The increased lactate secretion by B cells from people with obesity and aging is a stimulus for pathogenic autoimmune anti-dsDNA antibodies. The effects of lactate are mediated by phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and inhibited by a neutralizing antibody that blocks the lactate transporter SLC5A12, responsible for lactate uptake and activation of inflammatory and pathogenic responses.

ABSTRACT

Lactate is a metabolite with immunoregulatory functions. We evaluated lactate secretion and its effects on B cells from individuals with different body composition: Y_LEAN, Y_OBESE, and E_LEAN individuals. Results show higher serum metabolic profiles in Y_OBESE and E_LEAN versus Y_LEAN individuals, evaluated by levels of lactate dehydrogenase, the enzyme that converts pyruvate into lactate, which is associated with increased secretion of lactate in blood-derived B cells. Double negative (DN) B cells, which expand in the blood of Y_OBESE and E_LEAN individuals, are the major contributors to this metabolic profile. When lactate was added in vitro to B cells from Y_LEAN, Y_OBESE, and E_LEAN individuals, we found increased secretion of pathogenic autoimmune antibodies in B cells from Y_LEAN, compared to those from Y_OBESE and E_LEAN individuals, likely because B cells from Y_OBESE or E_LEAN individuals have already been exposed to, and chronically stimulated by lactate in vivo, becoming refractory to further stimulation. Mechanistically, the effects of lactate are mediated by phosphorylated signal transducer and activator of Transcription 3 (p-STAT3). These effects are inhibited in the presence of a neutralizing antibody that blocks the lactate transporter SLC5A12, responsible for lactate uptake and activation of inflammatory and pathogenic responses, and p-STAT3.