br Mechanisms of specific immunotherapy

Mechanisms of specific immunotherapy Several mechanisms may be involved in specific immunotherapy of EAMG by active immunization with the therapeutic vaccine in IFA. During the therapy, the therapeutic benefits result from diversion of autoantibody specificities away from pathogenic extracellular epitopes to pathologically irrelevant cytoplasmic epitopes [94]. However, suppression of pathogenic autoantibodies is not isotype-specific. Isotype switching is a long-term effect of therapy. The change in isotype long after the therapy may result from revealing the full effect of therapy on changing B cells after loss of long-lived antibody producing plasmacytes induced before the therapy began. These data suggest that the therapeutic effects might be achieved through a combination of antibody-mediated feedback suppression and regulatory T cell-mediated active suppression. These mechanisms are not mutually exclusive and may occur simultaneously. It has long been known that induction of immune responses to an antigen can be suppressed by passive transfer of antibody specific to the same antigen [96]. Hemolytic disease of the fetus and newborn can be prevented by administering histone methyltransferase inhibitor against D antigen from the plasma of d-alloimmunized donors to the mother [97]. The mechanism of antibody-mediated feedback suppression is that antigen-antibody complex cross-links the B-cell receptor and the inhibitory IgG receptor (FcγRIIB) on the B cell surface, thereby triggering apoptosis of antigen-specific B cells [96], [98], [99]. We found that i.p. administration of serum antibodies purified from rats immunized with the therapeutic vaccine is more effective at suppressing ongoing EAMG and reducing pathogenic autoantibodies to the MIR than i.p. administering an equivalent amount of normal rat IgG (J. Luo, unpublished observation). This suggests that antibody-mediated feedback suppression contributes to the benefits of therapy. This process is antigen-specific, but not epitope-specific. The therapeutic antibodies must recognize different epitopes on the AChR from those recognized by B-cell receptor on pathogenic B cells to allow antigen-antibody complex to bind to B-cell receptor. This explains why antibodies to epitopes on the extracellular surface can be suppressed by cytoplasmic domain fragments. Theoretically, an antibody to an epitope on the extracellular surface can apoptose B cells specific to other extracellular epitopes. However, the therapeutic effects of antibodies to the extracellular epitopes are hampered by many factors: (1) antibodies to the extracellular epitopes are potentially pathogenic; (2) the majority of autoantibodies to the extracellular epitopes compete with each other for binding to the MIR and thus are ineffective at apoptosing B cells specific to the MIR; and (3) antibodies to the extracellular epitopes can trigger apoptosis of B cells to AChR cytoplasmic domains, and thus can feedback suppress the therapeutic antibody response to the cytoplasmic domains. However, repeated doses of the therapeutic cytoplasmic domain antigens tip the balance in favor of suppressing the pathological response to the extracellular epitopes. The many epitopes in the therapeutic vaccine that encompasses the cytoplasmic domains of all five subunits should contribute to robustness and efficacy of the therapeutic response. A critical pathological event is complement-mediated attack on the postsynaptic membrane that causes shedding of AChR-rich membrane fragments into the synaptic cleft [57], [58], [60], [100]. These shed muscle AChRs trigger an immune response because immunization with the MIR/AChBP chimera that lacks cytoplasmic domains produces EAMG and many autoantibodies to muscle AChR cytoplasmic domains [34], [56]. We think that these endogenous AChRs drive a feed-forward cycle of autoimmune stimulation to muscle AChRs. Immune stimulation by endogenous AChR released in the immune assault may be a major factor in sustaining the autoimmune response in EAMG and MG, and may be a major target at which specific immunosuppressive therapy acts. The critical therapeutic event, killing pathogenic B cells, is mediated by a high concentration of antibodies to AChR cytoplasmic domains resulting from therapeutic vaccination.