The Unique Properties of IgG4 and its Roles in Health and Disease

2023-09-21 Hits(208)



IgG4 is the least abundant subclass of IgG in human serum and has unique functional features. IgG4 is largely unable to activate antibody-dependent immune effector responses and, furthermore, undergoes Fab (fragment antigen binding)-arm exchange, rendering it bispecific for antigen binding and functionally monovalent. These properties of IgG4 have a blocking effect, either on the immune response or on the target protein of IgG4. In this Review, we discuss the unique structural characteristics of IgG4 and how these contribute to its roles in health and disease. We highlight how, depending on the setting, IgG4 responses can be beneficial (for example, in responses to allergens or parasites) or detrimental (for example, in autoimmune diseases, in antitumour responses and in anti-biologic responses). The development of novel models for studying IgG4 (patho)physiology and understanding how IgG4 responses are regulated could offer insights into novel treatment strategies for these IgG4-associated disease settings.




Humoral (antibody-mediated) immune responses are important for protection against pathogen invasion but can also cause disease. Antibodies recognize and bind specific structures of pathogens through their Fab (fragment antigen binding) arms. In addition to mediating direct neutralization of the pathogen, this opsonization of pathogen structures can result in the activation of various immune effector pathways through the Fc (fragment crystallizable) region of antibodies. The antibody Fc region interacts with Fc receptors on immune cells such as macrophages, neutrophils and natural killer cells, resulting in antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP). The antibody Fc region can also interact with the complement system, resulting in antibody-dependent complement deposition, which further primes pathogens for cellular uptake and destruction. The ability of an antibody to elicit these immune responses depends on the type of Fc tail and modifications thereof (for example, glycosylation). In humans, five classes of antibody are recognized based on their Fc tail: IgM, IgD, IgE, IgA and IgG. IgM antibodies are produced in the early stages of a primary, adaptive immune response. IgM and IgD form the B cell receptors (BCRs) on naive B cells. The primary IgM response can be followed by a second, long-lasting wave of IgG or IgA antibodies, the latter being involved particularly in mucosal immune responses. IgE probably evolved as a defence against parasitic worms and is also involved in various allergic diseases. Such mature antibody responses are produced by antigen-stimulated B cells that have undergone a process known as class-switch recombination, in which a B cell rearranges its DNA to produce another class of antibody with the same specificity. B cells can undergo repeated rounds of class-switch recombination until the DNA has been recombined using the most 3'Fc tail gene segment.

Four subclasses of IgG exist, numbered according to the order of abundance. IgG1 has the largest relative contribution to total IgG, followed by IgG2 then IgG3 and IgG4. Although IgG4 is the least abundant IgG subclass overall, specific responses can be dominated by IgG4, often associated with chronic or repeated antigen exposure. IgG4 has a unique set of properties compared with the other IgG subclasses that has led to IgG4 being widely regarded as an anti-inflammatory, ‘benign’ antibody that may have beneficial functions in allergic disease. However, evidence is accumulating that IgG4 also has a pathogenic role in a range of diseases. Research in the past decade has shown that IgG4 can have detrimental roles in IgG4 autoimmune diseases (IgG4-AIDs), in tumour immunology and in IgG4-related diseases (IgG4-RDs). The IgG4-AIDs and IgG4-RDs are chronic conditions and for most patients no cure currently exists. Moreover, the increasing use of biological therapies warrants a better understanding of why certain drugs elicit IgG4 anti-drug responses that limit their efficacy.


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