Celiac disease (CD) is a malabsorptive disorder precipitated in genetically susceptible individuals by ingestion ofgluten . A significant part of the disease predisposition maps to the HLA class II region, but the primary HLA association is not known (1) . DR3 seems to be a susceptibility allele together with any other DR allele while DR7 is associated to CD almost only in combination with DR3 or DR5 (2, 3).The HLA-DR3DQw2 haplotype demonstrates the strongest association to CD (1-5) . We investigated whether DR3DQw2 negative patients might share parts of the genetic information ofthis HLA haplotype but encoded in trans position. When we compared amino acid sequences of different DQa and DQß chains we found that the DQa chain encoded by the DR3DQw2 haplotype is identical to that encoded by DR5DQw7 (6, 7), while the DQß chain of the DR3DQw2 haplotype is identical to that of DR7DQw2 except for a single amino acid difference in the second domain (8, 9; Lee, J. S., personal communication) . The pairing of a and ß chains seems to be determined by amino acid residues located in the first domains (10). Thus, individuals wao are DR5DQw7/DR7DQw2 heterozygous may by transcomplementation express the same (or almost the same) DQ a/0 heterodimers as those formed by DQAl and DQBI genes in cis position on the DR3DQw2 haplotype (see Fig . 1). As a first step to confirm this hypothesis we typed 94 CD children with synthetic DQA1 and DQB1 allele-specific oligonucleotide (ASO) probes. Here we report that all except one ofthese CD patients carry DQAI and DQB1 genes that may encode the same DQ a/ß heterodimer.

SummaryCeliac disease (CD) is most probably an immunological disease, precipitated in susceptible individuals by ingestion of wheat gliadin and related proteins from other cereals. The disease shows a strong human HLA association predominantly to the c/s or trans encoded HLA-DQ(o~I*O5OI,fll*0201) (DQ2) heterodimer. T cell recognition of gliadin presented by this DQ heterodimer may thus be of immunopathogenic importance in CD. We therefore challenged small intestinal biopsies from adult CD patients on a gluten-free diet in vitro with gluten (containing both gliadin and other wheat proteins), and isolated activated CD25 + T cells. Polyclonal T cell lines and a panel of T cell clones recognizing gluten were established. They recognized the gliadin moiety of gluten, but not proteins from other cereals. Inhibition studies with anti-HLA antibodies demonstrated predominant antigen presentation by HLA-DQ molecules. The main antigen-presenting molecule was established to be the CD-associated DQ(oel*0501, fl1"0201) heterodimer. The gluten-reactive T cell clones were CD4 +, CD8-, and carried diverse combinations of T cell receptor (TCR) Vc~ and Vfl chains. The findings suggest preferential mucosal presentation of gluten-derived peptides by HLA-DQ(c~I*OSO1,BI*0201) in CD, which may explain the HLA association.

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