TY - JOUR
T1 - Shared molecular amino acid signature in the HLA-DR peptide binding pocket predisposes to both autoimmune diabetes and thyroiditis
AU - Menconi, Francesca
AU - Osman, Roman
AU - Monti, Maria C.
AU - Greenberg, David A.
AU - Concepcion, Erlinda S.
AU - Tomer, Yaron
PY - 2010/9/28
Y1 - 2010/9/28
N2 - There is strong genetic association between type 1A diabetes (T1D) and autoimmune thyroid disease (AITD). T1D and AITD frequently occur together in the same individual, a condition classified as a variant of the autoimmune polyglandular syndrome type 3 (APS3). Because T1D and AITD are individually strongly associated with different HLA class II sequences, we asked which HLA class II pocket sequence and structure confer joint susceptibility to both T1D and AITD in the same individual (APS3v). We sequenced the HLA-DR gene in 105 APS3v patients and 153 controls, and identified a pocket amino acid signature, DRβ-Tyr-26, DRβ-Leu-67, DRβ-Lys-71, and DRβ-Arg-74, that was strongly associated with APS3v (P = 5.4 ± 10-14, odds ratio = 8.38). Logistic regression analysis demonstrated that DRβ-Leu-67 (P = 9.4 ± 10-13) and DRβ-Arg-74 (P = 1.21 ± 10 -13) gave strong independent effects on disease susceptibility. Structural modeling studies demonstrated that pocket 4 was critical for the development of T1D+AITD; all disease-associated amino acids were linked to areas of the pocket that interact directly with the peptide and, therefore, influence peptide binding. The disease-susceptible HLA-DR pocket was more positively charged (Lys-71, Arg-74) compared with the protective pocket (Ala-71, Gln-74). We conclude that a specific pocket amino acid signature confers joint susceptibility to T1D+AITD in the same individual by causing significant structural changes in the MHC II peptide binding pocket and influencing peptide binding and presentation. Moreover, Arg-74 is a major amino acid position for the development of several autoimmune diseases. Thesefindings suggest that blocking the critical Arg-74 pocket might offer a method for treating certain autoimmune conditions.
AB - There is strong genetic association between type 1A diabetes (T1D) and autoimmune thyroid disease (AITD). T1D and AITD frequently occur together in the same individual, a condition classified as a variant of the autoimmune polyglandular syndrome type 3 (APS3). Because T1D and AITD are individually strongly associated with different HLA class II sequences, we asked which HLA class II pocket sequence and structure confer joint susceptibility to both T1D and AITD in the same individual (APS3v). We sequenced the HLA-DR gene in 105 APS3v patients and 153 controls, and identified a pocket amino acid signature, DRβ-Tyr-26, DRβ-Leu-67, DRβ-Lys-71, and DRβ-Arg-74, that was strongly associated with APS3v (P = 5.4 ± 10-14, odds ratio = 8.38). Logistic regression analysis demonstrated that DRβ-Leu-67 (P = 9.4 ± 10-13) and DRβ-Arg-74 (P = 1.21 ± 10 -13) gave strong independent effects on disease susceptibility. Structural modeling studies demonstrated that pocket 4 was critical for the development of T1D+AITD; all disease-associated amino acids were linked to areas of the pocket that interact directly with the peptide and, therefore, influence peptide binding. The disease-susceptible HLA-DR pocket was more positively charged (Lys-71, Arg-74) compared with the protective pocket (Ala-71, Gln-74). We conclude that a specific pocket amino acid signature confers joint susceptibility to T1D+AITD in the same individual by causing significant structural changes in the MHC II peptide binding pocket and influencing peptide binding and presentation. Moreover, Arg-74 is a major amino acid position for the development of several autoimmune diseases. Thesefindings suggest that blocking the critical Arg-74 pocket might offer a method for treating certain autoimmune conditions.
KW - Autoimmunity
KW - Gene
KW - Structure
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U2 - 10.1073/pnas.1009511107
DO - 10.1073/pnas.1009511107
M3 - Article
C2 - 20837527
AN - SCOPUS:78049308447
SN - 0027-8424
VL - 107
SP - 16899
EP - 16903
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 39
ER -