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The Complement System
University of Cambridge, UK
The complement system has been known since the end of the nineteenth century and was long regarded as one of the more arcane immunological topics. It is indeed true that it is an unusual and complex system of triggered enzyme cascades but this complexity should be regarded as an index... read moreof its biological importance rather than as a reason for disregarding it. Surprisingly, the description of all the activation pathways was not completed (if it is yet completed) until quite recently and information on its functional importance is still expanding.
However, what has given the complement system a great boost in its interest to the wider biomedical community is the discovery that genetic polymorphisms of complement components show strong associations with a number of inflammatory diseases. Many of these, such as the various associated kidney diseases, are relatively uncommon. However, the discovery about ten years ago that alleles in several complement components, all of which act to upregulate the alternative complement pathway, are the strongest predisposing factors to age-related macular degeneration (AMD) has given a considerable impetus to developing therapeutics aimed at the complement system. AMD is an extremely common disease and this has whetted the appetite of the pharmaceutical industry.
In general, it has long been known that the complement system is extremely important in mediating resistance to bacterial infections in childhood when those exposed to the bacteria have made IgM antibodies but not yet IgG antibodies to them. In the presence of IgM antibodies only the complement system has a vital role in promoting phagocytosis. In later adult life, when people have acquired IgG antibodies to most of the organisms they are likely to meet, there is a much smaller, if any, role of complement in resisting bacteria – with the sole exception of Neisseria which require to be lysed within the circulation and which are carried round the body by polymorphs rather than being efficiently destroyed by them. Meningococcal disease is a risk associated with all forms of complement deficiency.
In later life, the role of complement as a mediator of the auto-inflammatory diseases of old age becomes probably more important. The role of complement in AMD and renal disease is well established. Whether it plays a part in such diseases as accelerated atherosclerosis, polymyalgia rheumatic and even Alzheimer’s disease remains uncertain. Paradoxically some complement deficiencies strongly predispose to the canonical autoimmune disease, Systemic Lupus Erythrmatosus.
There is evidence that complement also plays some role in rejection of organ transplants and that it can be exploited in the treatment of cancer.
There is thus a widespread and growing clinical interest in complement and the time is therefore ripe to present a detailed account of various aspects of complement and it is this that this lecture series intends to do.
The various pathways of complement activation and their effects will be covered as will complement genetics. Much has been learned about complement from the mechanisms that microorganisms have evolved to subvert it and these will also be covered. So will a number of diseases where complement is known to play an important role.