Research Papers: Immunology:
Novel CXCL13 transgenic mouse: inflammation drives pathogenic effect of CXCL13 in experimental myasthenia gravis
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Julia Miriam Weiss1,2,3,4, Marieke Robinet1,2,3,4, Revital Aricha5, Perrine Cufi1,2,3,4, Bérengère Villeret1,2,3,4, Frida Lantner5, Idit Shachar5, Sara Fuchs5, Miriam C. Souroujon6, Sonia Berrih-Aknin1,2,3,4,* and Rozen Le Panse1,2,3,4,*
1 INSERM U974, Paris, France
2 CNRS FRE3617, Paris, France
3 Sorbonne Universités, 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.