Update on IgG4-mediated autoimmune diseases: New insights and new family members.

Antibodies of IgG4 subclass are exceptional players of the immune system, as they are considered to be immunologically inert and functionally monovalent, and as such may be part of classical tolerance mechanisms. IgG4 antibodies are found in a range of different diseases, including IgG4-related diseases, allergy, cancer, rheumatoid arthritis, helminth infection and IgG4 autoimmune diseases, where they may be pathogenic or protective. IgG4 autoimmune diseases are an emerging new group of diseases that are characterized by pathogenic, antigen-specific autoantibodies of IgG4 subclass, such as MuSK myasthenia gravis, pemphigus vulgaris and thrombotic thrombocytopenic purpura. The list of IgG4 autoantigens is rapidly growing and to date contains 29 candidate antigens. Interestingly, IgG4 autoimmune diseases are restricted to four distinct organs: 1) the central and peripheral nervous system, 2) the kidney, 3) the skin and mucous membranes and 4) the vascular system and soluble antigens in the blood circulation. The pathogenicity of IgG4 can be validated using our classification system, and is usually excerted by functional blocking of protein-protein interaction.