RRC ID 57612
Author Otsuka K, Yamada A, Saito M, Ushio A, Sato M, Kisoda S, Shao W, Tsunematsu T, Kudo Y, Arakaki R, Ishimaru N.
Title Achaete-Scute Homologue 2-Regulated Follicular Helper T Cells Promote Autoimmunity in a Murine Model for Sjögren Syndrome.
Journal Am J Pathol
Abstract Follicular helper T (Tfh) cells contribute to various immune responses as well as to the pathogenesis of several immune diseases. However, the precise mechanism underlying the onset or development of autoimmunity via Tfh cells remains unclear. Herein, the detailed relationship between autoimmune disease and Tfh cells was analyzed using a murine model for Sjögren syndrome (SS) wherein the mice underwent neonatal thymectomy. Germinal center (GC) development was promoted in this SS model along with an increase of Tfh cells and GC B cells. The severity of the autoimmune lesions was correlated with the number of Tfh cells detected in the spleen of the SS model mice. In addition, treatment with an anti-CD20 monoclonal antibody effectively suppressed the autoimmune lesions with a reduction of Tfh cells and GC B cells. Comprehensive gene analysis revealed that several genes associated with Tfh cell differentiation, including achaete-scute homologue 2 (Ascl2), were up-regulated in peripheral CD25- CD4+ T cells in SS model mice compared with those in control mice. Moreover, an experiment using CD4CreBcl6fl/fl mice that received neonatal thymectomy treatment demonstrated that Ascl2 contributes to the Tfh cell differentiation associated with autoimmunity during the early stages, independent of Bcl6. In conclusion, our results indicate that abnormal Tfh cell differentiation via Ascl2 regulation might contribute to the pathogenesis of autoimmunity.
Volume 189(12)
Pages 2414-2427
Published 2019-12-1
DOI 10.1016/j.ajpath.2019.08.008
PII S0002-9440(19)30712-6
PMID 31539517
MeSH Animals Autoantibodies / immunology Autoantibodies / metabolism Autoimmunity / immunology* B-Lymphocytes / immunology* B-Lymphocytes / metabolism B-Lymphocytes / pathology Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism* Cell Differentiation Cytokines / immunology Cytokines / metabolism Disease Models, Animal* Female Germinal Center / immunology* Germinal Center / metabolism Germinal Center / pathology Mice Mice, Inbred C57BL Proto-Oncogene Proteins c-bcl-6 / genetics Proto-Oncogene Proteins c-bcl-6 / metabolism Sjogren's Syndrome / immunology* Sjogren's Syndrome / metabolism Sjogren's Syndrome / pathology T-Lymphocytes, Helper-Inducer / immunology* T-Lymphocytes, Helper-Inducer / metabolism T-Lymphocytes, Helper-Inducer / pathology
IF 3.762
Times Cited 1
Mice RBRC05663