Role of Glycine N-Methyltransferase in the Regulation of T-Cell Responses in Experimental Autoimmune Encephalomyelitis

Abstract

Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt-/mice developed hepatocellular carcinoma, we hypothesized that Gnmt-/mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T-cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was reduced significantly in Gnmt-/mice. Pathological examination of the spinal cords revealed that Gnmt-/mice had significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of proinflammatory cytokines, including interferon (IFN)-γ and interleukin (IL)-17A, were much lower in the spinal cord of Gnmt-/than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T-cell proliferation and induction of T-helper (Th)1 and Th17 cells were markedly suppressed in MOG 35-55-induced Gnmt-/mice. Moreover, the number of regulatory T (Treg) cells was increased significantly in these mice. When the T-cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were decreased significantly in Gnmt-/-CD4 + T cells via an IL-2-and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of Treg cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4 + T cells was much milder than in those with wild-type CD4 + T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4 + T-cell functions.

The risk association of plasma total homocysteine with acute myocardial infarction is modified by serum vitamin A

“…13,15,31 Notably, GNMT plays a role in the production of interferon-g, which drives synthesis of the macrophage-specific inflammatory marker neopterin. 18,32 This pteridine has been related to risk of major cardiovascular events in humans 32 and potentiated tHcy-mediated risk of CVD in the same core population as the present study. 4 Neopterin was higher among patients with elevated Vit-A in the present study, and the tHcyassociated risk we observed in our study may reflect pro-inflammatory conditions that contribute to atherosclerosis.…”

“…15 GNMT is involved not only in the regulation of intracellular homocysteine concentrations, 16 but also in lipid metabolism 17 and cellular immune activation. 18 Taken together, the association of plasma tHcy with risk of CVD may be modified by Vit-A through several biological mechanisms. However, evidence is limited, predominantly experimental and little is known about this relationship in humans.…”

“…15 GNMT is involved not only in the regulation of intracellular homocysteine concentrations, 16 but also in lipid metabolism 17 and cellular immune activation. 18…”

NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy

“…Maturation of BMDCs was determined by the upregulation of CD11c + and costimulatory molecules expression, the cells were stained with PE-conjugated anti-CD11c antibody, then with FITC-conjugated anti-CD40 or anti-CD86 antibodies (all from BD Biosciences), respectively, as described previously47. To measure percentage of CD4 + IL-17A + T cells, intracellular cytokine staining was performed and the cells were stained with APC-conjugated anti-CD4 antibody, then with PE-conjugated anti-IL-17 antibody (BD Biosciences) as described previously53. Cells were analyzed by a FACSCalibur (BD Biosciences) as described previously20.…”

An Exploratory Gene Expression Study of the Intestinal Mucosa of Patients with Non-Celiac Wheat Sensitivity

“…Glycine N-methyltransferase (GNMT) encodes a tumour suppressor gene recently associated with T cell immune response. In a mouse model of autoimmune encephalomyelitis, the knock down of GNMT reduced the severity of the disease [43]. CUB and sushi multiple domains 1 (CSMD1) is a complement control-related gene that inhibits the activation of complement C3 and has a possible role in lupus erythematosus and schizophrenia [44].…”