CD40 exon 8 deficiency causes a novel form of immunodeficiency with hyper-IgM (P3327)

Abstract

Abstract Introduction: The germinal center (GC) reaction generates switched memory B cells and plasma cells. Mutation of CD40L or other genes involved in the GC reaction causes hyper-IgM syndrome (HIM). Hypothesis: We evaluated a 56-year-old woman who had an immunological phenotype resembling HIM but only mild immunodeficiency. The age, gender, and clinical presentation were not readily explained by known HIM mutations and we hypothesized that the patient might have a novel mutation. Method: The patient’s immune function was evaluated and CD40 DNA/RNA sequences were determined. The patient’s CD40 cDNA lacking exon 8 (Δexon8) was cloned and transfected into 293 cells. Signaling downstream of CD40 was assessed. Results: By flow cytometry, the patient’s peripheral blood lacked switched memory B cells. The patient mounted a robust IgG response to tetanus toxoid immunization, but antibody levels dropped precipitously suggesting that there was a problem generating long-lived plasma cells. Although CD40 expression was mildly decreased, cDNA sequences showed a deletion of the entire exon 8 of CD40 in 67% of her cDNA clones. This was rare in controls. Expression of CD40-Δexon8 in 293 cells resulted in surface expression of CD40, but signaling downstream of CD40 upon sCD40L stimulation was impaired. Conclusion: This patient has a novel immunodeficiency syndrome due to deletion of exon 8 of CD40, which encodes a cytoplasmic domain critical for signal transduction.