Tofacitinib restores the balance of gamma delta Treg/gamma delta T17 cells in rheumatoid arthritis by inhibiting the NLRP3 inflammasome
Authors: Yang, Xinyu; Zhan, Ning; Jin, Yang; Ling, Hanzhi; Xiao, Chipeng; Xie, Zhen; Zhong, Hao; Yu, Xinxin; Tang, Runhua; Ma, Jinglan; Guan, Jubo; Yin, Guoyu; Wu, Gan; Lu, Liangjing; Wang, Jianguang
Objective: Tofacitinib (TOF) is a Janus kinase (JAK) inhibitor used in the treatment of rheumatoid arthritis (RA), but the mechanism of its action remains unclear. In this study, we investigated the influence of TOF on gamma delta regulatory T-cell (gamma delta Treg)/gamma delta T17 cell balance in RA and the role of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in this process. Methods: We detected levels of inflammatory factors in the serum of RA patients before and after administration of TOF using an enzyme-linked immunosorbent assay (ELISA). A collagen-induced arthritis (CIA) model was constructed to investigate the effect of TOF on arthritis symptoms, gamma delta Treg/gamma delta T17 cell balance and the NLRP3 inflammasome. We used bone marrow-derived macrophages (BMDMs) to study the effect of TOF on NLRP3 inflammasome activation. Nlrp3(-/-) mice were introduced to assess the influence of NLRP3 on.dT17 cell activation in RA. Results: TOF treatment decreased levels of gamma delta T17 cell-related cytokine interleukin-17 (IL-17) in RA patients. In addition, TOF intervention in the CIA model reduced joint inflammation and damage, rebalanced the gamma delta Treg/gamma delta T17 cell ratio and inhibited excessive NLRP3 inflammasome activation in draining lymph nodes and arthritic joints. BMDM intervention experiments demonstrated that TOF decreased the level of secreted IL-1 beta via downregulation of NLRP3. Furthermore, experiments using Nlrp3(-/-) mice verified that the NLRP3 inflammasome mediated the effect of TOF on gamma delta T17 cell activation. Conclusions: Recovery of gamma delta Treg/gamma delta T17 cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 played a pivotal role in the process of TOF-mediated gamma delta T17 cell activation.
Impaired Bone Health in Children With Biliary Atresia
JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION
Authors: Ruuska, Satu; Laakso, Saila; Leskinen, Outi; Hagfors, Anna; Jalanko, Hannu; Kolho, Kaija-Leena; Pakarinen, Mikko P.
Objectives: The aim of the study was to examine the frequency of rickets and bone fractures and to assess areal bone mineral density (aBMD) in childhood among patients with biliary atresia (BA). Methods: We gathered data on all patients diagnosed with BA in Finland that survived to >= 1 year of age between 1 January 2000 to 30 June 2018. Data on gestational age, birth weight, postsurgical medications, and history of rickets and bone fractures were collected retrospectively. Serum levels of 25-hydroxyvitamin D [25(OH)D] postportoenterostomy (PE) were collected. Plain radiographs and dual energy X-ray absorptiometry (DXA) measurements of study subjects were reviewed. Results: Out of 49 patients, 7 (14%) were diagnosed with rickets during infancy. Clearance of jaundice [odds ratio 0.055, 95% confidence interval [CI] 0.00266-0.393; P < 0.01] was a protective factor against rickets. Sufficient 25(OH)D levels were reached 3 months post-PE. Eleven (22%) patients suffered at least one bone fracture (range 1-9) during childhood and adolescence. In DXA measurements, median lumbar spine aBMD anthropometrically adjusted z-scores were as follows: in native liver survivors 0.8 (interquartile range [IQR] -1.9 to 1.4) at 5 and -0.3 (IQR -1.3 to 0.8) at 10 years and for liver transplanted patients 0.4 (IQR -0.2 to 1.1) at 5 and 0.6 (IQR -0.1 to 1.3) at 10 years. Conclusions: BA patients have an increased risk for rickets and bone fractures compared with the normal population. Most BA patients have aBMD within normal range between 5 and 10 years of age irrespective of liver transplantation status.