W5 - Human Aging, Autoimmunity, and Palmitate: The Fatty Acid Palmitate Induces Human B Cell Metabolic Reprograming and Autoimmunity in Aging and Obesity

This study demonstrates that increased palmitate in vitro mimics obesity-accelerated age defects including auto-antibodies in human B cells. Participants were young (30-50 years) and elderly (≥65 years), both lean (BMI< 24.9) and obese (BMI≥30).
Plasma and stimulated B cells from young lean (Y_L), elderly lean (E_L), young obese (Y_O), and elderly obese (E_O), analyzed for malondialdehyde (MDA) and adipocyte-derived (AD) “self” protein-specific IgG antibodies showed E_L greater than Y_L, Y_O equivalent to E_L, E_O greater than Y_O and E_L for both AD and MDA-specific antibodies, as well as for lipid accumulation, as evaluated by staining with LipidTOX.
We have previously shown that the secretion of autoimmune antibodies relies on an effective metabolic reprogramming needed to support B cell function. Therefore, we evaluated by mitostress test and Seahorse technology the metabolic profile of B cells from Y_L and E_L individuals, stimulated with CpG in the presence or absence of the fatty acid, palmitate. Results demonstrated that palmitate increased age defects in B cells from Y_L individuals inducing the secretion of IgG autoimmune antibodies and mRNA expression of T-bet, the transcription factor associated with autoimmunity, similar to levels observed in E_L individuals. Palmitate also induced an increase in the RNA expression of metabolic enzymes and extracellular acidification rate (ECAR) in CpG-stimulated B cells from both Y_L and E_L individuals, consistent with a metabolic switch to anaerobic glycolysis, necessary for expansion of pathogenic B cells. This study emphasizes the role of lipids/fatty acids in decreased B cell function in human aging and obesity.