Glucose is metabolized in two pathways to fuel cellular
functions: glycolysis, which splits glucose, yielding little energy but providing pyruvate
and other materials for synthesis, and oxidative phosphorylation, which degrades glucose in the mitochondria and produces ~15-fold
more energy. Glucose uptake is a limiting in activated T lymphocytes through CD28 costimulation. Glucose metabolism is dysregulated in T lymphocytes of
patients with the autoimmune disease Systemic Lupus Erythematosus (SLE, lupus, review).
These investigators blocked glycolysis with 2-deoxy-D-glucose (2DG) and oxidative phosphorylation with metformin (Met), and observed that
disease was reduced and even reversed in mice “triple congenic” (TC) with three
lupus-predisposing genetic regions: Sle1-Sle2-Sle3 (review). 2DG is glucose with its 2-hydroxl group replaced by a
hydrogen, thereby blocking glycolysis. Met is a small molecule that was discovered in 1920s to
reduce blood glucose, probably by interfering with mitochondrial respiration. The authors show here that Met reduces
extracellular acidification rate (ECAR) and 2DG reduces oxygen consumption rate
(OCR), both measures of glucose metabolism, in activated T cells (fig. 1).
Anti-nuclear antibodies (ANA), a hallmark of lupus, are particularly
dangerous because they damage glomeruli, the kidney’s filtration units, causing
glomerular nephritis (GN). The authors
show a remarkable reduction in ANA and spleen size (fig. 4, panels, C, D and a portion of panel E shown here) as
well as improvement in kidney pathology (fig. 4 panel I)
Although these metabolism inhibitors are not targeted to pathogenic
T cells, there are no obvious adverse consequences for the animal or even the
immune system. Treated mice raise
antibody responses following protein immunization, generating normal levels and
avidities of circulating antibodies (supplemental). Perhaps the limiting effect of glucose uptake
by pathogenic, chronically activated T cells make them more sensitive to
inhibition. How treatment influences
control of chronic infections (e.g., EBV, CMV) is also worth knowing. There was no change in body weight on Met.
Testing 2 other mouse models of lupus (NZB/W and chronic graft-vs-host
(cGVH)), they found a mixture of responses. For example, in cGVH, combined treatment
doesn’t reduce spleens (though Met alone does), while treatment of NZB/W mice reduces
ANA but doesn’t improve GN. Human
patients exhibit a range of symptoms and might also be expected to show a range
of responses. This is inspired and
inspiring work that cuts across as many disciplines as it does organ systems
and raises as many questions as hopes.
Y. Yin, S.-C. Choi, Z. Xu, D. J. Perry, H. Seay, B. P.
Croker, E. S. Sobel, T. M. Brusko, L. Morel, Normalization of CD4+ T cell
metabolism reverses lupus. Sci. Transl. Med. 7, 274ra18 (2015). 
