Key Points
In fibrosing mediastinitis, CD4+CD4+CTLs accumulate in lesions.
CD4+CTLs in the blood of patients respond to H. capsulatum Ags in vitro.
Abstract
Although fibrotic disorders are frequently assumed to be linked to TH2 cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4+CTLs. In both these diseases TH2 cell accumulation was found to be sparse. Fibrosing mediastinitis linked to Histoplasma capsulatum infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4+CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by H. capsulatum Ags. TH2 cells are relatively sparse at lesional sites. These studies support a general role for CD4+CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases.
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Footnotes
This work was supported by National Institutes of Health Grant U19AI110495 to S.P.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- FM
- fibrosing mediastinitis
- GZMA
- granzyme A
- IgG4-RD
- IgG4-related disease.
- Received April 21, 2020.
- Accepted November 13, 2020.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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