Brief CommunicationB cells from nuclear factor kB essential modulator deficient patients fail to differentiate to antibody secreting cells in response to TLR9 ligand

- Hypomorphic mutations in the NF-kB essential modulator (NEMO) result in HED with immunodeficiency (HED-ID, OMIM 300291).
- The Immunodeficiency is characterized by hypogammaglobulinemia, defect in the response to antigens and hyper-IgM.
- Little is known about the cause of the humoral defects which is explained only in part by alterations in the CD40 signaling..
- In HED-ID impaired B-cell differentiation, in response to CpG help explain the susceptibility to encapsulated bacteria.
- Memory B-cells from XLHED produce low levels of IgA or IgG, upon CpG stimulation suggesting an immunodefect in such patients.

Hypohidrotic ectodermal dysplasia (HED) consists of disorders resulting from molecular alterations of ectodysplasin-A (EDA) pathway. Hypomorphic mutations in NF-kB essential modulator, downstream EDA, result in HED with immunodeficiency (HED-ID), characterized by susceptibility to encapsulated pyogenic bacteria infections. Increased susceptibility to pneumococcal infections and poor response to polysaccharide antigens are associated with defect in T-independent B-cell immunity. We investigated B-cell differentiation and immunoglobulin secretion induced by the TLR9 ligand CpG in two HED-ID and in a HED patient caused by EDA mutations (XLHED). In HED-ID, only few B cells differentiated into plasma cells upon TLR9 stimulation and memory B cells did not produce IgG and IgA, but small amounts of IgM. Unexpectedly, memory B cells from XLHED patient failed to produce normal IgA or IgG amount upon TLR9 stimulation. Our findings expand the knowledge about the pathogenesis of humoral alterations in HED patients and help explain the susceptibility to pneumococcal infections.