Cell-mediated Immunity to Human Tamm-Horsfall Glycoprotein in Autoimmune Liver Disease with Renal Tubular Acidosis

Cell-mediated immune responses to Tamm-Horsfall glycoprotein isolated from human urine were investigated using the leucocyte migration test. Abnormal responses were found in 91% of patients with active chronic hepatitis or primary biliary cirrhosis with an associated renal tubular acidosis (R.T.A.) but in only 19% of those without R.T.A. In nearly all of a group of patients without autoimmune liver disease and in a control group of normal subjects results were within normal limits. In addition, using an immunofluorescent technique with rabbit antibody to human Tamm-Horsfall glycoprotein, it was possible to show the presence in human liver cell membrane of material reacting immunologically as Tamm-Horsfall. These findings suggest that the development of an immune response to this glycoprotein, initiated by release of cross-reacting antigens from damaged hepatocytes, could be the mechanism underlying the occurrence of R.T.A. in some patients with autoimmune liver disease.     

“Sicca Complex” in Liver Disease

Sixty-three patients with liver disease were studied for the presence of the components of Sjögren''s syndrome. The “sicca complex” (that is, patients without arthritis) was detected in 42% of patients with active chronic hepatitis, 72% with primary biliary cirrhosis, and 38% with cryptogenic cirrhosis. One patient with active chronic hepatitis and one with primary biliary cirrhosis had rheumatoid arthritis. No evidence of Sjögren''s syndrome was detected in seven patients with alcoholic cirrhosis. It is suggested that the sicca complex and autoimmune liver disease may be part of a systemic disorder in which immunological mechanisms are concerned in the pathogenesis.     

Cell-mediated Immune Response in Primary Biliary Cirrhosis to a Protein Fraction from Human Bile

Cell-mediated immune responses to a protein fraction of human bile have been demonstrated, using the leucocyte migration test, in eight out of 10 patients with primary biliary cirrhosis but in only three out of nine with active chronic hepatitis. In the latter condition sensitization to a liver-specific hepatocellular antigen was found more frequently (five out of nine patients) than in primary biliary cirrhosis (two out of 10). These results, as well as the granuloma formation observed histologically, suggest that the initial bile duct lesion in primary biliary cirrhosis may be associated with a cell-mediated response to antigens—perhaps derived from bile duct epithelial cells—which may be normal constituents of hepatic bile.     

Cell-mediated Immunity in Patients Positive for Hepatitis-associated Antigen

Cell-mediated immunity to antigens prepared from both serum and liver of patients positive for hepatitis-associated antigen (H.A.A.) was measured by using the leucocyte migration test. Altogether, 43 patients with H.A.A.-positive acute and chronic liver disease, eight with serum antibody to H.A.A., and 13 controls were studied. The cell-mediated immunity detected was specific for H.A.A. or other antigenic determinants of the associated infective agent and could be found only in patients with evidence of previous contact with H.A.A.Cell-mediated immunity to the H.A.A.-positive test antigens was found in all but one of the patients with acute hepatitis, in about half of the patients with chronic aggressive hepatitis or cirrhosis, rarely in those with chronic persistent hepatitis, and in none of the apparently healthy carriers.Our results support the hypothesis that the cellular immune response plays an important part in the clearance of the infective agent from H.A.A.-positive patients and in the pathogenesis of the associated liver cell injury.     

An association between α1-antitrypsin phenotype and chronic liver disease

Summary The phenotypes of alpha-1-antitrypsin have been analyzed by isoelectric focusing on polyacrylamide gels in 232 healthy Japanese blood donors and in 240 Japanese patients with chronic liver diseases: 69 with chronic active hepatitis, 122 with liver cirrhosis, 41 with hepatocellular carcinoma and 8 with primary biliary cirrhosis. The liver cirrhosis patients had a gene frequency of 0.07 forPI ^* M3, which was significantly higher (P<0.01) than that (0.03) in blood donors. The gene frequency of PI ^* M3 was significantly increased in cryptogenic liver cirrhosis (P<0.05), and there was a tendency toward an increased frequency of PI ^* M3 in post-transfusion groups, and in primary biliary cirrhosis. There were also tendenciestoward increased frequencies of PI ^* M3 in cryptogenic and post-transfusion groups of patients with chronic active hepatitis. The present study indicates that PI ^* M3 is a genetic or predisposing factor for chronic liver diseases, especially for cryptogenic and/or non A-non B viral chronic liver disease and also for primary biliary cirrhosis.     

T cells from patients with chronic liver diseases: abnormalities in PHA-induced expression of HLA class II antigens and in autologous mixed-lymphocyte reactions

The expression of HLA Class II antigens by resting and phytohemagglutinin (PHA)-activated T cells and their functional properties in autologous mixed-lymphocyte reactions (MLR) were investigated in patients with chronic active hepatitis, with alcoholic cirrhosis, and with primary biliary cirrhosis. In all groups of patients the percentage of resting T cells expressing HLA Class II antigens was significantly higher than that in controls. The percentage of T cells which acquired HLA Class II antigens following PHA stimulation was reduced in patients with chronic active hepatitis, serum hepatitis B surface antigen (HBsAg) positive, and in those with alcoholic cirrhosis, HBsAg negative, although the level of [3H] thymidine incorporation was within normal limits. The degree of proliferation in autologous MLR with PHA-T cells was significantly reduced in patients with chronic active hepatitis, HBsAb positive, and in those with alcoholic cirrhosis, HBsAg positive. A reduced proliferation was also detected in autologous MLR with non-T cells, in patients with chronic active hepatitis, HBsAg positive. The abnormalities of autologous MLR are selective, since the proliferative and stimulatory activities of cells from patients with chronic liver diseases in allogeneic MLR were within normal ranges. The immunoregulatory role of HLA Class II antigens and of autologous MLR suggests that the abnormalities we have identified may play a role in the immunological dysfunctions underlying chronic liver diseases.     

Lymphocyte cytotoxicity for kidney cells in renal tubular acidosis of autoimmune liver disease.

Sensitisation to a renal tubular antigen, Tamm-Horsfall glycoprotein, has been shown to be common in patients with renal tubular acidosis complicating autoimmune liver disease, and it has been suggested that this immune reaction, by damaging renal tubular cells, might be responsible for the acidification defect. The lymphocytes from 10 out of 13 patients with chronic active hepatitis or primary biliary cirrhosis and an associated renal tubular acidosis were shown to be cytotoxic for a kidney cell line known to secrete Tamm-Horsfall glycoprotein. The cytotoxic reaction was blocked by this antigen, but not by two other proteins, indicating that sensitisation to the renal glycoprotein was the likely cause of the target cell damage. Significant reduction in cytotoxicity after the addition of aggregated IgG suggested that the reaction was of the antibody-dependent cell-mediated type. These results, together with the finding of antigenic material in the surface membrane of liver cells that cross reacts immunologically with Tamm-Horsfall glycoprotein, provide an explanation for the association between chronic liver disease and renal tubular dysfunction.     

Quantitation of fibrosis in liver biopsies

After 15 years of subjectively estimating the degree of fibrosis in liver biopsies stained with Sirius red F3BA, the amounts of Sirius red-stained fibrotic areas were quantitated with the help of a Cortex IQ 130 image quantifier. The percentage of Sirius red-stained areas was lowest in normal livers, increasing significantly in fatty livers, with stepwise higher values in chronic persistent hepatitis, toxic damage, chronic active hepatitis, fatty livers with obvious fibrosis, biliary cirrhosis and portal cirrhosis. Cases of portal cirrhosis had tenfold higher values than did normal livers. The results indicate that Sirius red is a reliable histochemical stain that can be used to quantitatively demonstrate the various degrees of fibrosis in liver biopsies.     

Wilson's disease: a common liver disorder?

In two sibships 7 of 24 siblings were homozygous for Wilson''s disease. In family A, the largest kindred of this recessively inherited disease thus far reported, the proband presented with chronic active hepatitis, one sibling died of cirrhosis, a second had clinical evidence of chronic liver disease and two others had biochemical and histologic changes in liver biopsy specimens. In family B the proband had cirrhosis and portal hypertension and one sibling had biochemical and histologic evidence of liver disease. All six living patients had low serum concentrations of ceruloplasmin and copper and a high 24-hour urinary excretion of copper, which was greatly increased by administration of D-penicillamine. None showed neurologic abnormalities and only one had Kayser-Fleischer rings (detectable only by slit-lamp examination). Each patient had an erythrocyte sedimentation rate (ESR) of 8 mm/h or less. After 3 and 2 years, respectively, of D-penicillamine therapy the conditions of the two probands had improved. Liver function became normal in three siblings, and no abnormalities developed in the remaining one. Thus, since Wilson''s disease may present with chronic active hepatitis or cirrhosis with a normal ESR and without ocular or neurologic signs, it may be a more common cause of liver disease in young people than has been appreciated.     

Increased incidence of menstrual abnormalities and hysterectomy preceding primary biliary cirrhosis.

A study was performed to assess the incidence of previous hysterectomy and dilatation and curettage among women with primary biliary cirrhosis. In 87 patients with primary biliary cirrhosis hysterectomy or dilatation and curettage had been performed significantly more often than among 100 age matched normal controls and 80 age matched patients with chronic active hepatitis or alcoholic liver disease. Among the 47 patients with primary biliary cirrhosis who had undergone hysterectomy or dilatation and curettage operations had been performed at a mean of 10.7 years and 13.2 years, respectively, before the onset of disease. The main indication for hysterectomy among patients with primary biliary cirrhosis and controls was menorrhagia. These menstrual disorders may be a consequence of high concentrations of oestrogens in patients with primary biliary cirrhosis.     

应用酶联免疫吸附试验检测不同类型乙型肝炎中激活补体类HBsAg循环免疫复合物

本文以抗人C_(?)的羊IgG为包被抗体,以HRP-HBs抗体为指示抗体,建立了可检测激活补体类HBsAg循环免疫复合物(HBsAg/C3-CIC)的C_3捕捉法酶联免疫吸附试验。检测了236例六种类型临床诊断为乙型肝炎的病人血清标本,其阳性率分别为:无症状携带者(ASC)12.9％(4/31),急性肝炎(AH)36.7％(22/60),慢性迁延性肝炎(CPH)33.3％(7/21),慢性活动性肝炎(CAH)59.6％(34/57),重型肝炎(SH)77.8％(14/18),肝炎后肝硬化(PLC)67.3％(33/49),阳性率与肝损严重程度明显相关(P<0.01)。认为HBs-Ag/C3-CIC可能在乙型肝炎病毒引起的慢性活动性肝炎、重型肝炎和肝炎后肝硬化的发病过程中起重要作用,并可作为乙型肝炎的诊断、临床分型和预后判断的指标之一。     

Trigger factors and HL-A antigens in chronic active hepatitis

Forty-six patients with histologically verified chronic active hepatitis (CAH) were divided into three groups according to whether the CAH was virus-induced, drug-induced, or cryptogenic. The frequency of the HL-A antigens 1 and 8 was increased in the cryptogenic group while the other groups did not differ significantly from healthy controls. Autoantibodies were often found in high titres in the drug-induced and cryptogenic groups but were infrequent in the virus-induced group.     

Histocompatibility Antigens in Active Chronic Hepatitis and Primary Biliary Cirrhosis

The frequency of antigens HL-A 1 (48%) and HL-A 8 (52%) in 54 patients with active chronic hepatitis from south-east England was significantly higher than in 89 control subjects from the same region (22% and 17% respectively). No correlation could be detected with the age and sex of the patients or with the presence of a particular immunological abnormality but the frequency of HL-A 1 and HL-A 8 was much lower in the nine patients who were positive for HBAg than in the 45 HBAg-negative cases. These results provide further evidence of the importance of genetic factors in active chronic hepatitis. In contrast the frequency of HL-A 1 and HL-A 8 in primary biliary cirrhosis, both in 45 patients from south-east England and in 28 patients from western Scotland, was not significantly different from that found in control groups from the same regions.     

Apoptosis and apoptosis related proteins in chronic viral liver disease

Background: Apoptosis may be an important mechanism of hepatocyte death in chronic viral liver disease. Methods: We studied apoptosis in liver biopsies from 30 patients with chronic viral hepatitis and 8 patients with viral cirrhosis by the TUNEL method. 12 cases of non-alcoholic steatohepatitis and 12 cases of primary biliary cirrhosis were used as non-viral disease controls. Immunohistochemical expression of p53, p21/waf1, bcl-2 and mdm-2 proteins was also studied in the same patients. Results: A statistically significant increase of apoptotic liver cells was found in severe chronic viral hepatitis (5.3 ± 0.3%), cirrhosis (3.4 ± 0.5%) and PBC (4.4 ± 0.4%) cases compared to patients with non-alcoholic steatohepatitis (0.8 ± 0.3%). The expression of p53 protein was increased in the cases of viral cirrhosis and in chronic severe viral hepatitis whereas in the cases of chronic mild hepatitis, PBC and non-alcoholic steatohepatitis we found no expression of p53. P21/waf1 expression was increased in severe chronic hepatitis, cirrhosis and PBC cases compared to mild hepatitis and non-alcoholic steatohepatitis cases. However no induction of mdm-2 was observed in the subgroups of chronic liver disease. Bcl-2 was expressed only in epithelium of bile ducts and mononuclear cells of the portal tracts and liver lobules. A weaker Bcl-2 expression was noted in the epithelium of bile ducts of 7/12 PBC cases. Conclusion: Our results provide evidence of increased apoptosis in severe chronic viral liver disease, suggesting that apoptotic cell death might be involved in the pathogenesis of hepatocellular damage of viral hepatitis and cirrhosis. Furthermore we analysed part of the apoptotic pathways implicated in the above process and found an increased expression of p21/waf1, probably p53 mediated, without overexpression of the apoptosis inhibiting bcl-2 and mdm-2 proteins. By contrast p21/waf1 overexpression in PBC seems to be propagated by a p53 independent mechanism.     

Cirrhosis Associated with the Australia Antigen in an Infant Who Acquired Hepatitis from Her Mother

A 19-week-old English girl developed acute viral hepatitis, which became chronic with persistent hepatosplenomegaly and abnormal liver function tests. Liver biopsy at 1 year showed an active cirrhosis with multinucleated giant cells. The Australia (Au) antigen was detected repeatedly in the infant''s serum by immunodiffusion and by electron microscopy at the time of the acute attack and during the development of cirrhosis. She had apparently acquired the hepatitis from her mother, who had had jaundice at the end of pregnancy and for one month thereafter, and who was subsequently shown to be a carrier of Au antigen. Particles with surface projections resembling paramyxoviruses were observed in two of the later specimens of the infant''s serum.     

Cellular and humoral immunity to hepatitis-B surface antigen in active chronic hepatitis.

The hepatitis-B surface antigen (HBsAG) may be persistently present in the serum in a few cases of active chronic hepatitis but the cause of the disease in most patients is unknown. In a study of 39 HBsAg-negative cases cell-mediated immunity to HBsAg was observed in 24 (62%), suggesting a high frequency of previous infection with the hepatitis-B virus. Hepatitis-B surface antibody was detectable by radioimmunoassay in six patients, in all of whom complexes of HBsAg were present in the serum on electron microscopy. Out of 12 patients with HBsAg-positive active chronic hepatitis who were also studied eight, including all those untreated at the time, showed a cellular response to the antigen. Evidence of sensitization to a liver-specific cell surface lipoprotein was found with similar frequency in the two groups. These results are consistent with the hypothesis that hepatitis-B virus infection is important in initiating the disease in many cases of active chronic hepatitis and that sensitization to the liver cell membrane antigen is the autoimmune process responsible for the perpetuation of the liver injury.     

Cytokine-induced inflammatory liver injuries

IL-18 is a pleiotropic cytokine and is produced by various types of cells including activated macrophages, particularly Kupffer cells. IL-18 has potential to activate inflammatory responses through induction of IFN-gamma production in collaboration with IL-12. Somewhat paradoxically, IL-18 also has the capacity to induce allergic responses via induction of IL-4 production by T helper cells and to activate mast cells and basophils to release atopic effector molecules such as histamine. Indeed, IL-18 is involved in inflammatory tissue injuries, such as Crohn's disease and atherosclerosis, and also in hyper IgE and atopic dermatitis. IL-18 is particularly important for induction of experimental liver diseases. Endotoxin-induced liver injury or Fas ligand-induced hepatitis is caused by endogenous IL-18 in mice. Moreover, patients with liver diseases such as fulminant hepatitis, liver cirrhosis due to hepatitis virus infection and primary biliary cirrhosis show elevation of serum levels of IL-18, that correlates with the corresponding disease severity. Therefore, endogenous IL-18 plays a major role in induction of some types of liver injuries in mice and human. NKT cells that express both T cell receptor and NK cell marker are abundant in the liver of mice and human. Recent studies have revealed that NKT cells participate in some types of liver injuries, such as concanavalin A-induced T cell-mediated hepatitis and malaria hepatitis. In this review article, we focus on IL-18-involving liver damages and NKT-cell-mediated liver injuries.     

Evaluation of serum guanase in hepatic diseases

Serum guanase activity was measured in 20 healthy adults and in 62 patients with acute viral hepatitis, chronic active hepatitis, chronic persistent hepatitis, liver cirrhosis and fatty liver. Guanase and gamma-GT in patients were elevated in 87 and 64%, respectively. Elevated guanase activities were found in most cases of acute viral hepatitis, as well as in chronic hepatopathies. In patients with acute viral hepatitis pathologic activities of guanase were found following partial or total normalization of other liver function tests.     

Severe acquired immunodeficiency in European homosexual men.

Four previously healthy Danish homosexual men developed Kaposi''s sarcoma or opportunistic infections with fever of unknown origin and lymphadenopathy. One patient died of a Pneumocystis carinii pneumonia. Three patients had defective cell-mediated immunity with absent leucocyte interferon production and decreased proliferative response to mitogens and antigens. T lymphocyte helper subsets and natural killer cell activity were reduced. Unstimulated mononuclear cells produced leucocyte migration inhibitor factor. Two patients were sexual partners and three had never been to the USA, where cases of severe acquired immunodeficiency have been reported. Thus, the syndrome must also be suspected in European homosexual men who present with fever of unknown origin, opportunistic infections, or Kaposi''s sarcoma.