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

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.

Factor XII and uPAR upregulate neutrophil functions to influence wound healing

“…In contrast to other components of the coagulation system, FXII has 2 EGF domains and the zymogen has mitogenic activity in smooth muscle and endothelial cells where FXII stimulates angiogenesis through urokinase plasminogen activator receptor (uPAR) (20)(21)(22). Activation of dendritic cells by FXII also modulates adaptive immunity through uPAR-mediated cytokine production, contributing to neuroinflammation (23). These data indicate that zymogen FXII regulates cell biology independently of its protease function.…”

The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders

“…In particular, constituents of the plasmatic coagulation system and the contact systems have received interest [22,23]. Further, depositions of coagulation factors, such as fibrinogen or factor XII, were described in plaques of MS patients [23,24,25].…”

“…In particular, constituents of the plasmatic coagulation system and the contact systems have received interest [22,23]. Further, depositions of coagulation factors, such as fibrinogen or factor XII, were described in plaques of MS patients [23,24,25]. Besides the plasmatic coagulation, slight attention has also been given to platelets in the pathogenesis of MS in the past, despite the fact that early evidence from 1950s/60s pointed to platelet abnormalities in MS patients [26,27,28,29].…”

Effect of IgG from multiple sclerosis patients on amidolytic activity of coagulation and anticoagulation factors of hemostasis

“…fibrinopeptide A and D-dimer) have been shown to be significantly upregulated in individuals suffering from MS, while fibrinogen levels were found to be unaltered (Aksungar et al, 2008;Ehling et al, 2011;Liguori et al, 2014). These alterations were also significantly increased in blood samples of MS patients compared to healthy controls (Göbel et al, 2016b).…”

“…Although the role of hemostasis enzymes in the interactions with IgG need to be further studied, the described coagulation factors may represent key mediators in neuroinflammation (Bhat and Steinman, 2009;Göbel et al, 2016b). Accordingly, the interactions between IgG and coagulation factors may provide new targets for the development of future therapeutic strategies for MS and possibly other neuroimmunological diseases.…”