Manipulation of the glycan‐specific natural antibody repertoire for immunotherapy

Abstract

Summary Natural immunoglobulin derived from innate-like B lymphocytes plays important roles in the suppression of inflammatory responses and represents a promising therapeutic target in a growing number of allergic and autoimmune diseases. These antibodies are commonly autoreactive and incorporate evolutionarily conserved specificities, including certain glycan-specific antibodies. Despite this conservation, exposure to bacterial polysaccharides during innate-like B lymphocyte development, through either natural exposure or immunization, induces significant changes in clonal representation within the glycan-reactive B cell pool. Glycan-reactive natural antibodies have been reported to play protective and pathogenic roles in autoimmune and inflammatory diseases. An understanding of the composition and functions of a healthy glycan-reactive natural antibody repertoire is therefore paramount. A more thorough understanding of natural antibody repertoire development holds promise for the design of both biological diagnostics and therapies. In this article we review the development and functions of natural antibodies and examine three glycan specificities, represented in the innate-like B cell pool, to illustrate the complex roles environmental antigens play in natural antibody repertoire development. We also discuss the implications of increased clonal plasticity of the innate-like B cell repertoire during neonatal and perinatal periods, and the prospect of targeting B cell development with interventional therapies and correct defects in this important arm of the adaptive immune system.

Immunological Outcomes of Antibody Binding to Glycans Shared between Microorganisms and Mammals

“…In mammals, B cells and antibodies that react with self glycans exist naturally and function to promote homeostasis (11) by facilitating the clearance of dangerous and potentially inflammatory components, such as apoptotic cells (12), senescent red blood cells (13), and metabolic products such as oxidized lipids (14). Aside from these homeostatic functions, naturally occurring antibodies specific for mammalian glycoproteins or glycolipids recognize these structures when displayed by microorganisms as well as allergens, and can facilitate their clearance (10, 12, 15, 16).…”

“…Aside from these homeostatic functions, naturally occurring antibodies specific for mammalian glycoproteins or glycolipids recognize these structures when displayed by microorganisms as well as allergens, and can facilitate their clearance (10, 12, 15, 16). Many cellular processes such as engagement of SiglecG/CD22 (17), sequestration of autoreactive antigens (12), and induction of cellular anergy (18) exist to regulate and maintain autoreactive B cells within the B cell repertoire. In this review, we discuss the expression and interactions of B cells with selected glycan epitopes that are expressed on host cells, microbes, and allergens.…”

“…delivered anti-GlcNAc antibodies suppressed A. fumigatus -induced airway disease development (9). Serum antibodies against GlcNAc occur naturally, and may vary depending on the microbiome, blood type, as well as the history of infection (12). Accordingly, therapeutic manipulation of anti-GlcNAc antibody levels may protect against bacterial and protozoan infection as well as respiratory and food allergies associated with chitin-bearing organisms.…”

“…For example, GlcNAc subunits of mammalian glycans are usually capped by mannose or highly charged sialic acids, which prevent BCR receptor engagement (12). These antigens, which are normally sequestered intracellularly, may be exposed only as part of the apoptotic program or released during necrotic cell death.…”

Antibodies as leading tools to unlock the therapeutic potential in human disease

“…The first section covers examples of progress in areas of antibody generation and function that have so far been less understood. Specifically, the germinal center reaction in rodents and humans is reviewed, and the harnessing of the signals that contribute to this process for therapeutic intervention is discussed .…”