TY - JOUR
T1 - Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase Cγ2 that specifically increases external Ca2+ entry
AU - Yu, Philipp
AU - Constien, Rainer
AU - Dear, Neil
AU - Katan, Matilda
AU - Hanke, Petra
AU - Bunney, Tom D.
AU - Kunder, Sandra
AU - Quintanilla-Martinez, Leticia
AU - Huffstadt, Ulrike
AU - Schröder, Andreas
AU - Jones, Neil P.
AU - Peters, Thomas
AU - Fuchs, Helmut
AU - Hrabe De Angelis, Martin
AU - Nehls, Michael
AU - Grosse, Johannes
AU - Wabnitz, Philipp
AU - Meyer, Thomas P.H.
AU - Yasuda, Kei
AU - Schiemann, Matthias
AU - Schneider-Fresenius, Christian
AU - Jagla, Wolfgang
AU - Russ, Andreas
AU - Popp, Andreas
AU - Josephs, Michelle
AU - Marquardt, Andreas
AU - Laufs, Jürgen
AU - Schmittwolf, Carolin
AU - Wagner, Hermann
AU - Pfeffer, Klaus
AU - Mudde, Geert C.
N1 - Funding Information:
We thank H. Drexler, A. Servatius, N. Sandholzer, Y. Knack, K. Tentschert, U. Mollenhauer, P. Schropp, A. Wunderlich, A. Lohner, M. Weber, A. Wolf, K. Schneider, S. Stonawski, N. Kink, J. Müller, S. Holthaus, E. Samson, and L. Jennen for excellent technical assistance; E. Yu for help with the figures; J. Kraus and B. Kramer from 4SC, Martinsried, Germany for the 3D model; J. Arnason, G. Häcker, S. Bauer, I. Förster, and H. Kikutani (Osaka, Japan) for helpful discussion; and L. Nitschke (Erlangen, Germany) and D. Wang (Wisconsin, USA) for advice on Ca 2+ measurements. This work was supported by the Deutsche Forschungsgemeinschaft, SFB 456, SFB 391, NGFN, and a BMBF grant to J.G.
PY - 2005/4
Y1 - 2005/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=20244380494&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2005.01.018
DO - 10.1016/j.immuni.2005.01.018
M3 - Article
C2 - 15845450
AN - SCOPUS:20244380494
SN - 1074-7613
VL - 22
SP - 451
EP - 465
JO - Immunity
JF - Immunity
IS - 4
ER -