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Reward the creation of analyses for policymakers that are inclusive, rigorous, transparent and accessible, urge Christl A. Donnelly and colleagues.Reward the creation of analyses for policymakers that are inclusive, rigorous, transparent and accessible., Author(s): Christl A. Donnelly, Ian Boyd, Philip Campbell, Claire Craig, Patrick Vallance, Mark Walport, Christopher J. M. Whitty, Emma Woods, Chris WormaldAuthor Affiliations:Four principles to make evidence synthesis more useful [...]

The inflammatory kidney disease membranoproliferative glomerulonephritis type II (MPGN2) is associated with dysregulation of the alternative pathway of complement activation. MPGN2 is characterized by the presence of complement C3 along the glomerular basement membrane (GBM). Spontaneous activation of C3 through the alternative pathway is regulated by 2 plasma proteins, factor H and factor I. Deficiency of either of these regulators results in uncontrolled C3 activation, although the breakdown of activated C3 is dependent on factor I. Deficiency of factor H, but not factor I, is associated with MPGN2 in humans, pigs, and mice. To explain this discordance, mice with single or combined deficiencies of these factors were studied. MPGN2 did not develop in mice with combined factor H and I deficiency or in mice deficient in factor I alone. However, administration of a source of factor I to mice with combined factor H and factor I deficiency triggered both activated C3 fragments in plasma and GBM C3 deposition. Mouse renal transplant studies demonstrated that C3 deposited along the GBM was derived from plasma. Together, these findings provide what we believe to be the first evidence that factor I--mediated generation of activated C3 fragments in the circulation is a critical determinant for the development of MPGN2 associated with factor H deficiency., Introduction The complement system is an important part of the innate immune system that is composed of a complex group of proteins whose main biological functions include host defense, the [...]

Systemic lupus erythematosus is a disease considered to be caused by a defect in complement. The defect prevents dead cells and waste products from being removed, which then stimulate an autoimmune response.

The diseases caused by complement deficiency and abnormalities in the regulation of complement are reviewed. Topics include pyogenic infections, neisserial infections, mannose-binding lectin deficiency, activation of C3, C3 nephritic factor, factor H deficiency, C1 inhibitor deficiency, and paroxysmal nocturnal hemoglobinuria.

New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs. In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation, probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells (FDCs), which are a major extracerebral prion reservoir. FDCs trap immune complexes with Fc-[gamma] receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-[gamma] receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrP[sup.Sc] was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection., Author(s): Michael A. Klein [1]; Pascal S. Kaeser [1]; Petra Schwarz [1]; Heiko Weyd [1]; Ioannis Xenarios [8]; Rolf M. Zinkernagel [2]; Michael C. Carroll [3]; J. Sjef Verbeek [4]; [...]