The complement system and human autoimmune diseases

Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis. •Complement plays a role in autoimmune disease as well as host defense.•We will discuss putative mechanisms by which complement contributes to autoimmunity.•The clinical history, physical exam, and laboratory findings seen in patients with complement deficiencies will be reviewed.•C1q and C4 are most strongly associated with autoimmune disease.•In addition to complement's role in SLE, this review will also address autoimmune myopathy, arthritis, and type I diabetes mellitus.