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Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis.

ABSTRACT: We report that osteopenia is a prominent and previously unappreciated clinical feature of patients with X-linked hyper-IgM syndrome, an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L). We therefore conducted studies to determine the relationship between CD40L and osteoclastogenesis. Recognizing that activated T cells express surface receptor activator of NF-kappaB ligand (RANKL) and can induce osteoclast differentiation of myeloid cells expressing RANK, we assessed the capacity of wild-type T cells and CD40L(-/-) T cells to induce osteoclastogenesis in vitro. Relative to wild-type T cells, activated CD40L(-/-) T cells from both humans and mice promoted robust osteoclast differentiation of myeloid cells. Whereas activated CD40L(-/-) T cells had normal expression of RANKL, they were deficient in IFN-gamma production. In subsequent studies, we cultured activated CD40L(-/-) T cells in the presence of IFN-gamma, and we found that the osteoclastic capacity of CD40L(-/-) T cells could be greatly diminished. These results show that CD40L can influence RANKL signaling through T cell priming, and thus they demonstrate a regulatory role for CD40L in bone mineralization that is absent in patients with X-linked hyper-IgM syndrome.

SUBMITTER: Lopez-Granados E

PROVIDER: S-EPMC1817828 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mitochondrial DNA insert into CD40 ligand gene-associated X-linked hyper-IgM syndrome.

Project description:BackgroundX-linked hyper-IgM (X-HIGM), which results from mutations in the CD40LG gene located on chromosome Xq26.3, is the most common form of HIGM. To date, more than 130 variants of the CD40L gene have been reported. We described a patient with novel de novo nuclear mitochondrial DNA sequences (NUMTs) in the CD40LG gene that have resulted in X-HIGM.MethodsWhole-exome sequencing (WES) analysis was used to screen for causal variants in the genome, and the candidate breakpoint was confirmed by Sanger sequencing.ResultsA new mutation of CD40LG, which deletes A at position 17 followed by a 147-nucleotide from mitochondrial DNA copies insertion in exon 1, was detected in a 20-month-old boy harbouring an X-HIGM combined with immunodeficiency syndrome.ConclusionThis is one of the few cases of a human genetic disease caused by nuclear mitochondrial DNA sequences (NUMTs). The presented data serve to demonstrate that de novo NUMT transfer of nucleic acid is a novel mechanism of X-HIGM.

| S-EPMC8172197 | biostudies-literature

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand.

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Project description: Not available

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CD40 Ligand Deficient C57BL/6 Mouse Is a Potential Surrogate Model of Human X-Linked Hyper IgM (X-HIGM) Syndrome for Characterizing Immune Responses against Pathogens.

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| S-EPMC4433659 | biostudies-literature

Clinical and molecular features of X-linked hyper IgM syndrome - An experience from North India.

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Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome.

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