Fig. 15.29 The pathogenesis of rheumatoid arthritis. Inflammation of the synovial membrane, initiated by some unknown trigger, attracts autoreactive lymphocytes and macrophages to the inflamed tissue. Autoreactive effector CD4 T cells activate macrophages, and pro‑inflammatory cytokines such as IL‑1, IL‑6, IL‑17, and TNF‑α are produced. Fibroblasts activated by cytokines produce matrix metalloproteinases (MMPs), which contribute to tissue destruction. The TNF family cytokine RANK ligand, expressed by T cells and fibroblasts in the inflamed joint, is the primary activator of bone‑destroying osteoclasts. Antibodies against several joint proteins are also produced (not shown), but their role in pathogenesis is uncertain.
this complex cascade at multiple levels—including therapeutic antibodies against cytokines (TNF-α), B cells, and T-cell activation—have all been successful in treating the symptoms of the disease (discussed in Section 16-8).
Studies of the targets of autoantibodies in RA have yielded insights into how this disease develops, and have also identified a more global mechanism by which self proteins may be seen as foreign in other autoimmune conditions. During inflammation, the amino acid arginine can be converted into citrulline, and this change may result in structural alterations of the self protein that cause the immune system to now view it as nonself (Fig. 15.30). Experimental models have shown that antibodies against these altered proteins can be pathogenic, and diagnostic tests for anti-citrullinated protein antibodies (ACPAs) are highly specific for RA. Interestingly, smoking—long known as the most important environmental risk factor for RA development—has been associated with APCAs in patients with HLA risk alleles, suggesting that this tolerance-breaking mechanism may be an important node in the gene–environment interactions that lead to autoimmunity. Finally, other post-translational modifications (oxidation, glycosylation) of self proteins in the periphery have now been shown to stimulate Tand B-cell responses in other autoimmune diseases.
Summary.
Autoimmune diseases can be broadly classified into those that affect a specific organ and those that affect tissues throughout the body. Organ-specific autoimmune diseases include type 1 diabetes, multiple sclerosis, Graves’ disease, and Crohn’s disease. In each case the effector functions target autoantigens that are restricted to particular organs—insulin-producing β cells of the pancreas (type 1 diabetes), the myelin sheathing on axons in the central nervous system (multiple sclerosis), and the thyroid-stimulating hormone receptor (Graves’ disease)—or, in the case of Crohn’s disease, components of the intestinal microbiota. In contrast, systemic diseases such as systemic lupus erythematosus (SLE) cause inflammation in multiple tissues because their autoantigens, which include chromatin and ribonucleoproteins, are found in most cells of the body. In some organ-specific diseases, immune destruction of the target tissue and the unique self antigens it expresses leads to cessation of autoimmune activity, but systemic diseases tend to be chronically active if untreated, because their autoantigens cannot be cleared. Another way of classifying autoimmune diseases is according to the effector functions that are most important in pathogenesis. It is becoming clear, however, that many diseases once thought to be mediated solely by one effector function actually involve several. In this way, autoimmune diseases resemble pathogen-directed immune responses, which typically elicit the activities of multiple effectors—adaptive and innate.