TY - JOUR
T1 - Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells
AU - Göbel, Kerstin
AU - Pankratz, Susann
AU - Asaridou, Chloi Magdalini
AU - Herrmann, Alexander M.
AU - Bittner, Stefan
AU - Merker, Monika
AU - Ruck, Tobias
AU - Glumm, Sarah
AU - Langhauser, Friederike
AU - Kraft, Peter
AU - Krug, Thorsten F.
AU - Breuer, Johanna
AU - Herold, Martin
AU - Gross, Catharina C.
AU - Beckmann, Denise
AU - Korb-Pap, Adelheid
AU - Schuhmann, Michael K.
AU - Kuerten, Stefanie
AU - Mitroulis, Ioannis
AU - Ruppert, Clemens
AU - Nolte, Marc W.
AU - Panousis, Con
AU - Klotz, Luisa
AU - Kehrel, Beate
AU - Korn, Thomas
AU - Langer, Harald F.
AU - Pap, Thomas
AU - Nieswandt, Bernhard
AU - Wiendl, Heinz
AU - Chavakis, Triantafyllos
AU - Kleinschnitz, Christoph
AU - Meuth, Sven G.
N1 - Funding Information:
We would like to thank C. Butz and J. Budde for excellent technical assistance. We also thank Dr Weimer (CSL Behring GmbH) for providing rHA-Infestin-4 and the non-cleavable FXII. This work was supported by the Deutsche Forschungsgemeinschaft, DFG (GO 2505/1-1 to K.G., ME3283/5-1 and ME3283/6-1 to S.G.M, KFO274 to H.F.L.), EKFS (2015-A113 to K.G.), Medical Faculty Münster (Junior Research Group to K.G.), SFB 688 (TP A13 to C.K.), SFB (TRR 128/1 2012 TP B06 to S.G.M.), IMF (GÖ 1 1 14 01 to K.G.), CIM (to S.G.M.), Volkswagen Foundation (Lichtenberg Program to H.F.L.), Biogen Idec GmbH, 85737 Ismaning, Germany (unrestricted grant to analyse the role of blood coagulation in EAE to C.K.) and Novartis Pharma GmbH, 90429 Nürnberg, Germany (unrestricted grant to analyse the role of blood coagulation in EAE to C.K.).
PY - 2016/5/18
Y1 - 2016/5/18
N2 - Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
AB - Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
UR - http://www.scopus.com/inward/record.url?scp=84969921236&partnerID=8YFLogxK
U2 - 10.1038/ncomms11626
DO - 10.1038/ncomms11626
M3 - Article
C2 - 27188843
AN - SCOPUS:84969921236
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 11626
ER -