Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes, and Raynaud’s - Clinical Aspects and Therapeutics II
Session Type: Abstract Submissions (ACR)
Background/Purpose: Interstitial pneumonitis and lung fibrosis are frequent systemic complications of inflammatory arthritides, including systemic sclerosis (SSc), rheumatoid arthritis, or primary Sjögren’s syndrome. B lymphocytes are involved in the pathogenesis of such lung involvement. BAFF (B-cell activating factor of the TNF family) plays a crucial role in autoreactive B-cell activation and survival. We therefore investigated the pathogenic role of BAFF in fibrosis
Methods: Levels of BAFF were assessed using ELISA in serum of 150 patients with SSc and 80 healthy controls and in bronchoalveolar lavage of 12 patients with idiopathic pulmonary fibrosis (IPF) and 7 controls. Cocultures of B lymphocytes, stimulated or not with BAFF, and skin fibroblasts from patients with SSc and controls were performed. Lung fibrosis induced by bleomycin (BLM) was compared in BAFF -/- knock-out, BAFF-R-Ig treated mice and wild type (WT) mice. Lung BAFF expression was compared in BAFF IL-1R1-/-, IL-17A-/-, IL-17RA-/- mice after BLM challenge. Levels of IL-17 secreted by lung cells isolated from BLM-treated mice were analyzed after stimulation with anti-CD3 and BAFF
Results:
Serum BAFF level was significantly increased in SSc patients compared to controls (median 1.5 vs. 0.5; p< 0.0001). Patients with SSc and increased BAFF levels had a significantly higher incidence of pulmonary fibrosis assessed by lung CT scan (63% vs. 37%; p< 0.005). A significant increase in BAFF bronchoalveoar levels was observed in patients with IPF, especially in those with clinical exacerbation, compared to controls. Coculture of B lymphocytes and skin fibroblasts induced collagen secretion, which was further enhanced after BAFF stimulation. In the BLM model of lung fibrosis, a marked increase of BAFF, mainly secreted by infiltrating neutrophils, was detected in the bronchoalveolar lavage and in lung extracts. Inhibition of BAFF using BAFF-R-Ig or gene depletion (BAFF -/- mice) resulted in a marked decrease of lung fibrosis, assessed by histology, and quantification of TGF-beta and collagen by qPCR and ELISA. Interestingly, levels of BAFF were significantly decreased in IL-1R1-/-, IL-17A-/- and IL-17 RA-/- mice, in which lung fibrosis was significantly reduced after BLM challenge, compared to WT mice. In vitro, recombinant BAFF induced a dramatic increase in IL-17 secretion by lung cells isolated after BLM challenge.
Conclusion:
These results confirm the implication of B lymphocytes and sheds light to a new pathogenic role of BAFF in fibrosis according to consistent results in the bleomycin model, SSc and IPF. Taken together, these results suggest the following scenario: i) BAFF is induced by IL-1β and IL-17, which are potent pro-fibrogenic cytokines; ii)BAFF in turn induces IL-17 secretion by Th17 cells in an amplification loop. This study adds to the rationale of evaluating the therapeutic interest of BAFF inhibition in systemic sclerosis, inflammatory arthritis-related lung fibrosis and idiopathic pulmonary fibrosis.
Disclosure:
A. Francois,
None;
P. Schneider,
None;
A. Davidson,
None;
E. Chatelus,
None;
J. Avouac,
None;
Y. Allanore,
None;
B. Villeret,
None;
A. Gombault,
None;
P. Gasse,
None;
S. Marchand Adam,
None;
B. Ryffel,
None;
S. Bahram,
None;
P. Georgel,
None;
J. Sibilia,
None;
I. Couillin,
None;
J. E. Gottenberg,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-new-pathogenic-role-of-baff-as-a-critical-mediator-of-skin-and-lung-fibrosis-in-experimental-bleomycin-induced-pulmonary-fibrosis-systemic-sclerosis-and-idiopathic-pulmonary-fibrosis/