The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses and its loss causes fatal autoimmunity in mice. We investigated a large autosomal-dominant family with five individuals presenting with a complex immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with novel splice site and missense mutations in CTLA4. While clinical penetrance was incomplete (eight adults of a total of 19 CTLA4 mutation carriers were considered unaffected), CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in patients and carriers with CTLA4 mutations. Whilst Treg cells were generally present at elevated numbers, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers and antibody levels. Taken together, mutations in CTLA-4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding results in a complex syndrome with features of both autoimmunity and immunodeficiency.
Studies using genetically modified mice have revealed fundamental functions of the transcription factor Fos/AP-1 in bone biology, inflammation, and cancer. However, the biological role of the Fos-related protein Fra-2 is not well defined in vivo. Here we report an unexpected profibrogenic function of Fra-2 in transgenic mice, in which ectopic expression of Fra-2 in various organs resulted in generalized fibrosis with predominant manifestation in the lung. The pulmonary phenotype was characterized by vascular remodeling and obliteration of pulmonary arteries, which coincided with expression of osteopontin, an AP-1 target gene involved in vascular remodeling and fibrogenesis. These alterations were followed by inflammation; release of profibrogenic factors, such as IL-4, insulin-like growth factor 1, and CXCL5; progressive fibrosis; and premature mortality. Genetic experiments and bone marrow reconstitutions suggested that fibrosis developed independently of B and T cells and was not mediated by autoimmunity despite the marked inflammation observed in transgenic lungs. Importantly, strong expression of Fra-2 was also observed in human samples of idiopathic and autoimmune-mediated pulmonary fibrosis. These findings indicate that Fra-2 expression is sufficient to cause pulmonary fibrosis in mice, possibly by linking vascular remodeling and fibrogenesis, and suggest that Fra-2 has to be considered a contributing pathogenic factor of pulmonary fibrosis in humans.fra-2 transgenic mouse ͉ idiopathic pulmonary fibrosis ͉ osteopontin ͉ pulmonary arterial hypertension ͉ fibrosis mouse model
Growth hormone (GH)-activated signal transducer and activator of transcription 5 (STAT5) and the glucocorticoid (GC)-responsive glucocorticoid receptor (GR) are important signal integrators in the liver during metabolic and physiologic stress. Their deregulation has been implicated in the development of metabolic liver diseases, such as steatosis and progression to fibrosis. Using liver-specific STAT5 and GR knockout mice, we addressed their role in metabolism and liver cancer onset. STAT5 single and STAT5/GR double mutants developed steatosis, but only double-mutant mice progressed to liver cancer. Mechanistically, STAT5 deficiency led to the up-regulation of prolipogenic sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator activated receptor gamma (PPAR-γ) signaling. Combined loss of STAT5/GR resulted in GH resistance and hypercortisolism. The combination of both induced expression of adipose tissue lipases, adipose tissue lipid mobilization, and lipid flux to the liver, thereby aggravating STAT5-dependent steatosis. The metabolic dysfunctions in STAT5/GR compound knockout animals led to the development of hepatic dysplasia at 9 months of age. At 12 months, 35% of STAT5/GR-deficient livers harbored dysplastic nodules and ∼60% hepatocellular carcinomas (HCCs). HCC development was associated with GH and insulin resistance, enhanced tumor necrosis factor alpha (TNF-α) expression, high reactive oxygen species levels, and augmented liver and DNA damage parameters. Moreover, activation of the c-Jun N-terminal kinase 1 (JNK1) and STAT3 was prominent.ConclusionHepatic STAT5/GR signaling is crucial for the maintenance of systemic lipid homeostasis. Impairment of both signaling cascades causes severe metabolic liver disease and promotes spontaneous hepatic tumorigenesis. (hepatology 2011;54:1398–1409)
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