- Hyper-IgM Syndrome is caused by a defect in the interaction between B-cell CD40 and CD4+ T-cell CD40 ligand during the Humoral Immune Response which is required to induce Isotype switching of antibody in B-cells during B-cell Development. Most cases of Hyper-IgM Syndrome are caused by inactivating mutations in CD4+ T-cell CD40 Ligand, although other defects in downstream CD40 signaling components have been identified. Because isotype switching of antibody cannot occur, there is a selective hypogammaglobulinemia of IgG, IgA, and IgE. Because the IgM isotype can be produced without isotype switching, patients may display high levels of plasma IgM which is where the disease derives its namesake (Although in some cases IgM levels may be normal or even low).
- Disease manifests infection susceptibility to pyogenic bacteria due to reduced levels of IgG and IgA.
- Most cases are X-linked recessive as the CD40L gene is on the X-chromosome.