SOMATIC MUTATIONS IN HUMAN IG VARIABLE GENES CORRELATE WITH A PARTIALLY FUNCTIONAL CD40-LIGAND IN THE X-LINKED HYPER-IGM SYNDROME

X-linked hyper-IgM (HIGM-1) syndrome is a rare disorder resulting from mutations in the CD40-ligand (CD40L) gene. This defect is associated with normal or elevated serum levels of IgM, and with low to undetecta ble levels of serum IgG, IgA, and IgE. We analyzed the somatic mutatio n status in Ig V genes from three unrelated HIGM-1 patients by reverse -transcription PCR and sequence analysis. Two patients (B.S. and P.S.) expressed unmutated V(H)6 genes. In contrast, one patient (A.T.) was found to express mutated V(H)6 genes. Whether the presence of somatic mutations in this patient was related to a functional CD40L was assess ed by deriving T cell clones from his peripheral blood cells. Upon act ivation, these T cell clones expressed weakly and transiently surface CD40L, and were able to induce limited isotype switch of normal naive B cells, indicating residual CD40L function, Altogether, our results 1 ) confirm the central role played by CD40L in the generation of somati c mutation (patients B.S. and P.S.), 2) provide an unusual illustratio n of the relative dissociation between somatic mutation and isotype sw itching (patient A.T.), and 3) demonstrate a further complexity of the X-linked HIGM syndrome that may occur despite a partially functional CD40L.