The sensing of microbial genetic material by leukocytes often elicits beneficial pro-inflammatory cytokines, but dysregulated responses can cause severe pathogenesis. Genome-wide association studies have linked the gene encoding phospholipase D3 (PLD3) to Alzheimer's disease and have linked PLD4 to rheumatoid arthritis and systemic sclerosis. PLD3 and PLD4 are endolysosomal proteins whose functions are obscure. Here, PLD4-deficient mice were found to have an inflammatory disease, marked by elevated levels of interferon-γ (IFN-γ) and splenomegaly. These phenotypes were traced to altered responsiveness of PLD4-deficient dendritic cells to ligands of the single-stranded DNA sensor TLR9. Macrophages from PLD3-deficient mice also had exaggerated TLR9 responses. Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5' exonucleases, probably identical to spleen phosphodiesterase, that break down TLR9 ligands. Mice deficient in both PLD3 and PLD4 developed lethal liver inflammation in early life, which indicates that both enzymes are needed to regulate inflammatory cytokine responses via the degradation of nucleic acids.

No abstract

Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet αIIbβ3 integrin and GPIbα are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIbα-mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIbα and β3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIbα-mediated FNIT, which was far more frequent than in anti-β3-mediated FNIT. Dams with anti-GPIbα antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIbα (but not anti-β3) antiserum activated platelets and enhanced fibrin formation in vitro and thrombus formation in vivo. Importantly, treatment with either intravenous IgG or a monoclonal antibody specific for the neonatal Fc receptor efficiently prevented anti-GPIbα-mediated FNIT. Thus, the maternal immune response to fetal GPIbα causes what we believe to be a previously unidentified, nonclassical FNIT (i.e., spontaneous miscarriage but not neonatal bleeding) in mice. These results suggest that a similar pathology may have masked the severity and frequency of human anti-GPIbα-mediated FNIT, but also point to possible therapeutic interventions.

Summary1. Theoretical models predict that ejaculate expenditure will positively covary with the level of sperm competition but trade-offs between either different measures of sperm quality or sperm quality traits and sperm number are expected. However, empirical results have generally failed to find trade-offs between sperm number, size, velocity and longevity or viability. 2. We analyzed the sperm traits of the grass goby, Zosterisessor ophiocephalus , and the black goby, Gobius niger , two fish characterized by alternative male reproductive tactics, long lasting egg deposition and intra-specific variability in ejaculate characteristics. Indeed, in both species sneaker males release ejaculates with greater sperm number and lower seminal fluid content than territorial ones. 3. We showed that sperm of grass goby males have a similar quality, whereas in the black goby sneakers have faster swimming speeds, greater viability and higher ATP content than those of territorial males. The effectiveness of territorial male mate guarding differs in the two goby species and might account for the observed difference in the intra-specific variability of sperm quality. 4. The pattern of variation that we found in the investment of sperm numbers and sperm quality in goby territorial and sneaker males, supports the results found in other species of fish with alternative mating tactics, suggesting that ejaculate quality traits are usually not traded off one against the other when ejaculate effort is increased in response to increased levels of sperm competition.

Significance Lassa virus is, after dengue virus, the second most common cause of viral hemorrhagic fever. In susceptible individuals, Lassa virus infection is associated with vascular permeability, leading to tissue edema, organ failure, and death. Hemorrhagic fever viruses efficiently infect vascular endothelial cells, but are generally considered noncytopathic. Thus, the mechanism of virus-induced vascular injury remains unclear. Using the lymphocytic choriomeningitis virus variant clone 13, a prototype of Lassa virus, we show here that lethal vascular leakage in susceptible mice was completely prevented by type I IFN receptor blockade. Therefore, approaches that target type I IFNs or effector molecules induced by these cytokines may be considered for the treatment of Lassa fever and other severe hemorrhagic viral illnesses.