Regulation of autoimmunity by genetic and metabolic control of N-glycosylation

Multiple sclerosis (MS) is a T-cell mediated autoimmune/inflammatory demyelinating disease of the central nervous system with poorly understood genetic-environmental interaction. Women develop MS almost twice as often as men. Cell surface glycans modified by beta1,6 N-acetylglucosaminyltransferase V (Mgat5), an enzyme in the N-glycosylation pathway, have been shown to negatively regulate T-cell receptor (TCR) activation signaling, CTLA-4 mediated growth arrest, T-cell proliferation. T helper (Th) I differentiation and autoimmunity in mice. TCR associated Mgat5-modified glycans act as ligands for galectins sequestering TCR within a galectin-glycoprotein lattice restricting TCR clustering at the immune synapse and inhibiting cell activation and proliferation. Experimental autoimmune encephalomyelitis (EAE, a murine model of MS) susceptible mouse strains PL/J, SJL, and NOD (Non-obese diabetic) have reduced Mgat5-modified glycans. PL/J mice display the lowest levels, partial deficiencies in N-acetylalucosaminyltransferase I, II and V (i.e. Mgat1, 2 and 5). T-cell hyperactivity and spontaneous late onset inflammatory demyelination and neurodegeneration. GlcNAc treatment reduces the symptoms of autoimmune diseases in EAE-susceptible mouse strains, both PL/J and NOD. Further understanding genetic and metabolic control of autoimmunity provides a therapeutic strategy to regulate genetic determinants of autoimmunity. Estrogen, 17 beta-estradiol (E2), promotes T-cell activation by reducing Mgat5-modified N-glycans. These findings will stimulate further studies in the study of autoimmunity including its sexual dimorphism.