Interferon regulatory factor 3 as key element of the interferon signature in plasmacytoid dendritic cells from systemic lupus erythematosus patients: novel genetic associations in the Mexican mestizo population

Clinical and Experimental Immunology - Tập 178 Số 3 - Trang 428-437 - 2014
Karina Santana-de Anda1, Diana Gómez-Martı́n1, Adriana Monsiváis‐Urenda2, Mariana Salgado‐Bustamante3, Roberto González‐Amaro2, Jorge Alcocer‐Varela1
1Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Mexico City, México
2Departamento de Inmunología, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México
3Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México

Tóm tắt

SummaryMany genetic studies have found an association between interferon regulatory factors (IRF) single nucleotide polymorphisms (SNPs) and systemic lupus erythematosus (SLE); however, specific dendritic cell (DC) alterations have not been assessed. The aim of the present study was to address the expression of IRF3 and IRF5 on different DC subsets from SLE patients, as well as their association with interferon (IFN)-α production and novel SNPs. For the genetic association analyses, 156 SLE patients and 272 healthy controls from the Mexican mestizo population were included. From these, 36 patients and 36 controls were included for functional analysis. Two IRF3 SNPs − rs2304206 and rs2304204 – were determined. We found an increased percentage of circulating pDC in SLE patients in comparison to controls (8·04 ± 1·48 versus 3·35 ± 0·8, P = 0·032). We also observed enhanced expression of IRF3 (64 ± 6·36 versus 36·1 ± 5·57, P = 0·004) and IRF5 (40 ± 5·25 versus 22·5 ± 2·6%, P = 0·010) restricted to this circulating pDC subset from SLE patients versus healthy controls. This finding was associated with higher IFN-α serum levels in SLE (160·2 ± 21 versus 106·1 ± 14 pg/ml, P = 0·036). Moreover, the IRF3 rs2304206 polymorphism was associated with increased susceptibility to SLE [odds ratio (OR), 95% confidence interval (CI) = 2·401 (1·187–4·858), P = 0·021] as well as enhanced levels of serum type I IFN in SLE patients who were positive for dsDNA autoantibodies. The IRF3 rs2304204 GG and AG genotypes conferred decreased risk for SLE. Our findings suggest that the predominant IRF3 expression on circulating pDC is a key element for the increased IFN-α activation based on the interplay between the rs2304206 gene variant and the presence of dsDNA autoantibodies in Mexican mestizo SLE patients.

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Tài liệu tham khảo

Banchereau, 2000, Immunobiology of dendritic cells, Annu Rev Immunol, 18, 767, 10.1146/annurev.immunol.18.1.767

Liu, 2005, IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors, Annu Rev Immunol, 23, 275, 10.1146/annurev.immunol.23.021704.115633

Gottenberg, 2007, Dendritic cells and interferon-mediated autoimmunity, Biochimie, 89, 856, 10.1016/j.biochi.2007.04.013

Ytterberg, 1982, Serum interferon levels in patients with systemic lupus erythematosus, Arthritis Rheum, 25, 401, 10.1002/art.1780250407

Bennett, 2003, Interferon and granulopoiesis signatures in systemic lupus erythematosus blood, J Exp Med, 197, 711, 10.1084/jem.20021553

Feng, 2006, Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus, Arthritis Rheum, 54, 2951, 10.1002/art.22044

Kirou, 2005, Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease, Arthritis Rheum, 52, 1491, 10.1002/art.21031

Kyogoku, 2007, A compass that points to lupus: genetic studies on type I interferon pathway, Genes Immun, 8, 445, 10.1038/sj.gene.6364409

Niewold, 2007, High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus, Genes Immun, 8, 492, 10.1038/sj.gene.6364408

Forabosco, 2006, Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus, Genes Immun, 7, 609, 10.1038/sj.gene.6364338

Han, 2009, Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus, Nat Genet, 41, 1234, 10.1038/ng.472

Kim, 2009, Genetic studies of systemic lupus erythematosus in Asia: where are we now?, Genes Immun, 10, 421, 10.1038/gene.2009.24

Kelly, 2008, Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans, Genes Immun, 9, 187, 10.1038/gene.2008.4

Lee, 2009, Association between the rs2004640 functional polymorphism of interferon regulatory factor 5 and systemic lupus erythematosus: a meta-analysis, Rheumatol Int, 29, 1137, 10.1007/s00296-008-0801-7

Reddy, 2007, Genetic association of IRF5 with SLE in Mexicans: higher frequency of the risk haplotype and its homozygozity than Europeans, Hum Genet, 121, 721, 10.1007/s00439-007-0367-6

Sanchez, 2010, Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus, Arthritis Rheum, 62, 3722, 10.1002/art.27753

Feng, 2010, Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus, Arthritis Rheum, 62, 562, 10.1002/art.27223

Niewold, 2008, Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients, Arthritis Rheum, 58, 2481, 10.1002/art.23613

Rullo, 2010, Association of IRF5 polymorphisms with activation of the interferon alpha pathway, Ann Rheum Dis, 69, 611, 10.1136/ard.2009.118315

Akahoshi, 2008, Promoter polymorphisms in the IRF3 gene confer protection against systemic lupus erythematosus, Lupus, 17, 568, 10.1177/0961203308089340

Sanchez, 2009, No evidence for genetic association of interferon regulatory factor 3 in systemic lupus erythematosus, Lupus, 18, 230, 10.1177/0961203308096256

Hochberg, 1997, Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum, 40, 1725, 10.1002/art.1780400928

Bombardier, 1992, Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE, Arthritis Rheum, 35, 630, 10.1002/art.1780350606

Wagner, 2013, Monitoring gene expression: quantitative real-time rt–PCR, Methods Mol Biol, 1027, 19, 10.1007/978-1-60327-369-5_2

Fitzgerald, 2003, IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway, Nat Immunol, 4, 491, 10.1038/ni921

Salloum, 2011, Interferon regulatory factors in human lupus pathogenesis, Transl Res, 157, 326, 10.1016/j.trsl.2011.01.006

International Consortium for Systemic Lupus Erythematosus G, 2008, Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci, Nat Genet, 40, 204, 10.1038/ng.81

Blomberg, 2003, Expression of the markers BDCA-2 and BDCA-4 and production of interferon-alpha by plasmacytoid dendritic cells in systemic lupus erythematosus, Arthritis Rheum, 48, 2524, 10.1002/art.11225

Carvalheiro, 2012, Tolerogenic versus inflammatory activity of peripheral blood monocytes and dendritic cells subpopulations in systemic lupus erythematosus, Clin Dev Immunol, 2012, 1, 10.1155/2012/934161

Henriques, 2012, Functional characterization of peripheral blood dendritic cells and monocytes in systemic lupus erythematosus, Rheumatol Int, 32, 863, 10.1007/s00296-010-1709-6

Migita, 2005, Reduced blood BDCA-2+ (lymphoid) and CD11c+ (myeloid) dendritic cells in systemic lupus erythematosus, Clin Exp Immunol, 142, 84, 10.1111/j.1365-2249.2005.02897.x

Jin, 2008, Systemic lupus erythematosus patients have increased number of circulating plasmacytoid dendritic cells, but decreased myeloid dendritic cells with deficient CD83 expression, Lupus, 17, 654, 10.1177/0961203308089410

Ding, 2006, Aberrant phenotype and function of myeloid dendritic cells in systemic lupus erythematosus, J Immunol, 177, 5878, 10.4049/jimmunol.177.9.5878

Gerl, 2010, Blood dendritic cells in systemic lupus erythematosus exhibit altered activation state and chemokine receptor function, Ann Rheum Dis, 69, 1370, 10.1136/ard.2009.111021

Zhang, 2010, Interferon-alpha and interleukin-6 in SLE serum induce the differentiation and maturation of dendritic cells derived from CD34+ hematopoietic precursor cells, Cytokine, 50, 195, 10.1016/j.cyto.2010.02.017

Blanco, 2001, Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus, Science, 294, 1540, 10.1126/science.1064890

Crispin, 2012, Phenotype and function of dendritic cells of patients with systemic lupus erythematosus, Clin Immunol, 143, 45, 10.1016/j.clim.2011.12.004

Decker, 2006, Monocyte-derived dendritic cells over-express CD86 in patients with systemic lupus erythematosus, Rheumatology, 45, 1087, 10.1093/rheumatology/kel061

Dauer, 2003, Mature dendritic cells derived from human monocytes within 48 hours: a novel strategy for dendritic cell differentiation from blood precursors, J Immunol, 170, 4069, 10.4049/jimmunol.170.8.4069

Niewold, 2012, IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus, Ann Rheum Dis, 71, 463, 10.1136/annrheumdis-2011-200463

Fu, 2011, Association of a functional IRF7 variant with systemic lupus erythematosus, Arthritis Rheum, 63, 749, 10.1002/art.30193

Lin, 2011, The potential role of interferon-regulatory factor 7 among Taiwanese patients with systemic lupus erythematosus, J Rheumatol, 38, 1914, 10.3899/jrheum.101004

Pons-Estel, 2004, The GLADEL multinational Latin American prospective inception cohort of 1214 patients with systemic lupus erythematosus: ethnic and disease heterogeneity among ‘Hispanics’, Medicine, 83, 1, 10.1097/01.md.0000104742.42401.e2

Vila, 2004, Early clinical manifestations, disease activity and damage of systemic lupus erythematosus among two distinct US Hispanic subpopulations, Rheumatology, 43, 358, 10.1093/rheumatology/keh048

Tada, 2011, Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice, Arthritis Rheum, 63, 738, 10.1002/art.30183

Moser, 1998, Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees, Proc Natl Acad Sci USA, 95, 14869, 10.1073/pnas.95.25.14869

Stetson, 2006, Recognition of cytosolic DNA activates an IRF3-dependent innate immune response, Immunity, 24, 93, 10.1016/j.immuni.2005.12.003

Szabo, 2013, The two-component adjuvant IC31(R) boosts type I interferon production of human monocyte-derived dendritic cells via ligation of endosomal TLRs, PLOS ONE, 8, e55264, 10.1371/journal.pone.0055264

Long, 2014, Recruitment of phosphatase PP2A by RACK1 adaptor protein deactivates transcription factor IRF3 and limits type I interferon signaling, Immunity, 40, 515, 10.1016/j.immuni.2014.01.015

Salloum, 2010, Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients, Arthritis Rheum, 62, 553, 10.1002/art.27182

Smith, 2012, Enhanced interferon regulatory factor 3 binding to the interleukin-23p19 promoter correlates with enhanced interleukin-23 expression in systemic lupus erythematosus, Arthritis Rheum, 64, 1601, 10.1002/art.33494

Espinosa, 2009, Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway, J Exp Med, 206, 1661, 10.1084/jem.20090585

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Clinical and Experimental Immunology

Tập 178 Số 3

428-437

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