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Human Molecular Genetics, 2001, Vol. 10, No. 19 2025-2037
© 2001 Oxford University Press

A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins

Francesco Cucca+, Rosannna Lampis, Mauro Congia, Efisio Angius1, Sarah Nutland2, Stephen C. Bain3, Anthony H. Barnett3 and John A. Todd2

Dipartimento di Scienze Biomediche e Biotecnologie, University of Cagliari, Via Jenner, Cagliari 09121, Italy, 1Servizio di Diabetologia Pediatrica, Ospedale G.Brotzu, Via Peretti, Cagliari, Italy, 2JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK and 3Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK

In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.

+ To whom correspondence should be addressed. Tel: +39 070 6095681; Fax: +39 070 6095558; Email: fcucca@mcweb.unica.it Correspondence may also be addressed to John Todd at: Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, UK. Tel: +44 1223 762101; Fax: +44 1223 762102; Email: john.todd@cimr.cam.ac.uk


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