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      Association of Human Leukocyte Antigen (HLA) class II ( DRB1 and DQB1) alleles and haplotypes with Rheumatoid Arthritis in Sudanese patients


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          The aim of this study was to determine the Human Leukocyte Antigen (HLA) class II ( DRB1 and DQB1) alleles and haplotype frequency in Rheumatoid Arthritis (RA) in the Sudanese population. The frequency of HLA-DRB1 and - DQB1 alleles and DRB1-DQB1 haplotypes were determined in 122 RA patients and 100 controls. HLA alleles were genotyped by the polymerase chain reaction-sequence specific primers (PCR-SSP) method. In RA patients, HLA-DRB1*04 and *10 alleles were high in frequency (9.6% vs 14.2%, P = 0.038 and P = 0.042, respectively), and dependently on anti-citrullinated protein antibodies (ACPAs) seropositivity ( P = 0.044 and P = 0.027, respectively). In contrast, the frequency of the HLA-DRB1*07 allele was significantly low in patients than in controls (11.7% vs 5.0%, P = 0.010). Moreover, the HLA-DQB1*03 allele was strongly associated with RA risk (42.2%, P = 2.2x10 -8), whereas, HLA-DQB1*02 and *06 showed protective effects against RA (23.1% and 42.2%, P = 0.024 and P = 2.2x10 -6, respectively). Five different HLA haplotypes, DRB1*03-DQB1*03 ( P = 0.00003), DRB1*04-DQB1*03 ( P = 0.00014) , DRB1*08-DQB1*03 ( P = 0.027) , DRB1*13-DQB1*02 ( P = 0.004), and DRB1*13-DQB1*03 ( P = 3.79x10 -8) were significantly associated with RA risk, while 3 protective haplotypes , DRB1*03-DQB1*02 ( P c = 0.008), DRB1*07-DQB1*02 ( P c = 0.004) , and DRB1*13-DQB1*06 ( P c = 0.02) were identified. This is the first study determining the association between HLA class II alleles and haplotypes and RA risk in our population.

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          Most cited references47

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          2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

          The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis." In the new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1). This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis."
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            The immunopathogenesis of rheumatoid arthritis.

            Rheumatoid arthritis is a chronic inflammatory polyarthritis whose etiology remains uncertain. Recently we have learned that autoimmunity to citrullinated protein antigens has specificity for rheumatoid arthritis and defines a clinically and genetically distinct form of the disease. Multiple genes contribute to disease susceptibility, with the HLA locus accounting for 30% to 50% of overall genetic risk. Five risk loci have been identified and validated: HLA-DRB1, PTPN22, STAT4, a region in 6q23, and the TRAF1/C5 locus. Also, there is renewed interest in the contribution of T cells to ongoing inflammation in rheumatoid arthritis. Autoantibodies to citrullinated protein epitopes are specific for rheumatoid arthritis, are associated with a more aggressive disease course, and are pathogenic in an animal model of autoimmune arthritis. There is a strong association between shared-epitope-expressing HLA-DRB1 alleles and the development of rheumatoid arthritis associated with autoimmunity to citrullinated protein antigens.
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              Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles.

              Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles. To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles. Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type II collagen (C1(III)). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed. 72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients' sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1(III). These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles. Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                22 June 2023
                : 14
                : 1178546
                [1] 1 Department of Biochemistry and Nutrition, Faculty of Medicine, University of Gezira , Wad Medani, Sudan
                [2] 2 Department of Basic Medical Sciences, Faculty of Applied Medical Sciences, Al-Baha University , Al-Baha, Saudi Arabia
                [3] 3 Department of Pathology, Faculty of Medicine, University of Gezira , Wad Medani, Sudan
                [4] 4 Department of Internal Medicine, Faculty of Medicine, University of Gezira , Wad Medani, Sudan
                Author notes

                Edited by: Bin Yang, University of Leicester, United Kingdom

                Reviewed by: Luiza Guilherme, University of São Paulo, Brazil; Youssef Mosaad, Professor Clinical Pathology and Immunology Mansoura University, Egypt

                *Correspondence: Khalid Eltahir Khalid, khatahir12@ 123456gmail.com ; Mohammed Salman Akhtar, mdsalmanakhtar@ 123456yahoo.com ; milyas@ 123456bu.edu.sa
                Copyright © 2023 Ali, Khalid, Mohammed, Akhtar and Saeed

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 02 March 2023
                : 05 June 2023
                Page count
                Figures: 0, Tables: 6, Equations: 0, References: 47, Pages: 10, Words: 4975
                Original Research
                Custom metadata
                Alloimmunity and Transplantation

                rheumatoid arthritis,hla-drb1,hla-dqb1,anti-ccp,rheumatoid factor
                rheumatoid arthritis, hla-drb1, hla-dqb1, anti-ccp, rheumatoid factor


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