Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration

Abstract

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer’s disease (AD). However, mechanisms linking blood-brain barrier (BBB) disruption with neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8 targeted against the cryptic fibrin epitope γ 377–395 to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and proinflammatory gene expression. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced innate immune activation and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibits autoimmune- and amyloid-driven neurotoxicity and may have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis

“…Chronification of these pathological events may contribute not only to tissue damage and neurodegeneration, but also to inhibition of potential repair mechanisms. Targeting the coagulation pathway might therefore have therapeutic potential . It still remains unclear how the whole fibrinogen molecule or some of the protein subunits may diffuse in CSF and brain tissue.…”

Brain fibrinogen deposition plays a key role in MS pathophysiology – Yes

“…activation resulting in morphological changes, increased phagocytosis, upregulation of genes responsible for oxidative stress, and release of proinflammatory and cytotoxic mediators that damage neurons. 6,[8][9][10] Furthermore, fibrinogen impairs tissue repair processes by inhibiting oligodendrocyte precursor cell differentiation and inducing NADPH/ROS-mediated neurodegeneration. 3,10 Selective inhibition of fibrinogen-induced inflammation protects from MS-like disease Upon BBB disruption, several blood components and coagulation factors gain access to the CNS.…”

“…6,[8][9][10] Furthermore, fibrinogen impairs tissue repair processes by inhibiting oligodendrocyte precursor cell differentiation and inducing NADPH/ROS-mediated neurodegeneration. 3,10 Selective inhibition of fibrinogen-induced inflammation protects from MS-like disease Upon BBB disruption, several blood components and coagulation factors gain access to the CNS. The immediate initiation of coagulation results in the conversion of fibrinogen -a rather benign soluble molecule in the bloodstream -to fibrin -a potent activator of autoimmune responses in the CNS.…”

Integration of Mechanistic Immunological Knowledge into a Machine Learning Pipeline Increases Predictive Power

“…The single-cell evaluation of intracellular signaling responses is particularly valuable in characterizing this cellular network as it provides a functional assessment of an individual's immune system. In clinical settings, a deep understanding of functional immune responses not only provides diagnostic opportunities, but also is often the first step in developing immune therapies (recent examples include successful immune modulation in chronic lymphocytic leukemia 3 , neurodegeneration 4 , and Ebola 5 ).…”