Nature and functions of autoantibodies

Abstract

Antibodies that react with self-molecules occur in healthy individuals and are referred to as natural antibodies or autoantibodies. Natural autoantibodies are mainly IgM, are encoded by unmutated V(D)J genes and display a moderate affinity for self-antigens. They provide a first line of defense against infections, probably serve housekeeping functions and contribute to the homeostasis of the immune system. By contrast, high-affinity, somatically mutated IgG autoantibodies reflect a pathologic process whereby homeostatic pathways related to cell clearance, antigen-receptor signaling or cell effector functions are disturbed. In some autoimmune disorders, autoantibodies might be present before disease onset, show remarkable specificity and serve as biomarkers providing an opportunity for diagnosis and therapeutic intervention. In organ-specific autoimmune diseases, such as myasthenia gravis or pemphigus, autoantibodies directly bind to and injure target organs. In systemic autoimmune diseases, autoantibodies react with free molecules, such as phospholipids, as well as cell surface and nucleoprotein antigens, forming pathogenic antigen-antibody (immune) complexes. These autoantibodies injure tissues and organs through engagement of Fc gammaR activation of complement as well as internalization and activation of Toll-like receptors. Activation of intracellular Toll-like receptors in plasmacytoid dendritic cells leads to the production of type I interferon, whereas engagement of intracellular Toll-like receptors on antigen-presenting cells stimulates cell activation and the production of other inflammatory cytokines. Thus, immune complexes might perpetuate a positive feedback loop amplifying inflammatory responses.

Figure 1

Pathogenic autoantibodies cause inflammation and tissue injury. (A) Autoantibodies produced by B lymphocytes bind to self-antigens released by apoptotic or necrotic cells, forming antigen–antibody (immune) complexes. When antigens in the immune complexes contain nucleic acids and are endocytosed by pDCs, Toll-like receptors are activated and the pDCs secrete interferon-α. This cytokine activates B and T lymphocytes as well as APCs such as macrophages and dendritic cells. In addition, the immune complexes might be phagocytosed by APCs resulting in the release of other inflammatory cytokines (tumor necrosis factor-α, interleukin-6) and chemokines. (B) Immune complexes deposit in the vessels as well as the kidneys and lungs. The immune complexes activate inflammatory pathways through interaction with FcγRs and complement. Abbreviations: APC, antigen-presenting cell; pDC, plasmacytoid dendritic cell.