Membrane attack complex of complement is not essential for immune mediated demyelination in experimental autoimmune neuritis.
Antibody deposition and complement activation, especially membrane attack complex (MAC) formation are considered central for immune mediated demyelination. To examine the role of MAC in immune mediated demyelination, we studied experimental allergic neuritis (EAN) in Lewis rats deficient in complement component 6 (C6) that cannot form MAC. A C6 deficient Lewis (Lewis/C6-) strain of rats was bred by backcrossing the defective C6 gene, from PVG/C6- rats, onto the Lewis background. Lewis/C6- rats had the same C6 gene deletion as PVG/C6- rats and their sera did not support immune mediated haemolysis unless C6 was added. Active EAN was induced in Lewis and Lewis/C6- rats by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant (CFA), and Lewis/C6- rats had delayed clinical EAN compared to the Lewis rats. Peripheral nerve demyelination in Lewis/C6- was also delayed but was similar in extent at the peak of disease. Compared to Lewis, Lewis/C6- nerves had no MAC deposition, reduced macrophage infiltrate and IL-17A, but similar T cell infiltrate and Th1 cytokine mRNA expression. ICAM-1 and P-selectin mRNA expression and immunostaining on vascular endothelium were delayed in Lewis C6- compared to Lewis rats' nerves. This study found that MAC was not required for immune mediated demyelination; but that MAC enhanced early symptoms and early demyelination in EAN, either by direct lysis or by sub-lytic induction of vascular endothelial expression of ICAM-1 and P-selectin.
Tran
Giang T
GT
Faculty of Medicine, University of New South Wales, National Innovation Centre, Australian Technology Park, Eveleigh, NSW, Australia.
Hodgkinson
Suzanne J
SJ
Carter
Nicole M
NM
Killingsworth
Murray
M
Nomura
Masaru
M
Verma
Nirupama D
ND
Plain
Karren M
KM
Boyd
Rochelle
R
Hall
Bruce M
BM
D000818:Animals; D030801:Animals, Genetically Modified; D002417:Cattle; D003183:Complement C6 / Q000172:deficiency; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005620:Freund's Adjuvant / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009186:Myelin Sheath / Q000276:immunology; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D003183:Complement C6; D015938:Complement Membrane Attack Complex; D016207:Cytokines; D020381:Interleukin-17; D019007:P-Selectin; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D005620:Freund's Adjuvant