The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis
GENES AND IMMUNITY
Authors: Alcina, A.; Vandenbroeck, K.; Otaegui, D.; Saiz, A.; Gonzalez, J. R.; Fernandez, O.; Cavanillas, M. L.; Cenit, M. C.; Arroyo, R.; Alloza, I.; Garcia-Barcina, M.; Antigueedad, A.; Leyva, L.; Izquierdo, G.; Lucas, M.; Fedetz, M.; Pinto-Medel, M. J.; Olascoaga, J.; Blanco, Y.; Comabella, M.; Montalban, X.; Urcelay, E.; Matesanz, F.
Abstract
Genome-wide association studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously associated with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be associated with MS: rs1678542 in KIF5A (P = 0.001, odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.05-1.23); rs3184504 in SH2B3 (P = 0.00001, OR = 1.19, 95% CI = 1.10-1.27) and rs763361 in CD226 (P = 0.00007, OR = 1.16, 95% CI 1.08-1.25). These variants have previously been associated with rheumatoid arthritis and type 1 diabetes. The SH2B3 polymorphism has additionally been associated with systemic lupus erythematosus. Our results, in addition to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases. These data may help to shape the contribution of each pathway to different disorders. Genes and Immunity (2010) 11, 439-445; doi: 10.1038/gene.2010.30; published online 27 May 2010
Increased CD226 Expression on CD8(+) T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis
JOURNAL OF IMMUNOLOGY
Authors: Ayano, Masahiro; Tsukamoto, Hiroshi; Kohno, Kentaro; Ueda, Naoyasu; Tanaka, Atsushi; Mitoma, Hiroki; Akahoshi, Mitsuteru; Arinobu, Yojiro; Niiro, Hiroaki; Horiuchi, Takahiko; Akashi, Koichi
Abstract
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8(+) T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8(+) T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8(+) T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8(+) T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226 high CD8(+) T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226(+)CD8(+) T cells produced higher amount of various cytokines than CD226 2 ones, and CD226 high CD8(+) T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8(+) T cells against HUVECs. Finally, the neutralization of CD226 in CD8(+) T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8(+) T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.
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