Article

Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome

Department of Pediatrics and Biological Structure, University of Washington Medical School, Seattle, WA 98195-6320, USA.
Blood (Impact Factor: 10.43). 11/1998; 92(7):2421-34.
Source: PubMed

ABSTRACT X-linked hyper IgM syndrome (XHIM) is a primary immunodeficiency disorder caused by mutations of the gene encoding CD40 ligand (CD40L). We correlated mutations of the CD40L gene, CD40L expression, and the clinical manifestations observed in XHIM patients from 30 families. The 28 unique mutations identified included 9 missense, 5 nonsense, 9 splice site mutations, and 5 deletions/insertions. In 4 of 9 splice site mutations, normally spliced and mutated mRNA transcripts were simultaneously expressed. RNase protection assay demonstrated that 5 of 17 mutations tested resulted in decreased levels of transcript. The effect of the mutations on CD40L expression by activated peripheral blood mononuclear cells (PBMC) and T-cell lines or clones was assessed using one polyclonal and four monoclonal antibodies and a CD40-Ig fusion protein. In most patients, the binding of at least one antibody but not of CD40-Ig was observed, suggesting nonfunctional CD40L. However, activated PBMC from three patients and activated T-cell lines from two additional patients, each with different genotype, bound CD40-Ig at low intensity, suggesting functional CD40L. Thus, failure of activated PBMC to bind CD40-Ig is not an absolute diagnostic hallmark of XHIM and molecular analysis of the CD40L gene may be required for the correct diagnosis. Patients with genotypes resulting in diminished expression of wild-type CD40L or mutant CD40L that can still bind CD40-Ig appear to have milder clinical consequences.

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    • "CD40 ligand, a protein on T helper cells, normally interacts with CD40 protein on B cells. This interaction is needed for proper isotype switching, without which the B cells produce only IgM (Seyama et al. 1998). Also, if CD40 is not stimulated, these B cells do not upregulate the costimulatory molecules CD 80/86, which in turn allows T cells to become " tolerogenic " . "
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    • "CD40L also activates dendritic cells through CD40. Thus, defect of CD40L is associated not only with a humoral immunodeficieny but also represents a combined immunodeficiency characterized by opportunistic infections with pathogens, such as Pneumocystis carinii or Cryptosporidium pavium [6]. As CD40LG resides on the X chromosome and HIGM1 is an X-linked recessive disease, most of the patients are male and the female patients are asymptomatic carriers [7] [8]. "
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