B Cells, Be Gone — B-Cell Depletion in the Treatment of Rheumatoid Arthritis
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《新英格兰医药杂志》
CD20 protein is expressed on the surface membrane of pre-B lymphocytes and mature B lymphocytes. The protein is located in the B-cell membrane, with 44 amino acids exposed in the extracellular space. Rituximab is a chimeric anti-CD20 antibody whose variable (antigen-binding) region was derived from a mouse antibody so that it has high affinity for CD20. The binding of rituximab to the CD20 antigen interferes with the activation and differentiation of B cells.1
Hematopoietic stem cells, pro-B lymphocytes, and plasma cells do not express CD20. This distribution permits the specific elimination of B cells without preventing the regeneration of B cells from stem cells and pro-B lymphocytes and the production of immunoglobulin by plasma cells. Indeed, short courses of rituximab treatment in patients with non-Hodgkin's B-cell cancers or autoimmune diseases (idiopathic thrombocytopenic purpura, systemic lupus erythematosus, or rheumatoid arthritis) do not affect immunoglobulin levels. The absence of a pronounced increase in the rate of infections in patients who are treated with anti-CD20 antibody is attributable to the fact that committed plasma cells continue to produce the antibody. However, since plasma cells derive continuously from activated B cells, prolonged treatment with an anti-CD20 antibody will eventually reduce the serum immunoglobulin level.
How does the anti-CD20 antibody act? There are four possible mechanisms of action. First, after the antibody binds to the extracellular domain of the CD20 antigen, it may activate complement and lyse the targeted cell. Second, anti-CD20 antibody may permit antibody-dependent, cell-mediated cytotoxicity, which occurs after the Fc portion of the antibody is recognized by appropriate receptors on cytotoxic cells. Third, the antibody may alter the ability of B cells to respond to antigen or other stimuli. Finally, anti-CD20 antibody may initiate programmed cell death. All these mechanisms appear to be involved in variable degrees depending on the B-cell pool. For example, Fc-receptor–mediated cytotoxicity is prominent in the destruction of B cells in peripheral blood, whereas complement activation is involved in the killing of B cells in lymphoid organs.
What is the role of B cells in systemic autoimmunity? B cells contribute in important ways to the expression of autoimmunity. They produce antibodies that appear to direct the expression of disease. Examples include the cationic anti-DNA antibodies, which may bind to the basement membrane of the kidney and instigate inflammation, and antibodies that cross-react with the receptors on the surface of neuronal cells and cause cell death. B cells also produce cytokines (interleukins 6 and 10) that may alter the function of other cells, including immune cells, synoviocytes, and mesangial cells. Most important, B cells are highly competent antigen-presenting cells, and they present autoantigen to T cells. Studies in mice have shown that B cells are important in the pathogenesis of lupus nephritis, regardless of their ability to produce antibody.2
The study reported by Edwards et al. in this issue of the Journal (pages 2572–2581), like other studies, demonstrates that the depletion of peripheral-blood B cells with an anti-CD20 antibody in patients with autoimmune diseases reduces disease activity, despite the fact that serum immunoglobulin levels remain unchanged. This observation supports the proposition that B cells have an antibody-independent role in the pathogenesis of rheumatoid arthritis and systemic autoimmunity in general. It should be noted that clinical improvement after treatment with anti-CD20 antibody does not always correlate with a decrease in the autoantibody titer, at least in patients who are treated for idiopathic thrombocytopenic purpura or systemic lupus erythematosus. Yet it is possible that the depletion of B cells in the peripheral blood blocks the production of an unrecognized autoantibody that is involved in the development of disease either directly or through the formation of immune complexes, without affecting the overall immunoglobulin levels.
What is the role of B cells in arthritis? In many patients with rheumatoid arthritis, B cells are present in the rheumatoid synovium, where they are surrounded by T cells in follicle formation. B cells process autoantigen and contribute to the inflammatory process. Studies of animal models of rheumatoid arthritis show that B cells are needed for the activation of T cells. The contribution of B cells to T-cell activation in humans may now be studied in patients with rheumatoid arthritis who are treated with B-cell–depleting biologic agents. Conversely, T cells may contribute to B-cell activation, as may cytokines that promote B-cell function and survival, such as interleukin-6 and B-lymphocyte–stimulating factor. Combination treatments may enhance the overall therapeutic efficacy of B-cell depletion.
How does the depletion of B cells in the peripheral blood help patients with rheumatoid arthritis? We do not know whether the rituximab-mediated depletion affects the numbers or function of B cells that home to the synovium. Nor do we know which subgroups of B cells located in the spleen, lymph nodes, and other lymphoid organs are affected by the administration of anti-CD20 antibody or the extent to which they are affected. The therapeutic efficacy of rituximab in rheumatoid arthritis suggests that rituximab affects B cells in the synovium and causes clinically significant disruption of the inflammatory process (see Figure).3 Additional research may lead to strategies for selectively depleting certain subgroups of B cells or dislodging B cells from lymphoid tissues and the synovium before depleting them with anti-CD20 antibody.
Figure. Joint of a Patient with Rheumatoid Arthritis Showing Three Sites Where Anti-CD20 Antibody May Inhibit B Cells.
After activation and differentiation, B cells become antibody-producing cells. In patients with rheumatoid arthritis, some B cells migrate to the inflamed synovium and contribute to the inflammatory process by processing autoantigen and presenting it to T cells, as well as by producing cytokines and autoantibody. Treatment with anti-CD20 antibody destroys mature B cells in central lymphoid organs, the synovium, and the peripheral blood. B cells in central lymphoid organs continue to produce immunoglobulin.
According to the published studies, patients do not appear to become immunocompromised by short-term treatment with anti-CD20 antibody. However, treatment is likely to involve maintenance doses after the proposed two induction doses and possibly additional treatment with immunosuppressive or immunomodulatory agents for more than one year. Therefore, close monitoring is warranted to assess patients who are undergoing treatment for rheumatoid arthritis or other autoimmune diseases for a loss of immunocompetence.
The opinions expressed herein are those of the author and do not necessarily reflect those of the Department of Defense.
Source Information
From the Walter Reed Army Institute of Research, Silver Spring, Md.
References
Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003;48:1484-1492.
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.
Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2003;2:473-488.(George C. Tsokos, M.D.)
Hematopoietic stem cells, pro-B lymphocytes, and plasma cells do not express CD20. This distribution permits the specific elimination of B cells without preventing the regeneration of B cells from stem cells and pro-B lymphocytes and the production of immunoglobulin by plasma cells. Indeed, short courses of rituximab treatment in patients with non-Hodgkin's B-cell cancers or autoimmune diseases (idiopathic thrombocytopenic purpura, systemic lupus erythematosus, or rheumatoid arthritis) do not affect immunoglobulin levels. The absence of a pronounced increase in the rate of infections in patients who are treated with anti-CD20 antibody is attributable to the fact that committed plasma cells continue to produce the antibody. However, since plasma cells derive continuously from activated B cells, prolonged treatment with an anti-CD20 antibody will eventually reduce the serum immunoglobulin level.
How does the anti-CD20 antibody act? There are four possible mechanisms of action. First, after the antibody binds to the extracellular domain of the CD20 antigen, it may activate complement and lyse the targeted cell. Second, anti-CD20 antibody may permit antibody-dependent, cell-mediated cytotoxicity, which occurs after the Fc portion of the antibody is recognized by appropriate receptors on cytotoxic cells. Third, the antibody may alter the ability of B cells to respond to antigen or other stimuli. Finally, anti-CD20 antibody may initiate programmed cell death. All these mechanisms appear to be involved in variable degrees depending on the B-cell pool. For example, Fc-receptor–mediated cytotoxicity is prominent in the destruction of B cells in peripheral blood, whereas complement activation is involved in the killing of B cells in lymphoid organs.
What is the role of B cells in systemic autoimmunity? B cells contribute in important ways to the expression of autoimmunity. They produce antibodies that appear to direct the expression of disease. Examples include the cationic anti-DNA antibodies, which may bind to the basement membrane of the kidney and instigate inflammation, and antibodies that cross-react with the receptors on the surface of neuronal cells and cause cell death. B cells also produce cytokines (interleukins 6 and 10) that may alter the function of other cells, including immune cells, synoviocytes, and mesangial cells. Most important, B cells are highly competent antigen-presenting cells, and they present autoantigen to T cells. Studies in mice have shown that B cells are important in the pathogenesis of lupus nephritis, regardless of their ability to produce antibody.2
The study reported by Edwards et al. in this issue of the Journal (pages 2572–2581), like other studies, demonstrates that the depletion of peripheral-blood B cells with an anti-CD20 antibody in patients with autoimmune diseases reduces disease activity, despite the fact that serum immunoglobulin levels remain unchanged. This observation supports the proposition that B cells have an antibody-independent role in the pathogenesis of rheumatoid arthritis and systemic autoimmunity in general. It should be noted that clinical improvement after treatment with anti-CD20 antibody does not always correlate with a decrease in the autoantibody titer, at least in patients who are treated for idiopathic thrombocytopenic purpura or systemic lupus erythematosus. Yet it is possible that the depletion of B cells in the peripheral blood blocks the production of an unrecognized autoantibody that is involved in the development of disease either directly or through the formation of immune complexes, without affecting the overall immunoglobulin levels.
What is the role of B cells in arthritis? In many patients with rheumatoid arthritis, B cells are present in the rheumatoid synovium, where they are surrounded by T cells in follicle formation. B cells process autoantigen and contribute to the inflammatory process. Studies of animal models of rheumatoid arthritis show that B cells are needed for the activation of T cells. The contribution of B cells to T-cell activation in humans may now be studied in patients with rheumatoid arthritis who are treated with B-cell–depleting biologic agents. Conversely, T cells may contribute to B-cell activation, as may cytokines that promote B-cell function and survival, such as interleukin-6 and B-lymphocyte–stimulating factor. Combination treatments may enhance the overall therapeutic efficacy of B-cell depletion.
How does the depletion of B cells in the peripheral blood help patients with rheumatoid arthritis? We do not know whether the rituximab-mediated depletion affects the numbers or function of B cells that home to the synovium. Nor do we know which subgroups of B cells located in the spleen, lymph nodes, and other lymphoid organs are affected by the administration of anti-CD20 antibody or the extent to which they are affected. The therapeutic efficacy of rituximab in rheumatoid arthritis suggests that rituximab affects B cells in the synovium and causes clinically significant disruption of the inflammatory process (see Figure).3 Additional research may lead to strategies for selectively depleting certain subgroups of B cells or dislodging B cells from lymphoid tissues and the synovium before depleting them with anti-CD20 antibody.
Figure. Joint of a Patient with Rheumatoid Arthritis Showing Three Sites Where Anti-CD20 Antibody May Inhibit B Cells.
After activation and differentiation, B cells become antibody-producing cells. In patients with rheumatoid arthritis, some B cells migrate to the inflamed synovium and contribute to the inflammatory process by processing autoantigen and presenting it to T cells, as well as by producing cytokines and autoantibody. Treatment with anti-CD20 antibody destroys mature B cells in central lymphoid organs, the synovium, and the peripheral blood. B cells in central lymphoid organs continue to produce immunoglobulin.
According to the published studies, patients do not appear to become immunocompromised by short-term treatment with anti-CD20 antibody. However, treatment is likely to involve maintenance doses after the proposed two induction doses and possibly additional treatment with immunosuppressive or immunomodulatory agents for more than one year. Therefore, close monitoring is warranted to assess patients who are undergoing treatment for rheumatoid arthritis or other autoimmune diseases for a loss of immunocompetence.
The opinions expressed herein are those of the author and do not necessarily reflect those of the Department of Defense.
Source Information
From the Walter Reed Army Institute of Research, Silver Spring, Md.
References
Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003;48:1484-1492.
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.
Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2003;2:473-488.(George C. Tsokos, M.D.)