© 2004 Blackwell Publishing Ltd, European Journal of Immunogenetics 31, 63–71 63 Blackwell Publishing, Ltd. MICA polymorphism in a sample of the São Paulo population, Brazil M. L. C. Marin,*† C. R. Savioli,* J. H. Yamamoto,¶ Jorge Kalil*†‡ & A. C. Goldberg*‡§ Summary The major histocompatibility complex (MHC) class I chain-related A (MICA) gene, located near HLA-B, codes for protein products with structural similarities to those of classical MHC class I genes, but which neither bind β 2 - microglobulin nor present peptide. Expressed predomi- nantly on gastrointestinal and tumour epithelial cells, they are stress-induced and interact with C-type lectin like receptor (NKG2D) on γδ, αβ CD8+ T cells and natural killer (NK) cells. MICA is highly polymorphic, with 54 extracellular allelic sequences described. We typed 200 healthy subjects in a sample of the São Paulo population by extended polymerase chain reaction–sequence-specific primers (PCR-SSP) to characterize the MICA polymor- phism and analysed MICA/HLA-B linkage disequilib- rium. The MICA*008 group (g) was predominant (47%), with several HLA-B associations. Rare combina- tions MICA*008g-HLA-B37, MICA*008g-B72 and MICA*010-HLA-B52 were detected. Given the extent of this polymorphism and its possible relevance for disease association, we determined MICA and HLA-B alleles in 33 Behçet’s patients, in an attempt to clarify the associated genetic marker. Our results showed an increase of MICA*006, but not MICA*009, in the patient group (6/ 33) compared with controls (3/200) (18.2% vs. 1.5%; P c = 0.005). Both alleles were always in association with HLA-B51, suggesting that HLA-B is indeed the primary susceptibility locus ( P = 0.00008) and that MICA*006 may be an additional risk factor. Introduction The major histocompatibility complex (MHC) class I chain-related A (MICA) gene is a member of a new family of non-classical MHC molecules recently identified within the HLA class I region (Bahram et al., 1994). This family consists of seven members, MICA, -B, -C, -D, -E, -F and -G, but only the MICA and MICB genes encode expressed transcripts (Shiina et al., 1999). The MICA gene is located 46 kb centromeric to HLA-B and encodes a polypeptide of 383 amino acids (Bahram et al., 1994). Although they have a structure similar to that of MHC class I molecules, with three extracellular (α1, α2 and α3) domains, a trans- membrane (TM) domain, and a cytoplasmic tail, MICA molecules do not bind β 2 -microglobulin and show lower than usual homology (18 –30%) with classical HLA class I extracellular domains. Unlike the conventional MHC class I molecules, MICA does not require peptide ligands for cell surface expression and its pattern of tissue expression is apparently restricted. MICA products are expressed on the cell surface of gastric epithelium, endothelial cells and fibroblasts, but are not expressed on T or B cells (Groh et al., 1996; Zwirner et al., 1999). Recent studies have tried to pinpoint the function of these polymorphic molecules. Expression of MICA and MICB molecules is regulated by a short DNA segment with significant homology to heat shock protein (HSP) gene promoters and is strongly induced by stress (Groh et al., 1996). MICA and MICB molecules activate natural killer (NK), γδ T (Vδ1) and CD8+ αβ T cells through receptor, NKG2D, in conjunction with a transmem- brane signalling adapter protein, DNAX-activation pro- tein 10 (DAP10) (Bauer et al., 1999; Wu et al., 1999). More recently, Gilfillan et al. (2002) showed, in in vitro studies, that NKG2D is a versatile receptor that may provide costimulation in CD8+ T cells via DAP10. However, in DAP10-deficient mice, NK cells could mediate activation through another associated adapter, DAP12 DNAX- activation protein 10. These responses could be important in elimination of a variety of cells under stress, as happens in viral infections, in autoimmune processes and also in tumorigenesis (lung, kidney, ovary, prostate and colon carcinomas) where MICA molecules are expressed (Groh et al., 1999). In addition, it was recently shown that cytomegalovirus (CMV) upregulates the expression of MIC on cultured fibroblast and endothelial cells (Groh et al., 2001). Interaction of MICA with NKG2D * Laboratory of Immunology, Heart Institute-InCor, School of Medicine, University of São Paulo, São Paulo, Brazil, † Laboratory of Histocompatibility and Cellular Immunology, School of Medicine, University of São Paulo, São Paulo, Brazil, ‡ Institute for Investigation in Immunology, Millenium Institute, São Paulo, Brazil, § Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, Brazil and ¶ Department of Ophthalmology, School of Medicine, University of São Paulo, São Paulo, Brazil. Received 13 October 2003; revised 7 January 2004; accepted 20 January 2004 Correspondence: Anna Carla Goldberg, Laboratório de Imunologia, InCor, HC/FMUSP, Avenue Dr Enéas de Carvalho Aguiar,44, 9° andar, São Paulo, 05403-000, SP, Brazil. Tel.:/Fax: 55 11 30829350; E-mail: goldberg@usp.br