title: Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis.
abstract: Sarcoidosis is a systemic granulomatous disease of unknown aetiology that most commonly affects the lungs. Although elevated levels of regulatory T cells (Tregs ) have been reported, the extent to which they play a role in sarcoidosis pathogenesis remains unclear. Tumour necrosis factor (TNF) is thought to be one of the driving forces behind granuloma formation, illustrated by the efficacy of infliximab in severe sarcoidosis. Tregs express TNF receptor 2 (TNFR2) highly. Here, we examined the influence of infliximab therapy on Tregs and (soluble) TNFR2 levels in sarcoidosis, and correlated these with response to therapy. We observed that relative frequencies of Tregs were significantly higher in patients (n = 54) compared to healthy controls (n = 26; median 6·73 versus 4·36%; P < 0·001) and decreased following therapy (4·95; P < 0·001). Baseline TNFR2 expression on Tregs was increased significantly in patients versus controls (99·4 versus 96·2%; P = 0·031), and also in responders to therapy versus non-responders (99·6 versus 97·3%; P = 0·012). Furthermore, baseline soluble TNFR2 (sTNFR2) was higher in responders than in non-responders (mean 174 versus 107 pg/ml; P = 0·015). After treatment, responders showed a significant reduction in sTNFR2 levels in peripheral blood (-44·7 pg/ml; P < 0·001), in contrast to non-responders (+3·59 pg/ml). Our results demonstrated that Treg frequencies and TNFR2 expression on Tregs are increased in sarcoidosis, followed by a decline during infliximab therapy, suggesting a pathophysiological role of this T cell subset. Interestingly, sTNFR2 levels at baseline differed significantly between responders and non-responders, making it a potential marker in predicting which patients might benefit from infliximab.
authors.affiliation: Department of Pulmonology, Interstitial Lung Diseases Centre of Excellence.
authors.forename: A
authors.initials: A
authors.lastname: Verwoerd
authors.affiliation: Department of Pulmonology, Interstitial Lung Diseases Centre of Excellence.|Department of Medical Microbiology and Immunology.
authors.forename: D
authors.initials: D
authors.lastname: Hijdra
authors.affiliation: Department of Pulmonology, Interstitial Lung Diseases Centre of Excellence.
authors.forename: A D M
authors.initials: AD
authors.lastname: Vorselaars
authors.affiliation: Department of Pulmonology, Interstitial Lung Diseases Centre of Excellence.|Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein.
authors.forename: H A
authors.initials: HA
authors.lastname: Crommelin
authors.affiliation: Department of Pulmonology, Interstitial Lung Diseases Centre of Excellence.|Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: C H M
authors.initials: CH
authors.lastname: van Moorsel
authors.affiliation: Department of Pulmonology, Interstitial Lung Diseases Centre of Excellence.|Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Grutters
authors.affiliation: Department of Medical Microbiology and Immunology.
authors.forename: A M E
authors.initials: AM
authors.lastname: Claessen
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood* / Q000235:genetics*; D012507:Sarcoidosis / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab
keywords: TNFR2; Tregs; infliximab; sTNFR2; sarcoidosis