Deficiency of the complement regulator CD59a enhances disease severity, demyelination and axonal injury in murine acute experimental allergic encephalomyelitis

Abstract

There is a growing body of evidence implicating complement and, in particular, the terminal pathway (membrane attack complex; MAC) in inducing demyelination in multiple sclerosis and experimental allergic encephalomyelitis. In this paper, we examined the disease course and pathological changes in mice deficient in the major regulator of MAC assembly, CD59a, during the course of acute experimental allergic encephalomyelitis induced by immunisation with recombinant myelin oligodendrocyte glycoprotein. Disease incidence and severity were significantly increased in CD59a-deficient mice. The extent of inflammation, demyelination and axonal injury were assessed in spinal cord cross-sections from CD59a-deficient and control mice, and all these parameters were enhanced in the absence of CD59a. Areas of myelin loss and axonal damage in CD59a-deficient mice were associated with deposits of MAC, firmly implicating MAC as a cause of the observed injury. These findings are relevant to some types of human demyelination, where abundant deposits of MAC are found in association with pathology.

Absence of pathogenic mutations in CD59 in chronic inflammatory demyelinating polyradiculoneuropathy

“…In fact, complement deposits have been observed in areas of demyelination in sural nerve biopsies of patients with CIDP [11,12]. Also, CD59 -deficient mice show MAC deposits in the perivascular tissue in the areas of demyelination, and are more susceptible to experimental autoimmune encephalomyelitis, inflammation and axonal loss than wild type mice [13].…”

Complement component C5 is not involved in scrapie pathogenesis

“…The expression of sublytic levels of complement might act as a stress signal to stimulate cells to express increased levels of complement inhibitors. Whether TSE neuropathology is exacerbated in the absence of these complement inhibitors as observed in other CNS diseases is not known (Mead et al, 2004).…”

Microbial Neuraminidase Induces a Moderate and Transient Myelin Vacuolation Independent of Complement System Activation

“…The function of the complement system in myelinopathies (including demyelination) has been a matter of debate (26). While a protective role of complement in demyelination has been reported (27,28), other authors suggest that the complement does not participate in demyelination (35), or have a role in immune-mediated myelin diseases (29)(30)(31)(32)(33)(34). In the classical pathway of the complement, activated C1 induces the cleavage of C4 to form the anaphylatoxin C4a (75).…”

“…The role of the complement system in some demyelinating disorders is an issue of debate and the precise function of complement in such processes remains elusive (26). So, while some reports speak about a protective role of complement in demyelinating processes (27,28), others point to its involvement in immune-mediated myelin diseases (29)(30)(31)(32)(33)(34), or even its lack of participation (35). In neuromyelitis optica, an autoimmune disease of the CNS displaying intramyelinic edema and tissue vacuolation, the complement activation is observed in damaged tissue (36).…”