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

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.

Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica)

“…In these cases the panel reckoned appropriate to proceed to further more targeted analyses (genomic DNA mutation study for Shwachman-Diamond, mitochondrial DNA analysis for Pearson's syndrome, erythrocyte ADA and mutation search for Blackfan-Diamond syndrome) [18][19][20][21] aiming to make a firm diagnosis of these diseases (Table VII) In the case of early, severe and recurrent infections associated to decreased Ig serum levels, increased CRP and positive markers LGL syndrome Associated to hypersplenism (AEanemia, AEthrombocytopenia) Associated to sequestration in infectious foci of infections, overall suggesting an immunodeficiency, peripheral blood immunophenotype, response to vaccines including polysaccharide antigens, lymphocyte proliferation to mytogens are indicated before referring the patient to an Immunodeficiency Reference Center where study of mutations of genes involved in neutropenia associated with immunodeficiency can be addressed [22][23][24][25][26][27][28][29][30][31][32][33][34] (Table VII) …”

Allogeneic hematopoietic stem cell transplantation for seven children with X‐linked hyper‐IgM syndrome: A single center experience

“…The disease is caused by defective expression of the CD40 ligand (CD40L) on the surface of activated T cells [2][3][4][5]. Interaction of CD40L with CD40 on both B cells and monocyte derived cells is critical for immunoglobulin isotype switching as well as for activation of macrophages and functional differentiation of T cells [6].…”

Critical role of lipid rafts in CD154‐mediated T cell signaling

“…The absence of CD154 leads to hyper-IgM syndrome, abrogation of germinal center formation and failure of B cells to proliferate and differentiate [5,16].…”