Hiromi Ishibashi

Genetic and familial considerations of primary biliary cirrhosis

The genetic basis of human autoimmune diseases is receiving increasing attention. Primary biliary cirrhosis (PBC) is a model autoimmune disease reflective of other organ-specific autoimmune pathology. PBC is an enigmatic autoimmune disease that predominantly affects women and leads to destruction of intrahepatic bile ducts. The serological hallmark of this disease is characterized by antimitochondrial antibodies that specifically react with the E2 components of 2-oxodehydrogenase enzymes, including PDC-E2. There are no clear major histocompatibility complex associations with the development of PBC, despite the observation that first-degree relations of index patients with PBC have a 4-6% prevalence of development of PBC. This risk factor is comparable or higher than any other human autoimmune disease and suggests that a genome-wide approach towards dissection of genetic associations would lead to valuable new insights. In this review, we place these concepts in perspective and highlight in particular the genetic associations in PBC and the importance of studying siblings with PBC who are concordant for disease.

Serum amyloid A-induced IL-6 production by rheumatoid synoviocytes

In this study, we investigated the role of serum amyloid A protein (SAA) in the production of interleukin‐6 (IL‐6) using rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLS). Recombinant SAA stimulation induced the production of pro‐inflammatory cytokine, IL‐6, from RA‐FLS. The signaling events induced by SAA included the activation of the mitogen‐activated protein kineases, p38 and JNK1/2 and the activation of nuclear factor‐kappa B (NF‐κB). Inhibitor studies have shown SAA‐induced IL‐6 production to be down‐regulated by NF‐κB inhibition and partially inhibited by p38 or JNK inhibitors. Our findings demonstrate that SAA is a significant inducer of IL‐6, which is critically involved in RA pathogenesis.

Kupffer Cells May Autoregulate Interleukin 1 Production by Producing Interleukin 1 Inhibitor and Prostaglandin E2

Rat Kupffer cells stimulated with bacterial lipopolysaccharide (LPS) produced high levels of interleukin 1 (IL‐1), as determined by thymocyte proliferation assay. Indomethacin revealed a dose‐dependent augmentation in IL‐l production, in parallel with a dose‐dependent reduction in prostaglandin E2 production by Kupffer cells. The addition of exogenous prostaglandin E2, dibutyryl cAMP, or isoproterenol led to a dose‐dependent suppression of IL‐I production. The supernatant from UPS‐stimulated Kupffer cells also contained factors that Inhibited IL‐1‐induced thymocyte proliferation. Upon gel filtration, two inhibitory peaks, at apparent MW of 27,000 and 6000, were obtained. The latter but not the former fraction also affected Interleukin 2 (IL‐2)‐induced thymocyte proliferation. Increasing amounts of IL‐1 overcame the inhibitory activity derived from the 27,000 MW fraction. These results suggest to us that prostaglandin E2 and IL‐1 inhibitor released by Kupffer cells may be involved in negative self‐control in regulating IL‐1 production and its action.

Selective partial IgM deficiency:functional assessment of T and B lymphocytes in vitro

Seven patients with selective IgM deficiency (SIgMD) were studied for cell surface immunoglobulin (SmIg), T-cell subpopulations, and immunoglobulin (Ig) synthesisin vitro by peripheral blood lymphocytes (PBL). Serum IgM levels were less than 25 mg/dl, while IgA, IgG, and IgD were within normal levels. The patients had respiratory or urinary tract infections and two were diagnosed as having systemic lupus erythematosus (SLE). T/B-cell ratios in PBL were within normal ranges. Percentage ratios of B cells bearing SmIg were normal in five patients and decreased in two; however, normal values were seen after 7 days of culture in the presence of PWM. OKT4/OKT8 ratios decreased in five of seven patients, in whom two were due to a decrease in OKT4 and two to an increase in OKT8 cells. One showed a decrease in OKT4 and an increase in OKT8. Analysis of lymphocyte function for Ig synthesisin vitro, using a coculture of counterpart T and B cells from healthy individuals and patients with SIgMD, revealed that the increased function of IgM isospecific suppressor T cells (Ts) was responsible for the IgM deficiency in all seven patients.

Fulminant hepatic failure during perinatal period in a pregnant woman with Wilson's disease.

SummaryWilson’s disease associated with hepatic failure is not common and the underlying mechanism triggering the event is not known at present. We treated a 28-year-old Japanese woman with Wilson’s disease who developed hepatic failure associated with hemolytic crisis just after delivery. She was diagnosed as having Wilson’s disease at 12 years of age, at which time she started taking D-penicillamine. She had previously delivered two children without difficulty. When she found out she was pregnant this time, she stopped taking D-penicillamine in contrast to taking it faithfully during her first two pregnancies. On the day of delivery of her full-term baby, jaundice developed accompanied with severe hemolytic crisis. Plasma exchanges and blood transfusion were performed and D-penicillamine administration was started again. She gradually recovered and apparently was following a good clinical course. However, on day 30 the second hemolytic crisis occurred and subsequent liver failure led her to death on day 50. At autopsy her liver was cirrhotic and showed massive necrosis. Prophylactic oral administration of D-penicillamine and careful observation are therefore recommended to prevent hemolytic crisis during the perinatal period.

Kupffer cells modulate natural killer cell activity in vitro by producing prostaglandins

The effect of Kupffer cells on natural killer (NK) cell-mediated cytotoxicity was examined. Kupffer cells prepared from rat liver suppressed NK activity against K562 cells and other tumor cell lines through a soluble factor secreted into the culture supernatant. When human peripheral blood mononuclear cells were incubated with the Kupffer cell-culture supernatant, a significant reduction of the cytotoxic activity was observed in the 6-hr chromium-release assay. This activity was dose dependent and was evident at various effector/target cell ratios. Lipopolysaccharide stimulated generation of the suppressive factor released from Kupffer cells in a dose-dependent manner. Suppression of the NK activity was observed when the Kupffer cell-culture supernatant was present in the assay system, whereas pretreatment of effector/target cells with the supernatant had minimal inhibitory effects. Autologous monocytes in human peripheral mononuclear cells were not related to this suppression. The suppressive factor in the fraction had a molecular weight below 10,000. Indomethacin, an inhibitor of prostaglandin synthesis, ameliorated the suppressive effects. These results suggest that Kupffer cells may modulate NK activity by producing PGs (E1, E2, and F2 alpha).

Atrophic Corpus Gastritis and Helicobacter pylori Infection in Primary Biliary Cirrhosis

Chronic atrophic corpus gastritis, termed as autoimmune corpus gastritis or type A gastritis, and primary biliary cirrhosis (PBC) are characterized by a common immunological process against the exocrine glandular structures of both the stomach and bile duct. However, there has been controversy over whether atrophic corpus gastritis is associated with PBC. Recently, it has been suggested that Helicobacter pylori plays an important role in the early stage of atrophic corpus gastritis due to the induction of autoantibodies that are reactive with a protein in the gastric parietal cells. One hypothesis is that molecular mimicry, possibly resulting from H. pylori infection, might be responsible for initiating an autoimmune response in a predisposed host due to cross-reactivity among gastric mucosal, bile ductular, and bacterial antigens. The aim of this study is to assess whether atrophic changes of the gastric corpus could affect patients with PBC, and to determine the correlation with H. pylori infection. Sixteen patients with PBC were enrolled in this study. All patients were examined by serological studies of anti-pyruvate dehydrogenase (PDH) antibody, anti-H. pylori antibody, gastrin and vitamin B12. Gastroscopy was performed on all patients in order to verify the histological findings and to microscopically identify H. pylori. Atrophic corpus gastritis was found in 2 of 16 patients with PBC (12.5%), one of whom was confirmed to have pernicious anemia, a developed stage of atrophic corpus gastritis. H. pylori infection in the gastric corpus and the anti-H. pylori antibody were found in 7 (43.8%) and 11 (68.8%) of 16 patients, respectively. Anti-H. pylori antibody was confirmed to be positive in both of the patients with atrophic corpus gastritis, although H. pylori was absent in the gastric biopsy specimen. There was a positive correlation between anti-PDH antibodies and anti-H. pylori antibodies in sera from patients with PBC. Atrophic corpus gastritis is not frequently involved in PBC. However, H. pylori is a possible pathogenic factor in atrophic corpus gastritis in PBC patients because of the presence of anti-H. pylori antibody. A positive correlation between the titer of anti-PDH antibodies and the titer of anti-H. pylori antibodies was confirmed. Consequently, H. pylori infection could induce autoimmune responses in the development of both PBC and atrophic corpus gastritis. H. pylori infection associated with PBC requires further study.

Differences in survival based on the type of follow-up for the detection of hepatocellular carcinoma: an analysis of 547 patients.

The aim of this study was to identify any significant variables in the prognosis of 547 cases with hepatocellular carcinoma (HCC), and simultaneously confirm the survival among the different surveillance modalities for the initial detection of HCC in a closely followed-up group (regular periodic follow-up with monthly alpha-fetoprotein (AFP) and ultrasonography at least every 4 months), a not closely followed-up group (neither performed with AFP nor ultrasonography regularly) and an incidental group (incidentally discovered due to related symptoms). Five hundred and forty-seven consecutive patients with HCC diagnosed at the Internal Medicine Department of Saga Prefectural Hospital Koseikan from January 1989 to December 1998 were retrospectively analyzed. The 1-, 3- and 5-year survivals in all 547 cases were 69.7, 42.4 and 26.9%, respectively. The 1-, 3- and 5-year survivals in the cases found to have solitary HCC measuring 2 cm or less in diameter at the time of diagnosis were 97.3, 76.2 and 52.3%, respectively. Forty-seven point one percent of the closely followed-up group, which was the high-risk group were found to have solitary HCC measuring 2 cm or less in diameter (48 out of the 102 followed-up cases), while only 18.5 and 11.8% were found in the not closely followed-up group (46 out of 248 cases) and the incidental group (22 out of 186 cases), respectively. The 5-year survival in the closely followed-up, the not closely followed-up and the incidental groups were 42.9, 26.1 and 15.3%, respectively. The significant factors obtained in the closely followed-up group compared to those from the not closely followed-up group included AFP, tumor size, tumor number and portal thrombosis. These findings indicate the importance of a close follow-up for high-risk groups in order to identify HCC at an early stage, and thereby have a positive influence on survival.

CD56 DIRECTLY INTERACTS IN THE PROCESS OF NCAM-POSITIVE TARGET CELL-KILLING BY NK CELLS

The role of CD56 in the process of target cell killing by NK cells has been investigated. Addition of NK cells to HuH28 cells, a CD56‐expressing cell line, led to inhibition of the growth of the target cells, which exhibited morphological features of apoptosis. These changes were prevented by the addition of a polyclonal anti‐NCAM to the cultures. Since neither Fas antigen expression nor apoptotic changes were induced by addition to a mixed culture supernatant of NK and target cells, both the Fas‐Fas ligand system and soluble factors do not seem to participate in apoptosis in these circumstances. Increased secretion of interferon‐γ and tumour necrosis factor‐α by NK cells must therefore have been suppressed by the presence of the polyclonal antibody. These results lead us to conclude that CD56, through homophilic binding, plays an important role in the process of target cell killing by an apoptosis mechanism.

Human lymphocytes synthesize C-reactive protein

We obtained evidence for the synthesis and secretion of C-reactive protein (CRP) by peripheral mononuclear cells in culture. Human mononuclear cells isolated from peripheral blood, after depletion of platelets, were cultured in giutamine-depleted RPMI 1640 supplemented with [3H]glutamine in the presence of 10-O-tetradecanoyl-phorbol-13-acetate (TPA). Anti-CRP antiserum was added to the culture medium, and the resultant immunoprecipitate was analyzed in SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The immunoprecipitate consisted of CRP, heavy and light chains of IgG, and only the CRP protein band had radioactivity, indicating that CRP was synthesized by mononuclear cells. In the populations of mononuciear cells, T-cell preparations mainly synthesized CRP, under stimulation of a factor derived from activated monocytes. Studies using the inhibitors of phospholipid metabolism suggested that generation of the monocyte factor was relevant to metabolites of an arachidonate cascade.