Uncovering the Path to Neurodegeneration from Playingfield to Battlefield

Baas, Frank; Ramaglia, Valeria

doi:10.5772/57186

Cited by 1 publication

(1 citation statement)

References 164 publications

(211 reference statements)

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“…Early reports showing improved outcomes after TBI in mice treated with C1 inhibitor implicate the classical and/or lectin pathway (36), whereas others implicate the alternative pathway (6,11). Cell damage caused by mechanical shearing in TBI may expose axonal epitopes, cell contents, and/or flipped membranes, all "danger" signals recognized by C1q, resulting in antibody-independent classical pathway activation and MAC formation (37). MAC then breaches target membranes, releasing cell contents and driving further complement activation and opsonization of targets by C3b/iC3b, providing ligands for CR3-mediated phagocytic clearance of damaged tissue (38,39).…”

Section: Discussionmentioning

confidence: 99%

An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice

Ruseva

Ramaglia

Morgan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Activation of complement is a key determinant of neuropathology and disability after traumatic brain injury (TBI), and inhibition is neuroprotective. However, systemic complement is essential to fight infections, a critical complication of TBI. We describe a targeted complement inhibitor, comprising complement receptor of the Ig superfamily (CRIg) fused with complement regulator CD59a, designed to inhibit membrane attack complex (MAC) assembly at sites of C3b/iC3b deposition. CRIg and CD59a were linked via the IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited MAC formation and prevented complement-mediated lysis in vitro. CD59-2a-CRIg dimer bound C3b-coated surfaces with submicromolar affinity (KD). In experimental TBI, CD59-2a-CRIg administered posttrauma homed to sites of injury and significantly reduced MAC deposition, microglial accumulation, mitochondrial stress, and axonal damage and enhanced neurologic recovery compared with placebo controls. CD59-2a-CRIg inhibited MAC-induced inflammasome activation and IL-1β production in microglia. Given the important anti-infection roles of complement opsonization, site-targeted inhibition of MAC should be considered to promote recovery postneurotrauma.

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