Do RA associated HLA-DR molecules bind citrullinated peptides or peptides from PAD4 to help the development of RA specific antibodies to citrullinated proteins?. Issue 116 (January 2021)

• Record Type: Journal Article
• Authors: Balandraud, Nathalie; Auger, Isabelle; Roudier, Jean
• Is Part Of: Journal of autoimmunity. Issue 116(2020)
• Publication Date: 2021-01
• Subjects: Rheumatoid arthritis -- HLA-DR association -- Anticitrullinated protein antibodies -- Citrullinated peptide binding -- PAD4 peptide binding -- Prevention; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2020.102542
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Purpose: Rheumatoid arthritis (RA) is associated with HLA-DRB1 genes encoding a five amino acid basic motive, the shared epitope SE). Each HLA-DRB1 genotype defines a genotype specific risk of developing RA. RA is preceded by the emergence of anti citrullinated protein antibodies (ACPAs). Citrullin is a neutral version of arginin, a basic amino acid, formed after post translational modification by Peptidyl Arginyl Deiminases (PADs). HLA-DRB1 genes associated with RA are also associated with ACPAs. Two models might explain this association. Here we tested both models for prediction of HLA-DRB1 genotypic risks of developing RA. Methods: We calculated the likelihoods for the 2 HLA-DR molecules encoded by 12 common HLA-DRB1 genotypes to bind at least one randomly chosen peptide from PAD4 or fibrinogen(native or citrullinatd) and compared them with the 12 respective HLA-DRB1genotypic risks of developing RA. Results: HLA-DRB1 Genotypic risks of developing RA correlate with likelihoods of binding PAD4 peptides, not citrullinated Fibrinogen peptides. Thus, the molecular basis for the association of HLA-DR and ACPA positive RA is most likely the capability for RA associated HLA-DR molecules to bind peptides(s) from PAD4. Highlights: HLA-DR genes cause anticitrullinated protein positive rheumatoid arthritis (RA). RA associated HLA-DR molecules do not bind citrullinated peptides well. RA associated HLA-DR molecules bind peptidyl arginyl deiminase peptides better. HLA-DRB1 genotype risk to develop RA matches PAD4 peptide binding by HLA-DR molecules.