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Murine Model of CD40-activation of B cells
Published on: March 6, 2010
Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation
Ashish Jain1, Chi A Ma, Eduardo Lopez-Granados
1Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland 20892, USA. ajain@niaid.nih.gov
The Journal of Clinical Investigation
|December 4, 2004
Summary
Mutations in NEMO cause X-linked hyper-IgM syndrome with ectodermal dysplasia, impairing B cell antibody responses. This study reveals NEMO
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Hypomorphic mutations in NEMO cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED).
- B cells in XHM-ED patients exhibit defective immunoglobulin (Ig) somatic hypermutation (SHM) and class switch recombination (CSR).
Purpose of the Study:
- To investigate the molecular mechanisms underlying defective B cell function in XHM-ED.
- To elucidate the role of NEMO-dependent NF-kappaB signaling in CSR and SHM.
Main Methods:
- Analysis of patient B cells.
- Stimulation with CD40 ligand and IL-4.
- Microarray analysis.
Main Results:
- Patient B cells showed absent SHM and defective CSR despite normal activation-induced cytidine deaminase (AID) induction.
- Impaired activation of p65 and c-Rel NF-kappaB components was observed.
- IL-4 enhanced p65 activity but not c-Rel activity.
- Microarray analysis identified downstream effects of impaired NF-kappaB signaling.
Conclusions:
- AID expression alone is insufficient for effective antibody responses.
- NEMO-dependent NF-kappaB signaling, particularly c-Rel activation, is crucial for CSR and SHM.
- IL-4 differentially affects NEMO-dependent NF-kappaB pathways.
- Identification of candidate factors essential for B cell CSR and SHM.
