Epistasis with HLA DR3 Implicates the P2X7 Receptor in the Pathogenesis of Primary Sjögren's Syndrome

Overview

Journal Arthritis Res Ther

Publisher Biomed Central

Specialty Rheumatology

Date 2013 Jul 4

PMID 23819992

Citations 8

Authors

Susan Lester

Leanne Stokes

Kristen K Skarratt

Ben J Gu

Kathy L Sivils

Christopher J Lessard

James S Wiley

Maureen Rischmueller

Affiliations

Soon will be listed here.

Abstract

Introduction: The aim of this study was to examine the association between functional polymorphisms in the pro-inflammatory P2X7 receptor and the Ro/La autoantibody response in primary Sjögren's syndrome (pSS).

Methods: Twelve functional P2RX7 polymorphisms were genotyped in 114 pSS patients fulfilling the Revised American-European Consensus Criteria for pSS, and 136 controls. Genotyping of the A1405G (rs2230912) polymorphism was performed on a replication cohort consisting of 281 pSS patients and 534 controls. P2X7 receptor function in lymphocytes and monocytes was assessed by measurement of ATP-induced ethidium+ uptake. Serum IL-18 levels were determined by ELISA.

Results: The minor allele of P2RX7 A1405G is a tag for a common haplotype associated with gain in receptor function, as assessed by ATP-induced ethidium+ uptake. A positive association between 1405G and anti-Ro±La seropositive pSS patients was observed in Cohort 1. Although not replicated in Cohort 2, there was a consistent, significant, negative epistatic interaction effect with HLA-DR3 in seropositive pSS patients from both cohorts, thereby implicating this gain of function variant in the pathogenesis of pSS. Serum IL-18 was elevated in seropositive pSS patients, but was not influenced by P2RX7 A1405G.

Conclusions: The P2RX7 1405G gain-of-function haplotype may be a risk factor for seropositive pSS in a subset of subjects who do not carry HLA risk alleles, but has no effect in subjects who do (epistasis). Potential mechanisms relate to autoantigen exposure and inflammatory cytokine expression. The observed elevation of IL-18 levels is consistent with P2X7 receptor activation in seropositive pSS patients. Collectively these findings implicate P2X7 receptor function in the pathogenesis of pSS.

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References

Szodoray P, Alex P, Brun J, Centola M, Jonsson R . Circulating cytokines in primary Sjögren's syndrome determined by a multiplex cytokine array system. Scand J Immunol. 2004; 59(6):592-9. DOI: 10.1111/j.0300-9475.2004.01432.x. View

Fuller S, Stokes L, Skarratt K, Gu B, Wiley J . Genetics of the P2X7 receptor and human disease. Purinergic Signal. 2009; 5(2):257-62. PMC: 2686826. DOI: 10.1007/s11302-009-9136-4. View

Gilboa-Geffen A, Wolf Y, Hanin G, Melamed-Book N, Pick M, Bennett E . Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome. PLoS One. 2011; 6(12):e28727. PMC: 3235165. DOI: 10.1371/journal.pone.0028727. View

Portales-Cervantes L, Nino-Moreno P, Salgado-Bustamante M, Garcia-Hernandez M, Baranda-Candido L, Reynaga-Hernandez E . The His155Tyr (489C>T) single nucleotide polymorphism of P2RX7 gene confers an enhanced function of P2X7 receptor in immune cells from patients with rheumatoid arthritis. Cell Immunol. 2012; 276(1-2):168-75. DOI: 10.1016/j.cellimm.2012.05.005. View

Labasi J, Petrushova N, Donovan C, McCurdy S, Lira P, Payette M . Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J Immunol. 2002; 168(12):6436-45. DOI: 10.4049/jimmunol.168.12.6436. View

Kim M, Jiang L, Wilson H, North R, Surprenant A . Proteomic and functional evidence for a P2X7 receptor signalling complex. EMBO J. 2001; 20(22):6347-58. PMC: 125721. DOI: 10.1093/emboj/20.22.6347. View

Gu B, Rathsam C, Stokes L, McGeachie A, Wiley J . Extracellular ATP dissociates nonmuscle myosin from P2X(7) complex: this dissociation regulates P2X(7) pore formation. Am J Physiol Cell Physiol. 2009; 297(2):C430-9. DOI: 10.1152/ajpcell.00079.2009. View

Forchap S, Anandacoomarasamy A, Wicks J, Di Virgilio F, Baricordi O, Rubini M . P2X7 gene polymorphisms do not appear to be a susceptibility gene locus in sporadic cases of systemic lupus erythematosus. Tissue Antigens. 2008; 72(5):487-90. DOI: 10.1111/j.1399-0039.2008.01136.x. View

Mahoney J, Rosen A . Apoptosis and autoimmunity. Curr Opin Immunol. 2005; 17(6):583-8. DOI: 10.1016/j.coi.2005.09.018. View

10.

Chen L, Brosnan C . Regulation of immune response by P2X7 receptor. Crit Rev Immunol. 2007; 26(6):499-513. DOI: 10.1615/critrevimmunol.v26.i6.30. View

11.

Novak I . Purinergic signalling in epithelial ion transport: regulation of secretion and absorption. Acta Physiol (Oxf). 2010; 202(3):501-22. DOI: 10.1111/j.1748-1716.2010.02225.x. View

12.

Beer R, Rischmueller M, Coates T, Purcell A, Keech C, McCluskey J . Nonprecipitating anti-La(SS-B) autoantibodies in primary Sjögren's syndrome. Clin Immunol Immunopathol. 1996; 79(3):314-8. DOI: 10.1006/clin.1996.0084. View

13.

Denlinger L, Coursin D, Schell K, Angelini G, Green D, Guadarrama A . Human P2X7 pore function predicts allele linkage disequilibrium. Clin Chem. 2006; 52(6):995-1004. DOI: 10.1373/clinchem.2005.065425. View

14.

Rischmueller M, Lester S, Chen Z, Champion G, van den Berg R, Beer R . HLA class II phenotype controls diversification of the autoantibody response in primary Sjögren's syndrome (pSS). Clin Exp Immunol. 1998; 111(2):365-71. PMC: 1904917. DOI: 10.1046/j.1365-2249.1998.00504.x. View

15.

Nordmark G, Alm G, Ronnblom L . Mechanisms of Disease: primary Sjögren's syndrome and the type I interferon system. Nat Clin Pract Rheumatol. 2006; 2(5):262-9. DOI: 10.1038/ncprheum0173. View

16.

Sluyter R, Shemon A, Wiley J . Glu496 to Ala polymorphism in the P2X7 receptor impairs ATP-induced IL-1 beta release from human monocytes. J Immunol. 2004; 172(6):3399-405. DOI: 10.4049/jimmunol.172.6.3399. View

17.

Pochet S, Metioui M, Grosfils K, Gomez-Munoz A, Marino A, Dehaye J . Regulation of phospholipase D by muscarinic receptors in rat submandibular ductal cells. Cell Signal. 2002; 15(1):103-13. DOI: 10.1016/s0898-6568(02)00059-1. View

18.

Taylor S, Gonzalez-Begne M, Dewhurst S, Chimini G, Higgins C, Melvin J . Sequential shrinkage and swelling underlie P2X7-stimulated lymphocyte phosphatidylserine exposure and death. J Immunol. 2007; 180(1):300-8. DOI: 10.4049/jimmunol.180.1.300. View

19.

Cruz-Tapias P, Rojas-Villarraga A, Maier-Moore S, Anaya J . HLA and Sjögren's syndrome susceptibility. A meta-analysis of worldwide studies. Autoimmun Rev. 2011; 11(4):281-7. DOI: 10.1016/j.autrev.2011.10.002. View

20.

Alzola E, Kabre E, Fogarty D, Metioui M, Chaib N, MACARULLA J . Activation by P2X7 agonists of two phospholipases A2 (PLA2) in ductal cells of rat submandibular gland. Coupling of the calcium-independent PLA2 with kallikrein secretion. J Biol Chem. 1998; 273(46):30208-17. DOI: 10.1074/jbc.273.46.30208. View