Journal
JOURNAL OF IMMUNOLOGY
Volume 203, Issue 11, Pages 2837-2849Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1900473
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Funding
- National Institutes of Health (NIH) Medical Science Training Program [T32 GM007356]
- NIH/National Institute of Arthritis and Musculoskeletal Skin Disease [T32 AR053459, P30 AR069655, K08 AR067885, R01 AR56702]
- NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant [HD068373]
- NIH/National Institute on Aging [R01 AG051456]
- NIH/National Cancer Institute [R01 CA220467]
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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 wildtype 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.
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