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Abstract Number: 2610

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

Antoine Francois1, Pascal Schneider2, Anne Davidson3, Emmanuel Chatelus4, Jérôme Avouac5, Yannick Allanore6, Bérengère Villeret7, Aurélie Gombault7, Paméla Gasse8, Sylvain Marchand Adam9, Bernhard Ryffel10, Siamak Bahram11, Philippe Georgel12, Jean Sibilia13, Isabelle Couillin8 and Jacques-Eric Gottenberg14, 1Laboratory of Physiopathology of Arthritises, University of Strasbourg, Illkirch-Strasbourg, France, 2Department of Biochemistry, University of Lausanne, Lausanne, Switzerland, 3Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, NY, 4Rheumatology, Strasbourg University Hospital, Strasbourg, France, 5Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France, 6Rheumatology, Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France, 7Molecular Immunology and Embryology, University of Orleans and National Center for Scientific Research, Orléans, France, 8Molecular Immunology and Embryology, University of Orleans and National Center for Scientific Research, Orleans, France, 9Francois Rabelais University, National institute of the health and the medical research, Tours, France, 10UMR6218, Molecular Immunology, University and CNRS, 3b rue de la Ferollerie, Orleans, France, 11Fédération of Translational Medicine of Strasbourg (FMTS), Immunorhumatology Molécular, Strasbourg, France, 12Université de Strasbourg, Laboratoire d'ImmunoGénétique Moléculaire Humaine, Strasbourg, France, 13Rheumatology, CHU Hautepierre, Strasbourg, France, 14Strasbourg University Hospital, Strasbourg, France

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: BAFF, fibroblasts and systemic sclerosis, Pulmonary Involvement

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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/

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