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

Abstract

Glycans constitute basic cellular components of living organisms across biological kingdoms (Table 1), and glycan-binding antibodies participate in many cellular interactions during immune defense against pathogenic organisms (Figure 1). Glycan epitopes are expressed as carbohydrate-only entities or as oligomers or polymers on proteins and lipids. Such epitopes on glycoproteins may be formed by post-translational modifications or neoepitopes resulting from metabolic/catabolic processes, and can be altered during inflammation. Pathogenic organisms can display host-like glycans to evade the host immune response. However, antibodies to glycans, shared between microorganisms and the host, exist naturally. These antibodies are able to not only protect against infectious disease, but are also involved in host housekeeping functions and can suppress allergic disease. Despite the reactivity of these antibodies to glycans shared between microorganisms and host, diverse tolerance-inducing mechanisms permit the B cell precursors of these antibody-secreting cells to exist within the normal B cell repertoire.

Bacterially derived synthetic mimetics of mammalian oligomannose prime antibody responses that neutralize HIV infectivity

“…There is of course some concern that, if elicited, anti-glycan antibodies could cross-react with shared glyco-epitopes on human glycoproteins, leading to autoimmune disorders. At least some of this concern is allayed by the observation that antibodies to shared epitopes have been shown to reside in the body naturally without readily causing autoimmune manifestation 38 . Nevertheless, the development of autoreactive antibodies by a vaccine would likely be undesirable.…”

Serum alpha-mannosidase as an additional barrier to eliciting oligomannose-specific HIV-1-neutralizing antibodies

“…For practical purposes, the mimetic was conjugated initially to BSA 31 . 6 We subsequently conjugated it to CRM 197 , a more clinically apt carrier protein 34 that stimulates robust T-follicular helper (Tfh) responses [35][36][37][38] . As before 31 , the glycomimetic, equipped at the reducing end with an amine linker, was conjugated to lysine residues present on the protein carrier, via an isothiocyanate intermediate.…”

“…The occurrence of these oligomannose-type glycans, even though not abundant, may be sufficient to limit the frequency of naïve B cells with receptors capable of binding oligomannose or render such 'self-reactive' B cells anergic 5 . Indeed, tolerance mechanisms are known to limit the repertoire frequency of naïve B cells with capacity to bind host glycan structures 6 . The identification of B cells with autoreactive signatures in HIV-infected individuals [7][8][9] , including those from whom oligomannose-specific bnAbs have been recovered 9 , has strengthened the notion that eliciting bnAbs, at least those to nominal self-glycans, may require tolerance restrictions to be overcome in some manner.…”

Development of smart anti-glycan reagents using immunized lampreys

“…Historically, mice have been the prototypical model system to generate mAbs to protein and glycan antigens. However, investigators have had difficulties in generating a broad repertoire of anti-glycan mAbs due to the limitations inherit within the murine immune system, such as self-tolerance 17,39 . We set out to more directly compare murine vs. lamprey systems for generating antiglycan antibodies, by immunizing with human type AB erythrocytes and inactivated Simian immunodeficiency virus (SIV) particles by three separate intraperitoneal injections every 2 weeks (3×).…”