A New Classification System for IgG4 Autoantibodies

Abstract

IgG4 autoimmune diseases are characterized by the presence of antigen-specific autoantibodies of the IgG4 subclass and contain well-characterized diseases such as muscle-specific kinase myasthenia gravis, pemphigus, and thrombotic thrombocytopenic purpura. In recent years, several new diseases were identified, and by now 14 antigens targeted by IgG4 autoantibodies have been described. The IgG4 subclass is considered immunologically inert and functionally monovalent due to structural differences compared to other IgG subclasses. IgG4 usually arises after chronic exposure to antigen and competes with other antibody species, thus "blocking" their pathogenic effector mechanisms. Accordingly, in the context of IgG4 autoimmunity, the pathogenicity of IgG4 is associated with blocking of enzymatic activity or protein-protein interactions of the target antigen. Pathogenicity of IgG4 autoantibodies has not yet been systematically analyzed in IgG4 autoimmune diseases. Here, we establish a modified classification system based on Witebsky's postulates to determine IgG4 pathogenicity in IgG4 autoimmune diseases, review characteristics and pathogenic mechanisms of IgG4 in these disorders, and also investigate the contribution of other antibody entities to pathophysiology by additional mechanisms. As a result, three classes of IgG4 autoimmune diseases emerge: class I where IgG4 pathogenicity is validated by the use of subclass-specific autoantibodies in animal models and/or in vitro models of pathogenicity; class II where IgG4 pathogenicity is highly suspected but lack validation by the use of subclass specific antibodies in in vitro models of pathogenicity or animal models; and class III with insufficient data or a pathogenic mechanism associated with multivalent antigen binding. Five out of the 14 IgG4 antigens were validated as class I, five as class II, and four as class III. Antibodies of other IgG subclasses or immunoglobulin classes were present in several diseases and could contribute additional pathogenic mechanisms.

Keywords: IgG4; IgG4 autoimmunity; IgG4-related disease; autoimmunity; muscle-specific kinase myasthenia gravis; neuronal autoantibodies; pemphigus; thrombotic thrombocytopenic purpura.

Figure 1

The structure of IgG4 allows for Fab-arm exchange (FAE). (A) Structure of IgG4. One single amino acid change in the IgG4 hinge allows for greater structural flexibility and two different hinge isomers, with either interchain disulfide bonds that connect the two different heavy chains, or intrachain disulfide bridges within the same heavy chains. Under reducing conditions, the two isoforms are in a dynamic equilibrium. Figure adapted from Ref. (147). (B) When the two half-antibodies (HL) are not connected by interchain disulfide bonds they can then split up. HL of different idiotypes recombine randomly, resulting in antibodies that recognize two different antigens and are bispecific. (C) Antibodies are produced with light chains of either κ or λ type. Upon FAE, antibodies with both κ and λ light chains can be generated.

Figure 2

IgG4 autoantibodies rely on pathogenic mechanisms that are independent of Fc effector function or multivalent binding.

Figure 3

Selected pathogenic mechanisms of IgG autoantibodies. (A) Pathogenic mechanisms of IgG4 autoantibodies. * = hypogalactosylated glycan side chain of IgG4. (B) Selected pathogenic mechanisms of IgG1–3 autoantibodies.