The role of HLA-DR-DR and HLA-DR-DP interactions in genetic susceptibility to rheumatoid arthritis

Perdriger, Aleth; Guggenbuhl, Pascal; Chalès, Gérard; Dantec, P. Le; Yaouanq, J.; Genetet, B; Pawlotsky, Y; Sémana, G.

doi:10.1016/0198-8859(95)00217-0

Cited by 32 publications

(22 citation statements)

References 26 publications

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“…Interestingly, the DPB1*04:01 allele has been associated with other autoimmune diseases showing both a protective effect for type 1 diabetes (21) and for multiple sclerosis ( 22 ), as well as an increased risk for rheumatoid arthritis (23), pemphigus (24), and vasculitis (25). To our knowledge, the association between DPB1*04:01 and CDA or CD has not been described before.…”

Section: Discussionmentioning

confidence: 99%

HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

Hadley

Hagopian

Liu

et al. 2015

American Journal of Gastroenterology

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OBJECTIVES Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% ( n =1,813) carried DR3-DQ2/DR3-DQ2, 39% ( n =3,359) carried DR3-DQ2/DR4-DQ8, 20% ( n =1701) carried DR4-DQ8/DR4-DQ8, and 17% ( n =1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case–control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. RESULTS After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53–0.96, P =0.025). This association of time to CDA and HLA-DPB1* 04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI= 0.73–0.96, P =0.013). CONCLUSIONS HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.

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Section: Discussionmentioning

confidence: 99%

HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

Hadley

Hagopian

Liu

et al. 2015

American Journal of Gastroenterology

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“…The RA-associated alleles (DRB1*0401, *0404, *0405, *0408, *1402, *0101, *0102, and *1001) share a short sequence motif, the shared epitope (SE), at residues 67-74 in the third hypervariable region of the DRB chain (6,7). Notably, this motif is not found in closely related nonassociated alleles, implying that this region of the DR molecule is important in disease pathogenesis.…”

Section: R Heumatoid Arthritis (Ra)mentioning

confidence: 99%

Rheumatoid Arthritis (RA)-Associated HLA-DR Alleles Form Less Stable Complexes with Class II-Associated Invariant Chain Peptide Than Non-RA-Associated HLA-DR Alleles

Patil

Pashine

Belmares

et al. 2001

The Journal of Immunology

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Certain HLA-DR alleles confer strong susceptibility to the autoimmune disease rheumatoid arthritis (RA). We compared RA-associated alleles, HLA-DR*0401, HLA-DR*0404, and HLA-DR*0405, with closely related, non-RA-associated alleles, HLA-DR*0402 and HLA-DR*0403, to determine whether they differ in their interactions with the class II chaperone, invariant chain (Ii). Ii binds to class II molecules in the endoplasmic reticulum, inhibits binding of other ligands, and directs class II-Ii complexes to endosomes, where Ii is degraded to class II-associated Ii peptide (CLIP). To evaluate the interaction of Ii and CLIP with these DR4 alleles, we introduced HLA-DR*0401, *0402, and *0404 alleles into a human B cell line that lacked endogenous HLA-DR or HLA-DM molecules. In a similar experiment, we introduced HLA-DR*0403 and *0405 into an HLA-DM-expressing B cell line, 8.1.6, and its DM-negative derivative, 9.5.3. Surface abundance of DR4-CLIP peptide complexes and their susceptibility to SDS-induced denaturation suggested that the different DR4-CLIP complexes had different stabilities. Pulse-chase experiments showed CLIP dissociated more rapidly from RA-associated DR molecules in B cell lines. In vitro assays using soluble rDR4 molecules showed that DR-CLIP complexes of DR*0401 and DR*0404 were less stable than complexes of DR*0402. Using CLIP peptide variants, we mapped the reduced CLIP interaction of RA-associated alleles to the shared epitope region. The reduced interaction of RA-associated HLA-DR4 molecules with CLIP may contribute to the pathophysiology of autoimmunity in RA.

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“…[18][19][20][21][22][23][24][25][26] Our result in a UK cohort together with previous studies in Swedish and North American populations 14,15 provides strong evidence that HLA-DPB1-COL11A2 is a genuine RA risk locus independent of HLA-DRB1 and the rest of the xMHC region. Several SNPs were found to be associated with RA in this intergenic region, distributed in two different LD blocks.…”

Section: Discussionmentioning

confidence: 60%

HLA-DPB1-COL11A2 and three additional xMHC loci are independently associated with RA in a UK cohort

et al. 2011

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The role of HLA-DR-DR and HLA-DR-DP interactions in genetic susceptibility to rheumatoid arthritis

Cited by 32 publications

References 26 publications

HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

Rheumatoid Arthritis (RA)-Associated HLA-DR Alleles Form Less Stable Complexes with Class II-Associated Invariant Chain Peptide Than Non-RA-Associated HLA-DR Alleles

HLA-DPB1-COL11A2 and three additional xMHC loci are independently associated with RA in a UK cohort

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