Interleukin-18 impairs the pulmonary host response to Pseudomonas aeruginosa

Interleukin-18 (IL-18) is a potent cytokine with many different proinflammatory activities. To study the role of IL-18 in the pathogenesis of Pseudomonas pneumonia, IL-18-deficient (IL-18(-/-)) and wild-type mice were intranasally inoculated with Pseudomonas aeruginosa. IL-18 deficiency was associated with reduced outgrowth of Pseudomonas in the lungs and diminished dissemination of the infection. In addition, pulmonary inflammation (histopathology) and levels of tumor necrosis factor alpha, IL-6, and macrophage inflammatory protein-2 in lungs and plasma were lower in IL-18(-/-) mice. Consistent with results obtained for IL-18(-/-) mice, treatment of wild-type mice with a neutralizing IL-18 binding protein-immunoglobulin G Fc fusion construct also attenuated outgrowth of Pseudomonas compared with that for mice treated with a control protein. These results demonstrate that the presence of endogenous IL-18 activity facilitates inflammatory responses in the lung during Pseudomonas pneumonia, concurrently impairing bacterial clearance.     

Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis

BACKGROUND: The high-affinity receptor for IgE (FcepsilonRI) on myeloid dendritic cells has been shown to play a major role in atopic dermatitis (AD). Plasmacytoid dendritic cells (pDCs), which are instrumental in the defense of viral infections, are present in reduced amounts in the skin of patients with AD, which is characterized by a high susceptibility to viral infections. OBJECTIVE: We explored phenotypical and functional characteristics of pDC in the peripheral blood of patients with AD and healthy individuals. METHODS: Blood dendritic cell antigen-2+CD123+ pDCs were enriched from the peripheral blood of patients with AD and studied in functional assays. RESULTS: Skin-homing molecules such as cutaneous lymphocyte antigen and L-selectin CD62L were expressed in lower levels on pDCs of patients with AD. pDCs expressed high amounts of IgE-occupied FcepsilonRI. Further, FcepsilonRI aggregation on pDCs impaired the surface expression of MHC I and II, induced the production of IL-10, and enhanced the apoptosis of pDCs. Importantly, FcepsilonRI preactivated pDC produced less IFN-alpha and IFN-beta after stimulation with CpG motifs and enhanced the outcome of immune responses of the TH2 type. CONCLUSION: From these data, we conclude that FcepsilonRI-bearing pDCs from patients with AD (1) are different from pDCs of healthy individuals, (2) might be important in the pathophysiology of AD, and (3) contribute to the enhanced susceptibility of patients with AD to viral infections.     

Sarcocystis gigantea lectin — mitogen and polyclonal B-cell activator

The present study further examined the in vitro response of human mononuclear cells (MNC) to theSarcocystis gigantea lectin (SGL). The results confirm our previous report that SGL is mitogenic for human MNC. We now report that SGL is not only a potent mitogen but also a polyclonal activator for human peripheral B cells. As was true for pokeweed mitogen (PWM, 2 g/ml), the addition of SGL (25 g protein/ml) to cultures of MNC caused lymphocyte proliferation and B-cell maturation, indicated by a marked increase in IgG and IgM production. As measured by the [³H]-thymidine incorporation assay, SGL induced significantly higher proliferative responses than PWM (P<0.01,n=24). The values obtained by SGL and PWM for IgG and IgM synthesis were essentially identical. As opposed to SGL, the sarcotoxin-containing fraction (SGTF) did not induce antibody formation or proliferative responses in human MNC.     

Impact of maternal age and maternal somatic characteristics on newborn size

Pregnancies during early adolescence were commonly thought to represent special risks, such as preterm delivery or low‐weight newborns, resulting in increased mortality and morbidity of mother and child. An important biopsychosocial interaction can be assumed. In the present study the impact of maternal age and maternal somatic characteristics such as prepregnancy weight, stature, or pregnancy weight gain on newborn somatometric features (birth weight, birth length, head circumference, and arcomial circumference) using a dataset of 8,011 single term births were analyzed. The offspring of 215 extremely young mothers ages 12–16 years were significantly (P < 0.0001) lighter and smaller in all body dimensions than the offspring of older adolescent mothers, ages 17–19 years, and the offspring of adult gravida, ages 20–29 years, although no increased incidence of low‐weight newborns (<2,500g) could be observed. As expected, the youngest mothers were also significantly smaller and lighter than their older, biologically more mature counterparts, although the relative weight gain during pregnancy was highest in the youngest age group (23.4% vs. 22.9 and 22.1%, respectively). In general, age but also pregnancy weight gain and prepregnancy weight status were significantly associated with pregnancy outcome. Within term births taking place under sufficient psychosocial support, maternal somatic features had an important impact on newborn size. Am. J. Hum. Biol. 15:220–228, 2003. ©2003 Wiley‐Liss, Inc.     

Histological,immunohistochemical, and ultrastructural features of a rat medullary thyroid carcinoma transfected with a corticotropin-releasing hormone cDNA expression vector

Clonal cell lines producing corticotropin-releasing hormone (CRH) have been generated by transfection of the W2 rat medullary thyroid carcinoma (MTC) cell with a CRH-encoding CMV/ SV40 expression vector. Here, we report the morphological, immunohistochemical, and ultrastructural features of rat tumors derived by implantation of CRH-producing W2CRH-7 cells and compare them with non-CRH-producing W2 MTCs. Both types of tumors grew rapidly and consisted of sheets and nests of pleomorphic cells infiltrating adjacent adipose tissue. Immunohistochemistry revealed CRH in only W2CRH-7 tumors; scattered cells in these tumors also were immunoreactive for chromogranin and for vasoactive intestinal peptide. Otherwise, the two tumor types exhibited similar profiles of various neuroendocrine markers, including neuron-specific enolase, synaptophysin, calcitonin, and somatostatin. Ultrastructurally, the tumors contained abundant dilated rough endoplasmic reticulum, a prominent Golgi apparatus, and numerous lysosomes. Very few secretory granules were noted in the W2 tumors; by contrast, secretory granules, although still not numerous in the majority of W2CRH-7 cells, were more abundant in scattered cells of those tumors. The positive immunostaining for CRH is consistent with the observations of increased plasma CRH and pituitary-adrenal activation induced by these transplanted tumors. This system provides a valuable model for CRH excess mimicking tumoral CRH-dependent Cushing’s syndrome in human patients.     

Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice

To determine the role of Toll-like receptor 4 (TLR4) in the immune response to pneumonia, C3H/HeJ mice (which display a mutant nonfunctional TLR4) and C3H/HeN wild-type mice were intranasally infected with either Streptococcus pneumoniae (a common gram-positive respiratory pathogen) or Klebsiella pneumoniae (a common gram-negative respiratory pathogen). In cases of pneumococcal pneumonia, TLR4 mutant mice showed a reduced survival only after infection with low-level bacterial doses, which was associated with a higher bacterial burden in their lungs 48 h postinfection. In Klebsiella pneumonia, TLR4 mutant mice demonstrated a shortened survival after infection with either a low- or a high-level bacterial dose together with an enhanced bacterial outgrowth in their lungs. These data suggest that TLR4 contributes to a protective immune response in both pneumococcal and Klebsiella pneumonia and that its role is more important in respiratory tract infection caused by the latter (gram-negative) pathogen.     

Immunohistochemical Localization of p53 in Human Thyroid Neoplasms: Correlation with Biological Behavior

Molecular analyses of thyroid tumors have documented mutations in the tumor suppressor p53 gene almost exclusively in anaplastic carcinomas. In contrast, immunohistochemistry has localized p53 in differentiated papillary and follicular thyroid cancers. To establish the significance of p53 immunolocalization in these lesions, 78 thyroid tumors of follicular derivation were examined. All tumors were classified by strict criteria and the extent of tumor was determined morphologically. Immunohistochemical staining for p53 was performed on paraffin sections of formalin-fixed tumor tissue. The results of staining were correlated with diagnosis, tumor extent and clinical outcome. Immunopositivity for p53 was diffuse and strong in all five anaplastic carcinomas examined. There was no staining in five of six follicular adenomas. Four of nine follicular carcinomas had some degree of nuclear staining, but this was focal; all nine tumors were confined to the thyroid at the time of examination. Of 49 papillary carcinomas, 26 were intrathyroidal, and 7 of these were occult; there was no p53 positivity in any occult lesion and only 5 of the 19 palpable lesions stained. In contrast, among 23 papillary carcinomas with extrathyroidal extension or metastases, only 9 were negative for p53 immunoreactivity. Five of seven tall cell papillary carcinomas and one of two insular carcinomas had p53 immunopositivity and this correlated with aggressive behavior. These results support the tumorigenic role of p53 mutations postulated for anaplastic thyroid carcinomas and indicate that localization of p53 by immunohistochemistry is a useful prognostic index of clinical behavior in differentiated thyroid carcinomas of follicular cell derivation.