Covalent Binding Antibodies Suppress Advanced glycation: On the Innate Tier of Adaptive Immunity

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Non-enzymatic protein glycation is a source of metabolic stress that contributes to cytotoxicity and tissue damage. Hyperglycemia has been linked to elevation of advanced glycation endproducts, which mediate much of the vascular pathology leading to diabetic complications. Enhanced glycation of immunoglobulins and their accelerated vascular clearance is proposed as a natural mechanism to intercept alternative advanced glycation endproducts, thereby mitigating microvascular disease. We reported that antibodies against the glycoprotein KLH have elevated reactivity for glycopeptides from diabetic serum. These reactions are mediated by covalent binding between antibody light chains and carbonyl groups of glycated peptides. Diabetic animals that were immunized to induce reactive antibodies had attenuated diabetic nephropathy, which correlated with reduced levels of circulating and kidney-bound glycation products. Molecular analysis of antibody glycation revealed the preferential modification of light chains bearing germline-encoded lambda V regions. We previously noted that antibody fragments carrying V regions in the germline configuration are selected from a human Fv library by covalent binding to a reactive organophosphorus ester. These Fv fragments were specifically modified at light chain V region residues, which map to the combining site at the interface between light and heavy chains. These findings suggest that covalent binding is an innate property of antibodies, which may be encoded in the genome for specific physiological purposes. This hypothesis is discussed in context with current knowledge of the natural antibodies that recognize altered self molecules and the catalytic autoantibodies found in autoimmune disease.

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The generation of an enormous diversity of antibodies in response to the multitude of possible antigens is a signature of instructive or adaptive immunity. The structural basis for adaptive immunity is expressed in the variability of the antigen binding sites displayed on antibodies and B cell receptors. Thus, antibodies are conventionally associated with the genetic recombination and accumulated mutations in their variable (V) regions that incrementally improve the complementarity between the antibody combining site and groups on the antigen. In contrast to affinity that matures gradually over time through multiple weak interactions, binding through strong forces such as a covalent bond could enable a more rapid and efficient way to capture certain antigens. Is there any case where antibodies use this form of binding and what purpose could such a binding mechanism serveAntibodies that bind ligands covalently have been sought in approaches to generate enzyme-like catalytic antibodies (1). Covalent binding is used by enzymes to stabilize reactive intermediates in catalysis of many types of reactions. Reactive immunization was conceived as a strategy to elicit antibodies that bind their ligands through a covalent complex (2). Such antibody complexes might mimic enzyme intermediates to catalyze the transformation of the bound substrate. The premise assumes that this form of binding could be evoked through the conventional affinity maturation process for antibody induction. Implicitly, such antibodies would have experimentally conferred, and therefore artificial, activity. In the prototypical example, immunization against synthetic antigens containing a reactive dicarbonyl group provided antibodies that bind through Schiff base - enamine adducts. The covalently reactive clones were shown to possess remarkable aldolase activity (2). As predicted, the covalent binding function arises from the somatically mutated V region genes, positioning one or more nucleophilic lysine residues in the combining site (3).
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