Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry |
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Authors: | Yu Philipp Constien Rainer Dear Neil Katan Matilda Hanke Petra Bunney Tom D Kunder Sandra Quintanilla-Martinez Leticia Huffstadt Ulrike Schröder Andreas Jones Neil P Peters Thomas Fuchs Helmut de Angelis Martin Hrabe Nehls Michael Grosse Johannes Wabnitz Philipp Meyer Thomas P H Yasuda Kei Schiemann Matthias Schneider-Fresenius Christian Jagla Wolfgang Russ Andreas Popp Andreas Josephs Michelle Marquardt Andreas Laufs Jürgen Schmittwolf Carolin Wagner Hermann Pfeffer Klaus Mudde Geert C |
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Affiliation: | Ingenium Pharmaceuticals AG, Fraunhoferstrasse 13, 82152 Martinsried, Munich, Germany. philipp.yu@lrz.tum.de |
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Abstract: | The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype. |
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