Complement activation and expression during chronic relapsing experimental autoimmune encephalomyelitis in the Biozzi ABH mouse

Abstract

SummaryChronic relapsing experimental autoimmune encephalomyelitis (crEAE) in mice recapitulates many of the clinical and histopathological features of human multiple sclerosis (MS), making it a preferred model for the disease. In both, adaptive immunity and anti-myelin T cells responses are thought to be important, while in MS a role for innate immunity and complement has emerged. Here we sought to test whether complement is activated in crEAE and important for disease. Disease was induced in Biozzi ABH mice that were terminated at different stages of the disease to assess complement activation and local complement expression in the central nervous system. Complement activation products were abundant in all spinal cord areas examined in acute disease during relapse and in the progressive phase, but were absent in early disease remission, despite significant residual clinical disease. Local expression of C1q and C3 was increased at all stages of disease, while C9 expression was increased only in acute disease; expression of the complement regulators CD55, complement receptor 1-related gene/protein y (Crry) and CD59a was reduced at all stages of the disease compared to naive controls. These data show that complement is activated in the central nervous system in the model and suggest that it is a suitable candidate for exploring whether anti-complement agents might be of benefit in MS.

Depletion of CD52‐positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune‐tolerance promoting CD8 T‐cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis

“…32,33 This may relate to the mechanism of depletion of alemtuzumab that centres on antibodydependent cellular cytotoxicity rather than complement fixation. 32 Although ABH mice express normal complement components, unlike some laboratory mice, and can promote complement-mediated lysis by antibodies, 35,36 ABH mice have abnormal Fc receptors that could influence function. 37 This may account for subtle differences in depletion kinetics between mouse strains.…”

Systemic inhibition of the membrane attack complex impedes neuroinflammation in chronic relapsing experimental autoimmune encephalomyelitis

“…Each animal received 1 mg of SCH and 60 μg mycobacteria [ Mycobacterium tuberculosis H37Ra, Mycobacterium butyricum (4:1); Difco, BD Biosciences, San Jose, CA, USA] per injection [ 5 , 35 ]. Body weight and clinical signs were assessed daily, as previously described [ 61 ], using the following five-point scoring system: 0, normal; 1, loss of tail tone; 2, impaired righting reflex; 3, partial hind limb paralysis, with 1 limb affected; 4, complete hind limb paralysis, with both limbs affected; and 5, moribund. Severity of clinical disability was further analyzed by quantitative (q) PCR analysis for selected immune genes (Additional file 1 : Table S1).…”

“…Here, we used the chronic relapsing experimental autoimmune encephalomyelitis (EAE) model of chronic neuroinflammation [ 35 ]. This model is used to study mechanisms of degeneration [ 44 ] and shows complement activation in the CNS [ 61 ]. Inhibition of the complement cascade was started after full induction of the disease, when T lymphocytes were activated.…”

An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases

“…In these mice, immunization with homogenates of the syngeneic spinal cord (SCH) in complete Freund’s adjuvant induces a chronic relapsing form of EAE (Baker et al, 1990 ), which pathologically is characterized by inflammatory demyelinating lesions in the spinal cord and substantial axonal injury (Jackson et al, 2009 ). In terms of inflammation, these spinal cord lesions are populated by macrophages, CD4 + T lymphocytes (Butter et al, 1991 ), and deposits of TCC/MAC (Ramaglia et al, 2015 ). Notably, post-symptomatic treatment of crEAE with an antisense oligonucleotide that specifically targets CNS-extrinsic production of murine C6 mRNA (a component necessary for the formation of the TCC/MAC complex), inhibited TCC/MAC deposition inside the CNS, prevented relapses and protected from relapse-induced axonal and synaptic damage (Michailidou et al, 2018 ).…”