Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase Cγ2 that specifically increases external Ca2+ entry

Philipp Yu, Rainer Constien, Neil Dear, Matilda Katan, Petra Hanke, Tom D. Bunney, Sandra Kunder, Leticia Quintanilla-Martinez, Ulrike Huffstadt, Andreas Schröder, Neil P. Jones, Thomas Peters, Helmut Fuchs, Martin Hrabe De Angelis, Michael Nehls, Johannes Grosse, Philipp Wabnitz, Thomas P.H. Meyer, Kei Yasuda, Matthias SchiemannChristian Schneider-Fresenius, Wolfgang Jagla, Andreas Russ, Andreas Popp, Michelle Josephs, Andreas Marquardt, Jürgen Laufs, Carolin Schmittwolf, Hermann Wagner, Klaus Pfeffer, Geert C. Mudde

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)451-465
Number of pages15
JournalImmunity
Volume22
Issue number4
DOIs
Publication statusPublished or Issued - Apr 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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