Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry.
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.
Yu
Philipp
P
Ingenium Pharmaceuticals AG, Fraunhoferstrasse 13, 82152 Martinsried, Munich, Germany. philipp.yu@lrz.tum.de
Constien
Rainer
R
Dear
Neil
N
Katan
Matilda
M
Hanke
Petra
P
Bunney
Tom D
TD
Kunder
Sandra
S
Quintanilla-Martinez
Leticia
L
Huffstadt
Ulrike
U
Schröder
Andreas
A
Jones
Neil P
NP
Peters
Thomas
T
Fuchs
Helmut
H
de Angelis
Martin Hrabe
MH
Nehls
Michael
M
Grosse
Johannes
J
Wabnitz
Philipp
P
Meyer
Thomas P H
TP
Yasuda
Kei
K
Schiemann
Matthias
M
Schneider-Fresenius
Christian
C
Jagla
Wolfgang
W
Russ
Andreas
A
Popp
Andreas
A
Josephs
Michelle
M
Marquardt
Andreas
A
Laufs
Jürgen
J
Schmittwolf
Carolin
C
Wagner
Hermann
H
Pfeffer
Klaus
K
Mudde
Geert C
GC
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
D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium