Obesity Accelerates Age Defects in Human B Cells and Induces Autoimmunity

Aging is associated with systemic inflammation and decreased production of protective antibodies while the production of autoimmune antibodies is increased. Our results have shown that the human obese adipose tissue (AT), which increases in size with aging, contributes to systemic and B cell intrinsic inflammation, reduced protective and increased pathogenic B cell responses leading to increased secretion of autoimmune antibodies. With this R56 funding, we have been able to investigate the cellular and molecular mechanisms by which the human obese AT induces intrinsic B cell inflammation and dysfunctional B cell responses, stimulates the secretion of autoimmune antibodies, whose specificity has been characterized, and engages different AT cell types in antigen presentation pathways to allow secretion of these autoimmune antibodies. Briefly, immune cells are recruited to the AT by chemokines released by both non-immune (adipocytes) and by resident and infiltrating immune cells. We have identified several mechanisms responsible for the release of "self" antigens, and we have shown that reduced oxygen availability and hypoxia, cell cytotoxicity and DNA damage induce cell death and lead to further release of pro-inflammatory cytokines, "self" protein antigens, cell-free DNA and lipids. We have also identified different antigen presenting cells in the AT, responsible for the activation of pathogenic B cells, class switch and secretion of autoimmune IgG antibodies. The experiments performed have allowed the discovery of novel mechanisms for pathogenic responses and the identification of pathways to target in order to promote better humoral immunity during aging.