Novel CXCL13 transgenic mouse: inflammation drives pathogenic effect of CXCL13 in experimental myasthenia gravis.

// Julia Miriam Weiss 1,2,3,4 , Marieke Robinet 1,2,3,4 , Revital Aricha 5 , Perrine Cufi 1,2,3,4 , Berengere Villeret 1,2,3,4 , Frida Lantner 5 , Idit Shachar 5 , Sara Fuchs 5 , Miriam C. Souroujon 6 , Sonia Berrih-Aknin 1,2,3,4,* and Rozen Le Panse 1,2,3,4,* 1 INSERM U974, Paris, France 2 CNRS FRE3617, Paris, France 3 Sorbonne Universites, UPMC University Paris 06, Paris, France 4 AIM, Institut de Myologie, Paris, France 5 Department of Immunology, Weizmann Institute of Science, Rehovot, Israel 6 Open University of Israel, Raanana, Israel * The authors have contributed equally to this work Correspondence to: Rozen Le Panse, email: // Keywords : chemokine, autoimmunity, thymus, B cells, CXCL13-CXCR5, Immunology and Microbiology Section, Immune response, Immunity Received : September 29, 2015 Accepted : December 23, 2015 Published : January 11, 2016 Abstract Abnormal overexpression of CXCL13 is observed in many inflamed tissues and in particular in autoimmune diseases. Myasthenia gravis (MG) is a neuromuscular disease mainly mediated by anti-acetylcholine receptor autoantibodies. Thymic hyperplasia characterized by ectopic germinal centers (GCs) is a common feature in MG and is correlated with high levels of anti-AChR antibodies. We previously showed that the B-cell chemoattractant, CXCL13 is overexpressed by thymic epithelial cells in MG patients. We hypothesized that abnormal CXCL13 expression by the thymic epithelium triggered B-cell recruitment in MG. We therefore created a novel transgenic (Tg) mouse with a keratin 5 driven CXCL13 expression. The thymus of Tg mice overexpressed CXCL13 but did not trigger B-cell recruitment. However, in inflammatory conditions, induced by Poly(I:C), B cells strongly migrated to the thymus. Tg mice were also more susceptible to experimental autoimmune MG (EAMG) with stronger clinical signs, higher titers of anti-AChR antibodies, increased thymic B cells, and the development of germinal center-like structures. Consequently, this mouse model finally mimics the thymic pathology observed in human MG. Our data also demonstrated that inflammation is mandatory to reveal CXCL13 ability to recruit B cells and to induce tertiary lymphoid organ development.