Negligible Role of Antibodies and C5 in Pregnancy Loss Associated Exclusively with C3-Dependent Mechanisms through Complement Alternative Pathway

CD59 is a GPI-linked membrane protein that inhibits formation of the membrane attack complex of complement. We reported recently that mice have two CD59 genes (termed mCd59a and mCd59b), and that the targeted deletion of mCd59b (mCd59b−/−) results in spontaneous hemolytic anemia and progressive loss of male fertility. Further studies of the reproductive abnormalities in mCd59b−/− mice reported in this study revealed the presence of abnormal multinucleated cells and increased apoptotic cells within the walls of the seminiferous tubules, and a decrease in the number, motility, and viability of sperm associated with a significant increase in abnormal sperm morphologies. Both the capacitation-associated tyrosine phosphorylation and the ionophore-induced acrosome reaction as well as luteinizing hormone, follicle-stimulating hormone, and testosterone serum levels were similar in mCd59b−/− and mCd59b+/+. Surprisingly, the functional deficiency of the complement protein C3 did not rescue the abnormal reproductive phenotype of mCd59b−/−, although it was efficient in rescuing their hemolytic anemia. These results indicate that the male reproductive abnormalities in mCd59b−/− are complement-independent, and that mCd59 may have a novel function in spermatogenesis that is most likely unrelated to its function as an inhibitor of membrane attack complex formation.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Further Characterization of Reproductive Abnormalities in mCd59b Knockout Mice: A Potential New Function of mCd59 in Male Reproduction

Qin

Dobarro

Bedford

et al. 2005

“…Recent studies have shown that similar to I/R-induced injury, complement activation is required (27,28). Further studies have identified roles for neutrophils, the anaphylatoxin, C5a, and the alternative complement cascade (38,44) in the expression of anti-PL Ab-associated pathology. Because each of these components is involved in mesenteric I/R (5,6,33,35,45), it is possible that Abs with anti-PL specificities are involved.…”

Section: Figure 6 Human Anti-cl Mab Restores I/r-induced Injury In Cr2mentioning

confidence: 99%

Anti-Phospholipid Antibodies Restore Mesenteric Ischemia/Reperfusion-Induced Injury in Complement Receptor 2/Complement Receptor 1-Deficient Mice

Fleming

Egan

Chai

et al. 2004

Complement receptor 2-deficient (Cr2−/−) mice are resistant to mesenteric ischemia/reperfusion (I/R) injury because they lack a component of the natural Ab repertoire. Neither the nature of the Abs that are involved in I/R injury nor the composition of the target Ag, to which recognition is lacking in Cr2−/− mice, is known. Because anti-phospholipid Abs have been shown to mediate fetal growth retardation and loss when injected into pregnant mice, we performed experiments to determine whether anti-phospholipid Abs can also reconstitute I/R injury and, therefore, represent members of the injury-inducing repertoire that is missing in Cr2−/− mice. We demonstrate that both murine and human monoclonal and polyclonal Abs against negatively charged phospholipids can reconstitute mesenteric I/R-induced intestinal and lung tissue damage in Cr2−/− mice. In addition, Abs against β2 glycoprotein I restore local and remote tissue damage in the Cr2−/− mice. Unlike Cr2−/− mice, reconstitution of I/R tissue damage in the injury-resistant Rag-1−/− mouse required the infusion of both anti-β2-glycoprotein I and anti-phospholipid Ab. We conclude that anti-phospholipid Abs can bind to tissues subjected to I/R insult and mediate tissue damage.

“…Perhaps most compelling is the finding that homozygous Crry deficiency is lethal in utero in mice (26), and the placentae of mice carrying Crry Ϫ/Ϫ fetuses demonstrate C3 deposition. This phenotype is rescued when the Crry Ϫ/Ϫ mice are crossed with either C3 Ϫ/Ϫ mice (26) or fB Ϫ/Ϫ mice (70), but crossing them with C4 Ϫ/Ϫ mice or B cell-deficient mice does not promote survival (70). Thus, spontaneous fetal loss in Crry Ϫ/Ϫ mice is due to activation of the alternative pathway and does not require the classical pathway.…”

Section: Spontaneous Fetal Lossmentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

393

350

The complement system is increasingly recognized as important in the pathogenesis of tissue injury in vivo following immune, ischemic, or infectious insults. Within the complement system, three pathways are capable of initiating the processes that result in C3 activation: classical, alternative, and lectin. Although the roles that proinflammatory peptides and complexes generated during complement activation play in mediating disease processes have been studied extensively, the relative contributions of the three activating pathways is less well understood. Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation products in vivo. In addition, we discuss new concepts regarding the mechanisms by which the alternative pathway is activated in vivo, as recent clinical findings and experimental results have provided evidence that continuous active control of this pathway is necessary to prevent unintended targeting and injury to self tissues.