Early Complementopathy After Multiple Injuries in Humans

Abstract

After severe tissue injury, innate immunity mounts a robust systemic inflammatory response. However, little is known about the immediate impact of multiple trauma on early complement function in humans. In the present study we hypothesized that multiple trauma results in immediate activation, consumption and dysfunction of the complement cascade and that the resulting severe “complementopathy” may be associated with morbidity and mortality. Therefore a prospective multicenter study with 25 healthy volunteers and 40 polytrauma patients (mean injury severity score [ISS] = 30.3 ± 2.9) was performed. After polytrauma serum was collected as early as possible at the scene, upon admission to the emergency room and 4, 12, 24, 120 and 240 hours post trauma and analysed for the complement profile. Complement hemolytic activity (CH-50) was massively reduced within the first 24 h after injury, recovered only 5 days after trauma and discriminated between lethal and non-lethal 28-day outcome. Serum levels of the complement activation products C3a and C5a were significantly elevated throughout the entire observation period and correlated with the severity of traumatic brain injury and survival. The soluble terminal complement complex SC5b-9 and mannose-binding lectin (MBL) showed a biphasic response after trauma. Key fluid phase inhibitors of complement, such as C4b-binding protein (C4BP) and factor I, were significantly diminished early after trauma. The present data indicate an almost synchronically rapid activation and dysfunction of complement suggesting a trauma-induced “complementopathy” early after injury. These events may participate to the impairment of the innate immune response observed after severe trauma.

Innate immune responses to trauma

“…In particular, the serine protease system, composed of the kinin, coagulation and complement cascades, can detect DAMPs and PAMPs, become rapidly activated after trauma 18,19 and be further bolstered in acidic (for example, hypoxic) microenvironments 20 . Either directly or via such activated systems, DAMPs and PAMPs can transmit their signals to leukocytes through pattern-recognition receptors (PRRs) such as TLRs, NLRs, RAGE, purinergic receptors or complement receptors 11,12,21 .…”

Inhibition of the Membrane Attack Complex of the Complement System Reduces Secondary Neuroaxonal Loss and Promotes Neurologic Recovery after Traumatic Brain Injury in Mice

“…tudies of traumatic brain injury (TBI) in human and experimental models have identified the complement system as an early mediator of posttraumatic neuroinflammation and secondary neuronal damage, ultimately leading to behavioral, emotional, and cognitive problems (1)(2)(3)(4)(5)(6)(7)(8). Therefore, timely intervention to target activation of the complement system may be a promising therapy to reduce neuropathology and improve neurologic outcome in patients with TBI.…”

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

“…traumatic brain injury | complement | therapy | CD59 | CRIg C ognitive, behavioral, and emotional sequelae of traumatic brain injury (TBI) are largely due to neuroaxonal damage secondary to the mechanical injury (1,2). Complement is an early determinant of posttraumatic neuroinflammation and secondary neuropathology (3)(4)(5)(6)(7); therefore, timely intervention to block complement activation may reduce neuroinflammation, neurodegeneration, and neurologic decline. Previous studies showed that complement inhibition protects in experimental TBI; however, most agents targeted the C3 convertase, the point of activation pathway convergence, resulting in broad inhibition of complement (8,9).…”