RESUMO
IFN-γ(-/-) NOD.H-2h4 mice develop autoimmune disease with extensive hyperplasia and proliferation of thyroid epithelial cells (TEC H/P) and fibrosis. Splenic T cells from donors with severe TEC H/P transfer TEC H/P to SCID recipients. The goal of this study was to determine what factors control TEC H/P development/progression by examining T cells, markers of apoptosis, senescence and proliferation in thyroids of SCID recipients over time. At 28days, T cell infiltration was maximal, thyrocytes were proliferating, and fibrosis was moderate. At days 60 and 90, thyroids were larger with more fibrosis. T cells, cytokines and thyrocyte proliferation decreased, and cell cycle inhibitor proteins, and anti-apoptotic molecules increased. T cells and thyrocytes had foci of phosphorylated histone protein H2A.X, indicative of cellular senescence, when TEC H/P progressed and thyrocyte proliferation declined. Some thyrocytes were regenerating at day 90, with irregularly shaped empty follicles and ciliated epithelium. Proliferating thyrocytes were thyroid transcription factor (TTF1)-positive, suggesting they derived from epithelial cells and not brachial cleft remnants.
Assuntos
Histonas/metabolismo , Linfócitos T/imunologia , Células Epiteliais da Tireoide/metabolismo , Glândula Tireoide/patologia , Tireoidite Autoimune/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Senescência Celular , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Fibrose , Humanos , Hiperplasia , Interferon gama/genética , Camundongos , Camundongos Knockout , Camundongos SCID , Células Epiteliais da Tireoide/patologia , Tireoidite Autoimune/patologia , Fatores de TranscriçãoRESUMO
Recent in vitro studies suggest that calcitonin gene-related peptide (CGRP) inhibits early B cell differentiation; however, there is no evidence in the intact animal for a role for CGRP in B cell development. Here, we show that in vivo treatment of mice with CGRP reduces the number of IL-7 responsive B cell progenitors in bone marrow. A single CGRP treatment reduces IL-7-responsive B cell progenitors by up to 40% for up to 72 h. The reduction is dose-dependent and can be blocked by a CGRP receptor antagonist, CGRP(8-37). CGRP in serum following injection is highly elevated at 30 min but returns to basal levels by 4 h, suggesting that a single injection of CGRP has long-lasting effects on B cell development. This report provides the first direct in vivo evidence that CGRP, a neuropeptide with multiple effects on mature lymphocytes, also plays a regulatory role in early B cell development in the bone marrow.