Increased bcl-2 expression in lymphocytes and its association with hepatocellular damage in patients with autoimmune hepatitis.
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The proto-oncogene product bcl-2 is known to inhibit apoptotic cell death, and its dysregulation might play a critical role in the development of autoimmune disease. To elucidate the role of bcl-2 in autoimmune hepatitis (AIH), its expression in peripheral blood mononuclear cells (PBMC) and in liver-infiltrating lymphocytes (LIL) was investigated. Increased bcl-2 expression in PBMC was found in AIH patients compared with that in chronic hepatitis C (CHC) patients and in healthy controls. The level of bcl-2 expression significantly correlated with serum ALT level. Further analysis showed that CD4+ T cells are enriched in bcl-2-expressing PBMC. To characterize the Th1/Th2 profile of bcl-2-expressing CD4+ T cells, intracellular interferon-gamma (IFN-gamma) and IL-4 were analysed. The results revealed that most of the bcl-2-expressing cells were found to be IFN-gamma-secreting Th1 cells. In three patients for whom their clinical courses could be followed, bcl-2 expression was decreased after the initiation of immunosuppressive therapy with corticosteroids. However, the level of IFN-gamma + cells was not altered. Immunohistochemical analysis also showed that large amounts of bcl-2+ cells were observed in periportal area in the liver. In conclusion, bcl-2-expressing cells were shown to be increased in peripheral blood and liver in AIH and the bcl-2 product was expressed mainly in CD4+ Th1-type cells, suggesting that these cells might promote the cellular immune response and contribute to the development of hepatitis and hepatocellular damage in AIH. (+info)
High mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 are significant target antigens of perinuclear anti-neutrophil cytoplasmic antibodies in autoimmune hepatitis.
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BACKGROUND: High mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 have been identified as novel antigens of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCAs), and the existence of anti-HMG1 and anti-HMG2 antibodies in a population of patients with ulcerative colitis has been reported. AIMS: To investigate whether HMG1 and HMG2 are target antigens for p-ANCAs in autoimmune hepatitis (AIH). PATIENTS: Serum samples from 28 patients with AIH, 44 patients with primary biliary cirrhosis (PBC), 27 patients with chronic hepatitis C, and 23 patients with chronic hepatitis B were tested. METHODS: ANCAs were detected by routine indirect immunofluorescence (IIF). Anti-HMG1 and anti-HMG2 antibodies were assayed by enzyme linked immunosorbent assay. RESULTS: p-ANCAs were detected in 89% (25/28) of patients with AIH, 36% (16/44) of patients with PBC, 11% (3/27) of patients with chronic hepatitis C, and 13% (3/23) of patients with chronic hepatitis B. Anti-HMG1 and/or anti-HMG2 antibodies were detected in 89% (25/28) of patients with AIH, 70% (31/44) with PBC, 26% (7/27) with chronic hepatitis C, and 9% (2/23) with chronic hepatitis B. In AIH, anti-HMG1 and/or anti-HMG2 antibodies were detected in 96% (24/25) of p-ANCA positive patients. The p-ANCA staining pattern detected by IIF using sera from patients with AIH disappeared or decreased in titre after preincubation with a mixture of HMG1/HMG2. The presence and titres of those antibodies in AIH correlated significantly with those of p-ANCA, but not with those of anti-nuclear antibody or anti-smooth muscle antibody. CONCLUSIONS: HMG1 and HMG2 are significant target antigens of p-ANCA in AIH. (+info)
Clinical manifestations and immunological features of primary Sjogren's syndrome with liver involvement: analysis of thirty cases.
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OBJECTIVE: To evaluate the incidence, severity, clinical manifestations and immunological features relevant to liver involvement in 135 cases of primary Sjogren's syndrome. METHODS: One hundred and thirty-five patients with definite primary Sjogren's syndrome were analyzed retrospectively for liver involvement by the abnormalities of the liver enzymes, bilirubin level and liver biopsied section. RESULTS: The liver involvement in 30 patients (22.2%) could be etiologically ascribed to Sjogren's syndrome itself. The clinical spectrum and severity of this entity differed widely, 36.6% showed no relevant clinical symptoms, however jaundice was found in 46.7% of patients. Six patients showed pathological changes of chronic active hepatitis. 73.3% of all patients with liver involvement responded to steroid and immunosuppressive drugs, yet with a tendency to relapse (two cases). Liver cirrhosis was developed in five cases. The spectrum of serum autoantibodies in the patients with liver involvement showed no difference from those without liver involvement. Most of them were compatible with the serum profile of autoimmune hepatitis type-1. CONCLUSIONS: Liver involvement was complicated in 22.2% patients of primary Sjogren's syndrome. Clinical manifestations were non-specific and the main pathological change was chronic active hepatitis. The differential diagnosis between Sjogren's syndrome with liver involvement and type-1 autoimmune hepatitis could be only ascribed to other systemic clinical manifestations of Sjogren's syndrome. (+info)
An aged male patient with autoimmune hepatitis complicated by hepatocellular carcinoma.
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An 82-year-old male patient was admitted for liver dysfunction. Laboratory test showed the following data; aspartate aminotransferase (AST) 79 IU/l, alanine aminotransferase (ALT) 28 IU/l, total bilirubin (T. Bil) 0.9 U, zinc sulfate turbidity test (ZTT) 48.9 U, gamma-globulin 4.9 g/dl, immunoglobulin G (IgG) 5,046 mg/dl, anti-nuclear antibodies x 320, anti-mitochondrial antibodies (-), hepatitis B virus surface antigen (HBsAg) (-), HBcAb (-), anti-hepatitis C virus (anti-HCV) (-), hepatitis C virus (HCV-RNA) (-), anti-hepatitis G virus (anti-HGV) (-), alpha-fetoprotein 306.8 ng/ml, carcinoembryonic antigen (CEA) 2.3 ng/ml, carbohydrate antigen (CA) 19-9 77.2 U/ml. Abdominal ultrasonography and computed tomography showed a large mass occupying most of the right lobe and portal thrombosis in the liver. Liver biopsy revealed cirrhosis with inactive hepatitis in the nontumorous lesion and well-differentiated hepatocellular carcinoma in the tumorous lesion. We report a rare case of an aged male patient with autoimmune hepatitis complicated by hepatocellular carcinoma. (+info)
A case of Graves' disease associated with autoimmune hepatitis and mixed connective tissue disease.
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The patient was a woman of forty-eight. Liver dysfunction was pointed out at the age of forty-five. She was admitted to hospital because of her hyperthyroidism. Her palmar skin was wet and her fingers were swollen like sausages. She had a diffuse and elastic hard goiter with a rough surface. The serum levels of free T3 (9.6 pg/mL) and free T4 (3.76 ng/dL) were high and that of TSH (0.11 microU/mL) was low. The activity of TSH-binding inhibitory immunoglobulin (TBII) was 89%. The uptake rate of 123I to the thyroid was 55.1% and the uptake pattern was nearly diffuse. The goiter was proved to contain several nodules by ultrasonography, but aspiration cytology showed no malignant cells. She was diagnosed to have Graves' disease with adenomatous goiter. She also had high ALT (34 IU/L) and gamma-globulin (1.97 g/dL). She had positive antinuclear antibody (speckled type), positive anti-ribosomal nuclear protein antibody, and positive LE cell phenomenon. The liver biopsy revealed mononuclear cell infiltration with fibrosis in the portal area. These data indicated that she also had autoimmune hepatitis (AIH) and mixed connective tissue disease (MCTD). The analysis of human leukocyte antigen (HLA) showed positive A11 which had been reported to relate to Graves' disease, and positive DR4 which had been reported to relate to AIH and MCTD. These results suggested that HLA would determine susceptibility to three distinct autoimmune diseases in this case. (+info)
Overlapping but distinct specificities of anti-liver-kidney microsome antibodies in autoimmune hepatitis type II and hepatitis C revealed by recombinant native CYP2D6 and novel peptide epitopes.
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Anti-liver-kidney microsome antibodies (anti-LKM) occur in autoimmune hepatitis (AIH) type II and in a subset of patients with hepatitis C. Anti-LKM1 in AIH are directed against cytochrome P4502D6 (CYP2D6), but conflicting data exist concerning the specificity of anti-LKM in hepatitis C. The aim of this study was to evaluate binding specificities of anti-LKM antibodies in both diseases using novel test antigens as well as their inhibitory capacity on CYP2D6 enzyme activity. Sera from 22 patients with AIH type II and 17 patients with hepatitis C being anti-LKM-positive in the immunofluorescence test were investigated for binding to native recombinant CYP2D6 and liver microsomes by ELISA and immunoblotting, and to synthetic peptides covering the region 254-339 (254-273, 257-269, 270-294, 291-310, 307-324, 321-339, 373-389) as well as the novel peptide 196-218 by ELISA. Furthermore, all sera were tested for inhibition of CYP2D6-dependent bufuralol 1'-hydroxylase activity. Twenty of the 22 AIH type II sera (91%) and nine of the 17 hepatitis C sera (53%) were positive for CYP2D6 by ELISA and/or immunoblotting. The previously described major peptide epitope comprising CYP2D6 amino acids 257-269 was recognized by 16 of the 22 AIH sera but by only one hepatitis C serum. A further epitope, 196-218, could be defined for the first time as another immunodominant epitope for AIH because it was recognized by 15 of the 22 AIH (68%) but only three of the 17 hepatitis C sera (18%). With the exception of the peptide 254-273, the other peptides showed no significant reactivity. Analysing the inhibitory properties of anti-LKM antibodies it emerged that 95% of AIH sera and 88% of hepatitis C sera inhibited enzyme function. These data indicate that anti-LKM antibodies in AIH and hepatitis C react with CYP2D6, as shown by their inhibitory activity, and that besides the known epitope 257-269 a further immunodominant epitope exists on CYP2D6 which is recognized by sera from patients with AIH II but hardly by sera from patients with hepatitis C. (+info)
Enzyme immunoassay for autoantibodies to human liver-type arginase and its clinical application.
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BACKGROUND: Arginase is an enzyme of the urea cycle, and one of the two isoenzymes is the liver-type enzyme. We examined serum autoantibodies to this liver-type enzyme in patients with hepatitis. METHODS: Antibodies to recombinant human liver-type arginase were measured by ELISA in 95 patients and 55 healthy controls. RESULTS: The mean absorbance values in the ELISA assays of patients with definite autoimmune hepatitis (n = 11; P <0.0001), probable autoimmune hepatitis (n = 31; P <0.0001), and hepatitis C (HCV; n = 20; P <0.01) were significantly different from those of healthy controls, but the values in patients with hepatitis B (HBV; n = 23) and other autoimmune diseases (n = 10) were not significantly different from those of healthy controls. When the cutoff was fixed at the upper 95th percentile of the absorbance value in healthy controls, positive reactions were found in 18.2%, 32.3%, 20.0%, 13. 0%, and 10.0% of patients with definite autoimmune hepatitis, probable autoimmune hepatitis, HCV hepatitis, HBV hepatitis, and other autoimmune diseases, respectively. All of these positive reactions were abolished by inhibition of serum with recombinant antigen. The specificity and sensitivity of this ELISA were 96% and 29%, respectively. The intraassay and interassay coefficients of variation were 2.3-7.5% and 9.8-11%, respectively. There was no relationship between these antibodies and anti-nuclear, anti-smooth muscle, or anti-cytochrome P450IID6 antibodies. CONCLUSIONS: The ELISA for anti-liver-type arginase autoantibody improved the detectability of autoimmune hepatitis when compared with established assays for liver-specific autoantibodies. (+info)
Sjogren's syndrome complicated with autoimmune hepatitis and antiphospholipid antibody syndrome.
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A 56-year-old Japanese female simultaneously developed thrombocytopenia, sicca symptoms, and an elevation of transaminase. Antiphospholipid antibodies were detected in her serum. The presence of anti-SS-A antibodies in the serum and sialectasis, disclosed by sialography, suggested the presence of primary Sjogren's syndrome (SjS). The laboratory data and the biopsy of the liver showed compatible findings with autoimmune hepatitis (AIH). Thrombocytopenia and liver dysfunction satisfactorily responded to corticosteroid. To our knowledge, this is the first reported case of SjS with AIH and antiphospholipid antibody syndrome (APAS). Analysis of serum cytokine levels showed a predominance of Th0-Th1 response, which is not compatible with AIH, in this complicated autoimmune state. (+info)