title: Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry.
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.
authors.affiliation: Ingenium Pharmaceuticals AG, Fraunhoferstrasse 13, 82152 Martinsried, Munich, Germany. philipp.yu@lrz.tum.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Yu
authors.forename: Rainer
authors.initials: R
authors.lastname: Constien
authors.forename: Neil
authors.initials: N
authors.lastname: Dear
authors.forename: Matilda
authors.initials: M
authors.lastname: Katan
authors.forename: Petra
authors.initials: P
authors.lastname: Hanke
authors.forename: Tom D
authors.initials: TD
authors.lastname: Bunney
authors.forename: Sandra
authors.initials: S
authors.lastname: Kunder
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Ulrike
authors.initials: U
authors.lastname: Huffstadt
authors.forename: Andreas
authors.initials: A
authors.lastname: Schröder
authors.forename: Neil P
authors.initials: NP
authors.lastname: Jones
authors.forename: Thomas
authors.initials: T
authors.lastname: Peters
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Martin Hrabe
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Michael
authors.initials: M
authors.lastname: Nehls
authors.forename: Johannes
authors.initials: J
authors.lastname: Grosse
authors.forename: Philipp
authors.initials: P
authors.lastname: Wabnitz
authors.forename: Thomas P H
authors.initials: TP
authors.lastname: Meyer
authors.forename: Kei
authors.initials: K
authors.lastname: Yasuda
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiemann
authors.forename: Christian
authors.initials: C
authors.lastname: Schneider-Fresenius
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jagla
authors.forename: Andreas
authors.initials: A
authors.lastname: Russ
authors.forename: Andreas
authors.initials: A
authors.lastname: Popp
authors.forename: Michelle
authors.initials: M
authors.lastname: Josephs
authors.forename: Andreas
authors.initials: A
authors.lastname: Marquardt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Laufs
authors.forename: Carolin
authors.initials: C
authors.lastname: Schmittwolf
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Geert C
authors.initials: GC
authors.lastname: Mudde
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology; D002118:Calcium / Q000378:metabolism*; D003872:Dermatitis / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D051966:Phospholipase C gamma; D017354:Point Mutation; D010738:Type C Phospholipases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium