Regulatory dendritic cell treatment prevents the development of vasopressin-induced preeclampsia

The concept that persistent feto-placental intolerance is important in the pathogenesis of preeclampsia (PE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion during pregnancy induces cardiovascular, renal, and immune alterations in mice consistent with human PE. These findings identify AVP as a potential contributor to poor fetal tolerance and the development of PE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCregs) express low levels of co-stimulatory markers, produce anti-inflammatory cytokines, induce T regulatory cells, and promote tolerance. In mice, DCregs are able to prevent pro-inflammatory responses and induce antigen-specific tolerance. Given these known functions of DCregs, we hypothesize that DCregs will prevent the development of AVP-induced PE

Betamethasone: a novel therapeutic intervention for preeclampsia

The early pathogenesis of preeclampsia (PE) involves a systemic inflammatory immune response. Recent data demonstrate that increased circulating arginine vasopressin (AVP) in humans is predictive of PE and that infusion of AVP in mouse dams phenocopies the pregnancy-specific cardiovascular and immune alterations observed in human PE. Specifically, AVP suppresses anti-inflammatory cytokines and cells. Betamethasone (BMTZ), commonly given to women at risk for preterm birth, is both an AVP and immune response modulator. We hypothesize that early treatment with BMTZ will prevent the development of AVP-induced PE

Impact of vasopressin receptors on regulation of immune response in preeclampsia

Preeclampsia is a common disorder of pregnancy resulting in increased blood pressure and end organ effects. The pathogenesis of preeclampsia is multi-factorial. Arginine vasopressin (AVP) is increased in preeclampsia, and the chronic infusion of AVP throughout gestation has previously been shown to be sufficient to produce a phenotype of preeclampsia in C57BL/6J mice representative of some of the cardiovascular and renal events seen in humans. Alterations in T-helper cell populations and their effector cytokines are also known to occur in preeclampsia. Therefore, we proposed that the increased secretion of AVP may be responsible for the immune changes that occur in preeclampsia. We also hypothesized that known pharmacological AVP antagonist, vaptans, may be able to reverse the effects of AVP infusion

Effects of Streptococcus pneumoniae Strain Background on Complement Resistance

Background: Immunity to infections caused by Streptococcus pneumoniae is dependent on complement. There are wide variations in sensitivity to complement between S. pneumoniae strains that could affect their ability to cause invasive infections. Although capsular serotype is one important factor causing differences in complement resistance between strains, there is also considerable other genetic variation between S. pneumoniae strains that may affect complement-mediated immunity. We have therefore investigated whether genetically distinct S. pneumoniae strains with the same capsular serotype vary in their sensitivity to complement mediated immunity.Methodology and Principal Findings: C3b/iC3b deposition and neutrophil association were measured using flow cytometry assays for S. pneumoniae strains with different genetic backgrounds for each of eight capsular serotypes. For some capsular serotypes there was marked variation in C3b/iC3b deposition between different strains that was independent of capsule thickness and correlated closely to susceptibility to neutrophil association. C3b/iC3b deposition results also correlated weakly with the degree of IgG binding to each strain. However, the binding of C1q (the first component of the classical pathway) correlated more closely with C3b/iC3b deposition, and large differences remained in complement sensitivity between strains with the same capsular serotype in sera in which IgG had been cleaved with IdeS.Conclusions: These data demonstrate that bacterial factors independent of the capsule and recognition by IgG have strong effects on the susceptibility of S. pneumoniae to complement, and could therefore potentially account for some of the differences in virulence between strains

TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26

Interleukin 17–producing helper T cells (T(H)17 cells) have a major role in protection against infections and in mediating autoimmune diseases, yet the mechanisms involved are incompletely understood. We found that interleukin 26 (IL-26), a human T(H)17 cell–derived cytokine, is a cationic amphipathic protein that kills extracellular bacteria via membrane-pore formation. Furthermore, T(H)17 cell–derived IL-26 formed complexes with bacterial DNA and self-DNA released by dying bacteria and host cells. The resulting IL-26–DNA complexes triggered the production of type I interferon by plasmacytoid dendritic cells via activation of Toll-like receptor 9, but independently of the IL-26 receptor. These findings provide insights into the potent antimicrobial and proinflammatory function of T(H)17 cells by showing that IL-26 is a natural human antimicrobial that promotes immune sensing of bacterial and host cell death