Summary
The attaching-and-effacing (A/E) lesion-causing enteric pathogen, Citrobacter rodentium, was used to probe the importance of GM-CSF in mucosal protection against enteric bacterial infection. C. rodentium infection increased GM-CSF production and CD11c+ dendritic cells (DC) in the colon of wild-type mice. After infection, mice lacking GM-CSF (GM-CSF-/-) had significantly fewer mucosal CD11c+ DC, greater bacterial burden, increased mucosal inflammation and systemic spread of infection, decreased antibody responses to C. rodentium, and delayed pathogen clearance. The defective mucosal response to infection in GM-CSF-/- mice was rescued by GM-CSF and mimicked by CD11c+ DC depletion in infected wild-type mice, indicating that CD11c+ DC are major targets of GM-CSF in the intestinal mucosa in vivo. Diminished mucosal DC numbers in infected GM-CSF-/- mice reflected decreased DC survival and recruitment within the colon mucosa. The latter was related to a failure to upregulate epithelial cell production of the DC chemoattractant chemokine, CCL22, in the absence of GM-CSF.
Granulocyte macrophage colony-stimulating factor (GM-CSF) is a cytokine that promotes myeloid cell development and maturation, and dendritic cell differentiation and survival in vitro. Growing evidence supports the notion that GM-CSF has a major role in some inflammatory and autoimmune reactions and in the host’s response to pulmonary infection, but few studies have addressed its functions and importance in the GI tract. Recent studies demonstrated that administration of GM-CSF can result in clinical improvement in patients with Crohn’s disease. Mice deficient in GM-CSF (GM-CSF−/−) developed more severe intestinal and systemic infection after an enteric infection, and more severe colitis in response to enteric exposure to dextran sodium sulfate. Both the severity of infection and colitis were largely prevented by GM-CSF administration. Such studies indicate that GM-CSF has an important role in the regulation of intestinal immune and inflammatory responses.
GM-CSF is a growth factor that promotes the survival and activation of macrophages and granulocytes, and dendritic cell (DC) differentiation and survival in vitro. The mechanism by which exogenous GM-CSF ameliorates the severity of Crohn’s disease in humans and colitis in murine models has been considered mainly to reflect its activity on myeloid cells. We used GM-CSF deficient (GM-CSF−/−) mice to probe the functional role of endogenous host-produced GM-CSF in a colitis model induced after injury to the colon epithelium. Dextran sodium sulfate (DSS) at doses that resulted in little epithelial damage and mucosal ulceration in wild type (WT) mice resulted in marked colon ulceration and delayed ulcer healing in GM-CSF−/− mice. Colon crypt epithelial cell proliferation in vivo was significantly decreased in GM-CSF−/− mice at early times after DSS injury. This was paralleled by decreased expression of crypt epithelial cell genes involved in cell cycle, proliferation, and wound healing. Decreased crypt cell proliferation and delayed ulcer healing in GM-CSF−/− mice were rescued by exogenous GM-CSF, indicating the lack of a developmental abnormality in the epithelial cell proliferative response in those mice. Non-hematopoietic cells and not myeloid cells produced the GM-CSF important for colon epithelial proliferation after DSS-induced injury as revealed by bone marrow chimera and DC depletion experiments, with colon epithelial cells being the cellular source of GM-CSF. Endogenous epithelial cell produced GM-CSF has a novel non-redundant role in facilitating epithelial cell proliferation and ulcer healing in response to injury of the colon crypt epithelium.
Oral fluid specimens (OF) have been widely used to know the HIV prevalence in several key populations. Here, we aim to validate in OF specimens an existing HIV chemiluminiscence assay for serum specimens. Paired OF and serum specimens were collected from 83 known HIV-positives and 83 known HIV-negatives in order to validate the performance characteristics of the automated chemiluminiscence Liaison XL Murex HIV Ag/Ab assay (Diasorin Inc, Iberia) for HIV antibody detection in OF specimens. Among the previously known HIV-seropositive group, HIV antibodies were detected in 69 out of 83 OF specimens. All serum and OF specimens collected from 83 HIV seronegative individuals were negative. The sensitivity and specificity of this assay were 83.13% and 100% respectively in OF. The PPV and NPV values were 100% and 85.57% respectively. The correlation obtained between both specimens was (
K
: 0.83, [95%
CI
: 0.748–0.915]) according to the kappa index. The ROC curve analysing the optimal cut-off of the Liaison XL Murex HIV Ag/Ab to detect positive OF specimens revealed that a cut-off of 0.497 showed sensitivity and specificity values of 98.8% and 97.59% respectively. Taking into account this cut-off, the overall sensitivity and NPV of the Liaison XL Murex HIV Ag/Ab assay could rise from 83.1 to 98.8% and from 85.5 to 97.7%, respectively. Our results suggest that the Liaison XL HIV Ag/Ab assay is suitable for the detection of HIV antibodies in OF specimens.
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