Autoimmune diseases can be grouped according to the predominant type of immune response and the mechanism by which it damages tissues. In many autoimmune diseases, several immunopathogenic mechanisms operate in parallel. This is illustrated here for rheumatoid arthritis, which appears in more than one category of immunopathogenic mechanism.
In most autoimmune diseases, however, several mechanisms of pathogenesis operate. Thus, helper T cells are almost always required for the production of pathogenic autoantibodies. Reciprocally, B cells often have an important role in the maximal activation of T cells that mediate tissue damage or help auto-antibody production. In type 1 diabetes and rheumatoid arthritis, for example, both T-celland antibody-mediated pathways cause tissue injury. SLE is an example of autoimmunity that was previously thought to be mediated solely by antibodies and immune complexes but is now known to have a component of T-cell-mediated pathogenesis. Moreover, in virtually all autoimmune diseases, innate immune cells contribute to inflammation and antibodyor T-cell-mediated tissue injury. We will first examine how autoantibodies cause tissue damage, then consider self-reactive T-cell responses and their role in autoimmunity.
15-13 Autoantibodies against blood cells promote their destruction.
IgG or IgM responses to antigens located on the surface of blood cells lead to the rapid destruction of these cells. An example of this is autoimmune hemolytic anemia, in which antibodies against self antigens on red blood cells trigger destruction of the cells, leading to anemia. This can occur in two ways (Fig. 15.20). Red cells with bound IgG or IgM antibody can be rapidly cleared from the circulation by interaction with Fc or complement receptors, respectively, on cells of the mononuclear–macrophage phagocytic system, particularly in the spleen. Alternatively, the autoantibody-sensitized red blood cells can be lysed by formation of the membrane-attack complex of complement. In autoimmune thrombocytopenic purpura, autoantibodies against the GpIIb:IIIa fibrinogen receptor or other platelet-specific surface antigens can cause thrombocytopenia (a depletion of platelets), which can in turn cause hemorrhage.
Lysis of nucleated cells by complement is less common because these cells are better defended by complement-regulatory proteins, which protect cells against immune attack by interfering with the activation of complement components (see Section 2-15). Nevertheless, circulating nucleated cells targeted by autoantibodies are still destroyed by cells of the mononuclear phagocytic system or NK cells via antibody-dependent cell-mediated cytotoxicity (ADCC). Autoantibodies against neutrophils, for example, cause neutropenia, which increases susceptibility to infection with pyogenic bacteria. In all these cases, accelerated clearance of autoantibody-sensitized cells is the cause of their depletion. One therapeutic approach to this type of autoimmunity is removal of the spleen, the organ in which the main clearance of red cells, platelets, and leukocytes occurs. Another is the administration of large quantities of nonspecific IgG (termed IVIG, for intravenous immunoglobulin), which among other mechanisms inhibits the Fc receptor-mediated uptake of antibody-coated cells and activates inhibitory Fc receptors to suppress production of inflammatory mediators by myeloid cells.
15-14 The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response.