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). 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) It is the most common class switch recombination defect and accounts for approximately 50% of the patients in this category. It leads to defective B-cell responses and the absence of immunoglobulin class-switching, which are typified 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, patients with XL-HIGM are particularly prone to opportunistic infections with Pneumocystis jiroveci, Cryptosporidium, and Toxoplasma gondii.(1)

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 variants 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 patients with XL-HIGM have activated CD4 T cells with normal surface expression of CD40L but aberrant function.(4)

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