Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA

Journal of Clinical Investigation

Volumn 125, Issue 1, 2015, Pages 275-291

  Miyadera, Hiroko ^a,b   Ohashi, Jun ^c,e   Lernmark, Åke ^d   Kitamura, Toshio ^e   Tokunaga, Katsushi ^a  

^a UNIVERSITY OF TOKYO   (Japan)

^b NATIONAL CENTER FOR GLOBAL HEALTH AND MEDICINE   (Japan)

^c UNIVERSITY OF TSUKUBA   (Japan)

^d LUND UNIVERSITY   (Sweden)

^e UNIVERSITY OF TOKYO   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

HLA DQ ANTIGEN; HLA DQA1 ANTIGEN;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; AUTOIMMUNITY; CASE CONTROL STUDY; CONTROLLED STUDY; DISEASE ASSESSMENT; GENETIC RISK; GENETIC VARIABILITY; HAPLOTYPE; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; JAPANESE (PEOPLE); NONHUMAN; PROTEIN LOCALIZATION; PROTEIN STABILITY; SWEDISH CITIZEN; 3T3 CELL LINE; AMINO ACID SUBSTITUTION; ANIMAL; CELL MEMBRANE; GENE FREQUENCY; GENETIC POLYMORPHISM; GENETIC PREDISPOSITION; GENETICS; METABOLISM; MOLECULAR EVOLUTION; MOUSE;

AMINO ACID SUBSTITUTION; ANIMALS; CASE-CONTROL STUDIES; CELL MEMBRANE; DIABETES MELLITUS, TYPE 1; EVOLUTION, MOLECULAR; GENE FREQUENCY; GENETIC PREDISPOSITION TO DISEASE; HLA-DQ ANTIGENS; HUMANS; MICE; NIH 3T3 CELLS; POLYMORPHISM, GENETIC; PROTEIN STABILITY;

EID: 84920381515     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI74961     Document Type: Article

References (141)

1. Jones EY, Fugger L, Strominger JL, Siebold C. MHC class II proteins and disease: a structural perspective. Nat Rev Immunol. 2006;6(4):271-282.
2. Price P, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev. 1999;167:257-274.
3. de Bakker PI, et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 2006;38(10):1166-1172.
4. Fernando MM, et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008;4(4):e1000024.
5. Rioux JD, et al. Mapping of multiple susceptibility variants within the MHC region for 7 immunemediated diseases. Proc Natl Acad Sci U S A. 2009;106(44):18680-18685.
6. Weinstock C, et al. Autoimmune polyglandular syndrome type 2 shows the same HLA class II pattern as type 1 diabetes. Tissue Antigens. 2011;77(4):317-324.
7. National Human Genome Research Institute. Division of Genomic Medicine. A Catalog of Published Genome-Wide Association Studies. NIH Web site. http://www.genome.gov/gwas-tudies/. Updated November 9, 2014. Accessed November 10, 2014.
8. Kawabata Y, et al. Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and-DQ haplotypes to susceptibility to type 1 diabetes. Diabetes. 2002;51(2):545-551.
9. Katahira M, Ishiguro T, Segawa S, Kuzuya-Nagao K, Hara I, Nishisaki T. Reevaluation of human leukocyte antigen DR-DQ haplotype and genotype in type 1 diabetes in the Japanese popula-tion. Horm Res. 2008;69(5):284-289.
10. Kawabata Y, et al. Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset. Diabetologia. 2009;52(12):2513-2521.
11. Hashimoto K, et al. Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandu-lar syndrome type III in Japanese population. Horm Res. 2005;64(5):253-260.
12. Matsushita S, Takahashi K, Motoki M, Komoriya K, Ikagawa S, Nishimura Y. Allele specificity of structural requirement for peptides bound to HLA-DRB1∗0405 and-DRB1∗0406 complexes: implication for the HLA-associated susceptibility to methimazole-induced insulin autoimmune syndrome. J Exp Med. 1994;180(3):873-883.
13. Wucherpfennig KW, et al. Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris. Proc Natl Acad Sci U S A. 1995;92(25):11935-11939.
14. Wall M, et al. High affinity for class II molecules as a necessary but not sufficient characteristic of encephalitogenic determinants. Int Immunol. 1992;4(7):773-777.
15. Valli A, et al. Binding of myelin basic protein pep-tides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients. J Clin Invest. 1993;91(2):616-628.
16. Wucherpfennig KW, et al. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med. 1994;179(1):279-290.
17. Yu B, Gauthier L, Hausmann DH, Wucherpfennig KW. Binding of conserved islet peptides by human and murine MHC class II molecules associated with susceptibility to type I diabetes. Eur J Immunol. 2000;30(9):2497-2506.
18. Hall FC, et al. Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes. Eur J Immunol. 2002;32(3):662-670.
19. Fairchild PJ, Wildgoose R, Atherton E, Webb S, Wraith DC. An autoantigenic T cell epitope forms unstable complexes with class II MHC: a novel route for escape from tolerance induction. Int Immunol. 1993;5(9):1151-1158.
20. Mason K, Denney DW, Denney DW Jr, McCon-nell HM. Myelin basic protein peptide complexes with the class II MHC molecules I-Au and I-Ak form and dissociate rapidly at neutral pH. J Immunol. 1995;154(10):5216-5227.
21. Fugger L, Liang J, Gautam A, Rothbard JB, McDe-vitt HO. Quantitative analysis of peptides from myelin basic protein binding to the MHC class II protein, I-Au, which confers susceptibility to experimental allergic encephalomyelitis. Mol Med. 1996;2(2):181-188.
22. Muraro PA, et al. Immunodominance of a low-affinity major histocompatibility complex-binding myelin basic protein epitope (residues 111-129) in HLA-DR4 (B1∗0401) subjects is associated with a restricted T cell receptor repertoire. J Clin Invest. 1997;100(2):339-349.
23. Boyton RJ, et al. Glutamic acid decarboxylase T lymphocyte responses associated with susceptibility or resistance to type I diabetes: analysis in disease discordant human twins, non-obese diabetic mice and HLA-DQ transgenic mice. Int Immunol. 1998;10(12):1765-1776.
24. He XL, Radu C, Sidney J, Sette A, Ward ES, Garcia KC. Structural snapshot of aberrant antigen presentation linked to autoimmunity: the immu-nodominant epitope of MBP complexed with I-Au. Immunity. 2002;17(1):83-94.
25. Levisetti MG, Suri A, Petzold SJ, Unanue ER. The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form. J Immunol. 2007;178(10):6051-6057.
26. Levisetti MG, Lewis DM, Suri A, Unanue ER. Weak proinsulin peptide-major histocompatibil-ity complexes are targeted in autoimmune diabetes in mice. Diabetes. 2008;57(7):1852-1860.
27. Stadinski BD, et al. Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol. 2010;11(3):225-231.
28. Stadinski BD, Zhang L, Crawford F, Marrack P, Eisenbarth GS, Kappler JW. Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Proc Natl Acad Sci U S A. 2010;107(24):10978-10983.
29. Crawford F, et al. Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. Proc Natl Acad Sci U S A. 2011;108(40):16729-16734.
30. Ettinger RA, Kwok WW. A peptide binding motif for HLA-DQA1∗0102/DQB1∗0602, the class II MHC molecule associated with dominant protection in insulin-dependent diabetes mellitus. J Immunol. 1998;160(5):2365-2373.
31. Harfouch-Hammoud E, et al. Identification of peptides from autoantigens GAD65 and IA-2 that bind to HLA class II molecules predisposing to or protecting from type 1 diabetes. Diabetes. 1999;48(10):1937-1947.
32. Astill TP, Ellis RJ, Arif S, Tree TIM, Peakman M. Promiscuous binding of proinsulin pep-tides to type 1 diabetes-permissive and-protective HLA class II molecules. Diabetologia. 2003;46(4):496-503.
33. Carrasco-Marin E, Shimizu J, Kanagawa O, Unanue E. The class II MHC I-Ag7 molecules from non-obese diabetic mice are poor peptide binders. J Immunol. 1996;156(2):450-458.
34. Reizis B, et al. Molecular characterization of the diabetes-associated mouse MHC class II protein, I-Ag7. Int Immunol. 1997;9(1):43-51.
35. Nabavieh A, et al. Development of an I-Ag7-expressing antigen-presenting cell line: Intrinsic molecular defect in compact I-Ag7 dimer generation. J Autoimmun. 1998;11(1):63-71.
36. Ettinger RA, Liu AW, Nepom GT, Kwok WW. Exceptional stability of the HLA-DQA1∗0102/DQB1∗0602 αβ protein dimer, the class II MHC molecule associated with protection from insulin-dependent diabetes mellitus. J Immunol. 1998;161(11):6439-6445.
37. Sadegh-Nasseri S, Germain RN. How MHC class II molecules work: peptide-dependent completion of protein folding. Immunol Today. 1992;13(2):43-46.
38. Nelson CA, Petzold SJ, Unanue ER. Identification of two distinct properties of class II major histocompatibility complex-associated peptides. Proc Natl Acad Sci U S A. 1993;90(4):1227-1231.
39. Verreck FA, Termijtelen A, Koning F. HLA-DR β chain residue 86 controls DR αβ dimer stability. Eur J Immunol. 1993;23(6):1346-1350.
40. Nelson C, et al. Amino acid residues on the I-Ak α-chain required for the binding and stability of two antigenic peptides. J Immunol. 1996;156(1):176-182.
41. Nelson CA, Viner NJ, Young SP, Petzold SJ, Unanue ER. A negatively charged anchor residue promotes high affinity binding to the MHC class II molecule I-Ak. J Immunol. 1996;157(2):755-762.
42. Wu S, Gorski J, Eckels DD, Newton-Nash DK. T cell recognition of MHC class II-associated peptides is independent of peptide affinity for MHC and sodium dodecyl sulfate stability of the peptide/MHC complex. Effects of conservative amino acid substitutions at anchor position 1 of influenza matrix protein19-31. J Immunol. 1996;156(10):3815-3820.
43. Reizis B, Altmann DM, Cohen IR. Biochemical characterization of the human diabetes-associated HLA-DQ8 allelic product: Similarity to the major histocompatibility complex class II I-Ag7 protein of non-obese diabetic mice. Eur J Immunol. 1997;27(10):2478-2483.
44. Natarajan SK, Stern LJ, Sadegh-Nasseri S. Sodium dodecyl sulfate stability of HLA-DR1 complexes correlates with burial of hydrophobic residues in pocket 1. J Immunol. 1999;162(6):3463-3470.
45. Ettinger RA, Liu AW, Nepom GT, Kwok WW. β57-Asp plays an essential role in the unique SDS stability of HLA-DQA1∗0102/DQB1∗0602 αβ protein dimer, the class II MHC allele associated with protection from insulin-dependent diabetes mellitus. J Immunol. 2000;165(6):3232-3238.
46. Verreck FAW, et al. The generation of SDS-stable HLA DR dimers is independent of efficient peptide binding. Int Immunol. 1996;8(3):397-404.
47. Norcross MA, Bentley DM, Margulies DH, Germain RN. Membrane Ia expression and antigen-presenting accessory cell function of L cells transfected with class II major histocompatibility complex genes. J Exp Med. 1984;160(5):1316-1337.
48. Austin P, Trowsdale J, Rudd C, Bodmer W, Feldmann M, Lamb J. Functional expression of HLA-DP genes transfected into mouse fibroblasts. Nature. 1985;313(5997):61-64.
49. Sant AJ, Hendrix LR, Coligan JE, Maloy WL, Germain RN. Defective intracellular-transport as a common mechanism limiting expression of inappropriately paired class-Ii major histocom-patibility complex alpha/beta chains. J Exp Med. 1991;174(4):799-808.
50. Ceman S, Wu S, Jardetzky TS, Sant AJ. Alteration of a single hydrogen bond between class II molecules and peptide results in rapid degradation of class II molecules after invariant chain removal. J Exp Med. 1998;188(11):2139-2149.
51. Arneson LS, Katz JF, Liu M, Sant AJ. Hydrogen bond integrity between MHC class II molecules and bound peptide determines the intracellu-lar fate of MHC class II molecules. J Immunol. 2001;167(12):6939-6946.
52. Kitamura T, et al. Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics. Exp Hematol. 2003;31(11):1007-1014.
53. Morita S, Kojima T, Kitamura T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 2000;7(12):1063-1066.
54. Giles RC, DeMars R, Chang CC, Capra JD. Allelic polymorphisms and transassociation of molecules encoded by the HLA-DQ subregion. Proc Natl Acad Sci U S A. 1985;82(6):1776-1780.
55. Nepom BS, Schwarz D, Palmer JP, Nepom GT. Transcomplementation of HLA genes in IDDM. HLA-DQ alpha-and beta-chains produce hybrid molecules in DR3/4 heterozygotes. Diabetes. 1987;36(1):114-117.
56. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary association of celiac disease to a particular HLA-DQ α/β het-erodimer. J Exp Med. 1989;169(1):345-350.
57. Ronningen KS, Markussen G, Iwe T, Thorsby E. An increased risk of insulin-dependent diabetes mellitus (IDDM) among HLA-DR4, DQw8/DRw8, DQw4 heterozygotes. Hum Immunol. 1989;24(3):165-173.
58. Khalil I, Deschamps I, Lepage V, al-Daccak R, Degos L, Hors J. Dose effect of cis-and trans-encoded HLA-DQ αβ heterodimers in IDDM susceptibility. Diabetes. 1992;41(3):378-384.
59. Koeleman BPC, et al. Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease. Genes Immun. 2004;5(5):381-388.
60. Kwok W, Schwarz D, Nepom B, Hock R, Thur-tle P, Nepom G. HLA-DQ molecules form α-β heterodimers of mixed allotype. J Immunol. 1988;141(9):3123-3127.
61. Kwok W, Thurtle P, Nepom G. A genetically controlled pairing anomaly between HLA-DQα and HLA-DQβ chains. J Immunol. 1989;143(11):3598-3601.
62. Kwok W, Kovats S, Thurtle P, Nepom G. HLA-DQ allelic polymorphisms constrain patterns of class II heterodimer formation. J Immunol. 1993;150(6):2263-2272.
63. Raymond CK, et al. Ancient haplotypes of the HLA class II region. Genome Res. 2005;15(9):1250-1257.
64. Moore K, Cooper SA, Jones DB. Use of the monoclonal antibody WR17, identifying the CD37 gp40-45 Kd antigen complex, in the diagnosis of B-lym-phoid malignancy. J Pathol. 1987;152(1):13-21.
65. Monos DS, Czanky E, Ono SJ, Radka SF, Kappes D, Strominger JL. L cells expressing DQ molecules of the DR3 and DR4 haplotypes: reactivity patterns with mAbs. Immunogene tics. 1995;42(3):172-180.
66. Kozono H, White J, Clements J, Marrack P, Kappler J. Production of soluble MHC class II proteins with covalently bound single peptides. Nature. 1994;369(6476):151-154.
67. Busch R, Cloutier I, Sekaly RP, Hammerling GJ. Invariant chain protects class II histocompat-ibility antigens from binding intact polypep-tides in the endoplasmic reticulum. EMBO J. 1996;15(2):418-428.
68. Fallang L-E, et al. Complexes of Two Cohorts of CLIP Peptides and HLA-DQ2 of the Autoimmune DR3-DQ2 Haplotype Are Poor Substrates for HLA-DM. J Immunol. 2008;181(8):5451-5461.
69. Henderson KN, et al. A structural and immu-nological basis for the role of human leukocyte antigen DQ8 in celiac disease. Immunity. 2007;27(1):23-34.
70. Siebold C, et al. Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc Natl Acad Sci U S A. 2004;101(7):1999-2004.
71. Reichstetter S, et al. Mutational analysis of critical residues determining antigen presentation and activation of HLA-DQ0602 restricted T-cell clones. Hum Immunol. 2002;63(3):185-193.
72. Kim CY, Quarsten H, Bergseng E, Khosla C, Sollid LM. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci U S A. 2004;101(12):4175-4179.
73. Lee KH, Wucherpfennig KW, Wiley DC. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol. 2001;2(6):501-507.
74. Hughes AL, Nei M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature. 1988;335(6186):167-170.
75. Hughes AL, Nei M. Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci U S A. 1989;86(3):958-962.
76. Yang Z, Bielawski JP. Statistical methods for detecting molecular adaptation. Trends Ecol Evol. 2000;15(12):496-503.
77. Pugliese A, et al. The 13th International Histocom-patibility Working Group for Type 1 Diabetes (T1D) Joint Report. In: Hansen JA, editor. Immunobiology of the Human MHC: Proceedings of the 13th International Histocompatibility Workshop and Congress. Vol 1. Seattle, Washington, USA: IHWG Press; 2007:788-796.
78. Steenkiste A, et al. 14th International HLA and Immunogenetics Workshop: report on the HLA component of type 1 diabetes. Tissue Antigens. 2007;69(suppl 1):214-225.
79. Thomson G, et al. Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analy-sis. Tissue Antigens. 2007;70(2):110-127.
80. Erlich H, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008;57(4):1084-1092.
81. Noble JA, Johnson J, Lane JA, Valdes AM. HLA class II genotyping of African American type 1 diabetic patients reveals associations unique to African haplotypes. Diabetes. 2013;62(9):3292-3299.
82. Park Y, et al. Common susceptibility and transmission pattern of human leukocyte antigen DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes. J Clin Endo-crinol Metab. 2000;85(12):4538-4542.
83. Bugawan TL, et al. The association of specific HLA class I and II alleles with type 1 diabetes among Filipinos. Tissue Antigens. 2002;59(6):452-469.
84. Redondo MJ, et al. DR-and DQ-associated protection from type 1A diabetes: comparison of DRB1∗1401 and DQA1∗0102-DQB1∗0602. J Clin Endocrinol Metab. 2000;85(10):3793-3797.
85. Khalil I, et al. A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest. 1990;85(4):1315-1319.
86. Sanjeevi CB, Landin-Olsson M, Kockum I, Dahl-quist G, Lernmark Å. The combination of several polymorphic amino acid residues in the DQα and DQβ chains forms a domain structure pattern and is associated with insulin-dependent diabetes mellitus. Ann N Y Acad Sci. 2002;958:362-375.
87. Todd JA, Bell JI, McDevitt HO. HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987;329(6140):599-604.
88. Morel PA, Dorman JS, Todd JA, McDevitt HO, Trucco M. Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc Natl Acad Sci U S A. 1988;85(21):8111-8115.
89. Acha-Orbea H, McDevitt HO. The first external domain of the nonobese diabetic mouse class II I-A β chain is unique. Proc Natl Acad Sci U S A. 1987;84(8):2435-2439.
90. Kwok WW, Domeier ME, Johnson ML, Nepom GT, Koelle DM. HLA-DQB1 codon 57 is critical for peptide binding and recognition. J Exp Med. 1996;183(3):1253-1258.
91. Kwok WW, Domeier ML, Raymond FC, Byers P, Nepom GT. Allele-specific motifs characterize HLA-DQ interactions with a diabetes-associated peptide derived from glutamic acid decarboxylase. J Immunol. 1996;156(6):2171-2177.
92. Oiso M, Nishi T, Ishikawa T, Nishimura Y, Matsushita S. Differential binding of peptides substituted at putative C-terminal anchor residues to HLA-DQ8 and DQ9 differing only at β5 7. Hum Immunol. 1997;52(1):47-53.
93. Suri A, Vidavsky I, van der Drift K, Kanagawa O, Gross ML, Unanue ER. In APCs, the autologous peptides selected by the diabetogenic I-Ag7 molecule are unique and determined by the amino acid changes in the P9 pocket. J Immunol. 2002;168(3):1235-1243.
94. Suri A, Walters JJ, Gross ML, Unanue ER. Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity. J Clin Invest. 2005;115(8):2268-2276.
95. Yoshida K, Corper AL, Herro R, Jabri B, Wilson IA, Teyton L. The diabetogenic mouse MHC class II molecule I-Ag7 is endowed with a switch that modulates TCR affinity. J Clin Invest. 2010;120(5):1578-1590.
96. Sidney J, del Guercio M-F, Southwood S, Sette A. The HLA molecules DQA1∗0501/B1∗0201 and DQA1∗0301/B1∗0302 share an extensive overlap in peptide binding specificity. J Immunol. 2002;169(9):5098-5108.
97. Johansen BH, Jensen T, Thorpe CJ, Vartdal F, Thorsby E, Sollid LM. Both α and β chain polymorphisms determine the specificity of the disease-associated HLA-DQ2 molecules, with β chain residues being most influential. Immunogenetics. 1996;45(2):142-150.
98. van de Wal Y, Kooy YM, Drijfhout JW, Amons R, Papadopoulos GK, Koning F. Unique peptide binding characteristics of the disease-associated DQ(α 1∗0501, β 1∗0201) vs the non-disease-associated DQ(α 1∗0201, β 1∗0202) molecule. Immunogenetics. 1997;46(6):484-492.
99. Liu GY, Fairchild PJ, Smith RM, Prowle JR, Kioussis D, Wraith DC. Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity. 1995;3(4):407-415.
100. James EA, Kwok WW. Low-affinity major histo-compatibility complex-binding peptides in type 1 diabetes. Diabetes. 2008;57(7):1788-1789.
101. Kim DT, Rothbard JB, Bloom DD, Fathman CG. Quantitative analysis of T cell activation: role of TCR/ligand density and TCR affinity. J Immunol. 1996;156(8):2737-2742.
102. Baumgartner CK, Ferrante A, Nagaoka M, Gorski J, Malherbe LP. Peptide-MHC class II complex stability governs CD4 T cell clonal selection. J Immunol. 2010;184(2):573-581.
103. O'Garra A, Gabrysova L, Spits H. Quantitative events determine the differentiation and function of helper T cells. Nat Immunol. 2011;12(4):288-294.
104. Corse E, Gottschalk RA, Allison JP. Strength of TCR-peptide/MHC interactions and in vivo T cell responses. J Immunol. 2011;186(9):5039-5045.
105. Gottschalk RA, et al. Distinct influences of peptide-MHC quality and quantity on in vivo T-cell responses. Proc Natl Acad Sci U S A. 2012;109(3):881-886.
106. Eerligh P, et al. Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes. Genes Immun. 2011;12(6):415-427.
107. van Lummel M, et al. The type 1 diabetes associated HLA-DQ8-trans dimer accomo-dates a unique peptide repertoire. J Biol Chem. 2012;287(12):9514.
108. Schmidt D, Verdaguer J, Averill N, Santamaria P. A mechanism for the major histocompatibility complex-linked resistance to autoimmunity. J Exp Med. 1997;186(7):1059-1075.
109. Nepom GT. A unified hypothesis for the complex genetics of HLA associations with IDDM. Diabetes. 1990;39(10):1153-1157.
110. Deng H, et al. Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease. J Exp Med. 1993;178(5):1675-1680.
111. Resic-Lindehammer S, et al. Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk. Acta Diabetologica. 2008;45(4):231-235.
112. Carlsson A, et al. Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden. Int J Obes. 2011;36(5):718.
113. Patil NS, et al. Rheumatoid arthritis (RA)-as-sociated HLA-DR alleles form less stable complexes with class II-associated invariant chain peptide than non-RA-associated HLA-DR alleles. J Immunol. 2001;167(12):7157-7168.
114. Hou T, et al. An insertion mutant in DQA1∗0501 restores susceptibility to HLA-DM: implications for disease associations. J Immunol. 2011;187(5):2442-2452.
115. Busch R, De Riva A, Hadjinicolaou AV, Jiang W, Hou T, Mellins ED. On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes. Expert Rev Mol Med. 2012;14:e15.
116. Busch R, et al. Achieving stability through editing and chaperoning: regulation of MHC class II peptide binding and expression. Immunol Rev. 2005;207:242-260.
117. Zhou Z, Jensen PE. Structural characteristics of HLA-DQ that may impact DM editing and susceptibility to Type-1 diabetes. Front Immunol. 2013;4:262.
118. Zhong G, Castellino F, Romagnoli P, Germain RN. Evidence that binding site occupancy is necessary and sufficient for effective major histocompatibility complex (MHC) class II transport through the secretory pathway redefines the primary function of class II-associated invariant chain peptides (CLIP). J Exp Med. 1996;184(5):2061-2066.
119. Cotner T. Unassembled HLA-DR beta monomers are degraded rapidly by a nonlysosomal mechanism. J Immunol. 1992;148(7):2163-2168.
120. Cotner T, Pious D. HLA-DR beta chains enter into an aggregated complex containing GRP-78/BiP prior to their degradation by the pre-Golgi degradative pathway. J Biol Chem. 1995;270(5):2379-2386.
121. Apanius V, Penn D, Slev PR, Ruff LR, Potts WK. The nature of selection on the major his-tocompatibility complex. Crit Rev Immunol. 1997;17(2):179-224.
122. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res. 2010;39(Database issue):D913-D919.
123. Devaux B, Wilson KJ, Aguilar B, Jorgensen B, Rothbard JB. Differential stability of HLA-DR alleles independent of endogenous peptides. J Immunol. 1995;155(4):1921-1929.
124. Nei M, Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynon-ymous nucleotide substitutions. Mol Biol Evol. 1986;3(5):418-426.
125. Jukes TH, Cantor CR. Evolution of protein molecules. In: Munro HN, ed. Mammalian Protein Metabolism. New York, New York, USA: Academic Press; 1969:21-132.
126. Korber B. HIV signature and sequence variation analysis. In: Rodrigo AG, Learn GH, eds. Computational Analysis of HIV Molecular Sequences. Dordrecht, Netherlands: Kluwer Academic Publishers; 2000:55-72.
127. Ho CS, et al. Nomenclature for factors of the SLA system, update 2008. Tissue Antigens. 2009;73(4):307-315.
128. Robinson J, Mistry K, McWilliam H, Lopez R, Parham P, Marsh SG. The IMGT/HLA database. Nucleic Acids Res. 2010;39(Database issue):D1171-D1176.
129. de Groot NG, et al. Nomenclature report on the major histocompatibility complex genes and alleles of Great Ape, Old and New World monkey species. Immunogene tics. 2012;64(8):615-631.
130. Robinson J, Halliwell JA, McWilliam H, Lopez R, Marsh SG. IPD - the Immuno Polymorphism Database. Nucleic Acids Res. 2013;41(Database issue):D1234-D1240.
131. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res. 2011;39(Database issue):D913-D919.
132. Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol. 2007;24(8):1569-1599.
133. Klitz W, et al. New HLA haplotype frequency reference standards: high-resolution and large sample typing of HLA DR-DQ haplotypes in a sample of European Americans. Tissue Antigens. 2003;62(4):296-307.
134. Hashimoto M, et al. Gene frequencies and haplo-typic associations within the HLA region in 916 unrelated Japanese individuals. Tissue Antigens. 1994;44(3):166-173.
135. Renquin J, et al. HLA class II polymorphism in Aka Pygmies and Bantu Congolese and a reassessment of HLA-DRB1 African diversity. Tissue Antigens. 2001;58(4):211-222.
136. Agrawal S, Khan F, Bharadwaj U. Human genetic variation studies and HLA class II loci. Int J Immunogenet. 2007;34(4):247-252.
137. Spurkland A, Sollid LM, Polanco I, Vartdal F, Thorsby E. HLA-DR and-DQ genotypes of celiac disease patients serologically typed to be non-DR3 or non-DR5/7. Hum Immunol. 1992;35(3):188-192.
138. Ferreira RC, et al. High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency. PLoS Genet. 2012;8(1):e1002476.
139. Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214-219.
140. Tsuchiya N. Genetics of ANCA-associated vasculi-tis in Japan: a role for HLA-DRB1∗09:01 haplotype. Clin Exp Nephrol. 2012;17(5):628-630.
141. Mignot E, et al. Complex HLA-DR and-DQ interactions confer risk of narcolepsy-cata-plexy in three ethnic groups. Am J Hum Genet. 2001;68(3):686-699.