慢性肾炎患者外周血共刺激分子CD28和CD137水平变化研究

目的　研究慢性肾炎患者外周血共刺激分子CD2 8和CD1 37的表达特点及其在慢性肾炎免疫病理机制中的作用。方法　采用免疫荧光标记和流式细胞仪分析 ,对 5 2例慢性肾炎患者外周血共刺激分子CD2 8、CD1 37和T淋巴细胞亚群的表达进行检测。结果　慢性肾炎患者T细胞亚群明显失衡 ,表现为CD4减少 ,CD8增加 ,CD4 CD8比值显著降低。共刺激分子CD2 8表达显著低于正常对照组 (P <0 0 1) ,且CD+4 CD+2 8T细胞和CD+8CD+2 8T细胞均显著减少 (P <0 0 1)。共刺激分子CD1 37表达显著高于正常对照组 (P <0 0 1)。结论　慢性肾炎患者外周血T细胞亚群失衡和T细胞活化所必需的共刺激分子CD2 8、CD1 37异常表达 ,可能在慢性肾炎发生和病变进展中起着重要作用     

Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile

BACKGROUND AND AIMS: Progressive familial intrahepatic cholestasis (PFIC) is characterized by pruritus, intrahepatic cholestasis, low serum gamma-glutamyltransferase levels, and characteristic "Byler bile" on electron microscopy. Many patients require liver transplantation, but partial external biliary diversion (PEBD) has shown therapeutic promise. However, the effect of PEBD on liver morphology and bile composition has not been evaluated. METHODS: We reviewed liver biopsy specimens from 3 children with low gamma-glutamyltransferase PFIC before and after PEBD. Follow-up liver biopsies were performed 9-60 months after PEBD. Light and electron microscopic features were scored blindly. Biliary bile acid composition was analyzed by gas chromatography-mass spectrometry before and after PEBD in 1 patient and after PEBD in 2 patients. RESULTS: Following PEBD, all patients improved clinically. Preoperative biopsy specimens showed characteristic features of PFIC, including portal fibrosis, chronic inflammation, cholestasis, giant cell transformation, and central venous mural sclerosis. Ultrastructural findings included coarse, granular canalicular Byler bile, effaced canalicular microvilli, and proliferative pericanalicular microfilaments. Following diversion, histology showed almost complete resolution of cholestasis, portal fibrosis, and inflammation with resolution of ultrastructural abnormalities. Biliary bile acids before PEBD consisted predominantly of cholic acid. After PEBD, the proportion of chenodeoxycholic acid increased significantly in 1 patient and was above the PFIC range in a second patient. CONCLUSIONS: The resolution of hepatic morphologic abnormalities following PEBD supports PEBD as an effective therapy for PFIC. The improved biliary bile acid composition suggests enhanced bile acid secretion after PEBD, perhaps by induction of alternative canalicular transport proteins.     

Effects of transmembrane region variability on cell surface expression and allorecognition of HLA-DP3

The functional relevance of polymorphisms outside the peptide binding groove of HLA molecules is poorly understood. Here we have addressed this issue by studying HLA-DP3, a common antigen relevant for functional matching algorithms of unrelated hematopoietic stem cell transplantation (HSCT) encoded by two transmembrane (TM) region variants, DPB1^*03:01 and DPB1^*104:01. The two HLA-DP3 variants were found at a overall allelic frequency of 10.4% in 201 volunteer stem cell donors, at a ratio of 4.2:1. No significant differences were observed in cell surface expression levels of the two variants on B lymphoblastoid cell lines (BLCL), primary B cells or monocytes. Three different alloreactive T cell lines or clones showed similar levels of activation marker CD107a and/or CD137 upregulation in response to HLA-DP3 encoded by DPB1^*03:01 and DPB1^*104:01, either endogenously on BLCL or after lentiveral-vector mediated transfer into the same cellular background. These data provide, for the first time, direct evidence for a limited functional role of a TM region polymorphism on expression and allorecognition of HLA-DP3 and are compatible with the notion that the two variants can be considered as a single functional entity for unrelated stem cell donor selection.     

Apurinic/apyrimidinic endonuclease immunoreactivity in germ cells of experimental varicocele-induced rat testes

Increased germ cell apoptosis is related to oxidative DNA damage; therefore, we investigated whether there was a significant change in apurinic/apyrimidinic endonuclease (APE) in varicoceles. Experimental varicoceles were created by partial ligation of the left renal vein of adult male Sprague-Dawley rats, which were sacrificed at 1, 3 and 6 weeks after varicocele creation. Testicular tissues were sampled for TUNEL, Western blotting and immunohistochemistry. There was a significant increase in apoptotic germ cells in the ipsilateral testes 6 weeks after varicocele creation. Increased activation of p53, Bax and cleaved caspase-3 in the left testes was also noted. APE increased activation until 3 weeks after varicocele creation, and then decreased at 6 weeks after varicocele surgery. The spermatocytes were immunostained for both 8-hydroxy-2′-deoxyguanosine and APE, but the spermatogonia revealed only APE immunopositivity in the defective tubules. These results suggest that repression of APE is an underlying mechanism of augmented p53-dependent apoptosis in varicocele-induced rat testes and that remaining APE in the spermatogonia plays a decisive role in regaining testicular spermatogenic function after varicocelectomy.     

Prazosin,an α1-adrenoceptor antagonist,prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease

Noradrenergic deficits have been described in the hippocampus and the frontal cortex of Alzheimer's disease brains, which are secondary to locus coeruleus degeneration. Locus coeruleus is the brain stem nucleus responsible for synthesis of noradrenaline and from where all noradrenergic neurons project. In addition, it has been suggested that noradrenaline might play a role in modulating inflammatory responses in Alzheimer's disease. In this study we aimed to investigate the effect of various agonists and antagonists for adrenergic receptors on amyloid precursor protein processing. Among them, we found that prazosin, an α₁-adrenoceptor antagonist, was able to reduce the generation of amyloid β in N2a cells. Treatment of transgenic APP23 mice with prazosin prevented memory deficits over time. Although prazosin did not influence amyloid plaque load, it induced astrocytic proliferation and increased the release of apolipoprotein E and anti-inflammatory cytokines. These findings suggest that chronic treatment with prazosin leads to an anti-inflammatory response with potential beneficial effects on cognitive performance.     

Regulation of Myelopoiesis by CD137L Signaling

CD137 ligand (CD137L) has emerged as a powerful regulator of myelopoiesis that links emergency situations, such as infections, to the generation of additional myeloid cells, and to their activation and maturation. CD137L is expressed on the cell surface of hematopoietic stem and progenitor cells (HSPC) and antigen presenting cells (APC) as a transmembrane protein. The signaling of CD137L into HSPC induces their proliferation and differentiation to monocytes and macrophages, and in monocytes CD137L signaling induces differentiation to potent dendritic cells (DC). CD137L signaling is initiated by CD137 which is expressed by T cells, once they become activated. Some of these activated, CD137-expressing T cells migrate from the site of infection to the bone marrow where they interact with HSPC to induce myelopoiesis, or they induce monocyte to DC differentiation locally at the site of infection. Therapeutically, induction of CD137L signaling can be utilized to reinitiate myeloid differentiation in acute myeloid leukemia cells, and to generate potent DC for immunotherapy.     

MHC Restricted Recognition by Cloned T Cells

The critical role of major histocompatibility complex (MHC) gene products in T cell activation was appreciated and extensively studied well before the availability of monoclonal T cell populations. However, the availability of cloned T cells has dramatically enhanced the ability to characterize the nature of MHC-restricted recognition by T cells. In certain areas, the use of monoclonal T cells has allowed substantial extension of principles already established through the use of heterogeneous T cells. In other cases, studies employing T cell clones have led to findings which were inaccessible to approaches using only heterogeneous T cell populations. On balance, it should also be pointed out that a significant number of critical questions concerning the MHC-restricted T cell repertoire remain best approached by studying the development of interactions of functionally heterogeneous T cell populations. The present review will focus upon recent progress in several areas in which the use of cloned T cells has been particularly important in characterizing the nature of MHC-restricted recognition. In particular, the restriction of T cell recognition by class II MHC products (Ia) is examined in detail.     

Chlamydia trachomatis inhibits telomeric DNA damage signaling via transient hTERT upregulation

Epidemiological data exist to support a positive association between Chlamydia trachomatis (Ctr) infection and gynecological cancers; however, putative cellular mechanisms for this association are lacking. Here, we identified Ctr-induced perturbations to host cell phenotypes in vitro that persisted after clearance of infection and could directly contribute to host cell transformation. In particular, human telomerase catalytic subunit (hTERT) mRNA expression and catalytic subunit activity were increased in acute infected late passage IMR90E1A cells. hTERT upregulation was accompanied by recruitment of ceramide, a known regulator of hTERT, to the chlamydial inclusion and was abrogated following doxycycline-mediated infection clearance. In cells cleared of Ctr infection, average telomere length was slightly increased and immunofluorescence staining of the DNA damage marker γH2A.X was reduced after clearance of infection compared with cells that had not been infected. Reduced p53 binding to the promoter of the cell cycle checkpoint regulator p21 was also detected in cells cleared of infection and p21 levels were reduced; moreover, this cell population exhibited increased resistance to etoposide-induced DNA damage. Thus, Ctr infection altered cell aging and survival pathways, which persisted after infection clearance. Cells that survive infection are likely to exhibit altered physiology, as evidenced by an increased resistance to DNA damage-induced apoptosis, which may support cellular transformation.