Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
The Variant of MHC Class I Polypeptide-Related Sequence (MICA) Is a Genetic Risk Factor for SLE Independent of HLA-DRB1 and Modulates the Behavior of NK Cell Via NKG2D Receptor.
Yoshida1, Kohsuke, Komai2, Koichiro, Shiozawa7, Kazuko, Mashida2, Aya, Horiuchi6, Takahiko, Tanaka4, Yuki, Nose5, Masato
Dept. of Biophysics, Kobe Univ. Graduate School of Health Sciences, Kobe, Hyogo, Japan
Dept. of Biophysics, Kobe Univ. Graduate School of Health Sciences, Kobe, Japan
Dept. of Biophysics, Kobe Univ. Graduate School of Health Sciences/Department of Medicine, Kobe University Graduate School of Medicine/The Center for Rheumatic Diseases, Kobe University Hosp., Kobe, Japan
Dept. of Clinical Immunology, Rheumatology, and Infectious Diseases, Kyushu Univ., Fukuoka, Japan
Dept. of Pathogenomics, Ehime Univ. Graduate School of Medicine, Ehime, Japan
Div. of Genome Analysis, Medicine Institute of Bioregulation, Kyushu Univ., Fukuoka, Japan
Rheumatic Diseases Center, Konan-Kakogawa Hosp., Kakogawa, Japan
MIC (MHC class I polypeptide-related sequence) molecules interacts with NKG2D (natural-killer group 2, member D) and stimulates NK cells to release cytokines such as IFNg and to exert cytotoxicity against its cellular targets. The expression of MICA is normally restricted to the intestinal and thymic epithelium, but is often aberrantly expressed on rheumatoid synovial cells or peripheral blood CD14+ monocytes in patients with SLE. The MICA gene is located within the human leukocyte antigen (HLA) locus, and its exon5 coding transmembrane (TM) region contains a polymorphic microsatellite, which is classified according to the number of alanine-encoding GCT repeats as A4, A5, A5.1, A6 and A9. A single nucleotide polymorphism (SNP) at codon 129 in exon 3 of the MICA gene, Val129Met (rs1051792), has been shown to modulate the affinity of MICA to the NKG2D receptor. We previously showed that MICA 129Met and A9 alleles are genetically associated with the Japanese patients with SLE (Arthritis Rheum. 58: suppl (9). S815, 2008), but the genetic linkage between MICA 129, TM polymorphism and HLA-DRB1 in patients with SLE and the effect of MICA polymorphism on the function of NK cell remain unclear. Here, we show that MICA 129Met/A9 is a genetic risk factor for Japanese patients with SLE independent of HLA-DRB1 and modulates the behavior of NK cell via NKG2D receptor.
Japanese patients with SLE (n = 677) or controls (n = 350) were genotyped for MICA Val129Met (rs1051792), TM polymorphism and HLA-DRB1. The recombinant MICA-GST fusion proteins 129Val/A5 or 129Met/A9, which combine polymorphisms at 129Val and TMA5 or 129Met and TMA9, respectively, were tested on NK cell line NK92MI for the expression of NKG2D receptor, NK cell-mediated cytotoxicity against K562 target cells and IFNg production.
The MICA 129Met/A9 allele was significantly increased in the patients with SLE as compared with control: 178/647 (27.5%) vs. 56/321 (17.4%) (P < 0.001; OR = 1.6). Importantly, the frequency of MICA 129Met/A9 allele was also significantly increased in the patients with SLE: 24/100 (24.0%) vs. 31/234 (13.2%) (P= 0.01; OR = 2.2) as in the case with the population negative for the HLA-DRB1 *1501 previously indicated as the risk allele for SLE in the Japanese population. When the disease-associated MICA 129Met/A9 protein was incubated with NK92MI cells, it significantly suppressed both the expression of cell surface NKG2D on NK92MI cells and the NK cell-mediated cytotoxicity against K562 cells more strongly than those with the most prevalent non-disease-associated MICA 129Val/A5 (P < 0.05 and P < 0.01, respectively). These findings are consistent with previous findings showing that NK cell cytotoxicity is significantly decreased in SLE. Interestingly, we also observed that the 129Met/A9 protein enhanced the release of IFNg from NK92MI cells as compared with 129Val/A5 protein (P < 0.01), possibly because MICA 129Met variant has been shown to be higher affinity to the NKG2D receptor than the 129Val variant.
The MICA polymorphism is genetically associated with SLE independent of HLA-DRB1*1501, and MICA appears to contribute to the pathogenesis of SLE by modulating NK cell function.
To cite this abstract, please use the following information:
Yoshida, Kohsuke, Komai, Koichiro, Shiozawa, Kazuko, Mashida, Aya, Horiuchi, Takahiko, Tanaka, Yuki, et al; The Variant of MHC Class I Polypeptide-Related Sequence (MICA) Is a Genetic Risk Factor for SLE Independent of HLA-DRB1 and Modulates the Behavior of NK Cell Via NKG2D Receptor. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :511