Nature, functions, and clinical implications of IgG4 autoantibodies in systemic lupus erythematosus and rheumatoid arthritis.

Protective autoantibodies in homeostasis, clinical relevance, and therapeutic potential have gained wide attention. Recent studies showed that IgG4 autoantibodies play crucial roles in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In one aspect, IgG4 autoantibodies can bind autoantigens in competition with other classes of immunoglobulins (e.g., IgG1, IgG2a) to form noninflammatory immune-complexes (ICs), which have a limited ability to induce immune responses because of the low affinity of IgG4 for both Fc receptors and the C1 complement molecule, resulting in reduced inflammatory response in SLE and RA. In another aspect, the CH2 domain of IgG4, post antibody binding with autoantigens, might become a target for rheumatoid factors (RFs) in RA. The resultant bigger ICs containing RF-IgG4-autoantigens were shown to strongly induce immune responses and to cause tissue damage in RA. In addition, the roles of IgG4-IgG1 (IgG4-IgG2 or IgG4-IgG3)-complexes and bispecific IgG4 in SLE and RA are also reviewed. Overall, IgG4 autoantibodies may act as a monitor for the pathogenesis in SLE and RA and even as a treatment for SLE.