Hyper-IgM Syndrome

- In hyper-IgM syndrome the affected patients make IgM antibodies but are deficient in their ability to produce IgG, IgA, and IgE antibodies.
- It is now known  that the defect in this disease affects the ability of helper T cells to deliver activating signals to B cells and macrophages.
- Many of the functions of of CD4+ helper T cells require the engagement of CD40 on B cells, macrophages and dendritic cells by CD40L (also called CD154) expressed on antigen-activated T cells.
- This interaction triggers Ig class switching and affinity maturation in B cells, and stimulates the microbicidal functions of macrophages.
- Approximately 70% of individuals with hyper-IgM syndrome have the X-linked form of the disease, caused by mutations in the gene encoding CD40L located on Xq26.
- In the remaining persons the disease is inherited in an autosomal recessive pattern.
- Most of these patients have mutations in the gene encoding CD40 or the enzyme called activation-induced deaminase, a DNA-editing cytosine deaminase that is required for class switching and affinity maturation.

- The serum of persons with this syndrome contains normal or elevated levels of IgM but no IgA or IgE and extremely low levels of IgG.
- The number of B cells and T cells is normal.
- Many of the IgM antibodies react with elements of blood, giving rise to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia.
- In older patients there may be uncontrolled proliferation of IgM-producing plasma cells with infiltrations of the gastrointestinal tract.
- Although the proliferating B cells are polyclonal, extensive infiltration may lead to death.

- Clinically, individuals with hyper-IgM syndrome present with recurrent pyogenic infections, b/c the level of opsonizing IgG antibodies is low.
- In addition, those with CD40L mutations are also susceptible to pneumonia caused by the intracellular organism Pneumocysticis jiroveci, b/c of the defect in cell-mediated immunity.

References:
1. Kumar, Raminder et al.  Robbins and Cotran Pathologic Basis of Disease 8th Ed.  Sander Elsevier. 2010.