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Nat Commun. 2015 Sep 10;6:8164. doi: 10.1038/ncomms9164.

Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation.

Author information

1
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
2
Division of Neonatology, Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA.
3
Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.
4
Program in Immunology, University of California San Francisco, San Francisco, California 94143, USA.
5
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94158, USA.
6
Centre for Brain Research, Medical University of Vienna, Vienna A-1090, Austria.
7
Division of Experimental Hematology, Cincinnati Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.

Abstract

Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood-brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b(+) antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.

PMID:
26353940
PMCID:
PMC4579523
DOI:
10.1038/ncomms9164
[Indexed for MEDLINE]
Free PMC Article

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