Genetic deficiency of Irgm1 (LRG-47) suppresses induction of experimental autoimmune encephalomyelitis by promoting apoptosis of activated CD4+ T cells.
The immunity-related GTPase Irgm1, also called LRG-47, is known to regulate host resistance to intracellular pathogens through multiple mechanisms that include controlling the survival of T lymphocytes. Here, we address whether Irgm1 also plays a role in the pathogenesis of experimental autoimmune encephalitis (EAE). We find that Irgm1/LRG-47 is a significant factor in the progression of EAE and multiple sclerosis (MS). Expression of Irgm1 was robustly elevated in MS-affected lesions and in the central nervous system (CNS) of myelin basic protein (MBP)-induced EAE mice, especially in cells of lymphoid and mononuclear phagocyte origin. Homozygous Irgm1 null mice were resistant to MBP-induced EAE, and CD4(+) T cells in spleen and CNS of these mice displayed decreased proliferative capacity, increased apoptosis, and up-regulated interferon (IFN)-gamma induction. Therefore, Irgm1-induced survival of autoreactive CD4(+) T cells contributes significantly to the pathogenesis of EAE. Blockade of Irgm1 may be a potential therapeutic strategy for halting multiple sclerosis.
Xu
Hongwei
H
Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and Aging, College of Physicians and Surgeons, Columbia University, 650 West 168th St., New York, NY 10032, USA.
Wu
Zhi-Ying
ZY
Fang
Fang
F
Guo
Lan
L
Chen
Doris
D
Chen
John Xi
JX
Stern
David
D
Taylor
Gregory A
GA
Jiang
Hong
H
Yan
Shirley ShiDu
SS
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D013116:Spinal Cord
C096000:Ifi1 protein, mouse; D007371:Interferon-gamma; D019204:GTP-Binding Proteins