Despite the paradigm that carbohydrates are T cell-independent antigens, isotype-switched glycan-specific IgG antibodies and polysaccharide-specific T cells are found in humans. We employed a systems level approach combined with glycan array technology to decipher the repertoire of carbohydrate-specific IgG antibodies in intravenous and subcutaneous immunoglobulin (IVIG/SCIG) preparations. A strikingly universal architecture of this repertoire with modular organization among different donor populations revealed an association between immunogenicity or tolerance and particular structural features of glycans. Antibodies were identified with specificity not only for microbial antigens, but for a broad spectrum of host glycans that serve as attachment sites for viral and bacterial pathogens and/or exotoxins. Tumor-associated carbohydrate antigens were differentially detected by IgG antibodies, while non-IgG2 reactivity was predominantly absent. Our study highlights the power of systems biology approaches to analyze immune responses and reveals potential glycan antigen determinants that are relevant to vaccine design, diagnostic assays, and antibody-based therapies.
Various pathological processes are accompanied by release of high amounts of free heme into the circulation. We demonstrated by kinetic, thermodynamic, and spectroscopic analyses that antibodies have an intrinsic ability to bind heme. This binding resulted in a decrease in the conformational freedom of the antibody paratopes and in a change in the nature of the noncovalent forces responsible for the antigen binding. The antibodies use the molecular imprint of the heme molecule to interact with an enlarged panel of structurally unrelated epitopes. Upon heme binding, monoclonal as well as pooled immunoglobulin G gained an ability to interact with previously unrecognized bacterial antigens and intact bacteria. IgG-heme complexes had an enhanced ability to trigger complement-mediated bacterial killing. It was also shown that heme, bound to immunoglobulins, acted as a cofactor in redox reactions. The potentiation of the antibacterial activity of IgG after contact with heme may represent a novel and inducible innate-type defense mechanism against invading pathogens.
Polyspecific antibodies represent a first line of defense against infection and regulate inflammation, properties hypothesized to rely on their ability to interact with multiple antigens. We demonstrated that IgG exposure to pro-oxidative ferrous ions or to reactive oxygen species enhances paratope flexibility and hydrophobicity, leading to expansion of the spectrum of recognized antigens, regulation of cell proliferation, and protection in experimental sepsis. We propose that ferrous ions, released from transferrin and ferritin at sites of inflammation, synergize with reactive oxygen species to modify the immunoglobulins present in the surrounding microenvironment, thus quenching pro-inflammatory signals, while facilitating neutralization of pathogens.The immune system is capable of producing a large and diverse repertoire of antibodies that can recognize a wide variety of different molecular structures and conformations. Three models for antibodyantigen interactions have been described, differing by the role of molecular flexibility. The "lock-and-key" model proposes binding between geometrically optimized partners without substantial structural alterations. In contrast, antibodies that recognize epitopes according to the "induced fit" model undergo significant structural reorganization upon binding, resulting in increased antibody-antigen complementarity (1-3). Although the first model is typical for antigen recognition by affinity-matured antibodies, the second one is intrinsic for germ line antibodies (2-5). The "conformational isomerism" model proposes that a single antibody molecule may adopt several different binding site conformations, independently of the presence of the antigen. These antibody isomers exist in equilibrium and each may recognize unrelated antigens (6 -8).An antibody molecule that relies on the use of active site flexibility for antigen binding (according to the last two models) is usually capable of accommodating a large number of structurally unrelated antigens (2, 8 -10); i.e. such an antibody is polyspecific. Polyspecific antibodies in healthy individuals represent Ͼ20% of all circulating antibodies. They play a major role in preventing pathogen dissemination in pre-immune organisms through enhanced antigen trapping (11), a property attributed to their ability to bind multiple unrelated antigens (12). Interestingly, polyspecificity of a fraction of IgG antibodies, present in all healthy individuals, can be induced in vitro by transient exposure to protein-destabilizing agents (low or high pH, high salt concentration, or chaotropic agents) (13, 14), without concomitant denaturation of the immunoglobulin molecules. Thus, in their native state, these IgGs recognize a limited panel of antigens, but exposure to the destabilizing agents leads to a dramatic expansion of the spectrum of recognized antigens. The molecular mechanism and the biological significance of this "hidden" polyspecificity remain unclear. It is also not known whether this phenomenon occurs in vivo and whether the highl...
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