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Thymic Function in Juvenile Idiopathic Arthritis a R Lorenzi, T a Morgan, a Anderson, J Catterall, a M Patterson, H E Foster, J D Isaacs

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Thymic Function in Juvenile Idiopathic Arthritis a R Lorenzi, T a Morgan, a Anderson, J Catterall, a M Patterson, H E Foster, J D Isaacs Extended report Ann Rheum Dis: first published as 10.1136/ard.2008.088112 on 15 July 2008. Downloaded from Thymic function in juvenile idiopathic arthritis A R Lorenzi, T A Morgan, A Anderson, J Catterall, A M Patterson, H E Foster, J D Isaacs Musculoskeletal Research ABSTRACT under circumstances where the T cell pool is Group, Institute of Cellular Objective: Thymic function declines exponentially with depleted, such as in HIV-AIDS or during lympho- Medicine, Newcastle University, Newcastle-upon-Tyne, UK age. Impaired thymic function has been associated with ablative treatments such as bone marrow trans- autoimmune disease in adults but has never been formally plant or stem cell transplantation (SCT). This Correspondence to: assessed in childhood autoimmunity. Therefore, thymic (normal) decline in thymic function with ageing is Professor J D Isaacs, function in children with the autoimmune disease juvenile thought to explain the slower and often less Musculoskeletal Research Group, Institute of Cellular idiopathic arthritis (JIA) was determined. complete T cell reconstitution following SCT in Medicine, Newcastle University, Methods: Thymic function was measured in 70 children adults when compared with that in children.10 11 Newcastle-upon-Tyne NE2 4HH, and young adults with JIA (age range 2.1–30.8 (median JIA describes a heterogeneous group of diseases12 UK; [email protected] 10.4)) and 110 healthy age-matched controls using four ranging in severity from severe polyarticular ARL and TAM contributed independent assays. T cell receptor excision circles disease sometimes associated with systemic fea- + equally to this work (WBLogTREC/ml) and the proportion of CD4 tures, to more benign oligoarticular disease. The CD45RA+CD31+ T cells (representing recent thymic more severe JIA subtypes have a poor prognosis, Accepted 1 June 2008 Published Online First emigrants; %RTEs) were quantified and intrathymic with lack of response to intense immunosuppres- 14 July 2008 proliferation measured by calculating the aTREC/SbTREC sion in some cases.13 14 Autologous SCT has ratio. Lastly, regulatory T cells (TReg) of thymic origin recently been shown to induce prolonged, drug- (CD4+FOXP3+) were quantified in peripheral blood to free remission in a proportion of such refractory assess the ability of the thymus in JIA to generate this T patients.15 cell subset. Measuring thymic function in humans is com- Results: Thymic function was equivalent by all four plicated by the lack of a specific phenotype for parameters in JIA when compared with the control recent thymic emigrants (RTEs), although the population. Furthermore, there was no consistent effect of surface profile CD4+CD45RA+CD31+ has been JIA subtype on thymic function, although intrathymic proposed as a potential marker.16 Rearrangement proliferation was higher in the small rheumatoid factor of the T cell receptor a chain (TCRa) gene results (RF)+ polyarticular group. There were no significant effects in the formation of an episome of DNA called a ‘‘T of disease-modifying antirheumatic drugs (DMARDs) or cell receptor excision circle’’ (TREC).17 TRECs are oral corticosteroids on thymic function, although those present only in thymically derived T cells and do with the worst prognostic ILAR (International League of not divide with cellular mitosis. When quantified Associations for Rheumatology) subtypes were also those per millilitre of whole blood, TRECs are widely http://ard.bmj.com/ most likely to be on a DMARD. accepted to be the optimal measurement of thymic Conclusions: It is demonstrated that children and young function.18 adults with JIA, unlike adults with autoimmune diseases, In the current study we compare thymic have thymic function that is comparable with that of function in children with JIA and healthy controls. healthy controls. The varied pathologies represented by By measuring TRECs, the proportion of + + + the term ‘‘JIA’’ suggest this observation may not be CD4 CD45RA CD31 T cells and TReg in periph- disease specific and raises interesting questions about the eral blood, and intrathymic T cell development on September 23, 2021 by guest. Protected copyright. aetiology of thymic impairment in adult autoimmunity. using a novel assay, we demonstrate that thymic function is not compromised in JIA. The thymus plays a critical role in the development PATIENTS AND METHODS of normal immune tolerance.1 As well as negatively Study subjects selecting potentially autoreactive T cells, it also Following ethical approval and informed consent positively selects the naturally occurring regulatory from the child and/or a parent or guardian, 9 ml + + 2 T cell subset (TReg) (CD4 FOXP3 ). Cross-sec- blood samples were obtained from healthy control tional studies have demonstrated impaired thymic children undergoing simple surgical procedures. function in several adult autoimmune diseases.3–6 It Samples from young adults were donated by remains unclear whether the thymic defect is healthy volunteers. Study subjects were consecu- primary or secondary, although single gene defects tive attendees at the Newcastle Regional Paediatric affecting thymic integrity can predispose to auto- Rheumatology Service in Newcastle. All were given immunity.78In contrast to adults, thymic function a diagnosis of JIA classified according to the ILAR has not been formally quantified in childhood (International League of Associations for autoimmunity such as juvenile idiopathic arthritis Rheumatology) classification by a consultant (JIA). Paediatric Rheumatologist.12 Samples from older The normal thymus is largest in childhood and is patients were obtained at adolescent and young This paper is freely available online under the BMJ Journals well known to decline in size and function with adult rheumatology clinics. Blood was collected 9 unlocked scheme, see http:// increasing age. Whilst not normally of apparent into Vacuette EDTA K3 tubes (Greiner Bio-one, ard.bmj.com/info/unlocked.dtl consequence, this decline becomes important Kremsmu¨nster, Austria). Ann Rheum Dis 2009;68:983–990. doi:10.1136/ard.2008.088112 983 Extended report Ann Rheum Dis: first published as 10.1136/ard.2008.088112 on 15 July 2008. Downloaded from DNA extraction until use. Thawed cells were surface stained with CD4+– DNA was extracted from 300 ml of whole blood using the FITC and then FOXP3–APC (allophycocyanin) antibody Wizard Genomic DNA extraction kit (Promega, Madison, (eBiosciences, Wembley, UK) according to the manufacturer’s Wisconsin, USA) and stored at 4uC. Sample purity and quantity instructions. Flow cytometry was performed using a FACScan was determined by spectrophotometry (Nanodrop ND-100, and data were analysed using FloJOv6.1.2. Sample identities Wilmington, Delaware, USA). were blinded to the assessor. TREC quantification Statistical analysis We have developed a method quantifying TRECs/ml in DNA Statistical analyses were performed using SPSS 11th edition extracted from 300 ml of whole blood19. Briefly, WBLogTREC/ software. Values for WBLogTREC/ml were initially log trans- ml is determined from a simultaneously amplified standard formed to allow parameteric testing. Population distributions curve (range 107–101 TREC molecules) using quantitative real- were tested for normality with a one-sample Kolmogorov– time PCR (RQ-PCR), an ABI Prism 7900HT Sequence Detector Smirnov test. Correlations for normally distributed data were System and SDS2.2 software (Applied Biosystems, Warrington, tested for significance using Pearson’s correlation coefficient. UK). Differences between groups were assessed by analysis of Reactions (25 ml) contained primers CACATCCCTTTCAA covariance (ANCOVA) where other covariates were present, CCATGCT and GCCAGCTGCAGGGTTTAGG both at unless otherwise stated. Bonferroni corrections were applied to 700 nM, 150 nM Taqman hydrolysis probe (6-FAM-ACACCT correct for multiple comparisons. Results were considered CTGGTTTTTGTAAAGGTGCCCACT-TAMRA), 12.5 mlof significant when p(0.05. JumpStart Taq ReadyMix (Sigma, Poole, UK) and 200 ng of DNA. Thermal cycling conditions were 50uC for 2 min then RESULTS 95uC for 10 min, then 40 cycles of 95uC for 15 s and 60uC for Thymic function declines with age throughout childhood and 1 min. Experimental samples were run in duplicate and does not differ between patients with JIA and healthy controls averaged. WBLogTREC/ml was quantified in 70 patients with JIA and 110 healthy controls (HCs). Table 1 describes the cohort. One Quantification of intrathymic proliferation additional patient had DiGeorge syndrome (chromosome 22q11 Intrathymic proliferation was measured using a modified deletion-associated syndrome with thymic hypoplasia/aplasia) version (to allow for use with SYBR Green) of the method and a co-existing inflammatory arthritis. Figure 1A shows that 20 published by Dion et al. Ten TCRb chain DbRJb rearrange- there was no significant difference in thymic function between ments (bTRECs) and the TCRa chain drecRyJa rearrangement the groups after adjusting for age and gender (see below). (aTRECs) were quantified in separate, nested PCRs. A duplex Negative correlations with age were detected for both groups first round reaction with primers for individual bTRECs and (p,0.01). The patient with DiGeorge syndrome had markedly genomic CD3 was followed by individual RQ-PCRs. The CD3 deficient thymic function as evidenced by a 1.5Log deficit in copy number multiplied by 0.5 (since each cell contains two WBLogTREC/ml when compared with age-matched controls. copies) allowed the
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