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: 10.45). 11/1998; 92(7):2421-34.
Source: PubMed


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.

Download full-text


Available from: Hans D Ochs, Dec 17, 2015
  • 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.
    Full-text · Article · Feb 2015
  • Source
    • "Detection of CD154 expression on activated CD4+ T cells was performed by flow cytometry (FACScan, Becton Dickinson, USA) using specific fluorescent-labeled monoclonal antibodies according to the method described previously [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: X-linked hyper-IgM syndrome (XHIGM) is one type of primary immunodeficiency diseases, resulting from defects in the CD40 ligand/CD40 signaling pathways. We retrospectively analyzed the clinical and molecular features of 20 Chinese patients diagnosed and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to 2013. The median onset age of these patients was 8.5 months (range: 20 days-21 months). Half of them had positive family histories, with a shorter diagnosis lag. The most common symptoms were recurrent sinopulmonary infections (18 patients, 90%), neutropenia (14 patients, 70%), oral ulcer (13 patients, 65%), and protracted diarrhea (13 patients, 65%). Six patients had BCGitis. Six patients received hematopoietic stem cell transplantations and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations in CD40L gene were identified in these 20 patients from 19 unrelated families, with 12 novel mutations. We compared with reported mutation results and used bioinformatics software to predict the effects of mutations on the target protein. These mutations reflected the heterogeneity of CD40L gene and expanded our understanding of XHIGM.
    Full-text · Article · Aug 2014 · Research Journal of Immunology
  • Source
    • "This will confirm the diagnosis in the majority of cases in whom mutations result in a lack of protein expression on the cell surface. In a minority of cases with splice site (Seyama et al, 1998a) or cytoplasmic tail mutations (Yong et al, 2008a) some, or even normal, surface expression is seen making the diagnosis more difficult to confirm. In the neonatal period immaturity in T-cell responses results in failure of expression of this molecule using standard T-cell activation stimuli. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders resulting in defects of immunoglobulin class switch recombination (CSR), with or without defects of somatic hypermutation (SHM). They can be classified as defects of signalling through CD40 causing both a humoral immunodeficiency and a susceptibility to opportunistic infections, or intrinsic defects in B cells of the mechanism of CSR resulting in a pure humoral immunodeficiency. A HIGM picture can also be seen as part of generalized defects of DNA repair and in antibody deficiency syndromes, such as common variable immunodeficiency. CD40 signalling defects may require corrective therapy with bone marrow transplantation. Gene therapy, a potential curative approach in the future, currently remains a distant prospect. Those with a defective CSR mechanism generally do well on immunoglobulin replacement therapy. Complications may include autoimmunity, lymphoid hyperplasia and, in some cases, a predisposition to lymphoid malignancy.
    Full-text · Article · Feb 2010 · British Journal of Haematology
Show more