Exploring the depths of IgG4: insights into autoimmunity and novel treatments

Abstract

IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.

Keywords: IgG4; IgG4-AID; IgG4-RD; antibodies; immunotherapies.

Figure 1

Structure of antibodies, isotypes and IgG subclasses. (A) Antibodies are dimeric structures that consist of two identical antigen-binding sites, known as the variable region (VH and VL). This region, called the fragment-antigen binding (Fab) region, is formed by the combination of the light chain and the heavy chain and is the antigen binding site of the antibody. The hinge region connects the Fab region to the constant region (Fc region, CH1-CH3), which determines the antibody’s isotype and function. (B) The isotypes of IgM and IgD are associated with less experienced, or “naïve,” cells. IgM is found as a pentamer. (C) IgG, IgA, and IgE are linked to more matured antibodies. IgA has the ability to form dimeric structures, while IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4. IgG4 subclass antibodies can undergo Fab-arm exchange, allowing them to become bispecific. Figure created with Biorender.com.

Figure 2

CD20 expression on B cells and T cells. B cells. CD20 is expressed at almost all stages of B cell maturation, with the exception of plasma cells, Pro-B cells, and Pre-B-I cells. T cells. A small number of T cells express CD20, and there are three main theories explaining how these cells acquire CD20: One explanation proposes that T cells may acquire CD20 through trogocytosis, involving simultaneous transfer from B cells. Alternatively, CD20 acquisition might occur during T cell activation or result from the clonal expansion of CD20-expressing T cells. Figure created with Biorender.com.