Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells

Kerstin Göbel,Chloi-Magdalini Asaridou,Christoph Kleinschnitz,Alexander M Herrmann,Triantafyllos Chavakis,Tobias Ruck,Sven G Meuth,Ioannis Mitroulis,Friederike Langhauser,Sarah Glumm,Stefan Bittner,Marc W Nolte,Michael K Schuhmann,Thorsten F Krug,Con Panousis,Thomas Korn,Bernhard Nieswandt,Clemens Ruppert,Heinz Wiendl,Susann Pankratz,Denise Beckmann,Thomas Pap,Martin Herold,Luisa Klotz,Harald F Langer,Peter Kraft,Matthias Merker ,Judith Breuer ,Adelheid Korb‐Pap ,Catharina C Groß ,Stefanie Küerten ,Beate E Kehrel

doi:10.1038/ncomms11626

Abstract

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.

Highlights

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS)
To assess whether factor XII (FXII) is relevant during CNS autoimmunity in vivo, we first analysed the plasma, lymph nodes (LNs) and the inflamed CNS of myelin oligodendrocyte glycoprotein 35–55 (MOG35–55)-immunized wild-type (WT) mice
Extensive FXII depositions could be found in the inflamed CNS of immunized mice (Fig. 1a,b), implying a potential contribution of FXII to EAE pathology

Summary

Introduction

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. We identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. Autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis (MS), are mediated by the intimate interplay of many cellular and molecular immune components[1,2]. Recent studies suggest that both interferon (IFN)-g- and interleukin (IL)-17A-producing effector T-helper cells (TH1 and TH17, respectively) contribute to inflammation and tissue damage in the course of CNS autoimmunity[3,4,5]. Blood coagulation constituents, such as platelets, are thought to contribute to experimental autoimmune encephalomyelitis (EAE), the mouse model of human MS10. We showed that FXII drives pathologic adaptive immune reactions via CD87-mediated modulation of DC

Methods

Results

Conclusion