A novel activation-induced cytidine deaminase (AID) mutation in Brazilian patients with hyper-IgM type 2 syndrome.

Activation-induced cytidine deaminase (AID) is a DNA editing protein that plays an essential role in three major events of immunoglobulin (Ig) diversification: somatic hypermutation, class switch recombination and Ig gene conversion. Mutations in the AID gene (AICDA) have been found in patients with autosomal recessive Hyper-IgM (HIGM) syndrome type 2. Here, two 9- and 14-year-old Brazilian sisters, from a consanguineous family, were diagnosed with HIGM2 syndrome. Sequencing analysis of the exons from AICDA revealed that both patients are homozygous for a single C to G transversion in the third position of codon 15, which replaces a conserved Phenylalanine with a Leucine. To our knowledge, this is a new AICDA mutation found in HIGM2 patients. Functional studies confirm that the homologous murine mutation leads to a dysfunctional protein with diminished intrinsic cytidine deaminase activity and is unable to rescue CSR when introduced in Aicda(-/-)stimulated murine B cells. We briefly discuss the relevance of AICDA mutations found in patients for the biology of this molecule.

Pneumocystis jiroveci pneumonia revealing de novo mutation causing X-linked hyper-IgM syndrome in an infant male. The first case reported from French Guiana.

BACKGROUND: The X-linked hyper-IgM (XHIM) syndrome is a rare form of primary immunodeficiency disorder characterized by hypogammaglobulinemia and impaired cell immunity. OBSERVATION: We report history of Guianese family affected by XHIM syndrome. The eldest boy died at 7 months from pneumonia. The 5-month-old youngest boy presented with a potentially fatal episode of Pneumocystis jiroveci pneumonia. The diagnosis was done in the Pediatric Unit of Immunohematology of Hopital Necker in Paris. CONCLUSIONS: This report points to the importance of diagnosis of XHIM to allow early treatment to minimize serious infections and to detect carriers in XHIM families for genetic counseling.

Autoimmunity in hyper-IgM syndrome.

INTRODUCTION: Immunodeficiency with hyper-IgM (HIGM) results from genetic defects in the CD40-CD40 ligand (CD40L) pathway or in the enzymes required for immunoglobulin class switch recombination and somatic hypermutation. HIGM can thus be associated with an impairment of both B-cell and T-cell activation. RESULTS AND DISCUSSIONS: There are seven main subtypes of HIGM and the most frequent is X-linked HIGM, resulting from CD40L mutations. In addition to the susceptibility to recurrent and opportunistic infections, these patients are prone to autoimmune manifestations, especially hematologic abnormalities, arthritis, and inflammatory bowel disease. Furthermore, organ-specific autoantibodies are commonly found in HIGM patients. CONCLUSIONS: The mechanisms by which HIGM associates to autoimmunity are not completely elucidated but a defective development of regulatory T cells, the presence of IgM autoantibodies and an impaired peripheral B-cell tolerance checkpoint have been implicated. This article reviews the main subtypes of HIGM syndrome, the clinical autoimmune manifestations found in these patients, and the possible mechanisms that would explain this association.