Figure 1. Types of antibody–antigen complexes formed. (a) Antibodies of the class IgM, IgA, IgG or IgE can bind to IgG and form small soluble or larger insoluble complexes that are deposited in various tissues of the body. IgM rheumatoid factors are the most frequently formed and react with modified Fc regions of IgG. (b) Posttranslation modification of host proteins during stress can potentially lead to over stimulation of the immune response resulting in proteolytic fragments of self antigen eliciting an autoimmune response. (c) Peptides can be generated from host antisense DNA or peptides from microbes that arose from DNA sequences homologous to antisense DNA. The complementary peptides initiate the production of antibodies, which in turn trigger release of autoantibodies against self antigens. (d) The majority of circulating antibodies recognize and bind to either soluble ‘nonself’ or foreign antigens or attach to epitopes on the surface of microorganisms, enhancing complement fixation and lysis of microorganisms, followed by clearance by phagocytes.

Figure 2. Failure of maintaining self-tolerance to antigens due to posttranslational modification. (a) During the process of apoptosis, host proteins cluster in specific subcellular compartments. Ribosomal antigens and endoplasmic reticulum proteins localize in small blebs, while nuclear autoantigens cluster in apoptotic bodies. These are then recognized by various systemic proteins such as C1q, C-reactive protein and serum amyloid P and removed in a noninflammatory way by the phagocytic system. (b) However, if these clearance mechanisms are defective then the apoptotic bodies and blebs eventually release their intracellular components, which can be proteolytically cleaved by a number of enzymes or modified by oxidative stress conditions. (c) Modification of proteins by proteolytic enzymes can expose cleavage sites in proteins or generate distinct amino acid fragments that are targets for antibody in various autoimmune diseases. These modifications include proteolytic cleavage by caspases or granzyme B, transglutamination, (de)phosphorylation and also citrullination. Nonenzymatic modifications of proteins can arise from direct exposure to reactive oxygen, chlorine, sulfur or nitrogen species. These proteins can then be engulfed by professional antigen-presenting cells and then present modified host peptides to helper T cells, which in turn can trigger effector B cells to generate antibodies against modified self peptides.