Clinical Information

CD154 (CD40 ligand: CD40L) is required for the interaction of T cells and B cells as part of the normal adaptive immune response. Activation of T cells leads to the expression of the CD40L molecule on the cell surface. CD40L binds the CD40 receptor that is always present on B cells, monocytes, and macrophages (regardless of environmental conditions). This interaction of CD40L with CD40 is important in B-cell proliferation, differentiation, and class-switch recombination (isotype class-switching).

Patients with X-linked hyper-IgM (XL-HIGM) syndrome have defective CD40L expression on their activated helper CD4 T cells.(1,2) This leads to defective B-cell responses and the absence of immunoglobulin class-switching. These features are typified in these patients by a profound reduction or absence of isotype class-switched memory B cells (CD19+CD27+IgM-IgD-) with low or absent secreted IgG and IgA, and normal or elevated serum IgM levels.(1,2) Due to the impairment of T-cell function and macrophage activation, XL-HIGM patients are particularly prone to opportunistic infections with Pneumocystis jiroveci, Cryptosporidium, and Toxoplasma gondii.(1)

To date, more than 100 unique mutations of CD40LG, the gene that encodes CD40L, have been described, affecting the intracellular, transmembrane and, more commonly, extracellular domain containing the CD40-binding region.

A defect in surface expression of CD40L on activated CD4 T cells can be demonstrated using an anti-CD40L antibody and flow cytometry.(3,4) Since certain CD40LG mutations can maintain surface protein expression, albeit with loss of function, it is important to also evaluate CD40L-binding capacity to eliminate the possibility of false-negative results. A soluble recombinant, chimeric receptor protein, CD40-uIg, is incorporated into the assay, which assesses CD40L function by determining receptor-binding activity. Approximately 20% of XL-HIGM patients have activated CD4 T cells with normal surface expression of CD40L, but aberrant function.(4)

XL-HIGM is a severe type of primary immunodeficiency that affects males, and most patients are diagnosed within a few months to the first year of life. Females are typically carriers and asymptomatic. Consequently, this test is only indicated in young males (<10 years of age) or, to identify carriers, in females of child-bearing age (<45 years).