Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice.
Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still controversial. We hypothesized that specific HLA-DR pocket-sequence variants are associated with HT and that similar variants in the murine I-E locus (homologous to HLA-DR) predispose to experimental autoimmune thyroiditis (EAT), a classical mouse model of HT. Therefore, we sequenced the polymorphic exon 2 of the HLA-DR gene in 94 HT patients and 149 controls. In addition, we sequenced exon 2 of the I-E gene in 22 strains of mice, 12 susceptible to EAT and 10 resistant. Using logistic regression analysis, we identified a pocket amino acid signature, Tyr-26, Tyr-30, Gln-70, Lys-71, strongly associated with HT (P = 6.18 x 10(-5), OR = 3.73). Lys-71 showed the strongest association (P = 1.7 x 10(-8), OR = 2.98). This association was seen across HLA-DR types. The 5-aa haplotype Tyr-26, Tyr-30, Gln-70, Lys-71, Arg-74 also was associated with HT (P = 3.66 x 10(-4)). In mice, the I-E pocket amino acids Val-28, Phe-86, and Asn-88 were strongly associated with EAT. Structural modeling studies demonstrated that pocket P4 was critical for the development of HT, and pockets P1 and P4 influenced susceptibility to EAT. Surprisingly, the structures of the HT- and EAT-susceptible pockets were different. We conclude that specific MHC II pocket amino acid signatures determine susceptibility to HT and EAT by causing structural changes in peptide-binding pockets that may influence peptide binding, selectivity, and presentation. Because the HT- and EAT-associated pockets are structurally different, it is likely that distinct antigenic peptides are associated with HT and EAT.
Menconi
Francesca
F
Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Monti
Maria C
MC
Greenberg
David A
DA
Oashi
Taiji
T
Osman
Roman
R
Davies
Terry F
TF
Ban
Yoshiyuki
Y
Jacobson
Eric M
EM
Concepcion
Erlinda S
ES
Li
Cheuk Wun
CW
Tomer
Yaron
Y
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D017421:Sequence Analysis; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D000596:Amino Acids; D006684:HLA-DR Antigens; D010455:Peptides
Cell Immunol. 1985 Jun;93(1):132-43
3873286
Immunol Lett. 1993 Aug;37(2-3):235-9
7505005
Curr Opin Immunol. 2001 Dec;13(6):650-6
11677085
Ann N Y Acad Sci. 2003 Nov;1005:119-27
14679046
J Clin Endocrinol Metab. 1997 Dec;82(12):4130-2
9398726
Autoimmunity. 1992;14(2):155-8
1363895
Nature. 1987 Oct 15-21;329(6140):599-604
3309680
J Exp Med. 2002 Mar 4;195(5):571-81
11877480
Genes Immun. 2004 May;5(3):203-8
15029234
J Immunol. 1992 Jun 1;148(11):3405-11
1588039
Immunol Rev. 1987 Aug;98:115-41
3308686
Science. 1995 May 26;268(5214):1144-9
7761829
Tissue Antigens. 1981 Mar;17(3):265-8
6947505
Thyroid. 1993 Winter;3(4):331-3
8118228
Nat Immunol. 2001 Jun;2(6):501-7
11376336
N Engl J Med. 1978 Jul 20;299(3):133-4
78445
J Immunol. 1979 Jul;123(1):15-8
109534
Autoimmun Rev. 2002 Feb;1(1-2):97-103
12849065
J Clin Endocrinol Metab. 1990 Nov;71(5):1131-7
1977755
J Exp Med. 2002 Apr 15;195(8):1043-52
11956295
Immunology. 1976 Jan;30(1):63-8
1248862
Clin Endocrinol (Oxf). 1991 May;34(5):383-6
1676351
J Endocrinol Invest. 1994 Jul-Aug;17(7):477-95
7829823
Science. 1971 Dec 10;174(4014):1137-9
5133731
Baillieres Clin Endocrinol Metab. 1995 Jul;9(3):631-56
7575335
Thyroid. 2001 Feb;11(2):171-5
11288988
Immunology. 2003 Apr;108(4):556-61
12667218
Endocr Rev. 2003 Oct;24(5):694-717
14570752
Endocr Rev. 1993 Feb;14(1):107-20
8491150
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
Clin Immunol Immunopathol. 1997 Sep;84(3):223-43
9281381
J Clin Endocrinol Metab. 2002 Feb;87(2):489-99
11836274
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15119-24
14657345
Adv Immunol. 1994;56:389-466
7521116
Crit Rev Immunol. 1990;10(4):307-28
2285459
Clin Endocrinol (Oxf). 2002 Jul;57(1):81-8
12100074
Clin Immunol. 2004 Nov;113(2):187-92
15451476