{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:57:25Z","timestamp":1772931445873,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T00:00:00Z","timestamp":1627948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["842002001"],"award-info":[{"award-number":["842002001"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>C-C chemokine receptor 5 (CCR5) and polymorphisms in CCR5 gene are associated with sarcoidosis and L\u00f6fgren\u2019s syndrome. L\u00f6fgren\u2019s syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for L\u00f6fgren\u2019s syndrome and has an effect on CCR5 expression on monocytes and function of CCR5. A total of 106 patients with L\u00f6fgren\u2019s syndrome and 257 controls were genotyped for rs1799987. Expression of CCR5 on monocytes was measured by flowcytometry. We evaluated calcium influx kinetics following stimulation upon N-formylmethionyl-leucyl-phenylalanine (fMLP) and macrophage inflammatory protein-1\u03b1 (MIP-1\u03b1) on monocytes by measuring the median fluorescence intensity (MFI). The frequency of the G allele of rs1799987 was significantly higher in L\u00f6fgren\u2019s syndrome than in healthy controls (p = 0.0015, confidence interval (CI) 1.22\u20132.32, odds ratio (OR) 1.680). Patients with a GG genotype showed higher CCR5 expression on monocytes than patients with the AA genotype (p = 0.026). A significantly (p = 0.027) lower count of patients with the GG genotype showed a calcium influx reaction to simulation upon MIP-1 \u03b1, compared with patients with the AA genotype. The rs1799987 G allele in CCR5 gene is associated with susceptibility to L\u00f6fgren\u2019s syndrome and with quantitative and qualitative changes in CCR5, potentially effecting the inflammatory response.<\/jats:p>","DOI":"10.3390\/cells10081967","type":"journal-article","created":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T08:16:39Z","timestamp":1627978599000},"page":"1967","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Polymorphism in C-C Chemokine Receptor 5 (CCR5) Associates with L\u00f6fgren\u2019s Syndrome and Alters Receptor Expression as well as Functional Response"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9180-5239","authenticated-orcid":false,"given":"Bekir","family":"Karakaya","sequence":"first","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coline H. M.","family":"van Moorsel","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands"},{"name":"Division of Heart & Lungs, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"Veltkamp","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands"},{"name":"Division of Heart & Lungs, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Roodenburg-Benschop","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin M.","family":"Kazemier","sequence":"additional","affiliation":[{"name":"Division of Heart & Lungs, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands"},{"name":"Center for Translational Immunology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annette H. M.","family":"van der Helm-van Mil","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom W. J.","family":"Huizinga","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan C.","family":"Grutters","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands"},{"name":"Division of Heart & Lungs, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6948-6123","authenticated-orcid":false,"given":"Ger T.","family":"Rijkers","sequence":"additional","affiliation":[{"name":"Department of Science, University College Roosevelt, P.O. Box 94, 4330 AB Middelburg, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,3]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Sarcoidosis","volume":"5","author":"Grunewald","year":"2019","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1183\/09031936.97.10061207","article-title":"The source and role of RANTES in interstitial lung disease","volume":"10","author":"Petrek","year":"1997","journal-title":"Eur. Respir. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0165-2478(01)00324-8","article-title":"CC chemokine receptor 5 (CCR5) mRNA expression in pulmonary sarcoidosis","volume":"80","author":"Petrek","year":"2002","journal-title":"Immunol. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/S1043-4666(02)00493-3","article-title":"Chemokine\/chemokine receptor nomenclature","volume":"21","author":"Bacon","year":"2003","journal-title":"Cytokine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"304","DOI":"10.3109\/s10165-012-0665-2","article-title":"Association between the chemokine receptor 5 delta32 polymorphism and rheumatoid arthritis: A meta-analysis","volume":"23","author":"Lee","year":"2013","journal-title":"Mod. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4869","DOI":"10.1007\/s00018-019-03255-6","article-title":"Dual CCR5\/CCR2 targeting: Opportunities for the cure of complex disorders","volume":"76","author":"Fantuzzi","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.imlet.2016.05.018","article-title":"Chemokine genetic polymorphism in human health and disease","volume":"176","author":"Qidwai","year":"2016","journal-title":"Immunol. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/BF03401665","article-title":"Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: Studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk","volume":"3","author":"Zimmerman","year":"1997","journal-title":"Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/S0140-6736(98)04158-0","article-title":"CCR5 promoter polymorphism and HIV-1 disease progression","volume":"352","author":"McDermott","year":"1998","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1055\/s-2007-970329","article-title":"Sarcoidosis-Immunopathogenetic concepts","volume":"28","author":"Zissel","year":"2007","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1164\/rccm.200412-1707OC","article-title":"C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis","volume":"172","author":"Spagnolo","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s00109-008-0315-5","article-title":"Female-specific association of C-C chemokine receptor 5 gene polymorphisms with L\u00f6fgren\u2019s syndrome","volume":"86","author":"Fischer","year":"2008","journal-title":"J. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1055\/s-0037-1602380","article-title":"L\u00f6fgren\u2019s Syndrome: Diagnosis, Management, and Disease Pathogenesis","volume":"38","author":"Karakaya","year":"2017","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1182\/blood-2008-02-141275","article-title":"CD4-CCR5 interaction in intracellular compartments contributes to receptor expression at the cell surface","volume":"113","author":"Achour","year":"2009","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mehlotra, R.K. (2019). CCR5 Promoter Polymorphism -2459G > A: Forgotten or Ignored?. Cells, 8.","DOI":"10.3390\/cells8070651"},{"key":"ref_16","unstructured":"Statement on Sarcoidosis (1999). Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ER. Am. J. Respir. Crit. Care Med., 160, 736\u2013755."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fimmu.2013.00339","article-title":"Phenotypic Characterization of Human Intermediate Monocytes","volume":"4","author":"Hijdra","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1183\/09031936.00107809","article-title":"CC chemokine receptor 5 gene polymorphisms in beryllium disease","volume":"36","author":"Sato","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1136\/ard.2007.078048","article-title":"CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus","volume":"67","author":"Mamtani","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1111\/j.1399-0039.2012.01955.x","article-title":"CCR5 gene polymorphism is a genetic risk factor for radiographic severity of rheumatoid arthritis","volume":"80","author":"Han","year":"2012","journal-title":"Tissue Antigens"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/sj.gene.6364113","article-title":"CCR5-\u039432 mutation is strongly associated with primary sclerosing cholangitis","volume":"5","author":"Eri","year":"2004","journal-title":"Genes Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1093\/intimm\/12.9.1311","article-title":"Influence of nucleotide polymorphisms in the CCR2 gene and the CCR5 promoter on the expression of cell surface CCR5 and CXCR4","volume":"12","author":"Shieh","year":"2000","journal-title":"Int. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/S1521-6616(03)00147-5","article-title":"CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro","volume":"108","author":"Salkowitz","year":"2003","journal-title":"Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1073\/pnas.94.5.1925","article-title":"The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes","volume":"94","author":"Bleul","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11677","DOI":"10.1128\/JVI.79.18.11677-11684.2005","article-title":"Combined Effect of CCR5-\u039432 Heterozygosity and the CCR5 Promoter Polymorphism \u22122459 A\/G on CCR5 Expression and Resistance to Human Immunodeficiency Virus Type 1 Transmission","volume":"79","author":"Hladik","year":"2005","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1084\/jem.185.9.1681","article-title":"CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro","volume":"185","author":"Wu","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4962","DOI":"10.1128\/JVI.72.6.4962-4969.1998","article-title":"Expression of CCR5 Increases during Monocyte Differentiation and Directly Mediates Macrophage Susceptibility to Infection by Human Immunodeficiency Virus Type 1","volume":"72","author":"Tuttle","year":"1998","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1164\/ajrccm.162.3.2001022","article-title":"CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis","volume":"162","author":"Petrek","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1755-1536-4-10","article-title":"Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis","volume":"4","author":"Palchevskiy","year":"2011","journal-title":"Fibrogenes. Tissue Repair"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/PL00007643","article-title":"Expression of C-C chemokines in bronchoalveolar lavage cells from patients with granulomatous lung diseases","volume":"177","author":"Oshima","year":"1999","journal-title":"Lung"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/j.1365-2796.2003.01230.x","article-title":"Expression of Th1 markers by lung accumulated T cells in pulmonary sarcoidosis","volume":"254","author":"Katchar","year":"2003","journal-title":"J. Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1136\/thx.52.5.431","article-title":"Analysis of t cell subsets and \u03b2 chemokines in patients with pulmonary sarcoidosis","volume":"52","author":"Iida","year":"1997","journal-title":"Thorax"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ni1191","article-title":"T cell costimulation by chemokine receptors","volume":"6","author":"Molon","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1164\/rccm.200303-456OC","article-title":"C-C Chemokine Receptor 2 and Sarcoidosis: Association with L\u00f6fgren\u2019s Syndrome","volume":"168","author":"Spagnolo","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"83","DOI":"10.18176\/jiaci.0537","article-title":"An unexpected effect of maraviroc could make it a future treatment for sarcoidosis","volume":"31","author":"Goehringer","year":"2021","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/S1471-4906(01)01941-X","article-title":"Decoy receptors: A strategy to regulate inflammatory cytokines and chemokines","volume":"22","author":"Mantovani","year":"2001","journal-title":"Trends Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jim.2009.07.002","article-title":"Flow cytometric calcium flux assay: Evaluation of cytoplasmic calcium kinetics in whole blood leukocytes","volume":"348","author":"Schepers","year":"2009","journal-title":"J. Immunol. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1126\/science.7682337","article-title":"Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1\u03b1 and MIP-1\u03b2","volume":"260","author":"Taub","year":"1993","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/nature04651","article-title":"Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction","volume":"440","author":"Castellino","year":"2006","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1164\/ajrccm.165.2.2106084","article-title":"Increased macrophage inflammatory protein-1\u03b1 and macrophage inflammatory protein-1\u03b2 levels in bronchoalveolar lavage fluid of patients affected by different stages of pulmonary sarcoidosis","volume":"165","author":"Capelli","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_41","first-page":"223","article-title":"Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis","volume":"46","author":"Ziegenhagen","year":"1998","journal-title":"J. Investig. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.4049\/jimmunol.151.5.2852","article-title":"Macrophage inflammatory protein-1 alpha expression in interstitial lung disease","volume":"151","author":"Standiford","year":"1993","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1046\/j.1365-2249.1998.00519.x","article-title":"Correlation of plasma monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1\u03b1 (MIP-1\u03b1) levels with disease activity and clinical course of sarcoidosis","volume":"111","author":"Hashimoto","year":"1998","journal-title":"Clin. Exp. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/8\/1967\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:39:28Z","timestamp":1760164768000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/8\/1967"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,3]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cells10081967"],"URL":"https:\/\/doi.org\/10.3390\/cells10081967","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,3]]}}}