The induction of immune responses in vivo is typically performed with antigens administered in external adjuvants, like alum, complete Freund's adjuvant, LPS and, more recently, monophosphoryl lipid A (MPL). However, the role of the adjuvant is still poorly defined. The aim of this study was to test whether the MPL affects the function of antigen-presenting cells (APC) in vitro and in vivo. Antigen-pulsed APC [including macrophages, B cells and dendritic cells (DC)] were incubated or not with MPL, and their ability to sensitize naive T cells was tested in vitro and in vivo. The data show that MPL enhances the ability of macrophages and B cells to sensitize naive T cells, and confers to them the capacity to induce the development of T(h)1 and T(h)2. Administration of MPL i.v. in mice results in the redistribution of fully mature DC in the T cell area of the spleen. These observations suggest that MPL may induce an antigen-specific primary immune response by provoking the migration and maturation of DC that are the physiological adjuvant of the immune system. 相似文献
A genetic analysis was made of 58 patients and their 42 families with APECED (autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy). APECED is characterized by hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidosis, but none of its components is constant. Other endocrine deficiencies can occur as well and also dystrophy of dental enamel and nails. The proportion of affected siblings was 0.147 +/- 0.034 (S.D.) when corrected for truncate single ascertainment, 0.246 +/- 0.019 when corrected for a priori truncate complete ascertainment and 0.240 +/- 0.047 when corrected for a posteriori truncate complete ascertainment. The male/female ratio was 1.04. The results are compatible with autosomal recessive transmission. No heterozygous manifestations of the gene were found. The gene is enriched in isolated subpopulations in central and eastern Finland. APECED is part of the "Finnish heritage of disease". 相似文献
The pathogenesis of progressive bile duct loss in primary biliary cirrhosis remains unclear. In this study, the involvement of cellular senescence of biliary epithelial cells was examined in liver tissue samples from patients with primary biliary cirrhosis (n = 33), and compared with control diseased and normal livers (n = 83). In addition, cellular senescence was induced by oxidative stress in cultured mouse biliary epithelial cells. Biliary epithelial cells in small bile ducts in primary biliary cirrhosis, especially those in patients presenting with chronic non-suppurative cholangitis, frequently expressed senescence-associated beta-galactosidase, and senescence-associated p16(INK4) and p21(WAF1/CIP). In contrast, senescence-associated markers were rarely expressed in small bile ducts in control livers. The infiltration of myeloperoxidase-positive inflammatory cells into biliary epithelial cell layers was closely associated with the cellular senescence of biliary epithelial cells in early-stage PBC. Cellular senescence of cultured mouse biliary epithelial cells was induced by treatment with H2O2 via the p38MAPK-dependent pathway and nitric oxide-augmented H2O2-induced cellular senescence. Oxidative stress- and nitric oxide-mediated cellular senescence may be involved in bile duct lesions, which are followed by progressive bile duct loss in primary biliary cirrhosis. 相似文献
The Hedgehog (Hh) signalling pathway is crucial for normal development and patterning of numerous human organs including the gut. Hh proteins are also expressed during gastric gland development and gastric epithelial differentiation in adults. Recently, dysregulation of these developmentally important genes has been implicated in cancer, leading to the present study of the expression of Hh signalling proteins in colon cancer. In this study, normal colon and colonic lesions (hyperplastic polyp, adenoma, and colonic adenocarcinoma) were examined by immunohistochemistry using antibodies against Hh signalling molecules: the secreted protein Sonic hedgehog (SHH), its receptor Patched (PTCH), and the PTCH-associated transmembrane protein Smoothened (SMOH). The study shows that Hh signalling pathway members are expressed in normal colonic epithelium. SHH was expressed at the top of the crypts and in a few basally located cells, while PTCH was detected in the neuroendocrine cells and SMOH at the brush border of superficial epithelium. RT-PCR analysis of laser-microdissected crypts from normal human colon confirmed that mRNAs encoding these proteins were expressed in colonic epithelium. Expression of SHH, PTCH, and SMOH was up-regulated in hyperplastic polyps, adenomas, and adenocarcinomas of the colon, and SHH expression correlated with increased expression of the proliferation marker Ki-67 in all lesions examined. To address whether the Hh signalling pathway is functional in the gut, the effect of Shh on epithelial cells in vitro was explored by treating primary murine colonocytes with either Shh peptide or neutralizing anti-Shh antibody. The proportion of cells in the S-phase was assessed by bromodeoxyuridine (BrdU) incorporation. It was found that exogenous Shh promotes cell proliferation in colonocytes, while anti-Shh inhibits proliferation, suggesting that Shh is required during proliferation of epithelial cells in vitro. It is suggested that SHH is required during epithelial proliferation in the colon and that there is a possible role for Hh signalling in epithelial colon tumour progression in vivo. 相似文献
Cardiovascular ‘reactivity’ to graded splanchnic nerve stimulations was compared in adult spontaneously hypertensive rats (SHR) and normotensive controls (NCR), during abolished adrenal medullary secretion and neurogenic cardiac control and depressed reflex vascular adjustments. Arterial pressure, heart rate and cardiac output were measured, and total peripheral resistance (TPR) and stroke volume (SV) computed before, during and after nerve stimulation. The neurogenic resistance increases in the major gastrointestinal-renal-hepatic circuits expressed themselves as TPR elevations, which were much accentuated in SHR. This reflects an increased w/r1 of SHR resistance vessels rather than any altered effector sensitivity, since the responses were particularly accentuated at high discharge rates when noradrenaline junction concentrations approach maximal levels. The splanchnic capacitance responses expressed themselves as SV increases, being the most relevant aspect of capacitance control. SV increased less in SHR, mainly reflecting the reduced diastolic compliance of the hypertrophied SHR left ventricle and the consequent rightward shift of its Frank-Starling curve. The results indicate that an elevated resistance may well be maintained by a normal sympathetic discharge in established SHR hypertension. There seems, however, to be an increasing need for accentuated discharge to the capacitance side to maintain proper cardiac filling of the hypertrophied left ventricle. 相似文献
Introduction: Fungal diseases are a threat to human health. Therapies targeting the fungus continue to lead to disappointing results. Strategies targeting the host response represent unexplored opportunities for innovative treatments. To do so rationally requires the identification and neat delineation of critical mechanistic pathways that underpin human antifungal immunity. The study of humans with single-gene defects of the immune system, i.e. inborn errors of immunity (IEIs), provides a foundation for these paradigms.
Areas covered: A systematic literature search in PubMed, Scopus, and abstracts of international congresses was performed to review the history of genetic resistance/susceptibility to fungi and identify IEIs associated with fungal diseases. Immunologic mechanisms from relevant IEIs were integrated with current definitions and understandings of mycoses to establish a framework to map out critical immunobiological pathways of human antifungal immunity.
Expert opinion: Specific immune responses non-redundantly govern susceptibility to their corresponding mycoses. Defining these molecular pathways will guide the development of host-directed immunotherapies that precisely target distinct fungal diseases. These findings will pave the way for novel strategies in the treatment of these devastating infections. 相似文献
Summary Techniques are described for the rapid isolation, monolayer culture, and phenotypical characterization of embryonic Day 12 (E12) rat liver epithelial cells. In vitro assays of the differentiation potential of these cells are currently being performed under conditions that make use of-modified Eagle's medium supplemented with fetal bovine serum, insulin, and dexamethasone with or without sodium butyrate. In the absence of sodium butyrate, the cells differentiate along the hepatocytic cell lineage, whereas in its presence they express the phenotype of the biliary ductal epithelial cell lineage. 相似文献