Metabolic Reprogramming Is Required for Antibody Production That Is Suppressed in Anergic but Exaggerated in Chronically BAFF-Exposed B Cells

Abstract

Summary B cell activation leads to proliferation and antibody production that can protect from pathogens or promote autoimmunity. Regulation of cell metabolism is essential to support the demands of lymphocyte growth and effector function and may regulate tolerance. Here, we tested the regulation and role of glucose uptake and metabolism in the proliferation and antibody production of control, anergic, and autoimmune-prone B cells. Control B cells had a balanced increase in lactate production and oxygen consumption following activation, with proportionally increased glucose transporter Glut1 expression and mitochondrial mass upon either LPS or BCR stimulation. This contrasted with metabolic reprogramming of T cells, which had lower glycolytic flux when resting but disproportionately increased this pathway upon activation. Importantly, tolerance greatly affected B cell metabolic reprogramming. Anergic B cells remained metabolically quiescent, with only a modest increase in glycolysis and oxygen consumption with LPS stimulation. B cells chronically stimulated with elevated B cell Activating Factor (BAFF), however, rapidly increased glycolysis and antibody production upon stimulation. Induction of glycolysis was critical for antibody production, as glycolytic inhibition with the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA) sharply suppressed B cell proliferation and antibody secretion in vitro and in vivo. Further, B cell-specific deletion of Glut1 led to reduced B cell numbers and impaired antibody production in vivo. Together, these data show that activated B cells require Glut1-dependent metabolic reprogramming to support proliferation and antibody production that is distinct from T cells and that this glycolytic reprogramming is regulated in tolerance.

Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming

“…Activated dendritic cells, M1 macrophages, and effector T cells can switch their metabolic program from oxidative phosphorylation to aerobic glycolysis to meet the bioenergetic and biosynthetic demands of cell growth or effector functions (6,8,9). Although B cells share several features with T cells, it has recently been reported that B cells increase their rate of both glycolysis and oxidative phosphorylation in a relatively balanced fashion upon BCR or LPS stimulation (10). Moreover, in the intestinal immune system, IgA + plasma cells in the intestinal lamina propria use both glycolytic and oxidative metabolism, whereas naive B cells in Peyer's patches preferentially use oxidative metabolism (11).…”

Comparison of the effect of the aerobic glycolysis inhibitor dichloroacetate and of the Krebs cycle inhibitor LW6 on cellular and humoral alloimmunity

“…In addition, although upon activation murine B-cells exhibit a balanced increase in lactate production and oxygen consumption, the induction of glycolysis is critical for B-cell proliferation and antibody production since DCA abrogated both of these processes (14). However, in that study, the human B cells, when used, were isolated and stimulated with a TLR9 activator (14).…”

“…On the other hand, in a murine model of collagen type II-induced arthritis, DCA alleviated arthritis only in female mice, in which it decreased anti-collagen type II antibodies without affecting the T cell response (30). In addition, although upon activation murine B-cells exhibit a balanced increase in lactate production and oxygen consumption, the induction of glycolysis is critical for B-cell proliferation and antibody production since DCA abrogated both of these processes (14). However, in that study, the human B cells, when used, were isolated and stimulated with a TLR9 activator (14).…”

“…There is evidence that upon activation, B cells enhance both aerobic glycolysis and the Krebs cycle in a balanced manner (12)(13)(14). Glutamine again serves as a major Krebs cycle source (15).…”

A laktátdehidrogenáz (LDH) prognosztikai jelentősége az onkológiában

“…A B-sejtekre, a T-sejtekkel szemben, nem jellemző, hogy aktivá-lásuk hatására fokozódik a glikolízis. Azonban a glikolí-zis gátlása vagy a GLUT-1 B-sejt-specifikus deletiója in vivo csökkenti az antitesttermelést [31]. Így valószínűleg a B-sejtek egy csoportja közrejátszik a daganat általi tejsavtermelésben [4].…”