Generalized lymphoproliferative disease in mice, caused by a point mutation in the fas ligand

Takahashi, Tomohiro; Tanaka, Masato; Brannan, Camllynn I.; Jenkins, Nancy A.; Copeland, Neal G.; Suda, Takafumi; Nagata, Shinji

doi:10.1016/0092-8674(94)90375-1

Cited by 1,437 publications

(824 citation statements)

References 54 publications

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“…22 The gld mouse has a missense mutation in the extracellular domain of FasL, which abrogates its function. 23 The phenotype of these mutations, when bred onto the autoimmune MRL background, is very similar. However, the autoimmune features of the lpr mutation vary on other strains, generating, for example, a less severe phenotype in C57BL6, 129 or C3H mice.…”

Section: Introductionmentioning

confidence: 97%

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

et al. 2005

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Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC C/T as well as the FASÀ670G4A 0 -codon214 AC C/T 0 haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FASÀ670G, which affects STAT1 binding, leads to the highest activity. FASLÀ844C activity is modified by the cis acting À478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.

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Section: Introductionmentioning

confidence: 97%

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

et al. 2005

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“…In human pathology as well as in the mouse model, spontaneous mutations inactivating CD40 ligand (CD40L) and Fas receptor and its ligand have been described. [3][4][5][6][7][8][9][10] In the case of CD40L, the phenotype shown by patients affected by hyper immunoglobulin M (IgM) syndrome (HIGM1), in which the CD40L is defective, is characterized by a failure of B cells to proliferate and to switch from IgM production to Ig of other isotypes. 4,5,6,8,11,12 Conversely, in both human and mouse abnormalities of the Fas system, a lymphoproliferative and autoimmune phenotype is seen (reviewed in Refs.…”

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confidence: 99%

Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome

et al. 2000

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Mutations in the CD40 ligand (CD40L) are responsible for human hyper immunoglobulin M (IgM) syndrome. The absence of the interaction between CD40L, expressed by T lymphocytes, and the CD40 receptor present on the surface of B cells is responsible for the inability of B cells to carry out the isotype switch from IgM to the other Ig classes. This leads to a fatal immunodeficiency for which no cure exists. For these reasons, the CD40L gene is a good candidate for gene therapy studies. To investigate the possible effects of the expression of this tightly regulated gene in vivo, we produced transgenic mice in which CD40L expression was deregulated. Widespread ectopic expression appears to be lethal. Overexpression in mature T cells is compatible with life, but in one-third of the cases, mice developed atypical lymphoid proliferations which, occasionally, progressed into frank lymphomas. Even though gene therapy is one of the most promising approaches to cure human hyper IgM syndrome, these results suggest that when we modify very tightly regulated genes such as cytokines or other growth factors, particular care has to be taken to avoid excessive stimulation of the target cells.

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“…guard against emergence of auto-reactive lymphocytes. [11][12][13][14] Ipr mutant mice harbor either an early transposable element or a mutation in the Fas gene, which either severely reduce Materials and methods the expression of a full size Fas transcript, or abolish its ability Tissue sampling and study design and Fas mRNAs using reverse transcriptase-polymerase chain CD21, CD22, CD23, CD24, and immunoglobulin light chains, ␦, , ␥, and ␣ immunoglobulin heavy chains), T cells (CD2, CD3, CD4, CD5, CD7, CD8) and ReedSternberg/activated cells (CD30). For double-color flow cyto-CAT GAA CCC ATG TTT GCA-3′ (nucleotide positions: 2118-2142)) for Fas.…”

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confidence: 99%

Malignant and reactive cells from human lymphomas frequently express Fas ligand but display a different sensitivity to Fas-mediated apoptosis

et al. 1997

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Generalized lymphoproliferative disease in mice, caused by a point mutation in the fas ligand

Cited by 1,437 publications

References 54 publications

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome

Malignant and reactive cells from human lymphomas frequently express Fas ligand but display a different sensitivity to Fas-mediated apoptosis

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