In tissues stressed by wounds or infection, peptidyl arginine deiminase (PAD) activity is induced. By converting arginine residues to citrulline, PAD destabilizes proteins and makes them more susceptible to degradation. It also introduces novel B‑cell and T‑cell epitopes into tissue proteins that can stimulate an autoimmune response.
Fig. 15.31 Sex differences in the incidence of autoimmune disease.
Many autoimmune diseases are more common in females than males, as illustrated here by the cumulative incidence of diabetes in a population of diabetes‑prone NOD mice. Females (red line) get diabetes at a much younger age than do males, indicating their greater predisposition. Data kindly provided by S. Wong.
Fig. 15.32 Defects in cytokine production or signaling that can lead to autoimmunity. Some of the signaling pathways involved in autoimmunity have been identified by genetic analysis, mainly in animal models. The effects of overexpression or underexpression of some of the cytokines and intracellular signaling molecules involved are listed here (see the text for further discussion).
Incidence of diabetes in NOD mice (%) are genetically predisposed to develop intestinal inflammation. Treatment with broad-spectrum antibiotics that reduce or eliminate many components of the commensal flora can delay or eliminate disease onset, and raising susceptible mice under germ-free conditions (i.e., without a microbiota) eliminates disease. Conversely, certain intestinal microbes—such as segmented filamentous bacteria (SFB)—present in some mouse colonies promote intestinal TH17 responses that have been linked to intestinal inflammation. Although analogous organisms in humans have not been clearly identified, human studies suggest that components of the microbiota may predispose genetically susceptible individuals to autoimmune disease. For instance, although Crohn’s disease incidence in susceptible monozygotic twins is much higher than in dizygotic twins, the concordance rate is not 100%. The explanation for incomplete concordance could lie in variability in the intestinal microbiota, epigenetic differences, or factors yet to be defined.
15-19 Genomics-based approaches are providing new insight into the immunogenetic basis of autoimmunity.
Since the advent of gene knockout technology in mice (see Appendix I, Section A-35), many genes encoding immune system proteins have been experimentally disrupted. Several strains of mice that have been generated show signs of autoimmunity, including autoantibodies and infiltration of organs by T cells. The study of these mice has expanded our knowledge of the pathways that contribute to autoimmunity, and therefore their induced mutations might be candidates for identifying naturally occurring mutations. These mutations likely affect genes that encode cytokines, co-receptors, molecules involved in antigen-signaling cascades, co-stimulatory molecules, proteins involved in apoptosis, and proteins that clear antigen or antigen:antibody complexes. A number of cytokines and signaling proteins implicated in autoimmune disease are listed in Fig. 15.32. Other targeted or mutant genes with autoimmune phenotypes in mice are listed in Fig. 15.33, as are their corresponding human counterparts, where known.