Organ-specific autoimmunity is often characterized by
autoantibodies targeting
proteins expressed in the affected tissue. A subgroup of autoimmunopathies has recently emerged that is characterized by predominant
autoantibodies of the
IgG4 subclass (
IgG4-
autoimmune diseases;
IgG4-AID). This group includes
pemphigus vulgaris,
thrombotic thrombocytopenic purpura, subtypes of
autoimmune encephalitis, inflammatory neuropathies,
myasthenia gravis and
membranous nephropathy. Although the associated
autoantibodies target specific
antigens in different organs and thus cause diverse syndromes and diseases, they share surprising similarities in
genetic predisposition, disease mechanisms,
clinical course and response to
therapies. IgG4-AID appear to be distinct from another group of rare
immune diseases associated with
IgG4, which are the
IgG4-related diseases (IgG4-RLD), such as IgG4-related which have distinct clinical and serological properties and are not characterized by
antigen-specific
IgG4. Importantly, IgG4-AID differ significantly from diseases associated with
IgG1 autoantibodies targeting the same organ. This may be due to the unique functional characteristics of
IgG4 autoantibodies (e.g. anti-inflammatory and functionally monovalent) that affect how the
antibodies cause disease, and the differential response to
immunotherapies of the
IgG4 producing B cells/plasmablasts. These clinical and pathophysiological clues give important insight in the immunopathogenesis of IgG4-AID. Understanding
IgG4 immunobiology is a key step towards the development of novel,
IgG4 specific treatments. In this review we therefore summarize current knowledge on
IgG4 regulation, the relevance of class switching in the context of health and disease, describe the cellular mechanisms involved in
IgG4 production and provide an overview of treatment responses in IgG4-AID.