A Point Mutation in the <i>IL-12R</i>β2 Gene Underlies the IL-12 Unresponsiveness of <i>Lps-</i>Defective C57BL/10ScCr Mice

Poltorak, Alexander; Merlin, Thomas; Nielsen, Peter; Sandra, Olivier; Smirnova, I.; Schupp, Ingo; Boehm, Thomas; Galanos, Chris; Freudenberg, Marina A.

doi:10.4049/jimmunol.167.4.2106

Cited by 67 publications

(65 citation statements)

References 38 publications

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“…Unlike ScN mice, the Cr mice have an additional single-point mutation (substitution of a C for a G at position 2472) in the IL-12R␤2 gene, leading to a premature stop codon, which is responsible for IL-12 nonresponsiveness (36). The sequences of IL-12R␤1 cDNA from both strains are identical.…”

Section: Micementioning

confidence: 79%

“…To determine whether TLR4 signaling alone is necessary and sufficient to cause autoimmune GN, we generated a Tg mouse called TCr-5, whose genome contains multiple copies of the tlr4 gene on a TLR4-deficient C57/BL10ScCr (ScCr) background (34). We further crossed TCr-5 mice with TLR4-null C57/BL10ScN (ScN) (47) mice to rescue a loss-of-function mutation in the IL-12R␤2 gene in the original C57/BL10ScCr mice (36,47), to generate a mouse named TScN-5. ScCr mice were derived from ScN mice; the only known genetic difference between the two strains is the mutation of IL-12R␤2 gene in ScCr mice.…”

Section: Tlr4 Gene Amplification Is Sufficient To Induce Autoimmunitymentioning

confidence: 99%

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TLR4 Up-Regulation at Protein or Gene Level Is Pathogenic for Lupus-Like Autoimmune Disease

Liu

Yang

Dai

et al. 2006

The Journal of Immunology

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126

106

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TLR4 is the receptor for the Gram-negative bacterial cell wall component LPS. TLR4 signaling is controlled by both positive and negative regulators to balance optimal immune response and potential sepsis. Unchecked TLR4 activation might result in autoimmune diseases, a hypothesis that has not been formally resolved. In this study, we found that TLR4 signaling to LPS can be positively enforced by expressing gp96 on cell surfaces through the chaperone function of, but not the direct signaling by, gp96; TLR4 as well as the commensal flora are essential for the production of anti-dsDNA Ab and the immune complex-mediated glomerulonephritis in transgenic mice that express surface gp96. Moreover, a similar constellation of autoimmunity was evident in mice that encode multiple copies of tlr4 gene. Our study has revealed that increased TLR4 signaling alone without exogenous insult can break immunological tolerance. It provides a strong experimental evidence for TLR4 dysregulation as an etiology of lupus-like renal disease.

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Section: Micementioning

confidence: 79%

Section: Tlr4 Gene Amplification Is Sufficient To Induce Autoimmunitymentioning

confidence: 99%

TLR4 Up-Regulation at Protein or Gene Level Is Pathogenic for Lupus-Like Autoimmune Disease

Liu

Yang

Dai

et al. 2006

The Journal of Immunology

Self Cite

126

106

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“…Mice. MPS VII, B6, and TLR4 (lps−/−) (Jackson Laboratory) mice have been previously described (35)(36)(37). MPS VII and TLR4 (lps−/−) mice were interbred to obtain DKO animals.…”

Section: Methodsmentioning

confidence: 99%

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

Simonaro¹,

Ge²,

Eliyahu³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

165

175

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Enzyme replacement therapy is currently available for three of the mucopolysaccharidoses (MPSs) but has limited effects on the skeletal lesions. We investigated the involvement of the Toll-like receptor 4 (TLR4) signaling pathway in the pathogenesis of MPS bone and joint disease, and the use of the anti-TNF-α drug, Remicade (Centocor, Inc.), for treatment. TLR4 KO (TLR4 (lps−/−) ) mice were interbred with MPS VII mice to produce double-KO (DKO) animals. The DKO mice had longer and thinner faces and longer femora as revealed by micro-computed tomography analysis compared with MPS VII mice. Histological analyses also revealed more organized and thinner growth plates. The serum levels of TNF-α were normalized in the DKO animals, and the levels of phosphorylated STAT1 and STAT3 in articular chondrocytes were corrected. These findings led us to evaluate the effects of Remicade in MPS VI rats. When initiated at 1 month of age, i.v. treatment prevented the elevation of TNF-α, receptor activator of NF-κB, and other inflammatory molecules not only in the blood but in articular chondrocytes and fibroblast-like synoviocytes (FLSs). Treatment of 6-monthold animals also reduced the levels of these molecules to normal. The number of apoptotic articular chondrocytes in MPS VI rats was similarly reduced, with less infiltration of synovial tissue into the underlying bone. These studies revealed the important role of TLR4 signaling in MPS bone and joint disease and suggest that targeting TNF-α may have positive therapeutic effects.bone and joint disease | inflammation | glycosaminoglycans | growth plate

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“…Specifically with respect to respiratory syncytial virus, Kurt-Jones and colleagues [31] reported prolonged detection of virions in lung tissue of TLR4-gene-deleted C57BL/10ScCr strain of mice. Subsequent studies documented the existence of a point mutation in the IL-12Rβ2 rendering this background strain unresponsive to IL-12 [33], and, as an attempt to discern among the possibilities, Ehl and colleagues [32] determined that it was the lack of IL-12 response, rather than the TLR4 gene-deletion, that resulted diminished RSV-specific T cell immunity. In order to address this issue somewhat further, Desmecht and colleagues [34] compared the responses of wild type and TLR4 gene-deleted mice to infection with PVM.…”

Section: Role Of Tlr4mentioning

confidence: 99%

Pneumonia virus of mice: severe respiratory infection in a natural host

Rosenberg

Domachowske

2008

Immunology Letters

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Pneumonia virus of mice (PVM; family Paramyxoviridae, genus Pneumovirus) is a natural mouse pathogen that is closely related to the human and bovine respiratory syncytial viruses. Among the prominent features of this infection, robust replication of PVM takes place in bronchial epithelial cells in response to a minimal virus inoculum. Virus replication in situ results in local production of proinflammatory cytokines (MIP-1α, MIP-2, MCP-1 and IFNγ) and granulocyte recruitment to the lung. If left unchecked, PVM infection and the ensuing inflammatory response ultimately lead to pulmonary edema, respiratory compromise and death. In this review, we consider the recent studies using the PVM model that have provided important insights into the role of the inflammatory response in the pathogenesis of severe respiratory virus infection. We also highlight several works that have elucidated acquired immune responses to this pathogen, including T cell responses and the development of humoral immunity. Finally, we consider several immunomodulatory strategies that have been used successfully to reduce morbidity and mortality when administered to PVM infected, symptomatic mice, and thus hold promise as realistic therapeutic strategies for severe respiratory virus infections in human subjects.

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A Point Mutation in the IL-12Rβ2 Gene Underlies the IL-12 Unresponsiveness of Lps-Defective C57BL/10ScCr Mice

Cited by 67 publications

References 38 publications

TLR4 Up-Regulation at Protein or Gene Level Is Pathogenic for Lupus-Like Autoimmune Disease

TLR4 Up-Regulation at Protein or Gene Level Is Pathogenic for Lupus-Like Autoimmune Disease

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

Pneumonia virus of mice: severe respiratory infection in a natural host

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