Discovery of Novel Human Biomarkers using Variable Lymphocyte Receptor Antibodies of the Sea Lamprey

Diversity, specificity, and memory are the fundamentals of vertebrate immunity – an intricate system that arose in response to the necessary cohabitation of vertebrates with the most ancient forms of life as we know it, namely microbial life. Although microorganisms are a cause of disease, another critical postulate or determinant is the capacity or capability of one’s immune system. In other words, the same pathogen will not be harmful to all individuals and disease can arise from the immune system itself. Notably, cancer, autoimmunity, and viral infection expose the limitations of human immunity. Not unlike how we observe interindividual variation in disease susceptibility and immune capacity, differences are amplified when we compare different species. Can the strengths of an alternate immune system address the restrictions of ours? Recently, immunologists have acknowledged that organisms as evolutionarily distant as jawless vertebrates are also endowed with adaptive immunity. Pancer and colleagues were the first to elucidate the molecular origins of adaptive immunity in a lamprey. Adaptive immunity in this jawless fish functions through cells and mechanisms of shared ancestry with those of other vertebrates. In stark contrast however, lampreys rely upon distinct antigen receptors analogous but not homologous to T cell receptors and immunoglobulins. For research and therapeutic purposes, lamprey antibodies are potentially novel tools that may target markers of disease not readily recognized by mammalian immune systems and to which immunoglobulin antibodies are not easily elicited. We hypothesize that the evolutionary distance separating sea lampreys and humans, as well as the unique architecture of lamprey variable lymphocyte receptor antibodies can address tolerogenic constraints of mammalian immune systems, and structural constraints of immunoglobulins. Here, we detail strategies for isolating serum biomarker-specific variable lymphocyte receptor antibodies that may detect, diagnose, or prognose disease. Additionally, we characterize the variable lymphocyte receptor VLRB N8 antibody whose binding specifically to antigen-experienced human B cells is unlike that of any known antibody. Thus, we have described a potential plasma and memory B cell-specific modification of human leukocyte antigen class I, the antigen bound by VLRB N8, and gained insight into B cell biology.Ph.D