The most common form of hyperIgM syndrome is Xlinked hyperIgM syndrome, or CD40 ligand deficiency, which is caused by mutations in the gene encoding CD40 ligand (CD154) (see Fig. 13.5). CD40 ligand is normally expressed on activated T cells, enabling them to engage the CD40 protein on antigenpresenting cells, including B cells, dendritic cells, and macrophages (see Section 104). In males with CD40 ligand deficiency, B cells are normal, but in the absence of engagement of CD40, their B cells do not undergo isotype switching or initiate the formation of germinal centers (Fig. 13.6). These patients therefore have severe reductions in circulating levels of all antibody isotypes except IgM and are highly susceptible to infections by pyogenic extracellular bacteria.
Because CD40 signaling is also required for the activation of dendritic cells and macrophages for optimal production of IL12, which is important for the production of IFNγ by TH1 cells and NK cells, patients with CD40 ligand deficiency also have defects in type 1 immunity and thus manifest a form of combined immunodeficiency. Inadequate crosstalk between T cells and dendritic cells via CD40L–CD40 interaction can lead to lower levels of costimulatory molecules on dendritic cells, thus impairing their ability to stimulate naive T cells (see Section 917). These patients are therefore susceptible to infections by extracellular pathogens that require classswitched antibodies, such as pyogenic bacteria, but also have defects in the clearance of intracellular pathogens, such as mycobacteria, and are particularly prone to opportunistic infections by Pneumocystis jirovecii, which is normally killed by activated macrophages.
A similar syndrome has been identified in patients with mutations in two other genes. Not unexpectedly, one is the gene encoding CD40, mutations in which have been found in a few patients with an autosomal recessive variant of hyperIgM syndrome (see Fig. 13.5). In another form of Xlinked hyperIgM syndrome, known as NEMO deficiency, mutations occur in the gene encoding the protein NEMO (‘NFκB essential modulator’; also known as IKKγ, a subunit of the kinase IKK), which is an essential component of the intracellular signaling pathway downstream of CD40 that leads to activation of the transcription factor NFκB (see Fig. 3.15). This group of hyperIgM syndromes shows that mutations at different points in the CD40L–CD40 signaling pathway result in a similar combined immunodeficiency syndrome. In view of the role of NFκB signaling in many other pathways, NEMO deficiency results in additional immune dysfunction beyond its impairment of Bcell class switching (see Section 1315), as well as nonimmune manifestations, including abnormalities of the skin.