CD40 LIGAND MUTATIONS IN X-LINKED IMMUNODEFICIENCY WITH HYPER-IGM

SIGNALLING for the B-cell immunoglobulin isotype switch requires T-cell-derived cytokines and T-B cell interaction, which operates primarily through the CD40 molecule on B cells with its ligand (CD40L) on activated T cells (reviewed in ref. 1). The CD40L is a type II membrane protein2-5 with homology to tumour necrosis factor-alpha and -beta6,7, and has important functions in B-cell activation and differentiation2,4,8. Human CD40L maps on Xq26.3-27.1 (ref. 3), the region where a primary immunodeficiency characterized by an immunoglobulin isotype switch defect (the hyper-IgM immunodeficiency syndrome, HIGM1) has been localized9,10. The hypothesis that HIGM1 involves an abnormality of the CD40L has been tested. We report here the lack of CD40L expression in four unrelated male children with the hyper-IgM syndrome. CD40L transcripts in these patients showed either deletions or point mutations clustered within a limited region of the CD40L. extracellular domain. These genetic alterations with abnormal CD40L expression provide a molecular basis for immunoglobulin isotype switch defects observed in this immunodeficiency.