • Davidson A
        • Diamond B
        Autoimmune diseases.
        N Engl J Med. 2001; 345: 340-350
        • Hodgkin PD
        • Basten A
        B cell activation, tolerance and antigen-presenting function.
        Curr Opin Immunol. 1995; 7: 121-129
        • Lund FE
        • Garvy BA
        • Randall TD
        • Harris DP
        Regulatory roles for cytokine-producing B cells in infection and autoimmune disease.
        Curr Dir Autoimmun. 2005; 8: 25-54
        • Chan 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: 1639-1648
        • Martin F
        • Chan AC
        Pathogenic roles of B cells in human autoimmunity; insights from the clinic.
        Immunity. 2004; 20: 517-527
        • Carter RH
        B cell signalling as therapeutic target.
        Ann Rheum Dis. 2004; 63: ii65-ii66
        • Carter RH
        B cells: new ways to inhibit their function in rheumatoid arthritis.
        Curr Rheumatol Rep. 2004; 6: 357-363
        • Smolen JS
        • Steiner G
        Therapeutic strategies for rheumatoid arthritis.
        Nat Rev Drug Discov. 2003; 2: 473-488
        • Goldsby RA
        • Kindt TJ
        • Osborne BA
        Kuby Immunology. 4th ed. W. H. Freeman and Co, New York, NY2000
        • Parslow TG
        The immune response.
        in: Parslow TG Stites DP Terr AI Imboden JB Medical Immunology. 10th ed. McGraw-Hill, New York, NY2001: 66-71
        • IMGT, the international ImMunoGeneTics information system
        B-cell differentiation.
        (Accessibility verified January 18, 2006.)
        • McKean 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: 3180-3184
        • Brard 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: 691-704
        • Matzinger P
        The danger model: a renewed sense of self.
        Science. 2002; 296: 301-305
        • Lanzavecchia A
        Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes.
        Annu Rev Immunol. 1990; 8: 773-793
        • Linton PJ
        • Harbertson J
        • Bradley LM
        A critical role for B cells in the development of memory CD4 cells.
        J Immunol. 2000; 165: 5558-5565
        • Silverman GJ
        • Carson DA
        Roles of B cells in rheumatoid arthritis.
        Arthritis Res Ther. 2003; 5: S1-S6
        • Harris DP
        • Haynes L
        • Sayles PC
        • et al.
        Reciprocal regulation of polarized cytokine production by effector B and T cells.
        Nat Immunol. 2000; 1: 475-482
        • Mebius 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: 3836-3843
        • Nemazee D
        • Weigert M
        Revising B cell receptors.
        J Exp Med. 2000; 191: 1813-1817
        • Wardemann H
        • Yurasov S
        • Schaefer A
        • Young JW
        • Meffre E
        • Nussenzweig MC
        Predominant autoantibody production by early human B cell precursors.
        Science. 2003; 301: 1374-1377
        • Chen 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: 27-41
        • Nemazee D
        • Buerki K
        Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras.
        Proc Natl Acad Sci U S A. 1989; 86: 8039-8043
        • King LB
        • Norvell A
        • Monroe JG
        Antigen receptor-induced signal transduction imbalances associated with the negative selection of immature B cells.
        J Immunol. 1999; 162: 2655-2662
        • Radic MZ
        • Erikson J
        • Litwin S
        • Weigert M
        B lymphocytes may escape tolerance by revising their antigen receptors.
        J Exp Med. 1993; 177: 1165-1173
        • Gay D
        • Saunders T
        • Camper S
        • Weigert M
        Receptor editing: an approach by autoreactive B cells to escape tolerance.
        J Exp Med. 1993; 177: 999-1008
        • Li Y
        • Li H
        • Weigert M
        Autoreactive B cells in the marginal zone that express dual receptors.
        J Exp Med. 2002; 195: 181-188
        • Fulcher DA
        • Basten A
        Reduced life span of anergic self-reactive B cells in a double-transgenic model.
        J Exp Med. 1994; 179: 125-134
        • Shlomchik MJ
        • Craft JE
        • Mamula MJ
        From T to B and back again: positive feedback in systemic autoimmune disease.
        Nat Rev Immunol. 2001; 1: 147-153
        • Marshak-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.): 559-574
        • Rifkin 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: 1626-1633
        • Edwards JC
        • Cambridge G
        • Abrahams VM
        Do self-perpetuating B lymphocytes drive human autoimmune disease?.
        Immunology. 1999; 97: 188-196
        • Nath SK
        • Kilpatrick J
        • Harley JB
        Genetics of human systemic lupus erythematosus: the emerging picture.
        Curr Opin Immunol. 2004; 16: 794-800
        • Sobel 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: 1441-1449
        • Su 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: 7192-7199
        • Li 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: 3242-3252
        • Wilson 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: 1881-1894
        • de 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: 895-901
        • Ohmori H
        • Kanayama N
        Mechanisms leading to autoantibody production: link between inflammation and autoimmunity.
        Curr Drug Targets Inflamm Allergy. 2003; 2: 232-241
        • Pugh-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: 1061-1070
        • Zheng 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: 1188-1201
        • Yurasov S
        • Wardemann H
        • Hammersen J
        • et al.
        Defective B cell tolerance checkpoints in systematic lupus erythematosus.
        J Exp Med. 2005; 201: 703-711
        • Samuels J
        • Ng YS
        • Coupillaud C
        • Paget D
        • Meffre E
        Impaired early B cell tolerance in patients with rheumatoid arthritis.
        J Exp Med. 2005; 201: 1659-1667
        • Dorner T
        • Burmester GR
        The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets.
        Curr Opin Rheumatol. 2003; 15: 246-252
        • Mamula MJ
        • Fatenejad S
        • Craft J
        B cells process and present lupus autoantigens that initiate autoimmune T cell responses.
        J Immunol. 1994; 152: 1453-1461
        • Panayi GS
        The immunopathogenesis of rheumatoid arthritis.
        Br J Rheumatol. 1993; 32: 4-14
        • Takemura S
        • Klimiuk PA
        • Braun A
        • Goronzy JJ
        • Weyand CM
        T cell activation in rheumatoid synovium is B cell dependent.
        J Immunol. 2001; 167: 4710-4718
        • Roosnek E
        • Lanzavecchia A
        Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells.
        J Exp Med. 1991; 173: 487-489
        • Kim HJ
        • Krenn V
        • Steinhauser G
        • Berek C
        Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis.
        J Immunol. 1999; 162: 3053-3062
        • Matsumoto I
        • Maccioni M
        • Lee DM
        • et al.
        How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease.
        Nat Immunol. 2002; 3: 360-365
        • Monach PA
        • Benoist C
        • Mathis D
        The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease.
        Adv Immunol. 2004; 82: 217-248
        • Plosker GL
        • Figgitt DP
        Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.
        Drugs. 2003; 63: 803-843
        • Kosmas C
        • Stamatopoulos K
        • Stavroyianni N
        • Tsavaris N
        • Papadaki T
        Anti-CD20-based therapy of B cell lymphoma: state of the art.
        Leukemia. 2002; 16: 2004-2015
        • Maloney DG
        • Liles TM
        • Czerwinski DK
        • et al.
        Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.
        Blood. 1994; 84: 2457-2466
        • Reff ME
        • Carner K
        • Chambers KS
        • et al.
        Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.
        Blood. 1994; 83: 435-445
        • Maloney DG
        • Smith B
        • Rose A
        Rituximab: mechanism of action and resistance.
        Semin Oncol. 2002; 29: 2-9
        • McLaughlin P
        • Grillo-López AJ
        • Link BK
        • et al.
        Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.
        J Clin Oncol. 1998; 16: 2825-2833
        • Edwards JC
        • Szczepanski L
        • Szechinski J
        • et al.
        Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.
        N Engl J Med. 2004; 350: 2572-2581
        • De Vita S
        • Zaja F
        • Sacco S
        • De Candia A
        • Fanin R
        • Ferraccioli G
        Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells.
        Arthritis Rheum. 2002; 46: 2029-2033
        • Kramm H
        • Hansen KE
        • Gowing E
        • Bridges A
        Successful therapy of rheumatoid arthritis with rituximab: renewed interest in the role of B cells in the pathogenesis of rheumatoid arthritis.
        J Clin Rheumatol. 2004; 10: 28-32
        • Leandro MJ
        • Edwards JC
        • Cambridge G
        Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion.
        Ann Rheum Dis. 2002; 61: 883-888
        • Leandro MJ
        • Cambridge G
        • Edwards JC
        • Ehrenstein MR
        • Isenberg DA
        B-cell depletion in the treatment of patients with systematic lupus erythematosus: a longitudinal analysis of 24 patients.
        Rheumatology (Oxford). 2005; 44: 1542-1545
        • Looney RJ
        • Anolik JH
        • Campbell D
        • et al.
        B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab.
        Arthritis Rheum. 2004; 50: 2580-2589
        • Sfikakis PP
        • Boletis JN
        • Lionaki S
        • et al.
        Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial.
        Arthritis Rheum. 2005; 52: 501-513
      1. Albert D, Khan S, Stansberry J, et al. A phase I trial of rituximab (anti-CD20) for treatment of systematic lupus erythematosus. In: Program and abstracts of the American College of Rheumatology/Association of Rheumatology Health Professionals 68th Annual Meeting; October 16-21, 2004; San Antonio, Tex. Abstract 1125.

        • Stasi R
        • Stipa E
        • Forte V
        • Meo P
        • Amadori S
        Variable patterns of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura [letter].
        Blood. 2002; 99: 3872-3873
        • Keogh KA
        • Wylam ME
        • Stone JH
        • Specks U
        Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis.
        Arthritis Rheum. 2005; 52: 262-268
        • Becker YT
        • Becker BN
        • Pirsch JD
        • Sollinger HW
        Rituximab as treatment for refractory kidney transplant rejection.
        Am J Transplant. 2004; 4: 996-1001
        • Levine TD
        Rituximab in the treatment of dermatomyositis: an open-label pilot study.
        Arthritis Rheum. 2005; 52: 601-607
        • Smitt PS
        • Gratama JW
        • Shamsili S
        • Hooijkaas H
        • van't Veer M
        Rituximab induced depletion of circulating B cells in anti-Hu and anti-Yo associated paraneoplastic neurological syndromes.
        Neurology. 2003; 60 (Abstract S01.006.): A3
        • Pranzatelli MR
        • Travelstead AL
        • Tate ED
        • et al.
        B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes.
        Neurology. 2004; 62: 1526-1532
        • Levine TD
        • Pestronk A
        IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using rituximab.
        Neurology. 1999; 52: 1701-1704
        • Pestronk A
        • Florence J
        • Miller T
        • Choksi R
        • Al-Lozi MT
        • Levine TD
        Treatment of IgM antibody associated polyneuropathies using rituximab.
        J Neurol Neurosurg Psychiatry. 2003; 74: 485-489
        • Cree BA
        • Lamb S
        • Morgan K
        • Chen A
        • Waubant E
        • Genain C
        An open label study of the effects of rituximab in neuromyelitis optica.
        Neurology. 2005; 64: 1270-1272
        • Looney RJ
        B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis.
        Rheumatology. 2005; 44: ii13-ii17
        • Cambridge G
        • Leandro MJ
        • Edwards JC
        • et al.
        Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis.
        Arthritis Rheum. 2003; 48: 2146-2154
        • Gong Q
        • Ou Q
        • Ye S
        • et al.
        Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.
        J Immunol. 2005; 174: 817-826