The gene responsible for the X-linked form of HIGM (XHIGM) was mapped to the long arm of the X-chromosome (Xq26–27) and subsequently identified as CD40ligand (CD40L), expressed by activated CD4 + T cells. Recently, as more genes were found to be mutated in the syndrome with different clinical presentations, it was suggested to change the name to “defective Ig class switch recombination.” The important role of defective T helper cells was recognized in 1986, when the observation was made that B cells from male HIGM patients differentiated into IgG secreting cells if co-cultured in vitro with T lymphoblasts from a patient with a Sézary-like syndrome ( 5). The observation that many patients, especially those with the X-linked form, were also susceptible to opportunistic infections should have pointed to a possible T-cell defect. For more than 20 y it was hypothesized that B-lymphocytes from HIGM patients had an intrinsic inability to undergo Ig isotype switching ( 4). The nature of the immune defect(s) in HIGM remained elusive. In view of the dissociation between normal or elevated IgM and low-to-undetectable IgG and IgA, this syndrome was originally termed “dysgammaglobulinemia.” A World Health Organization working party, in 1974, named the syndrome immunodeficiency with hyper IgM (HIGM) ( 3). ( 1) described two brothers with recurrent infections, and Burtin ( 2) reported a similar patient who had low levels of 7S gamma-globulin (IgG) and elevated 19S gamma-globulin (IgM). Thus, the molecular definition of these rare primary immune deficiency disorders has shed light on the complex events leading to the production of high-affinity, antigen-specific antibodies of different isotypes. Mutations of Nuclear Factor κB Essential Modulator ( NEMO), an X-chromosome associated gene, result in hypohidrotic ectodermal dysplasia and immune deficiency. Mutations of Activation-Induced Cytidine Deaminase ( AICDA) and Uracil (DNA) Glycosylase ( UNG), both expressed by follicular B lymphocytes, lead to defective class switch recombination and somatic hypermutation. Mutations of CD40, the receptor for CD40L, cause a rare autosomal form of HIGM with a clinical phenotype similar to CD40L deficiency. Four other genes, expressed by B cells, have been associated with the HIGM phenotype. The most common HIGM syndrome is X-linked and due to mutations of CD40 ligand ( CD40L) expressed by activated CD4 + T lymphocytes. As a consequence, patients with HIGM have decreased concentrations of serum IgG and IgA and normal or elevated IgM, leading to increased susceptibility to infections. The hyper IgM syndromes (HIGM) are a group of primary immune deficiency disorders characterized by defective CD40 signaling by B cells affecting class switch recombination and somatic hypermutation.
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