MHC antigens in interferon γ (IFNγ) receptor deficient mice: IFNγ-independent up-regulation of MHC class II in renal tubules

MHC antigens in interferon γ (IFNγ) receptor deficient mice: IFNγ-independent up-regulation of MHC class II in renal tubules. MHC class II gene products in parenchymal cells, such as tubular epithelial cells in kidney, may play a role in the regulation of autoimmune reactions. Expression of MHC class II in renal tubular cells is normally very low, but it increases considerably under various pathologic conditions. The predominant role of IFNγ in up-regulation of MHC class II expression has been demonstrated repeatedly. We tested the existence of alternative pathways of MHC class II regulation using IFNγ receptor-deficient (IFNγR-/-) mice. Mutant and wild type mice received 50 µg bacterial endotoxin (LPS) i.p. Four days later the kidneys were removed for immunofluorescence examination. In agreement with published results LPS provoked an increase of immunoreactivity for MHC class I and MHC class II in proximal tubules of wild type mice. While MHC class I up-regulation was strictly IFNγ receptor-dependent, up-regulation of MHC II was still evident in mutant mice, although less than in wild type mice. Since injection of IFNγ induced proximal tubular MHC class II expression in wild type mice but not in IFNγR-/- mice, an alternative signaling pathway for IFNγ does not seem to exist. Thus, up-regulation of MHC class II expression in renal tubules does not necessarily require IFNγ. The markedly patchy pattern of immunofluorescence in IFNγR-/- mice suggests that induction of MHC class II after LPS injection may represent renal injury due to shock

Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-α double-deficient mice

To investigate the roles of tumor necrosis factor (TNF) and lymphotoxin (LT)-α in the development and function of the immune system, the Tnf and Ltα genes were simultaneously inactivated in mice by homologous recombination. These mutant mice are highly susceptible to Listeria monocytogenes infection and resistant to endotoxic shock induced by the combined administration of D-galactosamine (D-GaIN) and lipopolysaccharide (LPS). Their splenic microarchitecture is disorganized, characterized by the loss of the clearly defined marginal zone, ill defined T and B cell areas, and absence of MAdCAM-1 and reduced ICAM-1, VCAM-1 and Mac-1 expression. They are devoid of peripheral lymph nodes and Peyer's patches, and show a strong reduction of lgA+ plasma cells in the intestinal lamina propria. The alymphoplasia is accompanied by a marked B lymphocytosis and reduced basal Ig levels. Ig depositions in the renal glomerulus and a strong up-regulation of MHC class I antigen expression on endothelial cells of different tissues are observed. The primary humoral immune response towards sheep red blood cells reveals a defective IgG isotype switch, while that against vescicular stomatitis virus is normal. The cytotoxic T cell responses are attenuated, although still effective, against vaccinia, lymphocytic choriomeningitis virus (LCMV-ARM) and LCMV-WE. In conclusion, the combined inactivation of Tnf and Ltα confirms their essential role in the normal development and function of the immune syste

The Orphan Receptor CRF2-4 Is an Essential Subunit of the Interleukin 10 Receptor

The orphan receptor CRF2-4 is a member of the class II cytokine receptor family (CRF2), which includes the interferon receptors, the interleukin (IL) 10 receptor, and tissue factor. CRFB4, the gene encoding CRF2-4, is located within a gene cluster on human chromosome 21 that comprises three interferon receptor subunits. To elucidate the role of CRF2-4, we disrupted the CRFB4 gene in mice by means of homologous recombination. Mice lacking CRF2-4 show no overt abnormalities, grow normally, and are fertile. CRF2-4 deficient cells are normally responsive to type I and type II interferons, but lack responsiveness to IL-10. By ∼12 wk of age, the majority of mutant mice raised in a conventional facility developed a chronic colitis and splenomegaly. Thus, CRFB4 mutant mice recapitulate the phenotype of IL-10–deficient mice. These findings suggest that CRF2-4 is essential for IL-10–mediated effects and is a subunit of the IL-10 receptor

Defining new criteria for selection of cell-based intestinal models using publicly available databases

Peer reviewe

Theiler's virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors

International audienceThe Daniels strain of Theiler's virus causes a persistent infection of the white matter of spinal cord of susceptible mice, with chronic inflammation and primary demyelination. Inbred 129Sv mice are resistant to this infection; they present with mild encephalomyelitis and clear the infection within a matter of days. A very different outcome was observed with inbred 129Sv mice whose receptors for interferon ot//~ or interferon 3' had been inactivated by homologous recombination. The former presented severe encephalomyelitis with acute infection of neurons, particularly in brain and hippocampus, and extensive infection with necrosis of the choroid plexus. Most animals died of this acute disease. The latter, presented the same early encephalomyelitis as the control 129Sv mice. However, they remained persistently infected and developed a very severe late infection of the white matter with extensive primary demyelination. This late disease looked like an exacerbated form of the chronic demyelinating disease observed in susceptible inbred mice such as the SJL/J or FVB strains. Our results show that the two interferon systems play nonredundant roles in the resistance of the 129Sv mouse to the infection by Theiler's virus. They also lend support to the notion that the Ifg gene is involved in the resistance/susceptibility of inbred strains of mice to persistent infection by this picornavirus