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J Immunol. 2019 Dec 1;203(11):2837-2849. doi: 10.4049/jimmunol.1900473. Epub 2019 Oct 28.

TNF-Induced Interstitial Lung Disease in a Murine Arthritis Model: Accumulation of Activated Monocytes, Conventional Dendritic Cells, and CD21+/CD23- B Cell Follicles Is Prevented with Anti-TNF Therapy.

Author information

1
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
2
Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
3
Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
4
David H. Smith Center for Vaccine Biology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
5
Allergy, Immunology, and Rheumatology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
6
Department of Orthopaedics and Rehabilitation, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and.
7
Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Homaira_Rahimi@URMC.Rochester.edu.
8
Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.

Abstract

Interstitial lung disease (ILD) is a well-known extra-articular manifestation of rheumatoid arthritis (RA). RA-associated ILD (RA-ILD) exists on a wide spectrum, with variable levels of inflammatory and fibrotic activity, although all subtypes are regarded as irreversible pathologic conditions. In both articular and pulmonary manifestations, TNF is a significant pathogenic factor. Whereas anti-TNF therapy alleviates joint pathologic conditions, it exacerbates fibrotic RA-ILD. The TNF-transgenic (TNF-Tg) murine model of RA develops both inflammatory arthritis and an ILD that mimics a cellular nonspecific interstitial pneumonia pattern dominated by an interstitial accumulation of inflammatory cells with minimal-to-absent fibrosis. Given the model's potential to elucidate the genesis of inflammatory RA-ILD, we aim to achieve the following: 1) characterize the cellular accumulations in TNF-Tg lungs, and 2) assess the reversibility of inflammatory ILD following anti-TNF therapy known to resolve TNF-Tg inflammatory arthritis. TNF-Tg mice with established disease were randomized to anti-TNF or placebo therapy and evaluated with imaging, histology, and flow cytometric analyses, together with wild-type controls. Flow cytometry of TNF-Tg versus wild-type lungs revealed significant increases in activated monocytes, conventional dendritic cells, and CD21+/CD23- B cells that are phenotypically distinct from the B cells in inflamed nodes, which are known to accumulate in joint-draining lymph nodes. In contrast to human RA-ILD, anti-TNF treatment significantly alleviated both joint and lung inflammation. These results identify a potential role for activated monocytes, conventional dendritic cells, and CD21+/CD23- B cells in the genesis of RA-ILD, which exist in a previously unknown, reversible, prefibrotic stage of the disease.

PMID:
31659014
DOI:
10.4049/jimmunol.1900473

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