Historically, the mechanisms of tissue injury in autoimmunity have been classified according to a scheme adopted for ‘hypersensitivity’ reactions that were defined in the early 1960s, prior to a more modern understanding of immune mechanisms (Fig. 15.19; also see introduction to Chapter 14). We now recognize that the dominant types of immunity that are orchestrated for the clearance of different types of pathogens are the same ones that become dysregulated in autoimmunity, and that both B and T cells, as well as effector cells of the innate immune system, contribute—even in cases where a particular type of response (for example, autoantibody-mediated cellular injury) predominates in causing tissue damage. The antigen, or group of antigens, against which the autoimmune response is directed, and the mechanism by which the antigen-bearing tissue is damaged, together determine the pathology and clinical expression of the disease.
Type 2 immune responses mediated by IgE (previously referred to as type I hypersensitivity) typically cause allergic or atopic inflammatory disease (see Chapter 14) and play no major part in most forms of autoimmunity. By contrast, autoimmunity that damages tissues by autoantibodies—whether by binding of IgG or IgM to autoantigens located on cell surfaces or extracellular matrix (type II hypersensitivity) or by tissue localization of immune complexes composed of soluble autoantigens and their cognate autoantibodies (type III hypersensitivity)—often appears to be linked to dysregulated type 3 (TH17) or type 1 (TH1) immunity, or to T-cell-independent generation of IgM-producing B cells. Because antibody-mediated injury can target a specific cell or tissue type (for example, autoimmune thyroiditis), or it can result in immune complexes that are deposited in specific vascular beds (for example, rheumatoid arthritis), disease can be organ-specific or systemic. In some forms of autoimmunity, such as SLE, autoantibodies cause damage by both of these mechanisms. Finally, several organ-specific autoimmune diseases are due to a type 1 response in which TH1 cells and/or cytotoxic T cells directly cause tissue damage (type IV hypersensitivity; for example, type 1 diabetes); alternatively, some such diseases are due to a type 3 response in which TH17 cells promote inflammation at barrier tissues (for example, psoriasis or Crohn’s disease).
Antibodies made against Dsg-1 and Dsg-3 unzip the adhesive interactions in desmosomes EC1EC2EC3EC4EC5Dsg-3 EC1EC2EC3EC4EC5Dsg-1 keratinocyte extracellular matrix early epitope targeted in mucosal stage of disease late epitope targeted in skin stage of disease Different B-cell epitopes on desmogleins are targeted by autoantibodies
Fig. 15.18 Pemphigus vulgaris is a skin-blistering disease caused by autoantibodies specific for desmoglein.
An adhesion molecule in the cell junctions that hold keratinocytes together, desmoglein is a cell‑surface protein with five extracellular domains (EC1–EC5; upper panel). Early in the autoimmune response, antibodies are made against the EC5 domain of shed desmoglein‑3 (Dsg‑3), but do not cause disease. However, in time, intra‑and intermolecular epitope spreading occurs and IgG antibodies are made against the EC1 and EC2 domains of Dsg‑3 and Dsg‑1. These autoantibodies can inhibit adhesion of desmoglein in desmosomes (lower panel), and thereby interfere with the physiological adhesive interactions of desmoglein that are necessary for maintaining skin integrity. Consequently, the antibodies cause the outer layers of the skin to separate, producing blisters.