In the context of immunology, allotypes are defined as detectable variations in immunoglobulins in particular constant regions. They differ from idiotypes, which are the unique antigenic markers found on the variable domains of antigen binding receptors. Allotypes exist due to polymorphisms on the genes encoding the immunoglobulin polypeptide chain in the germ line. Therefore, polymorphic epitopes can be found on immunoglobulin constant regions on both heavy and light chains.1,2
In 1956, allotypes were first identified by ex vivo studies where certain donor sera caused agglutination of erythrocytes treated with human incomplete anti-Rh antibody.2 Now, there are known allotypes on the heavy chains of IgG1, IgG2, IgG3, and IgA2 (G1m, G2m, G3m, A2m allotypes), as well as on the kappa light chains (Km allotypes).3,4
Allotypes may be investigated for potential in monoclonal antibody therapeutics because while pathogenic targets can be neutralized by directly binding to antibody variable domains, when they are bound to the constant domain with specialized Fc receptors, this can trigger highly potent inflammatory or anti-inflammatory responses.5
Typically, therapeutic antibodies are of the IgG1 isotype. To prevent potential immune reactions, the constant region of the gamma1 chains can be modified by replacing the G1m3 allotype with the G1m17 allotype, which is considered to have lower immunogenicity.6
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Grubb, R. (1956). Agglutination Of Erythrocytescoated With “Incomplete” Anti-Rh By Certain Rheumatoid Arthritic Sera And Some Other Sera. Acta Pathologica Microbiologica Scandinavica, 39(3), 195–197. https://doi.org/10.1111/J.1699-0463.1956.TB03392.X
De Lange, G.G. (1989). Polymorphisms of human immunoglobulins: Gm, Am, Em and Km allotypes. Exp. Clin. Immunogenet. 6, 7-17.
Jefferis, R., & Lefranc, M. P. (2009). Human immunoglobulin allotypes: possible implications for immunogenicity. mAbs, 1(4), 332–338. https://doi.org/10.4161/mabs.1.4.9122
Warrender, A. K., & Kelton, W. (2020). Beyond Allotypes: The Influence of Allelic Diversity in Antibody Constant Domains. Frontiers in Immunology, 11, 569371. https://doi.org/10.3389/FIMMU.2020.02016/BIBTEX
Antibodies are versatile molecules that perform a range of effector functions, many of which engage different arms of the immune system. Their modes of action extend beyond simple antigen binding, enabling the activation of various immune mechanisms that lead to pathogen neutralization and clearance. These functions include blocking molecular interactions, activating the complement system, and linking the humoral immune response to cellular immune responses via Fc receptor engagement.
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In addition to isotypes and subtypes, antibodies exhibit genetic variation known as allotypes, which are polymorphic epitopes on immunoglobulins. These allotypic differences arise from allelic variations in immunoglobulin genes, causing certain antibody subtypes to differ between individuals or ethnic groups. The presence of these polymorphic forms can influence immune responses, particularly when an individual is exposed to a non-self allotype, potentially triggering an anti-allotype immune reaction.
In mammals, antibodies are classified into five major isotypes: IgA, IgD, IgE, IgG, and IgM. Each isotype is defined by the heavy chain it contains: alpha (IgA), delta (IgD), epsilon (IgE), gamma (IgG), or mu (IgM). These structural differences in the heavy chains determine the antibody's function, tissue localization, and role in the immune response. Furthermore, antibody light chains fall into two classes—kappa and lambda—with kappa being more common, though both exhibit similar functions despite differences in sequence.
