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Antibody Isotypes – The Devil in the Details

The immune system serves as the body’s primary defence mechanism against a wide array of infectious agents, ranging from bacteria and viruses to parasites and fungi. It is an intricate network of specialised cells, tissues, and molecules that work in concert to recognise and eliminate foreign invaders while preserving the integrity of the host organism. Coordination of the activities among the different immune cells is critical. Antibodies, products of B lymphocytes, are a unique soluble component of the immune system that engage with both foreign bodies and host innate immune cells.

Antibodies consist of two distinct regions, the Fab region, involved in antigen specificity and binding, and the Fc region involved in effector functions via Fc receptors expressed largely by innate immune cells (Figure 1). Both regions contain valuable information for research and discovery: the Fab region identifies disease-relevant proteins, including autoantigenic, and the Fc region provides information related to specific antibody functionality. While the Fab region possesses enormous diversity for identification of innumerous antigens,4 the Fc region can assume five structurally and functionally different structures, each characteristic of a different isotype: IgM, IgD, IgA, IgG, and IgE (Table 1, Figure 1). Through effector functions from both domains, antibodies help coordinate the activities of the innate and adaptive immune system, directing pathogen removal with different strategies for different pathogens. These strategies include neutralisation, agglutination, opsonisation and phagocytosis, degranulation, complement activation, and antibody-dependent cellular cytotoxicity. Pathogenesis-specific antibodies are often elicited years before a disease becomes clinically apparent. With high disease specificity, early detection, ease of obtaining, and durability during storage, antibodies make excellent biomarkers. Historically, antibodies were among the first pragmatic biomarkers used by clinicians. They make up a unique subset of the proteome, with over 1 trillion potential combinations.4 Identifying antibody specificity and isotype class within patients can improve diagnostic accuracy at early stages of disease prior to overt symptoms, has the potential to indicate anatomical/tissue compartment, most affected can provide greater precision for therapeutic intervention and improves our understanding of pathogenic mechanisms. Functional protein antigen microarrays are emerging with the capacity to simultaneously measure antibody specificity and isotypes using miniscule volumes of patient-derived biofluid. This provides a solid platform for disease understanding, antigen discovery, vaccine development, biomarker discovery, development of in vitro diagnostics, and true precision medicine.

Antibody Structure

Antibodies are produced and secreted by B lymphocytes, or B cells. Each B cell (referred to as a B cell clone) produces a unique antibody specificity that recognises a particular cognate antigen. Most antibodies can be membrane-bound or secreted into the lymph and blood. Each symmetric Y-shaped immunoglobulin is composed of two heavy and two light chains, held together by disulfide bonds. Heavy chain C-termini form the Fc region (the stem of the Y), while light chains together with heavy chain N-termini form the Fab region. Antibodies were originally classified into groups, or isotypes, by electrophoresis using Greek letters to designate each fraction.5 In addition to five distinct isotypes, four subclasses of IgG and two of IgA are also recognised. Some isotypes act as multimers, IgM can form pentamers, and IgA dimers (Figure 2). The most enigmatic isotype, IgD, exists predominantly in membrane-bound form.

At the N-terminus of the Fab region are three hypervariable loops produced through random gene segments recombination and somatic hypermutation. These loops help determine the specificity of the paratope, the region of the antibody that makes contact with a cognate epitope on an antigen. In the case of protein antigens, antibodies typically recognise non-continuous epitopes resulting from protein 3D conformational characteristics.8–10 Random recombination events result in an enormous potential antibody repertoire, up to 1018 combinations.4,11,12 While the Fab region confers antigen specificity, the Fc region interacts will soluble and cellular host components, determining antibody function. The Fc region constant domains are encoded by different genes that undergo alternative splicing and class switching during B cell development to generate the various isotypes. Class switching is irreversible, involving constant region deletional recombination.1 This region is involved in anchoring the antibody in the B cell membrane, transducing antigen-stimulated signaling, and when secreted, acts as a ligand to Fc receptors to bind with and regulate other immune cells.

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