Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Dec 21;31(166):220178.
doi: 10.1183/16000617.0178-2022. Print 2022 Dec 31.

Immune mechanisms in fibrotic pulmonary sarcoidosis

Praveen Weeratunga  1   2 , David R Moller  3 , Ling-Pei Ho  4   2
Affiliations
Review

Immune mechanisms in fibrotic pulmonary sarcoidosis

Praveen Weeratunga et al. Eur Respir Rev. .

Erratum in

Abstract

Sarcoidosis is an immune-mediated disorder. Its immunopathology has been steadily mapped out over the past few decades. Despite this, the underpinning mechanisms for progressive fibrotic sarcoidosis is an almost uncharted area. Consequently, there has been little change in the clinical management of fibrotic sarcoidosis over the decades and an unfocused search for new therapeutics. In this review, we provide a comprehensive examination of the relevant immune findings in fibrotic and/or progressive pulmonary sarcoidosis and propose a unifying mechanism for the pathobiology of fibrosis in sarcoidosis.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: P. Weeratunga has received support for the present manuscript from the University of Oxford Nuffield Department of Medicine Studentship. Conflict of interest: D.R. Moller has received support for the present manuscript from the National Heart, Lung and Blood Institute, payments made to Johns Hopkins. Royalties or licenses outside the submitted work: Hodder Education for editing a book on sarcoidosis, Taylor and Francis Group for editing a book on ILD. Consulting fees received outside the submitted work from: Roivant and SarcoMed. Speaker fees received from the Trinity Postgraduate Respiratory Conference, outside the submitted work. Patents planned, issued or pending: Patent No. 9,683,999 B2 (issued, not licensed or royalties), Patent No. 9,977,029 B2 (issued, not licensed or royalties), Patent No. 11,041,862 B2 (issued, not licensed or royalties), Patent Application No. 17/319,211 (pending, not licensed or royalties). Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Foundation for Sarcoidosis Research (former member of Scientific Advisory Board, unpaid). Other financial or non-financial interests: Chairman and Chief Technical Officer for Sarcoidosis Diagnostic Testing, LLC, the company goal is to develop a diagnostic blood test for sarcoidosis and the company has received funding including past salary support under the NHLBI STTR program, grant R41 HL129728 over 3 years ago. Conflict of interest: L-P. Ho has received support for the present manuscript from Medical Research Council core funding.

Figures

FIGURE 1
FIGURE 1
High-resolution computed tomographic section of a patient with active fibrotic sarcoidosis, with typical appearance of peri-hilar fibrocystic changes and accompanying ground-glass changes. Several patterns of fibrosis can be found but accompanying ground-glass changes could signify concomitant presence of cellular infiltrate or fine fibrosis.
FIGURE 2
FIGURE 2
Current key immune drivers of fibrosis in sarcoidosis. Red text highlights those cells/pathways with evidence from fibrotic sarcoidosis. Blue text indicates a likely contribution derived from evidence in chronic/progressive/active sarcoidosis. A heavy T-lymphocyte involvement is likely in active fibrotic sarcoidosis, possibly with secretion of interleukin (IL)-17 from activated T-lymphocytes. C-C motif chemokine ligand 18 (CCL-18) secreted by macrophages could promote accumulation of T-lymphocytes and secretion of collagen by macrophages. GREM1 polymorphisms which affect transforming growth factor-β (TGF-β) production in T-cells or macrophages is a potential contender. Strongest evidence probably lies with chronically increased mammalian target of rapamycin (mTOR) signalling and reduced autophagy in macrophages which allows persistence of antigen, chronically activated macrophages and perseverance of granuloma and disease activity. It is currently unclear which of these pathways are critical, and how many of these factors have to co-exist to result in progressive fibrotic disease in sarcoidosis. CTLA: cytotoxic T-lymphocyte-associated antigen; IFN: interferon; MHC: major histocompatibility complex; PAI-1: plasminogen activator inhibitor 1; PBMC: peripheral blood mononuclear cell; RAGE: receptor for advanced glycation end-products; SAA: serum amyloid antigen; Th: T-helper; TLR: Toll-like receptor; TNF: tumour necrosis factor; Treg: regulatory T-cell.
See this image and copyright information in PMC

References

    1. Facco M, Cabrelle A, Teramo A, et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax 2011; 66: 144–150. doi: 10.1136/thx.2010.140319 - DOI - PubMed
    1. Broos CE, Koth LL, van Nimwegen M, et al. Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes. Eur Respir J 2018; 51: 1701124. doi: 10.1183/13993003.01124-2017 - DOI - PubMed
    1. Ramstein J, Broos CE, Simpson LJ, et al. IFN-γ-producing T-helper 17.1 cells are increased in sarcoidosis and are more prevalent than T-helper type 1 cells. Am J Respir Crit Care Med 2016: 193: 1281–1291. doi: 10.1164/rccm.201507-1499OC - DOI - PMC - PubMed
    1. Miyara M, Amoura Z, Parizot C, et al. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006; 203: 359–370. doi: 10.1084/jem.20050648 - DOI - PMC - PubMed
    1. Korosec P, Rijavec M, Silar M, et al. Deficiency of pulmonary Vα24 Vβ11 natural killer T cells in corticosteroid-naïve sarcoidosis patients. Respir Med 2010; 104: 571–577. doi: 10.1016/j.rmed.2009.11.008 - DOI - PubMed