title: Microvascular alterations and the role of complement in dermatomyositis.
abstract: Different mechanisms have been proposed to explain the pathological basis of perifascicular muscle fibre atrophy in dermatomyositis. These include ischaemia due to immune-mediated microvascular injury, enhanced expression of type 1 interferon-induced gene transcripts in perifascicular capillaries and muscle fibres, and occlusion of larger perimysial blood vessels. Microvascular complement deposition is a feature of dermatomyositis pathology but the trigger for complement activation, the predominant complement pathway involved, or its role in the pathogenesis of the disease, has not been clearly defined. In the first step of this study we examined the density of capillaries and transverse vessels and searched for occlusion or depletion of larger perimysial blood vessels in 10 patients with dermatomyositis. This revealed an invariable association of perifascicular atrophy with capillary and transverse vessel depletion. The capillary and transverse vessel densities in non-atrophic fibre regions were not significantly different from those in muscle specimens of 10 age-matched controls. Next, in the same 10, as well as in 40 additional dermatomyositis patients, we searched for vascular deposits of IgG, IgM, and the C5b-9 complement membrane attack complex. Thirty-one of 50 dermatomyositis specimens contained C5b-9 reactive endomysial microvessels but none of these or other vessels reacted for IgG. Ten of 50 specimens harboured IgM-positive capillaries but only a few of these reacted for C5b-9. Finally, we analysed and compared different pathways of complement activation in dermatomyositis, lupus nephritis, and necrotic muscle fibres in Duchenne dystrophy. In lupus nephritis, C5-b9 deposits co-localized with IgG, IgM, C1q, and C4d, consistent with immune complex dependent activation of the classical complement pathway. In both dermatomyositis and Duchenne dystrophy, C5-b9 deposits co-localized with C1q and C4d and rarely with IgM indicating activation of the classical complement pathway. We conclude that: perifascicular atrophy in dermatomyositis is consistently associated with focal microvascular depletion, and that microvascular membrane attack complex deposits in dermatomyositis result from activation of the classical complement pathway triggered by direct binding of C1q to injured endothelial cells.
authors.affiliation: Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, USA.
authors.forename: Rajat
authors.initials: R
authors.lastname: Lahoria
authors.affiliation: Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, USA age@mayo.edu.
authors.forename: Duygu
authors.initials: D
authors.lastname: Selcen
authors.affiliation: Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D003882:Dermatomyositis / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D055806:Microvessels / Q000378:metabolism* / Q000473:pathology*; D008875:Middle Aged; D055815:Young Adult
chemical_list: D015938:Complement Membrane Attack Complex
keywords: complement activation; dermatomyositis; muscle microvasculature; perifascicular atrophy