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CD4+CTLs in Fibrosing Mediastinitis Linked to Histoplasma capsulatum

Hugues Allard-Chamard, Faisal Alsufyani, Naoki Kaneko, Kelly Xing, Cory Perugino, Vinay S. Mahajan, Joseph L. Wheat, George S. Deepe Jr., James Loyd and Shiv Pillai
J Immunol February 1, 2021, 206 (3) 524-530; DOI: https://doi.org/10.4049/jimmunol.2000433
Hugues Allard-Chamard
*Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
†Division de Rhumatologie, Faculté de Médecine et des Sciences de la Santé de l’Université de Sherbrooke et Centre de Recherche Clinique Étienne-Le Bel, Sherbrooke, Québec J1K 2R1, Canada;
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Faisal Alsufyani
*Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
‡King Fahad Specialist Hospital, Dammam 32253, Saudi Arabia;
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Naoki Kaneko
*Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
§Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka 814-0133, Japan;
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Kelly Xing
*Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
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Cory Perugino
*Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
¶Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA 02114;
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Vinay S. Mahajan
*Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
‖Division of Pathology, Brigham and Women’s Hospital, Boston, MA 02115;
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Joseph L. Wheat
#MiraVista Diagnostics, Indianapolis, IN 46241;
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George S. Deepe Jr.
**Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
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James Loyd
††Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Shiv Pillai
*Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
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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.

This article is featured in Top Reads, p.453

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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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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CD4+CTLs in Fibrosing Mediastinitis Linked to Histoplasma capsulatum
Hugues Allard-Chamard, Faisal Alsufyani, Naoki Kaneko, Kelly Xing, Cory Perugino, Vinay S. Mahajan, Joseph L. Wheat, George S. Deepe, James Loyd, Shiv Pillai
The Journal of Immunology February 1, 2021, 206 (3) 524-530; DOI: 10.4049/jimmunol.2000433

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CD4+CTLs in Fibrosing Mediastinitis Linked to Histoplasma capsulatum
Hugues Allard-Chamard, Faisal Alsufyani, Naoki Kaneko, Kelly Xing, Cory Perugino, Vinay S. Mahajan, Joseph L. Wheat, George S. Deepe, James Loyd, Shiv Pillai
The Journal of Immunology February 1, 2021, 206 (3) 524-530; DOI: 10.4049/jimmunol.2000433
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Print ISSN 0022-1767        Online ISSN 1550-6606