Innate antibodies revealed: Roles in homeostasis, autoimmunity and infection

Abstract

In ancestral sharks, 450 MYA, a rapid emergence in the evolution of the immune system occurred, giving jawed vertebrates the necessary components for the combinatorial immune response (CIR). To test the hypothesis that the natural antibody (NAb) repertoire of vertebrate species has the capacity to recognize any given antigen, and contains antigen-specific antibodies with consequent innate effector functions, we isolated NAbs from sharks and humans using a variety of antigens by immune-affinity chromatography. Sharks and humans have NAbs to TCR Valpha/Vbeta domains and lambda light chains that are directed against epitopes of the CDR1 and FR3. Both species additionally have NAbs to the human senescent cell antigen, which functions by marking aged cells for removal by phagocytes, as well as to numerous HIV proteins. Sharks and humans, therefore, representing the evolutionary extremes of species sharing the CIR, have NAbs to a broad range of antigens, indicating that essential features of the combinatorial repertoire and the capacity to recognize the potential universe of antigens is shared amongst jawed vertebrates. We have also generated B cell hybridomas from a patient with SLE that secrete natural IgG or IgM mAbs specific to the human Jurkat TCR and found that both affinity-purified and monoclonal anti-TCR NAbs demonstrated essentially the same activities in that they react with the CDR1 and FR3 segments. Lastly, building upon the finding that sharks and humans have NAbs to HIV, we included anti-HIV mAbs that were generated from HIV-infected persons in our studies. In addition to opsonizing, neutralizing or directing complement to their targets, some antibodies with the innate ability to mediate catalysis have been described. Based partly upon the fundamental aspects of TCR and Ig structure and function studied by this research group thus far, we specifically manipulated an innate activity of some antibodies by pairing the heavy chain from an anti-HIV mAb with a kappa light chain with known catalytic activity, thereby generating an anti-HIV catalytic antibody. In doing so, we establish proof of concept in that antibodies can be engineered with specific catalytic activity and generate support of antibodies as innate players of the combinatorial immune system.