CD40 Ligand Gene Defects Responsible for X-Linked Hyper-IgM Syndrome

TLDR

The CD40 ligand on activated T cells drives B‑cell proliferation and antibody secretion, and mutations in its gene cause X‑linked hyper‑IgM syndrome, characterized by high IgM and low other immunoglobulin isotypes. Mutations in CD40L identified in patients produce non‑binding proteins that fail to stimulate B‑cell proliferation or IgE production, and patient T cells lack CD40L expression, explaining the defective class switching despite normal B‑cell responsiveness to wild‑type ligand.

Abstract

The ligand for CD40 (CD40L) is a membrane glycoprotein on activated T cells that induces B cell proliferation and immunoglobulin secretion. Abnormalities in the CD40L gene were associated with an X-linked immunodeficiency in humans [hyper-IgM (immunoglobulin M) syndrome]. This disease is characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. CD40L complementary DNAs from three of four patients with this syndrome contained distinct point mutations. Recombinant expression of two of the mutant CD40L complementary DNAs resulted in proteins incapable of binding to CD40 and unable to induce proliferation or IgE secretion from normal B cells. Activated T cells from the four affected patients failed to express wild-type CD40L, although their B cells responded normally to wild-type CD40L. Thus, these CD40L defects lead to a T cell abnormality that results in the failure of patient B cells to undergo immunoglobulin class switching.