Schifferli, Jürg

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DOI 10.1007/s00281-005-0008-xORIGINAL ARTICLEJürg A. SchifferliComplement: a member of the innate immune systemPublished online: 6 October 2005# Springer-Verlag 2005IntroductionDuring recent years, the field of innate immunity has exploded, particularly since the dis-covery of Toll-like receptors. It suddenly became evident to many immunologists that theinitial inflammation induced by microorganisms was an essential trigger factor of the moreelaborate specific immunity. The initial response is pattern recognition, whether on cellsurfaces, as for Toll-like receptors, or in the fluid phase, as for complement and naturalantibodies. Complement activation in the innate immune response is due to natural IgMantibodies and CRP, but is also directly due to mannan-binding lectin (protein) and depo-sition of C3 by the alternative pathway. Once acquired immunity has allowed the productionof specific antibodies, complement again comes into play via the first recognized pathwayof complement—the classical activation pathway—which occurs when C1q binds to theantigen–antibody complex. During ontogeny, the roles of protection against intruders anddisposal of waste developed in parallel. In particular, apoptotic and necrotic cells have tobe cleared. It is therefore not surprising that innate immunity, complement in particular, isalso involved in helping to remove waste.The knowledge gained in the field of complement has exploded in recent years, and thisissue makes no claim to cover the topic completely. Rather, it is a selection of those fields inwhich there has been a development that might interest not only the immunologist but alsothe clinician who wants to understand more about specific aspects of diseases in whichcomplement plays a central role.The first complement deficiency to be identified was C1 inhibitor deficiency, although wenow recognize that the clinical syndrome of angioedema is related to the inhibition of thekinin cascade by C1 inhibitor and not to its capacity to control the complement cascade. If wehad to give a name to this molecule today, we might consider “kinin inhibitor” as moreJ. A. Schifferli ())Department of Medicine, University Hospital Basel, Basel, Switzerlande-mail: j.schifferli@unibas.chSpringer Semin Immun (2005) 27:273–275logical for clinicians, who first of all consider the pathophysiology of a disease. Cicardireviews the field from basic knowledge about the immunopathological processes to theclinical aspects and indicates possible future treatment options. And the future appears to benear.Anti-C1q autoantibodies were described initially by Agnello more than 30 years ago.Understanding of their role was hampered initially because C1q binds to IgG, and thus, thereverse reaction had to be indisputably established before the scientific world would acceptthe finding. Subsequently, the groups of Daha and Mannik established that such auto-antibodies were frequently found in SLE, specifically in lupus nephritis, and were depositedin the kidney. This field is in development, and the finding that C1q deficiency (alsoknockout in mice) leads to an SLE-like disease underlines the major role of the C1q protein inSLE. Marten Trendelenburg takes us through the recent literature concerning antiC1q.During the past decade, David Sacks has investigated the role of local synthesis ofcomplement proteins in kidney diseases and, in particular, in renal transplantation. He hasrecently demonstrated the role of locally produced C3 in regulating alloreactivity and organrejection. His article is a very thorough overview of the fascinating subject of renal pro-duction of complement.The next article by Véronique Frémeaux-Bacchi deals with the hemolytic uremic syn-drome (HUS) and complement abnormalities. The developments in this field in recent yearshave been fascinating, with the demonstration that specific mutations of factor H areassociated with HUS, but also that MCP contributes to the protection against this devastatingdisease. The suggestion that factor I mutation can lead to HUS, as well as the finding in somerare cases that anti-factor H autoantibodies may be involved, provides additional support forthe hypothesis that proper control of the alternative pathway is essential for protecting therenal glomerular endothelial cells against injury.John Atkinson reviews the multiple aspects of “membrane cofactor protein” (MCP),which he calls CD46 in the title of his article. This is certainly due to the multiple aspectsof MCP which are not directly related to its complement control activity, e.g., its interactionwith many human pathogens or its role in inducing T-lymphocyte regulatory cells. Thismolecule first described by complementologists appears to have more facets than originallyexpected.Following the description of mannan-binding lectin (MBP) many years ago, there hasbeen much activity aimed at finding out how this protein activates the complement cascade.Many investigators successively described different “mannan-binding protein associatedproteases” (MASPs), one of which—MASP2—emerged as the most likely protease linkingMBP to cleavage of C4 and C2. In this respect, the review of Rikke Sorensen and colleaguesis timely, not only to describe the biochemistry of MASP2 but also for its possible rolein preventing infection and autoimmunity, as suggested by the diseases associated withMASP2 deficiency in a unique patient.Parasites appear to be capable, when it suits them, of stealing fragments of the humangenome, for example, when the stolen fragment allows them to produce an inhibitor ofcomplement activation. Indeed, the expression of a complement inhibitor may be protectivefor parasites, such as schistosomes, which live in the blood stream. Jameel Inal speculateson such a horizontal gene transfer for complement C2 receptor inhibitor trispanning (CRIT),a molecule he first found in schistosomes, then in trypanosomes, and finally in humans.In the final article, David Pilzer and colleagues come back to a well-known phenomenon,i.e., the release of small vesicles by ectocytosis from cells which have been attacked by274 Springer Semin Immun (2005) 27:273–275complement. These small vesicles remove the membrane attack complex from the cellsurface, thereby protecting the cell. On the other hand, the biology of ectosomes has onlyrecently attracted the interest of biologists. These small vesicles have functions such asrelease of mediators, transfer of information from one cell to another, and modulating in-flammation and thrombosis.It has been a privilege to bring together these different contributions, thanks to a won-derful group of investigators and friends. We thank them all and hope that the reviewsprovided will be helpful for clinicians and scientists alike. Finally, our thanks to Mrs. JeanRingrose, who helped us to bring these reviews together in her very gentle way.Springer Semin Immun (2005) 27:273–275 275

Complement: a member of the innate immune system

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Complement: a member of the innate immune system

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