Complement Regulators And Reproduction

CReg are essential for successful reproduction, they protect the sperm on its arduous journey to the egg, and the foetus as it develops in the uterus. Sperm in the female genital tract are targets for attack from C, present in abundance in the secretions that lubricate the mucosa (157-159). Protection is provided by membrane CReg, DAF and CD59, expressed on the sperm (160-162), and by seminal fluid which contains soluble CReg such as clusterin and S-protein. Seminal plasma also contains prostasomes, small vesicles derived from prostatic epithelium which have DAF, MCP and CD59 on their surfaces (163,164). In vitro experiments demonstrate that the CReg on prostasomes can transfer to membranes of cells in their vicinity, including sperm, hence providing additional protection against C in the genital tract (165-167). The membrane CReg are expressed in abundance on the trophoblast throughout pregnancy, providing protection from maternal C at the interface between mother and foetus (168-170). The critical role of

CReg at this site has been elegantly demonstrated in mice engineered to delete Crry, a ubiquitously expressed homologue of MCP and DAF (171). The embryos of Crry-knockout mice die in utero due to C activation and inflammation in the placenta, however, breeding to C3 knockout mice rescued the embryos, demonstrating the crucial role for C in foetal destruction.

It is not surprising or novel to discover that CReg expressed on the surface of sperm and on the trophoblast function to protect these cells from C attack. However, a surprising alternative role for MCP in fertilisation and reproduction has come to light. It has been known for some time that MCP is found at high levels in the reproductive system; in fact, even before its characterisation as a regulator of the C system, MCP was identified by several different groups as an antigen found on the acrosomal region of sperm (172-174). MCP was localised to the inner acrosomal membrane and was only exposed to extracellular fluid following the acrosome reaction, an essential prelude to fertilisation. The cryptic site of expression suggested a role other than C regulation, possibly in the fertilisation process itself. This notion was supported by observations of abnormal MCP on the sperm of infertile men and by studies demonstrating that antibodies to the first SCR in MCP inhibited sperm/egg interaction (175-177). One report demonstrated an involvement of C3b in the penetration of the egg by sperm, raising the possibility that the MCP/C3b interaction itself might be involved in fertilisation. It may be of relevance that MCP on human sperm is truncated and hypo-glycosylated, and cDNAs for several novel isoforms of MCP, differing in their transmembrane and cytoplasmic regions, have been detected in the testis (161,178-181). Yet more compelling evidence for a role of MCP in the fertilisation process has come from studies in New World monkeys. MCP in these monkeys lacks the first SCR, perhaps due to selective pressure from the measles virus43. In testis and on sperm, however, an isoform of MCP that retains the first SCR has been found, strengthening the case for a specific role for MCP in this location (181). It is interesting also that rodents express MCP preferentially or exclusively in the testis (182,183). We have recently found that rat MCP is expressed only on the inner acrosomal membrane of spermatozoa, further implicating the molecule in sperm-egg interactions (184). These accumulating data all point towards a facilitating role for MCP in the reproductive process. The recent generation of an MCP knock-out, however, has muddied the water (185). Instead of the anticipated infertility, litter sizes sired by MCP-/- males were normal or higher than those by wild-type males and the MCP-/- sperm demonstrated an accelerated spontaneous acrosome reaction. These data are difficult to explain but might suggest that MCP on the inner acrosomal membrane stabilises the acrosome by interacting with unidentified components, thereby delaying the spontaneous acrosome reaction. The normal reproductive capacity of C3 knockout mice supports this hypothesis as clearly the interaction of MCP with its complement ligand, C3b, is not a prerequisite for successful fertilisation.

Pregnancy Guide

Pregnancy Guide

A Beginner's Guide to Healthy Pregnancy. If you suspect, or know, that you are pregnant, we ho pe you have already visited your doctor. Presuming that you have confirmed your suspicions and that this is your first child, or that you wish to take better care of yourself d uring pregnancy than you did during your other pregnancies; you have come to the right place.

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