Sunday, November 22, 2015

Normalizing T lymphocyte metabolism treats lupus autoimmunity

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).