Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic susceptibility to autoimmune hepatitis is associated with the human leukocyte antigen haplotype A1-B8-DR3 and DR4. To date, only one study in Japan has considered the human leukocyte antigen DP locus in this disease, and no studies have been reported in whites. In this study we used a series of sequence-specific oligonucleotide probes to determine human leukocyte antigen DPB1 genotypes in 101 unrelated white northern European patients and 105 racially and geographically matched controls. The aims of the study were twofold: first, to determine the degree of DPB-encoded susceptibility to autoimmune hepatitis, and, second, to establish whether susceptibility can be extended to include human leukocyte antigen DPB. None of 17 DPB1 alleles was significantly associated with the susceptibility to autoimmune hepatitis. Although one particular seven-locus haplotype A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201-++ +DPB1*0401 was significantly associated with the disease (27% vs. 7%, relative risk = 5.14, p < 0.0005), the association with this haplotype was weaker than that for the six-locus haplotype excluding DPB (40% vs. 11%, RR = 5.52, p < 0.0005). When the patients first seen at ages younger than 16 yr (pediatric patients) were considered separately, the greatest relative risk was for the seven-locus haplotype (41% vs. 7%; relative risk = 9.60, p < 0.0005). The results of this study further confirm that major histocompatibility complex-encoded susceptibility to autoimmune hepatitis is located at or close to the human leukocyte antigen DR locus; however, the A1-B8-DR3-DQ2-DPB1*0401 extended haplotype may be important in determining the age of onset and severity of disease.
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PMID:Human leukocyte antigen A1-B8-DR3-DQ2-DPB1*0401 extended haplotype in autoimmune hepatitis. 824 57

We investigated autoimmunity, as assessed by hypergammaglobulinemia and the presence of autoantibodies including anti-nuclear antibodies (ANA) and anti-liver membrane antibodies (LMA), in 149 patients with chronic hepatitis C, 55 patients with chronic hepatitis B and 11 patients with autoimmune hepatitis. There was no significant difference in the incidence of these autoantibodies between chronic hepatitis C and chronic hepatitis B. Nine patients with chronic hepatitis C satisfied the serological criteria of autoimmune hepatitis (ANA positive and gammaglobulin or serum IgG greater than 2500 mg/dl), but none of the patients with chronic hepatitis B met the criteria. This suggests that autoimmunity is greater in chronic hepatitis C than in chronic hepatitis B. Of the 9 patients with chronic hepatitis C, all 4 patients tested for human leukocyte antigen (HLA) phenotype had HLA-DR4, which is known to be associated with autoimmune hepatitis in Japanese patients. We believe that hepatitis C virus (HCV) infection enhances the initiation and perpetuation of autoimmunity in susceptible individuals.
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PMID:Autoimmune responses as assessed by hypergammaglobulinemia and the presence of autoantibodies in patients with chronic hepatitis C. 827 54

To assess the frequency and genetic predispositions of concurrent immunological diseases and immunoserological markers in autoimmune hepatitis and chronic viral hepatitis, we assessed 185 patients prospectively, including 122 patients with autoimmune hepatitis and 63 patients with viral disease. Human leukocyte antigens were determined in all patients. Sixty patients (32%) had concurrent immunological diseases, and the majority of the diseases (68%) had known human leukocyte antigen associations. Although patients with autoimmune hepatitis had concurrent immunological diseases more commonly than those with viral disease (38% vs. 22%; p = 0.04), the nature of the diseases was similar in both groups, as were the frequencies of human leukocyte antigen-DR4 (42% vs. 39%; p = 0.7). The presence of human leukocyte antigen-DR4 was associated with the concurrence of immunological diseases in both autoimmune (62% vs. 33%; p = 0.01) and viral hepatitis (75% vs. 29%; p = 0.009). In autoimmune hepatitis, human leukocyte antigen-DR4 was also associated with the expression of smooth muscle antibodies and high-titer antinuclear antibodies. We conclude that concurrent immunological diseases and immunoserological markers are common in autoimmune and chronic viral hepatitis. Both conditions have a common genetic predisposition for concurrent immunological disease associated with human leukocyte antigen-DR4. The expression of smooth muscle antibodies and high-titer antinuclear antibodies is associated with human leukocyte antigen-DR4 in autoimmune hepatitis only, suggesting that this response is associated with triggering antigens and immune recognition systems that are different from those in viral disease.
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PMID:Genetic predispositions for the immunological features of chronic active hepatitis. 840 54

The aim of this study was to clarify the relationship between human leukocyte antigen DR allele distribution and the degree of liver cell injury of hepatitis C virus (HCV) carriers in Japan. The subjects, 68 HCV carriers, were divided into two groups according to the laboratory data and liver histology. Those in the asymptomatic carrier group (n = 19) had normal ALT levels persistently for 8-153 months (mean 25.7 months) and were diagnosed histologically as normal liver, nonspecific reactive hepatitis or chronic persistent hepatitis. Those in the chronic active hepatitis group (n = 49) had elevated ALT levels and were diagnosed histologically with chronic active hepatitis. The human leukocyte antigen DR alleles of all subjects were defined using the polymerase chain reaction restriction fragment length polymorphism method. The expression of human leukocyte antigen class I antigen and intercellular adhesion molecule 1 on the hepatocyte membrane were also examined in 14 patients from each group using an indirect immunohistochemical method. The frequency of DR13 (42.1%) in the asymptomatic carrier group was significantly higher (Pc < 0.003) than that of the chronic active hepatitis group (4.1%). There were no significant differences for the other DR alleles. The frequencies of expression of human leukocyte antigen class I antigen and intercellular adhesion molecule 1 on the hepatocyte membrane of the asymptomatic carrier group were significantly less than those of the chronic hepatitis group (64% vs. 100% P < 0.05, 29% vs. 71% P < 0.05, respectively), although there was no significant difference in the serum HCV-RNA titer between the two groups (10(6.4 +/- 1.1) vs. 10(6.5 +/- 0.7) copies/mL). These results demonstrate that the cellular immune response of the asymptomatic carrier group is less activated than the response of the chronic active hepatitis group and that HLA DR13 may be closely associated with this low activity of hepatitis among HCV carriers.
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PMID:Increased frequency of HLA DR13 in hepatitis C virus carriers with persistently normal ALT levels. 882 3

We describe a hepatitis B virus carrier who satisfied the criteria of autoimmune hepatitis proposed by the International Autoimmune Hepatitis Group. A 43-year-old Japanese female showed human leukocyte antigen typing including DR4 in addition to hypergammaglobulinemia, presence of autoantibodies, and liver histology suggestive of autoimmune hepatitis. Moreover, the predominant presence of hepatitis B core antigen in nuclei rather than in cytoplasm of hepatocytes suggested less of a possibility of liver cell damage related to hepatitis B virus infection. She completely responded to immunosuppressive therapy and no clinical or biochemical relapse has been recognized to date.
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PMID:Hepatitis B virus carrier status linked to autoimmune hepatitis. 883 98

The T-cell-mediated immune response plays a crucial role in defense against hepatotropic viruses as well as in the pathogenesis of viral chronic hepatitides. However, very little is known about the role of specific T cells during hepatitis delta virus (HDV) infection in humans. In this study, the T-cell response to HDV in chronic hepatitis B virus (HBV) carriers with HDV superinfection was investigated at different levels. Analysis of peripheral blood mononuclear cell (PBMC) proliferation in response to a recombinant form of large hepatitis delta antigen (HDAg) revealed that 8 of 30 patients studied (27%) specifically responded to HDAg. By employing synthetic peptides spanning the entire HDAg sequence, we found that T-cell recognition was directed against different antigenic determinants, with patient-to-patient variation in the pattern of response to peptides. Interestingly, all responders had signs of inactive HDV-induced disease, while none of the patients with active disease and none of the control subjects showed any significant proliferation. More accurate information about the specific T-cell response was obtained at the clonal level. A panel of HDAg-specific CD4+ T-cell clones from three HDV-infected individuals and fine-specificity analysis revealed that the clones tested individually recognized four epitopes corresponding to amino acids (aa) 26 to 41, 50 to 65, 66 to 81, or 106 to 121 of HDAg sequence. The study of human leukocyte antigen (HLA) restriction revealed that peptides 50 to 65 and 106 to 121 were presented to specific T cells in association with multiple class II molecules. In addition, peptide 26 to 41 was efficiently generated after processing of HDAg through the endogenous processing pathway. Cytokine secretion analysis showed that all the CD4+ T-cell clones assayed were able to produce high levels of gamma interferon (IFN-gamma), belonging either to T helper-1 (Th1) or Th0 subsets and that some of them were cytotoxic in a specific assay. This study provides the first evidence that detection of a specific T-cell response to HDAg in the peripheral blood of individuals with hepatitis delta is related to the decrease of HDV-induced disease activity. The HDAg epitopes identified here and particularly those recognized by CD4+ T cells in association with multiple major histocompatibility complex class II molecules may be potentially exploited for the preparation of a vaccine for prophylaxis and therapy of HDV infection.
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PMID:Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles. 903 59

Cytotoxic T lymphocytes (CTL) are closely related to the mechanism of liver injury in chronic viral hepatitis. Recently, it has been suggested that antigen-specific T cell activation requires both presentation of antigen by major histocompatibility complex (MHC) molecules and the delivery of costimulatory signals. Such signals are provided by B7/BB-1, one of the most important accessory molecules, sufficient for causing antigen-specific MHC-restricted T cell activation. To evaluate the role of B7/BB-1 in chronic hepatitis C, we immunohistochemically studied its expression in liver tissues obtained from 61 patients with hepatitis C virus (HCV) infection and compared them based on hepatitis activity. In HCV-infected liver, B7/BB-1 was strongly expressed in the cytoplasm of hepatocytes. B7/BB-1-positive cells accompanied liver-infiltrating lymphocytes and were mainly detected in the periportal region. B7/BB-1 expression was closely correlated with the activity of viral hepatitis as evaluated from scores of periportal or intralobular inflammation and necrosis, or serum alanine transferase (ALT) levels. Further study by immunostaining with anti-HCV core and anti-human leukocyte antigen (HLA) class I antibody showed B7/BB-1 positive cells near HCV core antigen- and HLA class I-positive cells, with B7/BB-1-positive cells mostly included among HLA class I-positive cells. These findings suggested that B7/BB-1 expression by hepatocytes may be induced by HCV infection and may trigger generation and activation of CTL, which may cause damage to HCV-infected HLA class I-expressing hepatocytes.
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PMID:B7/BB-1 expression and hepatitis activity in liver tissues of patients with chronic hepatitis C. 904 24

To determine the significance of antibodies to single-stranded (anti-ssDNA) and double-stranded DNA (anti-dsDNA) in antinuclear antibody (ANA)-positive type 1 autoimmune hepatitis, sera from 53 patients were tested by enzyme immunosorbent assay (ELISA) and indirect immunofluorescence using the Crithidia luciliae substrate. Anti-dsDNA were detected in 18 patients (34%) by ELISA and 12 patients (23%) by the Crithidia-based assay. Twenty patients with anti-dsDNA by either assay (38%) had higher serum levels of immunoglobulin G (3971 +/- 270 mg/dL vs. 3201 +/- 247 mg/dL, P = .05) than seronegative patients. They also had human leukocyte antigen (HLA) DR4 more commonly than other patients (83% vs. 41%, P = .006) and normal subjects (83% vs. 30%, P = .00007). In contrast to patients seropositive by the Crithidia-based assay, those seropositive by ELISA failed corticosteroid therapy more commonly (24% vs. 3%, P = .04). Anti-ssDNA were found in 45 patients (85%) and they did not distinguish patients with different clinical features or outcomes. We conclude that anti-dsDNA are common in ANA-positive type 1 autoimmune hepatitis. HLA DR4 is associated with their production, and seropositivity by ELISA characterizes patients who have a poorer immediate response to corticosteroid treatment. Anti-ssDNA are common but they do not have important clinical implications.
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PMID:Antibodies to single-stranded and double-stranded DNA in antinuclear antibody-positive type 1-autoimmune hepatitis. 930 84

Enzymes of phase I (cytochromes P450) and phase II (UDP [uridine diphosphate]-glucuronosyltransferases) of drug metabolism are targets of autoimmunity in the following chronic liver diseases of different etiology: 1)autoimmune hepatitis (AIH); 2) hepatitis associated with the autoimmune polyendocrine syndrome type 1 (APS-1); 3) virus-induced autoimmunity; and 4) drug-induced hepatitis. AIH is diagnosed by the following: the absence of infection with hepatitis viruses; the presence of a threshold of relevant factors, including circulating autoantibodies, hypergammaglobulinemia, female sex (female/male ratio 4:1), human leukocyte antigen (HLA) B8, DR3, or DR4; and benefit from immunosuppression. Patients with autoimmune hepatitis type 2 (AIH-2) are characterized by antibodies directed against liver and kidney microsomes, by an early onset of autoimmune hepatitis, which is a more aggressive course of the disease, and by a higher prevalence of autoimmunity directed against other organs. The major target of autoimmunity in patients with AIH-2 is cytochrome P450 2D6. Epitope mapping experiments revealed four short linear epitopes on cytochrome P450 2D6, recognized by liver/kidney microsomal autoantibodies type 1 (LKM-1) in patients with AIH-2. In addition, about 10% of the patient sera contain autoantibodies that detect a conformational epitope on UDP-glucuronosyltransferases (UGTs) of family 1. Presently, LKM-1 autoantibodies are used as diagnostic markers for AIH-2. It is unclear whether these autoantibodies have a pathogenetic role. Hepatitis is found in some patients with APS-1. Presumably this also is an autoimmune liver disease. APS-1 patients with hepatitis may develop autoantibodies directed against microsomal P450 enzymes of the liver; however, these autoantibodies do not recognize cytochrome P450 2D6, but they do recognize cytochrome P450 1A2. Autoimmunity in patients with APS-1 usually is directed against several organs simultaneously, and several organ specific autoantibodies may exist. Interestingly, APS-1 patients may produce various anti-cytochrome P450 antibodies. In addition to the hepatic anti-cytochrome P450, 1A2 autoantibodies are directed against steroidogenic cytochromes P450, namely P450 c21, P450 scc, and P450 c17. These autoantibodies correlate with adrenal and ovarian failure and often these steroidal cell autoantibodies precede the manifestation of adrenal or ovarian dysfunction. Whether anti-P450 1A2 autoantibodies have a similar predictive value is not yet known. LKM autoantibodies are further found in association with chronic hepatitis C and D. In chronic hepatitis C, the major target of LKM autoantibodies is cytochrome P450 2D6. Predominantly, conformational epitopes are recognized by LKM-1 sera of patients with chronic hepatitis C. In 13% of patients with chronic hepatitis D, LKM-3 autoantibody is detectable. The target proteins are UGTs of family 1 and in a minority of sera UGTs of family 2. The epitopes are conformational. All hepatic diseases discussed earlier have in common that autoimmunity, which is directed against enzymes of drug metabolizing multigene families. Each disease is characterized by a specific pattern of autoantibodies, with apparently little overlap. For example, LKM-1 autoantibodies, which are directed against P450 2D6, seem to overlap between AIH and chronic hepatitis C. However, a close examination of these autoantibodies shows differences between LKM-1 autoantibodies from patients with chronic hepatitis C and with AIH. In AIH, LKM autoantibodies are more homogenous, titers are higher, and major autoepitopes on cytochrome P450 2D6 are small and linear. LKM autoantibodies in viral hepatitis C are more heterogeneous and there are multiple epitopes, many of which are conformational. These differences indicate the different mechanisms that are involved in the generation of autoimmunity. (ABSTRACT TRUNCATED)
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PMID:Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease. 932 34

The human leukocyte antigen is a crucial genetic factor that initiates or regulates immune response by presenting foreign or self antigens to T lymphocytes. The aim of this study was to investigate whether HLA polymorphism is associated with the onset or progression of liver injury in chronic hepatitis C virus (HCV) infection. We determined HLA class I antigens and class II alleles in 130 hepatitis C virus (HCV)-infected patients (33 carriers with persistently normal alanine transaminase [ALT] values and 97 patients with chronic liver disease [CLD]). HLA class I (A, B) was typed serologically, and class II (DRB1, DQB1) was typed by means of polymerase chain reaction-restriction fragment length polymorphism methods. The frequencies of DRB1*0405 and DQB1*0401 were higher in HCV-infected patients than in uninfected subjects. Among HCV-infected patients, the frequencies of B54, DRB1*0405, and DQB1*0401 were significantly higher in patients with CLD than in those carriers with persistently normal ALT values, whereas DRB1*1302, DRB1*1101, and DQB1*0604 were more frequently found in carriers with persistently normal ALT values than in patients with CLD. From extended haplotype analyses, in carriers with B54-DRB1*0405-DQB1*0401 haplotype, the risk of having liver injury was 13.2 times greater than in carriers with DRB1*0405-DQB1*0401 but without B54 [P = 0.0015, Haldane odds ratio = 13.2 (95% confidence interval, 1.7-103.8)]. In contrast, carriers with B44-DRB1*1302-DQB1*0604 had a 12.7-fold lower relative risk of developing liver injury compared to those with the haplotype containing B44 but not DRB1*1302-DQB1*0604 [P = 0.0076, Haldane odds ratio = 0.079 (0.009-0.695)]. Our findings show that extended haplotypes including class I B54 are closely associated with the progression of liver injury, whereas extended haplotypes including class II DRB1*1302-DQB1*0604 are associated with low hepatitis activity in chronic HCV infection.
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PMID:Influence of HLA haplotypes on the clinical courses of individuals infected with hepatitis C virus. 942 43


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