Critical Roles for Interleukin 1 and Tumor Necrosis Factor α in Antibody-induced Arthritis

In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)–α was also required, although seemingly less critically than IL-1, because a proportion of TNF-α–deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFα for bone destruction. The variability in the requirement for TNF-α, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes

Arthritogenic Monoclonal Antibodies from K/BxN Mice

Arthritis in the K/BxN mouse model is provoked by pathogenic antibodies (Abs) directed against a ubiquitously expressed protein, glucose-6-phosphate isomerase (GPI). To begin dissecting the repertoire of arthritogenic immunoglobulins (Igs) in the K/BxN model, and to provide a basis for comparison with RA patientswe have generated anti-GPI monoclonal Abs (mAbs) from spontaneously activated B cells in the lymphoid organs of arthritic mice. B cell clones with anti-GPI specificities were present at extraordinarily high frequencies in the spleen, and less frequently in other lymphoid organs and in the synovial fluid. None of the anti-GPI mAbs induced arthritis when injected individually into healthy recipients, but most were effective when combined in pairs or larger pools. Arthritogenic combinations depended on mAbs of the IgG1 isotype, which bound to GPI with Kd in the 10−9 M range, with no indication of cooperative binding between complementing pairs. Pathogenicity was not associated with recognition of a particular epitope, but the ability to form mAb/GPI multimers by simultaneous recognition of different epitopes was clearly required, consistent with the known role of complement and FcRs in this model. Sequence analysis revealed structural similarities amongst the mAbs, indicating that a particular subset of B cells may evade tolerance in K/BxN mice, and that affinity maturation by somatic mutation likely takes place. These results confirm that GPI itself, rather than a cross-reactive molecule, is the target of pathogenic Igs

Close correlation between β-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas

International audienceSeveral lines of evidence indicate that beta-catenin acquires oncogenic activity when its intracellular concentration increases as a result of either mutation in the beta-catenin gene itself or inactivation of the adenomatous polyposis coli (APC) gene. In an attempt to elucidate the molecular mechanisms underlying hepatocellular carcinogenesis, we have studied the frequency of beta-catenin gene alterations in exon 3, a region known to represent a mutation hot spot, and its inappropriate protein expression by immunohistochemistry in 73 hepatocellular carcinomas (HCCs). The results were correlated with different clinical and pathological data, particularly with the presence or not of an associated cirrhosis. Fourteen (19%) HCCs showed beta-catenin gene alterations with missense mutations in nine cases and interstitial deletions in five cases. These genetic alterations were present in both cirrhotic and non-cirrhotic groups. By contrast, we did not find any beta-catenin gene alterations in the nine fibromellar carcinomas we examined. Nuclear accumulation of the protein was observed in 18 of them (25%). Remarkably, these included ten of the 14 tumors harboring somatic mutations in the beta-catenin gene (P < 0.001). Our results indicate that accumulation of beta-catenin resulting from genetic mutations is a frequent event in non-fibrolamellar type hepatocellular carcinoma. The close association between increased beta-catenin protein stability and mutation indicates that immunohistochemistry may be a powerful method for the detection of the mutated protein in future clinical practice

Amiodarone Inhibits the Mitochondrial a-Oxidation of Fatty Acids and Produces Microvesicular Steatosis of the Liver in Mice

ABSTRACT Received for publication December 12, 1989

Vascular involvement of the liver in Turner's syndrome

International audienceUnexplained liver test abnormalities are frequent in patients with Turner's syndrome. This cohort study was performed to clarify the histopathologic features, causes, and long-term outcome of liver involvement in these patients. Thirty patients with persistently abnormal liver test results were followed-up for 8.8 +/- 5.2 years. Liver specimens were available in 27 patients. Marked architectural changes were present in 10 patients, including nodular regenerative hyperplasia in six, multiple focal nodular hyperplasia in two, and cirrhosis in two patients. These changes frequently were associated with obliterative portal venopathy lesions and with aortic malformations. There was mild to moderate portal fibrosis in 15 of the 17 other patients, inflammatory infiltrates in nine patients, and nonalcoholic fatty liver disease in 11 patients. Bile duct alterations resembling small duct sclerosing cholangitis were observed in 21 patients (with or without architectural changes). There was no viral, alcoholic, autoimmune, or drug-induced liver damage. Portal hypertension was observed in four patients with marked architectural changes, including three in whom refractory ascites or recurrent variceal bleeding developed, one of whom underwent transplantation. None of the patients without marked architectural changes experienced progressive or decompensated liver disease. There was no evidence of liver toxicity from estrogen replacement therapy. In conclusion, the main causes of liver involvement in Turner's syndrome are vascular disorders, probably of a congenital origin, and nonalcoholic fatty liver disease. In patients with vascular disorders, severe liver disease requiring liver transplantation may develop. Estrogen therapy does not appear to be pathogenically implicated

Hepatocellular carcinoma occurring in nonfibrotic liver: Epidemiologic and histopathologic analysis of 80 French cases

Comment in : Occurrence of hepatocellular carcinoma in nonfibrotic livers./Bioulac-Sage P, Le Bail BL, Winnock M, Balabaud C, Bemard C, Blanc JF, Saric J. Hepatology. 2000 Dec;32(6):1411-2. doi: 10.1053/jhep.2000.20819. PMID: 11186870International audienceHepatocellular carcinoma (HCC) occurring in nonfibrotic liver represents a rare, ill-defined subgroup of HCC without cirrhosis in which mechanisms of hepatocarcinogenesis remain unclear. The aim of our study was to assess epidemiological factors and detailed histopathologic changes in the nontumoral liver of patients developing such tumors. Of 330 HCCs resected in our institution between 1985 and 1998, we retrospectively analyzed 80 cases (53 men, 27 women; mean age, 51 +/- 16 years) in which the nontumoral liver showed no (n = 28) or minimal (n = 52) portal fibrosis without any septal fibrosis. In the group with no portal fibrosis there was no male predominance, and patients were significantly younger (44 +/- 19 years vs. 54 +/- 14 years) than those with minimal portal fibrosis. Sixty-seven tumors were typical HCCs, 8 were of fibrolamellar type, and 5 were hepatocholangiocarcinomas. Mean tumor size was 10 +/- 5 cm. Risk factors for HCC development were found in 30 patients: hepatitis B (n = 17) or C (n = 2) virus infections, alcohol consumption (n = 11), and hemochromatosis (n = 1). In the nontumoral liver, periportal and lobular necrosis, mild portal inflammation, steatosis, and iron overload were present in 15%, 57%, 52%, and 54% of cases, respectively. Liver cell changes were noted in 6%. This study emphasizes the need for strict criteria to classify HCC without cirrhosis. HCC in nonfibrotic liver is a distinct subgroup in which nontumoral liver shows nonspecific minimal changes without regeneration or premalignant lesion. Etiologic factors are often unidentified, although presence of HBV infection in 21% suggests a direct oncogenic role of this virus

Impaired adaptive resynthesis and prolonged depletion of hepatic mitochondrial DNA after repeated alcohol binges in mice

International audienceA single dose of alcohol causes transient hepatic mitochondrial DNA (mtDNA) depletion in mice followed by increased mtDNA synthesis and an overshoot of mtDNA levels. We determined the effect of repeated alcohol binges on hepatic mtDNA in mice