共查询到20条相似文献,搜索用时 0 毫秒
1.
T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis 总被引:4,自引:0,他引:4
Allina J Hu B Sullivan DM Fiel MI Thung SN Bronk SF Huebert RC van de Water J LaRusso NF Gershwin ME Gores GJ Odin JA 《Journal of autoimmunity》2006,27(4):232-241
Primary biliary cirrhosis (PBC) is characterized by loss of tolerance against ubiquitously expressed mitochondrial autoantigens followed by biliary and salivary gland epithelial cell (BEC and SGEC) destruction by autoreactive T cells. It is unclear why BECs and SGECs are targeted. Previous work demonstrated that the reduced form of the major PBC autoantigen predominated in apoptotic BECs and SGECs as opposed to an oxidized form in other apoptotic cells. This led to the hypothesis that presentation of novel self-peptides from phagocytosed apoptotic BECs might contribute to BEC targeting by autoreactive T cells. The effect of autoantigen redox status on self-peptide formation was examined along with the phagocytic ability of BECs. Oxidation of PBC autoantigens first was shown to be due to protein S-glutathionylation of lipoyllysine residues. Absence of protein S-glutathionylation generated novel self-peptides and affected T cell recognition of a lipoyllysine containing peptide. Liver biopsy staining revealed BEC phagocytosis of apoptotic BECs (3.74+/-2.90% of BEC) was present in PBC (7 of 7 cases) but not in normal livers (0 of 3). BECs have the ability to present novel mitochondrial self-peptides derived from phagocytosed apoptotic BECs. Apoptotic cell phagocytosis by non-professional phagocytes may influence the tissue specificity of autoimmune diseases. 相似文献
2.
Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strengthens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed. 相似文献
3.
4.
5.
Oertelt S Kenny TP Selmi C Invernizzi P Podda M Gershwin ME 《Clinical & developmental immunology》2005,12(4):259-263
Previous studies on primary biliary cirrhosis (PBC) have focused on the role of T lymphocytes as potential effectors of tissue injury. We hypothesized that single nucleotide polymorphisms (SNPs) of genes involved in lymphocyte proliferation would be responsible for uncontrolled expansion of T cells and autoreactivity. To address this, we genotyped DNA from 154 patients with PBC and 166 ethnically matched healthy controls for SNPs of five candidate genes (60G/A CTLA-4, 1858 C/T LYP, -IVS9 C/T foxp3, p1323 C/G ICOS and -9606 T/C CD25) using a TaqMan assay. We report herein a statistically significant decrease in homozygosity rate for the 60A*CTLA-4 allele in patients with PBC compared to controls (p = 0.0411). Moreover, we found a significant association of the same allele and of the LYP*T allele with anti-mitochondrial antibody (AMA) serum negativity (p = 0.0304 and 0.0094, respectively). No association between any of the other studied SNPs and PBC susceptibility, progression, or AMA status was observed. In conclusion, given the high prevalence of SNPs in CTLA-4 detected in numerous autoimmune diseases, we encourage a more detailed genetic analysis of this candidate gene. Further, although obtained from a limited number of AMA-negative subjects, our data suggest a potential genetic heterogeneity for this specific subgroup of patients with PBC. 相似文献
6.
Palmer JM Diamond AG Yeaman SJ Bassendine MF Jones DE 《Clinical and experimental immunology》1999,116(1):133-139
PBC is characterized by T cell-mediated destruction of the biliary epithelial cells lining the small intrahepatic bile ducts. The E2 and E3 binding protein (E3BP (protein X)) components of pyruvate dehydrogenase complex (PDC) are disease-specific autoantigens in PBC. Attempts to localize the T cell autoepitopes within PDC-E2 have, however, generated contradictory results. One study has suggested the presence of T cell epitopes throughout PDC-E2, whilst another has identified a single dominant 14 amino acid T cell epitope (p163) spanning the lipoic acid binding lysine residue in the inner lipoyl domain (ILD) of PDC-E2. The aim of the current study was to determine the prevalence of T cell responses to p163 and PDC-E2 ILD, and the role played by lipoylation of these antigens in their immunogenicity, in a UK PBC population. We found that the majority of the PBC patients showing a 6-day peripheral blood T cell proliferative response to native human PDC also responded, in a MHC class II-restricted fashion, to biochemically purified PDC-E2 and E3BP (which co-purify) (9/10 positive (SI > 2.76), mean SI 5.74 +/- 5.04 (PDC-E2/E3BP) versus 6.67 +/- 3.84 (PDC), P = NS), implying that the important PBC-specific T cell epitopes are contained within the PDC-E2 or E3BP components of PDC. Only a minority of patients responsive to PDC, however, responded to either lipoylated recombinant PDC-E2 ILD (4/10 positive, mean SI 1.98 +/- 1.24, P < 0.005 versus PDC response) or lipoylated p163 (4/12 positive, mean SI 1.90 +/- 1.58, P < 0.001). The lipoylation state did not affect the T cell response to either ILD or p163. Our findings suggest that in some UK patients with PBC there are immunodominant T cell autoepitopes within PDC-E2/E3BP which are outside the ILD of PDC-E2. 相似文献
7.
S. Berthoud J. N. Cox G. Thiebaud C. Bouzakoura 《Virchows Archiv : an international journal of pathology》1974,364(3):285-296
Summary The case of a patient suffering from liver schistosomiasis diagnosed by liver biopsies is presented. There were also lesions in the liver suggestive of non-suppurative destructive cholangitis and the serum-immunological studies strengthened the diagnosis of primary biliary cirrhosis. The eo-existence of these two affections and their possible interrelationship are discussed. The authors further discussed some clinical, biochemical, immunological and pathological aspects of these two conditions and evoked the eventuality of an auto-immune type of hepatic affection triggered by the presence of the schistosome eggs.The authors are grateful to Dr. A. Cruchaud for the immunological studies, to Mrs. M. Loup and Miss C. L. Seignemartin for secretarial services, and Mr. E. Denkinger for the photographs. 相似文献
8.
R N MacSween A A Laiwah A A Busuttil M A Thomas S K Ross G Watkinson I Millman B S Blumberg 《Journal of clinical pathology》1973,26(5):335-339
Sera from 64 patients with primary biliary cirrhosis have been examined for Australia antigen (Au). On immunodiffusion and immunoelectrophoresis all sera were negative. Using a radioimmunoprecipitation technique 15.6% of sera contained antigen compared with an incidence of 3.1% in matched controls, a significant difference (p = 0.015). Anti-Au was found in 9.4% of patients and in 7.8% of controls. In lymphocyte transformation studies lymphocytes from one of 24 patients with primary biliary cirrhosis transformed on stimulation with an Au-rich serum. 相似文献
9.
10.
Autoantigens in primary biliary cirrhosis 总被引:7,自引:0,他引:7
Jones DE 《Journal of clinical pathology》2000,53(11):813-821
The automimmune liver disease primary biliary cirrhosis (PBC) is characterised by serum autoantibodies directed at mitochondrial and nuclear antigens (seen in most patients and a subset of patients, respectively). The antimitochondrial antibodies (AMA) characteristic of PBC are directed at members of the 2-oxoacid dehydrogenase components of multienzyme complexes; in particular, the E2 and E3 binding protein (E3BP) components of the pyruvate dehydrogenase complex (PDC). The presence of autoantibodies reactive with PDC-E2 and/or E3BP is strongly predictive of the presence of PBC. Therefore, the detection of these antibodies plays a very important role in the diagnosis of PBC. Originally demonstrated using immunofluorescence approaches, AMA can now be detected by the use of commercially available enzyme linked immunosorbent assays (ELISAs). Although the ELISA based approaches have advantages in terms of laboratory practicality, they are slightly less sensitive for the diagnosis of PBC than immunofluorescence (occasional patients with PBC show reactivity with PDC related antigens not present in the antigen preparations available for use with ELISA). Therefore, immunofluorescence should continue to be available as a complementary diagnostic test for use in occasional patients. In a subset of patients with PBC, autoantibodies are directed at increasingly well characterised nuclear antigens. Antinuclear antibody (ANA) positive patients are typically AMA negative. There are no significant differences in disease phenotype between AMA positive and AMA negative groups. At present, the clinical detection of ANA is mostly by Hep2 immunofluorescence, although ELISA kits for individual nuclear antigens are increasingly becoming available. 相似文献
11.
Zhang W Ono Y Miyamura Y Bowlus CL Gershwin ME Maverakis E 《Journal of autoimmunity》2011,37(2):71-78
The intrahepatic biliary destruction of primary biliary cirrhosis (PBC) appears secondary to a multi-lineage response that includes autoantibodies, biliary apotopes, and cellular responses. Although there has been considerable effort in defining the role and specificity of anti-mitochondrial autoantibodies, a major challenge has been the characterization of T effector pathways. This difficulty is due in part to the limitation of current technologies for directly isolating and characterizing autoreactive T cells from patients. Herein, we successfully demonstrate a novel technology for characterizing the surface phenotype of T cell oligoclonal expansions directly ex vivo. Using PBC as a prototypic disease we were able to detect clonal T cell expansions in 15/15 patients examined. Although the T cell expansions from different patients expressed different TCRVβ gene segments, the surface phenotype of the cells was the same. The clonal T cell expansions in PBC patients are CX3CR1+ Fas+ effector-memory T cells, a finding of particular importance given the known up-regulation of fractalkine on injured biliary epithelial cells (BEC). In contrast to the persistent aberrantly expanded T cells observed in the PBC patients, T cell expansions detected in response to a herpes viral infection were very dynamic and resolved over time. This protocol can be used to characterize T cell expansions in other autoimmune diseases. 相似文献
12.
13.
Serology of primary biliary cirrhosis 总被引:3,自引:0,他引:3
14.
15.
16.
17.
CD4+T细胞活化诱导细胞凋亡在原发性胆汁性肝硬化小鼠模型中的作用研究 总被引:1,自引:1,他引:1
目的 研究CD4+T细胞活化诱导细胞凋亡(activation induced cell death, AICD)在poly I∶C诱导的原发性胆汁性肝硬化(primary biliary cirrhosis, PBC)小鼠模型中的作用.方法 30只C57BL/6雌性小鼠随机分为模型组和对照组,模型组小鼠腹腔注射poly I∶C 5 mg/kg,对照组小鼠注射等体积无菌PBS,16周后通过测定血清抗线粒体抗体(antimitochondrial antibody, AMA)、碱性磷酸酶(alkali phosphatase, ALP)及肝脏HE染色验证模型.磁珠分离小鼠脾脏CD4+ T细胞,分别以Con A和anti-CD3体外诱导细胞凋亡;实时荧光定量PCR测定T细胞中凋亡相关基因Fas、FasL和TRAIL(tumor necrosis factor-related apoptosis-inducing ligand)的表达;Western blot检测CD4+ T细胞中抗凋亡基因Bcl-2的表达.结果 poly I∶C注射16周后模型组小鼠血清AMA均为阳性,同时肝组织汇管区出现不同程度的炎性细胞浸润,而对照组AMA均为阴性,肝组织未出现明显病变.模型组小鼠血清ALP[(110.4±18.3) U/L]显著高于对照组[(52.2±15.4) U/L], P<0.001;模型组小鼠脾CD4+ T细胞AICD显著低于对照组(P<0.001),同时定量PCR结果表明:FasL mRNA水平较对照组有所降低(P<0.05),而两组Fas水平差异无统计学意义(P>0.05),TRAIL水平则显著低于对照组(P<0.001);Western blot结果表明模型鼠的抗凋亡蛋白Bcl-2的表达较对照组显著增高.结论 TH1细胞的凋亡缺陷可能在PBC小鼠模型的发病机制中有重要作用,该缺陷可能是由于自身免疫机制引起凋亡相关分子Fas体系及TRAIL的表达变化引起,同时通过上调Bcl-2的表达抑制自身反应性T细胞的凋亡. 相似文献
18.
《Expert Review of Clinical Immunology》2013,9(12):1667-1678
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized histologically by destruction of intrahepatic bile ducts and serologically by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC are increasing. Fatigue and pruritus are common symptoms in PBC, although the proportion of asymptomatic PBC is increasing due to the widespread use of screening biochemical tests and antimitochondrial antibody assays. PBC may eventually lead to cirrhosis and its consequent complications. In the 1980s, PBC was the leading indication for liver transplantation. Ursodeoxycholic acid is the only US FDA-approved therapeutic agent for PBC. Clinical trials have shown that the use of ursodeoxycholic acid in PBC results in reduction of liver biochemistries, a delay in histological progression, a delay in the development of varices and improvement in survival without liver transplantation. 相似文献
19.
Peripheral blood lymphocytes from patients with primary biliary cirrhosis previously have been reported to demonstrate reduced pokeweed mitogen-stimulated immunoglobulin synthesis and diminished function of suppressor T cells. To determine whether thymic hormone preparations reverse these immunologic defects in vitro, the effects of thymosin fraction 5 and thymosin alpha 1 on immunoglobulin synthesis and concanavalin A-induced suppression of immunoglobulin synthesis were investigated in normal subjects and patients with primary biliary cirrhosis. In normal subjects, no effects of thymosin were observed on unstimulated and pokeweed mitogen-stimulated immunoglobulin synthesis, nor on Con A-induced suppressor cell activity. Lymphocytes from patients with PBC synthesized less IgG and IgM than normals when stimulated by pokeweed mitogen, and this difference was enhanced by both thymosin fraction 5 and thymosin alpha 1. Con A suppression of immunoglobulin synthesis was abnormal in only one PBC subject so that thymosin effects on impaired suppressor T cell activity could not be tested. 相似文献
20.
Ruth Y. Lan Aftab A. Ansari Ross L. Coppel M. Eric Gershwin 《Clinical and Applied Immunology Reviews》2005,5(4):271
The role of adaptive as well as innate immune responses in the pathology of primary biliary cirrhosis (PBC) has been a major subject of investigation. Primary biliary cirrhosis is an autoimmune liver disease involving the destruction of small bile ducts, which eventually leads to liver cirrhosis. Adaptive immune responses involving autoantibody production by B cells and autoreactive T cells have been labeled as the most probable mediators of tissue destruction. Autoantibody production against mitochondrial antigens is used as a key diagnostic marker in PBC, being present in 90-95% of patient sera. Besides blood, these antimitochondrial antibodies are found in liver, bile, saliva, and urine of patients and target mitochondrial autoantigens that are well conserved between species. One possible mechanism of antibody-mediated tissue destruction is via the transcytosis of immunoglobulin A antimitochondrial antibodies through biliary epithelium. Another mechanism may involve the recognition by antimitochondrial antibodies of the mitochondrial autoantigens abnormally expressed on patient biliary epithelium. The second component of the adaptive immune response in PBC involves T cells, which comprise a large fraction of infiltrating leukocytes in diseased livers. Autoreactive CD4+ and CD8+ T cells recognizing mitochondrial antigens targeted by antimitochondrial antibodies have been isolated with specificity for epitopes that overlap with those of B cells. Cytokines production of such infiltrates indicates the involvement of both TH1 and TH2 responses in the diseased tissue. Besides adaptive responses, innate immunity effector mechanisms involving eosinophils, macrophages, and B cells hyperresponsive to bacterial DNA CpG motifs has been implicated in the pathology of PBC. Despite research efforts, the etiology of PBC still remains elusive, although theories involving the participation of genetic factors, molecular mimicry due to microorganisms, and a role for modification of native autoantigens by xenobiotics have been proposed. 相似文献