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Complement system on the attack in autoimmunity
John P. Atkinson
Washington University School of Medicine, St. Louis, Missouri, USA
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Published December 1, 2003 - More info
J Clin Invest. 2003;112(11):1639–1641. https://doi.org/10.1172/JCI20309.
© 2003 The American Society for Clinical Investigation
In the first autoimmune condition that was recognized as such over a century ago, antibody and complement were shown to lyse human red blood cells in a rare form of hemolytic anemia known as paroxysmal cold hemoglobinuria (1). Impressively, these same two factors had been found to mediate lysis of bacterial pathogens just three years earlier in 1892. While lysis was the end point in those early studies because it was both pathologically meaningful and easy to monitor, we now realize that it is the phlogistic and opsonic activities of complement that account for much of its physiologic and pathologic importance. The antiphospholipid syndrome (APS) is an autoimmune disease in which autoantibodies are synthesized to lipids and lipid-binding proteins. These antibodies bind to antigens expressed by endothelial cells and produce a clinical syndrome featuring thrombosis. Fetal wastage is caused by placental infarction. In this issue of the JCI, Girardi et al. report that activation of the complement cascade by the immune complexes is required for disease development in a mouse model of APS (2).
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Local requirements for complement activation
The complement-activation scheme is different in the two models. In the APS model, the classical pathway triggers the process by depositing a relatively small amount of C3b on the target, and then this C3b serves as a nidus for the AP’s self-amplifying feedback loop (Figure 1). The AP deposits the majority of the C3b and cleaves most of the C5. Another particularly intriguing aspect of this model is the indication that neutrophils enhance the complement-activation process. In the RA model, the AP alone can provide the necessary C3b and subsequent C5 activation (5). As noted, plasma and membrane complement regulators are particularly effective at blocking the feedback loop of the AP (16, 17) but are less able to control antibody-mediated classical-pathway activation. Thus, this potentially lethal amplification process occurs routinely and robustly against foreign materials (which in most cases lack regulators). This line of reasoning accounts for why large amounts of autoantibodies that activate the classical pathway are so damaging, yet low levels of autoantibodies or autoreactive lectins are so well tolerated.
Figure 1C3b can be deposited on a target by immune complexes that commonly engage the classical pathway, by lectins such as mannose-binding protein that bind to sugars, or through the continuous low-grade turnover of the AP. The deposited C3b serves as a nidus for amplification of C3b deposition via the positive feedback loop. Control of this amplification process is critical to prevent undesirable injury to host cells. The presence of antibodies or lectins on a membrane at a site relatively lacking in membrane regulators is conducive to excessive complement activation on self tissue.
Consequently, for excessive and unwanted complement activation to occur on self tissue, something is likely to be amiss relative to the host’s complement inhibitors (see Requirements for complement activation on self tissue in autoimmunity). This point is clearly illustrated in the arthritis model, where the evidence points to antibody binding and complement activation taking place at a site relatively deficient in regulators (5). Furthermore, the autoantibodies themselves serve as a protected site for complement activation (6). Genetic deficiencies of complement inhibitors reinforce these points. For example, in paroxysmal nocturnal hemoglobinuria, red blood cells are lysed because of an acquired clonal stem cell inactivation of the enzyme required to anchor two regulators of complement on the erythrocyte membrane (18). In atypical (nondiarrheal) hemolytic uremic syndrome, heterozygous deficiency of one of the complement inhibitors factor H or CD46 predisposes to a thrombotic microangiopathy because of excessive complement activation (17, 19). The take-home lessons from these reports are that complement activation on vessel walls must be rigorously controlled and that even heterozygous deficiency of an inhibitor predisposes to thrombosis if a vessel wall is under siege. A reasonable hypothesis, therefore, to explain clot formation in APS is that the developing placental vasculature is relatively deficient in complement-inhibitor function.
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