Summary
Genes in the HLA complex are by far the most important in determining genetic predisposition or resistance to Type 1 (insulin-dependent) diabetes mellitus. In this review evidence is presented that the HLA genes mainly involved are those encoding some particular HLA-DQ molecules. Both among Black, Caucasian and Japanese subjects particular cis or trans encoded DQ molecules are significantly associated with susceptibility, while others are associated with resistance. A varying degree of susceptibility or resistance seems to be conferred by these DQ molecules, where those determining resistance are dominant over those determining susceptibility. The degree of genetic predisposition to develop Type 1 diabetes carried by an individual would therefore be the result of his or her particular combination of DQ molecules. A primary association to particular DQ molecules explains previously found associations to other HLA complex genes by linkage disequilibrium. Some mechanisms by which particular DQ molecules may determine susceptibility or resistance are also discussed. Potential islet beta-cell reactive CD4+ T-cells may escape negative selection (deletion) in the thymus, but normally become anergized or remain ignorant extra-thymically. However, under particular circumstances they may be triggered. The DQ molecules associated with Type 1 diabetes susceptibility may preferentially bind and present triggering and/or beta-cell derived peptides to such T cells, causing beta-cell destruction. The finding that particular DQ molecules determine susceptibility may lead to new methods of preventing development of Type 1 diabetes in susceptible individuals.
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References
Barnett AH, Eff C, Leslie RDG, Pyke DA (1981) Diabetes in identical twins. Diabetologia 20: 87–93
Deschamps I, Lestradet H, Busson M, Hors J (1984) Evaluation of recurrence risk in siblings of diabetic children: importance of age and birth order in relation to HLA genotypes. Diabetes Res 1: 125–135
RØnningen KS, Spurkland A, Tait BD et al. (1993) HLA class II associations in insulin-dependent diabetes mellitus among Blacks, Caucasoids and Japanese. In: HLA 1991. Oxford University Press, Oxford, pp
Trowsdale J, Campbell RD (1992) Complexity in the major histocompatibility complex. Eur J Immunogenetics 19: 43–55
Bodmer JG, Marsch SGE, Albert ED et al. (1992) Nomenclature for factors of the HLA system, 1991. Tissue Antigens 39: 161–173
Tiwari JL, Terasaki PI (1985) Juvenile diabetes mellitus (insulin-dependent) In: Tiwari JL, Terasaki PI (eds) HLA and disease associations. Springer Verlag, New York, pp 185–210
Awata T, Kuzuya T, Matsuda A et al. (1990) High frequency of aspartic acid at position 57 of HLA-DQ Β-chain in Japanese Type 1 diabetes patients and nondiabetic subjects. Diabetes 39: 266–269
Thomson G, Robinson WP, Kuhner MK et al. (1988) Genetic heterogeneity, models of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet 43: 799–816
Owerbach D, Lernmark å, Platz P et al. (1983) HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals. Nature 303: 815–817
Cohen-Haguenauer O, Robbins E, Busson M et al. (1985) A systematic study of HLA class II-Β DNA restriction fragments in insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 82: 3335–3339
Festenstein H, Award J, Hitman GA et al. (1986) New HLA DNA polymorphisms associated with autoimmune diseases. Nature 322: 64–67
Nepom BS, Palmer J, Kim SJ et al. (1986) Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis. J Exp Med 164: 345–350
Owerbach D, Gunn S, Gabby KH (1989) Primary association of HLA-DQw8 with Type I diabetes in DR4 patients. Diabetes 38: 942–945
Nepom BS, Schwartz D, Palmer JP, Nepom GT (1987) Transcomplementation of HLA genes in Type 1 diabetes. HLA-DQ α- and Β-chains produce hybrid molecules in DR3/4 heterozygotes. Diabetes 36: 114–117
Todd JA, Bell JI, McDevitt HO (1987) HLA-DQΒ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 559–604
RØnningen KS, Iwe T, Halstensen TS, Spurkland A, Thorsby E (1989) The amino acid at position 57 of the HLA-DQΒ chain and susceptibility to develop insulin-dependent diabetes mellitus (type 1 diabetes). Human Immunol 26: 215–225
Lundin KEA, RØnningen KS, Aono S et al. (1989) HLA-DQ antigens in Japanese patients with insulin-dependent diabetes mellitus. Detection of a DRw8 DQw8 haplotype. Tissue Antigens 34: 233–241
Khalil I, dAuriol L, Gobet M et al. (1990) A combination of HLA-DQΒ Asp57-negative and HLA-DQα Arg52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest 85: 1315–1319
Khalil I, Deschamps I, Lepage V, Al-Daccak R, Degos L, Hors J (1992) Dose effect of cis and trans-encoded HLA-DQαΒ heterodimers in Type 1 diabetes susceptibility. Diabetes 41: 378–384
Vicario JL, Martinez-Laso J, Corell A et al. (1992) Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as type 1 (insulin-dependent) diabetes mellitus predictive risk markers in the Spanish population. Diabetologia 35: 475–481
RØnningen KS, Spurkland A, Iwe T, Vartdal F, Thorsby E (1991) Distribution of HLA-DRB1, -DQA1 and -DQB1 alleles and DQA1-DQB1 genotypes among Norwegian patients with insulin-dependent diabetes mellitus. Tissue Antigens 37: 105–111
Sheeny MJ, Scharf SJ, Rowe JR et al. (1989) A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles. J Clin Invest 83: 830–835
Deschamps I, Marcelli-Barge A, Poirier JC et al. (1988) Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in type 1 (insulin-dependent) diabetes. Diabetologia 31: 896–901
Degli-Esposti MA, Abraham LJ, McCann V et al. (1992) Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of type 1 diabetes. Immunogenetics 36: 345–356
Colonna M, Bresnahan M, Bahram S, Strominger JL, Spies T (1992) Allelic variants of the human putative peptide transporter involved in antigen processing. Proc Natl Acad Sci USA 89: 3932–3936
RØnningen KS, Gjertsen HA, Iwe T, Spurkland A, Hansen T, Thorsby E (1991) Particular HLA-DQ αΒ heterodimer associated with type 1 diabetes susceptibility in both DR4-DQw4 Japanese and DR4-DQw8/DRw8-DQw4 whites. Diabetes 40: 759–763
Kwok WW, Schwartz D, Nepom B, Thurtle P, Hock R, Nepom GT (1988) HLA-DQ molecules from α-Β heterodimers of mixed allotype. J Immunol 141: 312–327
Gjertsen HA, Lundin KEA, RØnningen KS, Gaudernack G, Thorsby E (1991) A T lymphocyte clone recognizing a DQ αΒ heterodimer encoded in cis by the DR4-DQw4 haplotype and in trans by DR4-DQw8/DR8-DQw4 heterozygous cells. Human Immunol 30: 226–232
Garcia-Pacheco JM, Herbut B, Cutbush S et al. (1992) Distribution of HLA-DQA1, -DQB1 and DRB1 alleles in black type 1 diabetes patients and controls from Zimbabwe. Tissue Antigens 40: 145–149
Erlich HA, Griffith RL, Bugawan TL et al. (1991) Implication of specific DQB1 alleles in genetic susceptibility and resistance by identification of type 1 diabetes siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes. Diabetes 40: 478–481
Zeliszewski D, Tiercy J-M, Boitard C et al. (1992) Extensive study of DRB, DQA, and DQB gene polymorphism in 23 DR2-positive, insulin-dependent diabetes mellitus patients. Human Immunol 33: 140–147
Charron D (1989) Molecular basis of human leukocyte antigen class II disease associations. Adv Immunol 48: 107–159
Bain SC, Prins JB, Hearne CM et al. (1992) Insulin gene region-encoded susceptibility to Type 1 diabetes is not restricted to HLA-DR4-positive individuals. Nature Genetics 2: 212–215
Cooke A (1990) An overview on possible mechanisms of destruction of the insulin-producing beta cell. Curr Top Microbiol Immunol 164: 125–142
Rothbard JB, Gefter ML (1991) Interactions between immunogenic peptides and MHC proteins. Annu Rev Immunol 9: 527–565
BjØrkman PJ, Saper MA, Samraoui B et al. (1987) Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329: 506–518
O'Sullivan D, Sidney J, Appella E et al. (1990) Characterization of the specificity of peptide binding to four DR haplotypes. J Immunol 145: 1799–1808
Blackman M, Kappler J, Marrack P (1990) The role of the T cell receptor in positive and negative selection of developing T cells. Science 248: 1335–1341
Schwartz RH (1990) A cell culture model for T lymphocyte clonal anergy. Science 248: 1349–1355
Zinkernagel RM, Pircher HP, Ohashi P et al. (1991) T and B cell tolerance and responses to viral antigens in transgenic mice: implications for the pathogenesis of autoimmune versus immunopathological disease. Immunol Rev 122: 133–171
Bottazzo GF, Bosi E, Bonifacio E, Mirakian R, Todd I, Pujol-Borrell R (1989) Pathogenesis of type 1 (insulin-dependent) diabetes: possible mechanisms of autoimmune damage. Brit Med Bull 45: 37–57
Karjalainen J, Julio MD, Martin MD et al. (1992) A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 327: 302–307
Möller E, Böhme J, Valugerdi MA, Ridderstad A, Olerup O (1990) Speculation on mechanisms of HLA associations with autoimmune diseases and the specificity of autoreactive T lymphocytes. Immunol Rev 118: 5–19
Pujol-Borrell R, Todd I, Doshi M et al. (1987) HLA class II induction in human islet cells by interferon-γplus tumour necrosis factor or lymphotoxin. Nature 326: 304–306
Nepom GT (1990) An unified hypothesis for the complex genetics of HLA associations with Type 1 diabetes. Diabetes 39: 1153–1157
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Thorsby, E., RØnningen, K.S. Particular HLA-DQ molecules play a dominant role in determining susceptibility or resistance to Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 36, 371–377 (1993). https://doi.org/10.1007/BF00402270
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DOI: https://doi.org/10.1007/BF00402270