HLA-DRB1 shared epitope genotyping using the revised classification and its association with circulating autoantibodies, acute phase reactants, cytokines and clinical indices of disease activity in a cohort of South African rheumatoid arthritis patients

Arthritis Research & Therapy

Pieter WA Meyer²  Bridget Hodkinson⁴  Mahmood Ally³  Eustasius Musenge⁵  Ahmed A Wadee¹  Heidi Fickl²  Mohammed Tikly⁴  Ronald Anderson² 

[1] Department of Immunology, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Hospital Street, Braamfontein, 2001, Johannesburg, South Africa

[2] Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, and Tshwane Academic Division of the National Health Laboratory Service, Bophelo Road, Pretoria, 0001, South Africa

[3] Department Internal Medicine, Faculty of Health Sciences, University of Pretoria, Bophelo Road, Pretoria, 0001, South Africa

[4] Division of Rheumatology, Chris Hani Baragwanath Hospital, Faculty of Health Sciences, University of the Witwatersrand, Chris Hani Road, Johannesburg, 2013, South Africa

[5] Epidemiology and Biostatistics Division, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, York Road, Johannesburg, 2193, South Africa

关键词: Th1/Th2 cytokines;    serum amyloid A;    rheumatoid factor;    macrophage cytokines;    fibroblast cytokines;    C-reactive protein;    anticyclic citrullinated peptide antibodies;   

Others  :  1098504
DOI  :  10.1186/ar3479

 received in 2011-03-02, accepted in 2011-10-06,  发布年份 2011

【 摘 要 】

Introduction

The revised shared epitope (SE) concept in rheumatoid arthritis (RA) is based on the presence (S) or absence (X) of the SE RAA amino acid motif at positions 72 to 74 of the third hypervariable region of the various human leucocyte antigen (HLA)-DRB1 alleles. The purpose of this study was to investigate SE subtypes on the basis of the American College of Rheumatology 1987 revised criteria for the classification of RA in a cohort of South African RA patients (n = 143) and their association with clinical and circulating biomarkers of disease activity (autoantibodies, acute phase reactants and cytokines).

Methods

Genomic DNA was analysed using high-resolution recombinant sequence-specific oligonucleotide PCR typing of the HLA-DRB1 allele. Subtypes of the SE were classified according to the amino acids at positions 72 to 74 for the RAA sequence, and further sub-divided according to the amino acids at positions 70 and 71, which either contribute to (S2, S3P), or negate (S1, S3D) RA susceptibility. Disease activity was assessed on the basis of (1) Disease Activity Score in 28 joints using C-reactive protein (CRP), (2) rheumatoid factor (RF), (3) CRP and (4) serum amyloid A by nephelometry, anticyclic citrullinated peptide antibodies (aCCP) by an immunofluorometric procedure, and cytokines by multiplex bead array technology.

Results

Of the 143 RA patients, 81 (57%) were homozygous (SS) and 50 (35%) were heterozygous (SX) for the SE alleles with significant overexpression of S2 and S3P (respective odds ratios (ORs) 5.3 and 5.8; P < 0.0001), and 12 (8%) were classified as no SE allele (XX). Both the SS and SX groups showed a strong association with aCCP positivity (OR = 10.2 and P = 0.0010, OR = 9.2 and P = 0.0028, respectively) relative to the XX group. Clinical scores and concentrations of the other biomarkers of disease activity (RF, CRP and T helper cell type 1 (Th1), Th2, macrophage and fibroblast cytokines) were also generally higher in the SS group than in the SX and XX groups.

Conclusions

RA susceptibility alleles investigated according to revised criteria for the classification of RA were significantly increased in South African RA patients and strongly associated with aCCP in particular as well as with circulating cytokines and disease severity.

【 授权许可】

   
2011 Meyer et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Pratt AG, Isaacs JD, Mattey DL: Current concepts in the pathogenesis of early rheumatoid arthritis. Best Pract Res Clin Rheumatol 2009, 23:37-48.
• [2]Nepom GT, Seyfried CE, Holbeck SL, Wilske KR, Nepom BS: Identification of HLA-Dw14 genes in DR4+ rheumatoid arthritis. Lancet 1986, 2:1002-1005.
• [3]Winchester R: Genetic determination of susceptibility and severity in rheumatoid arthritis. Ann Intern Med 1992, 117:869-871.
• [4]Winchester R: The molecular basis of susceptibility to rheumatoid arthritis. Adv Immunol 1994, 56:389-466.
• [5]Gregersen PK, Silver J, Winchester RJ: The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987, 30:1205-1213.
• [6]Gao XJ, Brautbar C, Gazit E, Segal R, Naparstek Y, Livneh A, Stastny P: A variant of HLA-DR4 determines susceptibility to rheumatoid arthritis in a subset of Israeli Jews. Arthritis Rheum 1991, 34:547-551.
• [7]du Montcel ST, Michou L, Petit-Teixeira E, Osorio J, Lemaire I, Lasbleiz S, Pierlot C, Quillet P, Bardin T, Prum B, Cornelis F, Clerget-Darpoux F: New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility. Arthritis Rheum 2005, 52:1063-1068.
• [8]Michou L, Croiseau P, Petit-Teixeira E, du Montcel ST, Lemaire I, Pierlot C, Osorio J, Frigui W, Lasbleiz S, Quillet P, Bardin T, Prum B, Clerget-Darpoux F, Cornélis F, European Consortium on Rheumatoid Arthritis Families: Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis. Arthritis Res Ther 2006, 8:R79. BioMed Central Full Text
• [9]Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ: Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998, 101:273-281.
• [10]Mattey DL, Hassell AB, Plant MJ, Cheung NT, Dawes PT, Jones PW, Thomson W, Poulton KV, Hajeer AH, Ollier WE: The influence of HLA-DRB1 alleles encoding the DERAA amino acid motif on radiological outcome in rheumatoid arthritis. Rheumatology (Oxford) 1999, 38:1221-1227.
• [11]van Boekel MA, Vossenaar ER, van den Hoogen FH, van Venrooij WJ: Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Res 2002, 4:87-93.
• [12]Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E: Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol 2003, 171:538-541.
• [13]Auger I, Sebbag M, Vincent C, Balandraud N, Guis S, Nogueira L, Svensson B, Cantagrel A, Serre G, Roudier J: Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum 2005, 52:3424-3432.
• [14]Huizinga TW, Amos CI, van der Helm-van Mil AH, Chen W, van Gaalen FA, Jawaheer D, Schreuder GM, Wener M, Breedveld FC, Ahmad N, Lum RF, de Vries RR, Gregersen PK, Toes RE, Criswell LA: Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum 2005, 52:3433-3438.
• [15]Raza K, Breese M, Nightingale P, Kumar K, Potter T, Carruthers DM, Situnayake D, Gordon C, Buckley CD, Salmon M, Kitas GD: Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol 2005, 32:231-238.
• [16]Samanci N, Ozdem S, Akbas H, Mutlu D, Gultekin M, Arman M, Donmez L: Diagnostic value and clinical significance of anti-CCP in patients with advanced rheumatoid arthritis. J Natl Med Assoc 2005, 97:1120-1126.
• [17]de Vries RRP, Huizinga TWJ, Toes REM: HLA and RA revisited: citrullinated food for the SE hypothesis, the DR6 effect, and NIMA. Hum Immunol 2006, 67:454-459.
• [18]Quinn MA, Gough AKS, Green MJ, Devlin J, Hensor EMA, Greenstein A, Fraser A, Emery P: Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology (Oxford) 2006, 45:478-480.
• [19]Barnetche T, Constantin A, Cantagrel A, Cambon-Thomsen A, Gourraud P: New classification of HLA-DRB1 alleles in rheumatoid arthritis susceptibility: a combined analysis of worldwide samples. Arthritis Res Ther 2008, 10:R26. BioMed Central Full Text
• [20]Okada Y, Yamada R, Suzuki A, Kochi Y, Shimane K, Myouzen K, Kubo M, Nakamura Y, Yamamoto K: Contribution of a haplotype in the HLA region to anti-cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA-DRB1. Arthritis Rheum 2009, 60:3582-3590.
• [21]Gyetvai A, Szekanecz Z, Soos L, Szabo Z, Fekete A, Kapitany A, Teodorescu M, Sipka S, Szegedi G, Lakos G: New classification of the shared epitope in rheumatoid arthritis: impact on the production of various anti-citrullinated protein antibodies. Rheumatology (Oxford) 2010, 49:25-33.
• [22]Kokkonen H, Söderström I, Rocklöv J, Hallmans G, Lejon K, Rantapää Dahlqvist S: Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum 2010, 62:383-391.
• [23]Deane KD, O'Donnell CI, Hueber W, Majka DS, Lazar AA, Derber LA, Gilliland WR, Edison JD, Norris JM, Robinson WH, Holers VM: The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum 2010, 62:3161-3172.
• [24]Hitchon CA, Alex P, Erdile LB, Frank MB, Dozmorov I, Tang Y, Wong K, Centola M, El-Gabalawy HS: A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis. J Rheumatol 2004, 31:2336-2346.
• [25]Alex P, Szodoray P, Knowlton N, Dozmorov IM, Turner M, Frank MB, Arthur RE, Willis L, Flinn D, Hynd RF, Carson C, Kumar A, El-Gabalawy HS, Centola M: Multiplex serum cytokine monitoring as a prognostic tool in rheumatoid arthritis. Clin Exp Rheumatol 2007, 25:584-592.
• [26]Chen DY, Hsieh TY, Chen YM, Hsieh CW, Lan JL, Lin FJ: Proinflammatory cytokine profiles of patients with elderly-onset rheumatoid arthritis: a comparison with younger-onset disease. Gerontology 2009, 55:250-258.
• [27]Boissier MC: Cell and cytokine imbalances in rheumatoid synovitis. Joint Bone Spine 2011, 78:230-234.
• [28]Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA Jr, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988, 31:315-324.
• [29]Inoue E, Yamanaka H, Hara M, Tomatsu T, Kamatani N: Comparison of Disease Activity Score (DAS)28- erythrocyte sedimentation rate and DAS28- C-reactive protein threshold values. Ann Rheum Dis 2007, 66:407-409.
• [30]Wells GA: Patient-driven outcomes in rheumatoid arthritis. J Rheumatol 2009, 36:33-38.
• [31]Robinson J, Waller MJ, Parham P, De Groot N, Bontrop R, Kennedy LJ, Stoehr P, Marsh SGE: IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 2003, 31:311-314.
• [32]Robinson J, Waller MJ, Fail SC, McWilliam H, Lopez R, Parham P, Marsh SGE: The IMGT/HLA database. Nucleic Acids Res 2009, 37:D1013-D1017.
• [33]Middleton D, Menchaca L, Rood H, Komerofsky R: New allele frequency database. [http://www.allelefrequencies.net] webciteTissue Antigens 2003, 61:403-407.
• [34]Mbayo K, Mbuyi-Muamba JM, Hallé L, Salmon D, Martageix C, Castellano F, Kaplan C, Lurhuma Z: HLA-DR gene frequencies in a Zairean population with particular reference to rheumatic diseases. Clin Rheumatol 1998, 17:105-109.
• [35]Del Rincόn I, Battafarano DF, Arroyo RA, Murphy FT, Fisbach M, Escalante A: Ethnic variation in the clinical manifestations of rheumatoid arthritis: role of HLA-DRB1 alleles. Arthritis Care Res 2003, 49:200-208.
• [36]Hughes LB, Morrison D, Kelley JM, Padilla MA, Vaughan LK, Westfall OA, Dwivedi H, Mikuls TR, Holers VM, Parrish LA, Alarcόn GS, Jonas BL, Callahan LF, Smith EA, Gilkeson GS, Howard G, Moreland LW, Patterson N, Reich D, Bridges SL Jr: The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis Rheum 2008, 58:349-358.
• [37]Mikuls TR, Sayles H, Yu F, Levan T, Gould KA, Thiele GM, Conn DL, Jonas BL, Callahan LF, Smith E, Brasington R, Moreland LW, Reynolds RJ, Bridges SL Jr: Associations of cigarette smoking with rheumatoid arthritis in African Americans. Arthritis Rheum 2010, 62:3560-3568.
• [38]Meyer PWA, Brighton SW, Anderson R: Association of the HLA-DRB1*04 allele and its subtypes with rheumatoid arthritis in South Africa. S Afr J Sci 2004, 100:305-306.
• [39]Klareskog L, Rönnelid J, Lundberg K, Padyukov L, Alfredsson L: Immunity to citrullinated proteins in rheumatoid arthritis. Ann Rev Immunol 2008, 26:206-209.
• [40]Engelmann R, Eggert M, Neeck G, Mueller-Hilke B: The impact of HLA-DRB alleles on the subclass titres of antibodies against citrullinated peptides. Rheumatology (Oxford) 2010, 49:1862-1866.
• [41]Hodkinson B, Meyer PW, Musenge E, Ally MM, Wadee AA, Anderson R, Tikly M: The diagnostic utility of the anti-CCP antibody test is no better than rheumatoid factor in South Africans with early rheumatoid arthritis. Clin Rheumatol 2010, 29:615-618.
• [42]Szodoray P, Szabó Z, Kapitány A, Gyetvai Á, Lakos G, Szántó S, Szücs G, Szekanecz Z: Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis. Autoimmun Rev 2010, 9:140-143.
• [43]Meyer PWA, Hodkinson B, Mahmood A, Musenge E, Wadee AA, Fickl H, Tikly M, Anderson R: Circulating cytokine profiles and their relationship with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Mediators Inflamm 2010, 2010:158154.
• [44]Singwe-Ngandeu M, Finckh A, Bas S, Tiercy JM, Gabay C: Diagnostic value of anti-cyclic citrullinated peptides and association with HLA-DRB1 shared epitope alleles in African rheumatoid arthritis patients. Arthritis Res Ther 2010, 12:R36. BioMed Central Full Text