Deficiency of the Mouse Complement Regulatory Protein mCd59b Results in Spontaneous Hemolytic Anemia with Platelet Activation and Progressive Male Infertility

Abstract

Basal complement activity presents a potential danger for "self" cells that are tightly protected by complement regulators including CD59. Mice express two Cd59 genes (mCd59a and mCd59b); mCd59b has approximately a 6-fold higher specific activity than mCd59a. Consistently, mCd59b knockout mice present a strong phenotype characterized by hemolytic anemia with increased reticulocytes, anisopoikilocytosis, echinocytosis, schistocytosis, free hemoglobin in plasma, hemoglobinuria with hemosiderinuria, and platelet activation. Remarkably, mCd59b(-/-) males express a progressive loss of fertility associated with immobile dysmorphic and fewer sperm cells after 5 months of age. This work indicates that mCd59b is a key complement regulator in mice and that CD59 is critical in protecting self cells; it also provides a novel model to study complement regulation in human diseases.

CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

“…Although these observations in gene-targeted mice indicate that CD59b may play an important role in protecting erythrocytes and sperm cells against complement-mediated damage, it is likely that the relative contribution of these molecules varies depending on the organ or tissue analyzed as well as on the mechanisms and/or level of complement activation (8,9). Importantly it has been demonstrated that the absence of either isoform of CD59 does not alter the tissue expression of the other isoform (7,10).…”

“…Mice with a targeted deletion of the mCd59b gene have recently been reported to develop a severe hemolytic anemia and progressive male infertility, whereas mice lacking the mCd59a gene developed a mild, spontaneous, intravascular hemolysis (7,8). Although these observations in gene-targeted mice indicate that CD59b may play an important role in protecting erythrocytes and sperm cells against complement-mediated damage, it is likely that the relative contribution of these molecules varies depending on the organ or tissue analyzed as well as on the mechanisms and/or level of complement activation (8,9).…”

Deficiency of the complement regulator CD59a enhances disease severity, demyelination and axonal injury in murine acute experimental allergic encephalomyelitis

“…Some contend that CD59b is broadly distributed, and is an important MAC regulator in tissues. 40,41 However, we have developed specific mAb to analyse the expression of the two forms of mouse CD59 and find CD59b expression only in testis. 28 In particular, a thorough analysis of mouse CNS cells and sections failed to detect any staining for CD59b (Figure 1 and our unpublished data).…”

The Role of Complement in the Pathogenesis of Artery Aneurysms

“…This subject expressed a severe PNH phenotype from the unusually young age of thirteen and also had a stroke that left him with permanent neurological damage (Yamashina et al, 1990). Not only does the Cd59 knockout out mouse exhibit a full PNH-like anemia as well as platelet activation, but it also exhibits progressive loss of fertility (Holt et al, 2001;Qin et al, 2009;Qin et al, 2003). Also, although the role of S-protein as an inhibitor of MAC formation in tissues has been suggested, the Sprotein knockout mouse did not show any detectable phenotype and instead developed normally and was fully fertile (Zheng et al, 1995).…”