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Thymic Involution and Altered Naive CD4 T Cell Homeostasis in Neuromyelitis Optica Spectrum Disorder

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Thymic Involution and Altered Naive CD4 T Cell Homeostasis in Neuromyelitis Optica Spectrum Disorder ORIGINAL RESEARCH published: 16 July 2021 doi: 10.3389/fimmu.2021.645277 Thymic Involution and Altered Naive CD4 T Cell Homeostasis in Neuromyelitis Optica Spectrum Disorder † † Haoxiao Chang 1,2 , Hengri Cong 1 , Huabing Wang 1,LiDu 1, De-Cai Tian 1, Yuetao Ma 1, Yun Xu 1, Yupeng Wang 1, Linlin Yin 1,2,3* and Xinghu Zhang 1* 1 Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, 2 China National Clinical Research Center for Neurological Diseases, Beijing, China, 3 Advanced Innovation Center for Human Brain Protection, Beijing, China Edited by: Circulating T helper cells with a type 17-polarized phenotype (TH17) and expansion of Wei Qiu, aquaporin-4 (AQP4)-specific T cells are frequently observed in patients with neuromyelitis Third Affiliated Hospital of Sun Yat-sen University, China optica spectrum disorder (NMOSD). However, naive T cell populations, which give rise to Reviewed by: T helper cells, and the primary site of T cell maturation, namely the thymus, have not been Jillian M. Richmond, studied in these patients. Here, we report the alterations of naive CD4 T cell homeostasis University of Massachusetts Medical School, United States and the changes in thymic characteristics in NMOSD patients. Flow cytometry was Tetsuya Akaishi, performed to investigate the naive CD4+ T cell subpopulations in 44 NMOSD patients and Tohoku University, Japan 21 healthy controls (HC). On immunological evaluation, NMOSD patients exhibited *Correspondence: increased counts of CD31+thymic naive CD4+ T cells and CD31-cental naive CD4+ T cells Linlin Yin + [email protected] along with significantly higher fraction and absolute counts of peripheral blood CD45RA Xinghu Zhang CD62L+ naive CD4+ T cells. Chest computed tomography (CT) images of 60 NMOSD [email protected] patients and 65 HCs were retrospectively reviewed to characterize the thymus in NMOSD. †These authors have contributed equally to this work Thymus gland of NMOSD patients exhibited unique morphological characteristics with respect to size, shape, and density. NMOSD patients showed exacerbated age- Specialty section: dependent thymus involution than HC, which showed a significant association with This article was submitted to fi Autoimmune and disease duration. These ndings broaden our understanding of the immunological Autoinflammatory Disorders, mechanisms that drive severe disease in NMOSD. a section of the journal Frontiers in Immunology Keywords: neuromyelitis optica spectrum disorder, thymic involution, CT, naive T cells, flow cytometry Received: 22 December 2020 Accepted: 30 June 2021 Published: 16 July 2021 INTRODUCTION Citation: Chang H, Cong H, Wang H, Neuromyelitis optica spectrum disorder (NMOSD) is a severe disabling autoimmune disease of the Du L, Tian D-C, Ma Y, Xu Y, Wang Y, central nervous system (CNS) associated with anti-aquaporin-4 (AQP4)-autoantibody. T helper Yin L and Zhang X (2021) Thymic subsets, which affect the differentiation of B cells into antibody-producing cells, have been Involution and Altered Naive CD4 T implicated in the pathogenesis of this autoimmune disorder (1). Changes in the circulating T-cell Cell Homeostasis in Neuromyelitis fi Optica Spectrum Disorder. pro le indicate a key role of T cells in NMOSD (2, 3). Thymus is the primary lymphoid organ, Front. Immunol. 12:645277. which regulates the development, selection, and maturation of T cells (4). However, alterations in doi: 10.3389/fimmu.2021.645277 the thymic characteristics or thymic function, if any, in NMOSD have not been elucidated. Frontiers in Immunology | www.frontiersin.org 1 July 2021 | Volume 12 | Article 645277 Chang et al. Thymic Involution in NMOSD Naive T cells are generated in the thymus and recirculate underwent flow cytometry to investigate the naive CD4+ T cell among lymphoid organs. Exposure of naïve T cells to foreign subpopulations. All patients with NMOSD were in the acute antigens induces their activation and differentiation into effector phase, and the samples were collected prior to treatment. None of and memory T cells (5, 6). Preservation of the peripheral naive T the NMOSD patients had any other autoimmune disease. Eligible cell pool in humans requires both thymic output and HC had no history of autoimmune diseases, thymoma, or other homeostatic proliferation (7–9). Interleukin-6 (IL-6) can underlying diseases. Women who were pregnant or breastfeeding promote the differentiation of naive T cells into within the last 6 months were ineligible for this study. The proinflammatory type 17 helper T cells, which, along with demographic and clinical characteristics of all participants are interleukin-6, promote the differentiation of B cells into summarized in Table 1. AQP4-IgG–producing plasmablasts (10–12). This phenomenon consistently aggravates the disease severity in Chest Computed Tomography patients with NMOSD. However, the naive T cell homeostasis We retrospectively reviewed chest CT images of 60 patients with in NMOSD patients is not well characterized. NMOSD from the Neurology Department, Beijing Tiantan Naive T cells are regarded as a fairly homogeneous and Hospital, from May 2018 to December 2019, and 65 age-, sex- quiescent cell population, differing only with respect to T-cell matched healthy adults from the Health Management Center, receptor (TCR) specificity; the size of the naive T cell population Beijing Tiantan Hospital as HC. Eligible HC with no history of depends on age and thymic output (13). Phenotypically, human autoimmune diseases, thymoma, or other underlying diseases naive CD4 + T cells express surface markers, such as CCR7, were enrolled for chest CT examination. Women who were CD45RA, CD62L, CD27, and CD28 (14, 15). Previous studies pregnant or breastfeeding within the last 6 months were have shown that surface CD31 expression distinguishes two ineligible for this study. The demographic and thymus subpopulations of CD45RA+ CD62L+ naive CD4+ Tcellswith characteristics of all participants are summarized in Table 3. distinct T-cell receptor excision circle (TREC) content in the peripheral blood of humans (13, 14, 16). CD31+thymicnaive Image Acquisition and Analysis CD4+ T cells were found to be enriched in TRECs, comprising All imaging was conducted on a 256 slice Discovery CT750 HD CT of recent thymic emigrants, whereas CD31- central naive CD4+ T Scanner (GE Healthcare, Waukesha, WI). Chest CT scans with axial cells displayed a rather low TREC content, characterized by technique 5-mm slice thickness were evaluated on a Picture striking TCR repertoire restrictions, seemingly generated by Archiving and Communication System (PACS) workstation homeostatic proliferation of naive CD4+ T cells (13). The (Neusoft Co., China). All images were reviewed on a PACS, using fraction and absolute count of CD31+thymicnaive CD4+ Tcells a mediastinal window setting (level, 50 HU; width, 350 HU). show a negative correlation with age and the age-related decline in thymic function, which can be regarded as direct marker of thymic Flow Cytometric Analysis of Naive CD4 T output (17). In contrast, the absolute number of CD31-central naive Cells Subpopulations ™ CD4+ T cells tends to remain stable over time, implying a Whole blood samples (100 ml) were stained in TruCount tubes peripheral regulation independent of thymic activity (18). with anti-CD45RA, CD3, CD4, CD31, and CD62L antibodies Thymic homing of activated CD4+ T cells has been shown to (Biolegend) after red blood cell lysis. The CytExpert software induce the degeneration of thymus gland (19); therefore, the (Beckman Coulter) was used for analysis. thymic characteristics and thymic function in NMOSD were unexpected observations on account of the CD4+ TH17 cells polarization. This complexity provides interesting insights into TABLE 1 | Clinical and demographic characteristics of participants who fl the pathogenesis of NMOSD. underwent ow cytometric analysis. In this study, we retrospectively reviewed the chest computed Characteristic NMOSD HC P tomography (CT) images to describe the characteristics of Value thymus in patients with NMOSD and measured the thymic Number 44 21 density as a representative marker of thymic function. In Agea, mean (SD), y 42.8 (15.8) 39.1 0.42 addition, we performed flow cytometric analysis of naive T (14.7) cells to investigate the homeostasis alteration and thymic output. Sexb, No. (%) Male 10 (22.7%) 1 (4.8%) 0.985 Female 34 (77.3%) 20 (95.2%) METHODS Disease duration, mean (range), m 31.9 (0.5–205.0) – Relapse times, median (interquartile range) 3.8 (3, 5) – Patient Selection EDSS at FCM analysis, median 4.2 (3.0, 6.0) – Flow Cytometry (interquartile range) Forty-four patients with NMOSD, who were diagnosed according Antibody status (Cell based assay) AQP4-IgG, No. (%) 31 (70.5%) – to 2015 International Panel for Neuromyelitis Optica Diagnostic a criteria at the Neurology department of the Beijing Tiantan Mann-Whitney U test. bDifferences of sex and thymus shapes between groups were assessed using Chi- Hospital between August 2019 and January 2020, and 21 squared test. y, year; m, month; FCM, flow cytometry; NMOSD, Neuromyelitis optica healthy controls (HC) from the Health Management Center spectrum disorder; HC, healthy controls; EDSS, Expanded Disability Status Scale. Frontiers in Immunology | www.frontiersin.org 2 July 2021 | Volume 12 | Article 645277 Chang et al. Thymic Involution in NMOSD Serum IL-6 Analysis in the Population used to analyze differences between NMOSD and HC, with Subjected to Flow Cytometry respect to scalar and nonparametric
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