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.

  • Source
    • "Neutropenia can be associated with a deficit of both innate and acquired immunity but in most cases the mechanism is not autoimmune. Two immunodeficiencies in which neutropenia is mainly autoimmune are HypeIgM syndrome [Seyama et al. 1998; Jasinska et al. 2013] where neutropenia is observed in 60% of patients, and Good syndrome [Notarangelo, 2010], characterized by the association of hypogammaglobulinemia with thymoma, where autoimmune cytopenias (especially red cell aplasia and/or neutropenia) are common. Neutropenia occurs also in a minority of patients with common variable immunodeficiency in which may remain the only symptom for long time. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmune neutropenia of infancy (AIN), also called primary autoimmune neutropenia, is a disease in which antibodies recognize membrane antigens of neutrophils, mostly located on immunoglobulin G (IgG) Fc receptor type 3b (FcγIIIb receptor), causing their peripheral destruction. It is the most frequent type of neutropenia in children under 3-4 years of age and in most cases shows a benign, self-limited course. The diagnosis is based on evidence of indirect antineutrophil antibodies, whose detection frequently remains difficult. In this review we have analyzed the literature regarding AIN and present our personal experience in diagnosis and management.
    02/2015; 6(1):15-24. DOI:10.1177/2040620714556642
  • Source
    • "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 " . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs) has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune manifestations. PIDs must be distinguished from secondary or acquired immunodeficiencies, which are far more common. In this review, we will place these immunodeficiencies in the context of both clinical and laboratory presentations as well as highlight the known genetic basis.
    Clinical and Developmental Immunology 06/2006; 13(2-4):223-59. DOI:10.1080/17402520600800705 · 2.93 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyper-IgM syndrome type 1 (HIGM1) is a primary immunodeficiency characterized by recurrent bacterial and opportunistic infections, associated with normal or high serum level of IgM and decreased serum levels of IgG, IgA and IgE due to the defect of class switch recombination. CD40LG, located in Xq26, has been reported to be mutated in male HIGM1 patients. Here, we report the second case of a female HIGM1 with the defect of CD40 ligand (CD40L) expression and of soluble serum CD40L. Clinical course and HIGM phenotype was indistinguishable from that of male HIGM1 including severe neutropenia. High-resolution chromosome banding revealed that this patient's karyotype is 46, X, t(X;14)(q26.3;q13.1), and FISH analysis demonstrated that the break point of the chromosomal translocation is within CD40LG. Using four chimeric cDNA clones obtained by 3' RACE method, the break point was identified within the intron 4 of CD40LG on X chromosome and non-coding region of chromosome 14. We also found an extremely skewed X-chromosome inactivation pattern by methylation-specific PCR. Thus, the reciprocal translocation caused the disruption of CD40LG, resulting in defective CD40L expression in the female patient with an extremely skewed X-inactivation pattern in T cells leading to the HIGM1 phenotype.
    Biochimica et Biophysica Acta 04/2006; 1762(3):335-40. DOI:10.1016/j.bbadis.2005.10.003 · 4.66 Impact Factor
Show more