A Molecular Analysis of the Shared Epitope Hypothesis: Binding of Arthritogenic Peptides to DRB1*04 Alleles

Anderson, Kirsten M.; Roark, Christina L.; Portas, Mary; Aubrey, Michael T.; Rosloniec, Edward F.; Freed, Brian M.

doi:10.1002/art.39636

Cited by 17 publications

(12 citation statements)

References 35 publications

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“…A common feature in RA is the presence of antibodies to citrullinated protein antigens (38), the generation of which has been associated with smoking (39). Further evidence suggests that citrullination enhances the binding affinity of some arithrogenic peptides to SE alleles (40), suggesting a pathway for interaction between smoking and HLA in RA. Our finding that citrullination increases the predicted affinity for HLA-DRB1 alleles protective in PD while decreasing the predicted affinity for HLA-DRB1 alleles predisposing to PD supports the notion that the epidemiologic association of smoking in both RA and PD is mediated by its posttranslational modification of antigens presented by HLA-DRB1 .…”

Section: Discussionmentioning

confidence: 99%

A specific amino acid motif ofHLA-DRB1mediates risk and interacts with smoking history in Parkinson’s disease

Hollenbach

Norman

Creary

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Parkinson’s disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70–74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the “shared epitope” (SE), the residues Q/R-K/R-R-A-A at positions 70–74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10−4; odds ratio, 0.51; 95% confidence interval, 0.36–0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08–2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.

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Section: Discussionmentioning

confidence: 99%

A specific amino acid motif ofHLA-DRB1mediates risk and interacts with smoking history in Parkinson’s disease

Hollenbach

Norman

Creary

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…For the majority of the SE alleles, it has been shown that these citrullinated peptides are accommodated in a more efficient fashion than the native forms [16, 17]. To the best of our knowledge, the capacity of HLA-DQ molecules to present citrullinated ligands has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

The increased ability to present citrullinated peptides is not unique to HLA-SE molecules: arginine-to-citrulline conversion also enhances peptide affinity for HLA-DQ molecules

et al. 2016

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BackgroundPresentation of citrullinated neo-epitopes by HLA-DRB1 molecules that carry the shared epitope (SE) sequence was proposed to explain the association between HLA and seropositive RA. Although it is shown that several HLA-DRB1-SE molecules display enhanced binding affinities for citrullinated ligands, the ability of other HLA molecules to present citrullinated epitopes has not been investigated in a systematic manner. To better understand the HLA-RA connection, we aimed to investigate if the enhanced capacity to present arginine-to-citrulline-converted peptides is unique for HLA-SE alleles.MethodsWe selected four HLA molecules (one HLA-DR and three HLA-DQ molecules) that could potentially prefer citrulline over arginine residues in specific pockets and in addition two HLA-SE alleles as a method validation control. The affinity of peptides containing arginine/citrulline residues at positions interacting with the various peptide-binding pockets was compared by HLA class II peptide affinity assays.ResultsPocket 4 of HLA-DRB1*04:04 and -DRB1*04:05 displayed a preference for citrulline over arginine, a property found in other pockets as well. HLA-DRB1*03:01 did not display an enhanced affinity for peptides containing a citrulline. In contrast, several peptide-binding pockets of the analyzed HLA-DQ molecules showed enhanced affinities for citrulline compared to arginine residues: i.e., pockets 4, 6, 7, and 9 of HLA-DQ2 and pockets 1, 6, and 9 of HLA-DQ7 and HLA-DQ8.ConclusionsArginine-to-citrulline conversion of peptides can also enhance the binding affinity for non-HLA-SE molecules. Hence the capacity to present citrullinated neo-epitopes is not confined to HLA-SE molecules, opening the possibility that also other HLA molecules could potentiate a possible breach of T cell tolerance toward citrullinated antigens.

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“…Interestingly, only changes of the latter three affect the shared epitope motif. Positions 70 and 71 have a significant role in presentation of vimentin, alpha-enolase, and collagen as well as in modulating the interaction with T-cell receptors [131]. Positions 67 and 86 may also affect the binding of possible arthritogenic peptides [132].…”

Section: Contribution To Diseasementioning

confidence: 99%

Role of Human Leukocyte Antigens (HLA) in Autoimmune Diseases

2018

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Since the discovery of HLA 60 years ago, it has contributed to the understanding of the immune system as well as of the pathogenesis of several diseases. Aside from its essential role in determining donor-recipient immune compatibility in organ transplantation, HLA genotyping is meanwhile performed routinely as part of the diagnostic work-up of certain autoimmune diseases. Considering the ability of HLA to influence thymic selection as well as peripheral anergy of T cells, its role in the pathogenesis of autoimmunity is understandable. The aim of this paper is to provide a brief overview of the role and current clinical relevance of HLA-B27 in spondyloarthritis and HLA-B51 in Behçet's disease as well as HLA-DQ2/DQ8 in celiac disease and HLA-DRB1 in rheumatoid arthritis and to discuss possible future implications.

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A Molecular Analysis of the Shared Epitope Hypothesis: Binding of Arthritogenic Peptides to DRB1*04 Alleles

Cited by 17 publications

References 35 publications

A specific amino acid motif ofHLA-DRB1mediates risk and interacts with smoking history in Parkinson’s disease

A specific amino acid motif ofHLA-DRB1mediates risk and interacts with smoking history in Parkinson’s disease

The increased ability to present citrullinated peptides is not unique to HLA-SE molecules: arginine-to-citrulline conversion also enhances peptide affinity for HLA-DQ molecules

Role of Human Leukocyte Antigens (HLA) in Autoimmune Diseases

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