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R L Fuleihan

Publications and source records attributed to R L Fuleihan.

11 recordsLinked to original sources
PubMed2001

A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA-->AAUGAA) leads to the IPEX syndrome.

The mouse scurfy gene, Foxp3, and its human orthologue, FOXP3, which maps to Xp11.23-Xq13.3, were recently identified by positional cloning. Point mutations and microdeletions of the FOXP3 gene were found in the affected members of eight of nine families with IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked; OMIM 304930). We evaluated a pedigree with clinically typical IPEX in which mutations of the coding exons of FOXP3 were not detected. Our reevaluation of this pedigree identified an A-->G transition within the first polyadenylation signal (AAUAAA-->AAUGAA) after the stop codon. The next polyadenylation signal is not encountered for a further 5.1 kb. This transition was not detected in over 212 normal individuals (approximately 318 X chromosomes), excluding the possibility of a rare polymorphism. We suggest that this mutation is causal of IPEX in this family by a mechanism of nonspecific degradation of the FOXP3 gene message.

Cells, Cultured↗
PubMed2001

The hyper IgM syndrome.

The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand/CD40-signaling pathway. X-linked hyper IgM is caused by defects in the CD40 ligand gene, while autosomal recessive hyper IgM is caused by defects in the CD40-activated RNA-editing enzyme, activation-induced cytidine deaminase, which is required for immunoglobulin isotype switching and somatic hypermutation in B cells. The loss of interaction between CD40 and its ligand in X-linked hyper IgM results in an impairment of T cell function, of B cell differentiation, and of monocyte function, while only B cell differentiation appears to be affected in autosomal recessive hyper IgM. With genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitely, to perform genetic screening, and to delineate the clinical manifestations of this syndrome. Further research may lead to novel and definitive therapeutic options for patients with hyper IgM syndrome.

CD40 Ligand↗
PubMed2001

Hyper IgM syndrome: the other side of the coin.

The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand/CD40-signaling pathway. X-linked hyper IgM is caused by defects in the CD40 ligand gene that prevent it from delivering an activation signal to antigen-presenting cells via CD40. Over the past year, defects in molecules involved in CD40 signaling have been shown to cause other forms of hyper IgM. These newly identified defects emphasize the importance of interaction between CD40 and its ligand in immunity and the role of these molecules in the pathogenesis of immune deficiency. With genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitively, to perform genetic screening, and to delineate the clinical manifestations of this syndrome. Further research may lead to novel and definitive therapeutic options for patients with hyper IgM syndrome.

Antigen-Presenting Cells↗
PubMed2000

Transcriptional activity of the distal CD40 ligand promoter.

CD40 ligand (CD40L, CD154) is a T cell cytokine with highly regulated expression that requires the transcription factor nuclear factor of activated T cells (NF-AT) to bind at two sites in the proximal CD40L promoter. We have determined that the distal CD40L promoter (-500 to -1300 bp from start of transcription) conveys superior promoter activity in reporter gene assays. Within the distal promoter, we have identified a third NF-AT binding site, at -761 to -756. Oligonucleotides incorporating each of the three NF-AT sites cross-compete for binding of nuclear extracts from activated T cells and bind NF-ATc2 by antibody supershift. Mutation of the distal NF-AT site reduces activity of the 1300 bp CD40L promoter construct to that of the proximal 500 bp construct, which includes only two NF-AT sites. This suggests that the newly identified NF-AT site is the major mediator of transcriptional activation in the distal CD40L promoter.

Base Sequence↗
PubMed1999

Calcium-dependent activation of TNF family gene expression by Ca2+/calmodulin kinase type IV/Gr and calcineurin.

CD40 ligand (L), FasL, and TNF-alpha are members of the TNF family of cytokines. All are expressed by T lymphocytes shortly after activation but have distinct effector functions. Transcription of these genes can be induced by stimulation of T cells by calcium ionophore alone and requires the calcineurin-dependent transcription factor NF of activated T cells. We have examined a second calcium-dependent signaling pathway, mediated by calcium/calmodulin-dependent kinase IV (CaMKIV) in transcriptional activation of TNF family genes. In reporter gene assays using constructs driven by the promoters of human CD40L, FasL, or TNF-alpha along with vectors expressing constitutively active CaMKIV and calcineurin, we have demonstrated that each promoter is activated by calcineurin and CaMKIV in a synergistic fashion. Furthermore, specific inhibition of CaMKIV by chemical means and by a dominant negative mutant of CaMKIV impairs the ionomycin-induced activity of all three promoters as well as protein expression of CD40L and TNF-alpha. Our results indicate that activation of gene expression by calcineurin and CaMKIV is common to members of the TNF cytokine family.

CD40 Antigens↗
PubMed1999

Transfer of activation-dependent gene expression into T cell lines by recombinant adeno-associated virus.

We examined the ability of recombinant adeno-associated virus (rAAV) to transfer regulated gene expression into T cell lines. An AAV-based vector containing the neomycin resistance gene and expressing the firefly luciferase (luc) gene under the regulatory control of the interleukin 2 promoter (pAAV-luc) was generated and adenovirus-free rAAV (rAAV-luc) was produced from this vector. Transfection of pAAV-luc into the human T cell line Jurkat resulted in luciferase expression while infection of Jurkat T cells with rAAV-luc resulted in significant luciferase expression only after selection for neomycin-resistant cells. Long-term growth of transduced Jurkat T cells showed that there was no detectable constitutive expression of luciferase and that luciferase gene expression remained inducible for at least 180 days. Luciferase expression was activated by PMA and ionomycin and by anti-CD3 antibodies and was inhibited by cyclosporin A. Examination of G418-resistant clones showed that rAAV-luc had integrated into the host chromosomes but that some of the clones lost some of the transferred DNA or lost expression from the transferred DNA. These results indicate that rAAV can transfer and integrate regulated gene expression into T cell lines but that the transferred genetic material may be lost or its expression may be silenced over time.

Dependovirus↗
PubMed1998

The X-linked hyperimmunoglobulin M syndrome.

X-linked hyperimmunoglobulin M (X-HIM) is a rare inherited immune deficiency disease that was first described in 1961. Affected patients suffer recurrent pyogenic and opportunistic infections, neutropenia, and an increased susceptibility to cancer. In 1993, five groups independently showed that this disease results from defects in the CD40 ligand gene. CD40 ligand is a 39-kDa protein expressed on the surface of activated CD4+ T cells that delivers contact-dependent signals to CD40-expressing cells: B cells, monocytes, dendritic cells, epithelial cells, endothelial cells, and fibroblasts. The loss of interaction between CD40 and its ligand results in an impairment of T-cell function, of B-cell differentiation, and of monocyte function. Identification of the genetic defect in X-HIM has provided a definitive diagnosis of the disease, a better description of the clinical manifestations, and the capacity for genetic screening. Studies of the role of CD40 and its ligand in the immune response from many laboratories around the world have provided a better understanding of the pathogenesis of the disease. Further research may lead to novel and definitive therapeutic options for patients with X-HIM.

B-Lymphocytes↗