Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation

Ashish Jain; Chi A Ma; Eduardo Lopez-Granados; Gary Means; William Brady; Jordan S Orange; Shuying Liu; Steven Holland; Jonathan M J Derry

doi:10.1172/JCI21345

Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation

J Clin Invest. 2004 Dec;114(11):1593-602. doi: 10.1172/JCI21345.

Authors

Ashish Jain¹, Chi A Ma, Eduardo Lopez-Granados, Gary Means, William Brady, Jordan S Orange, Shuying Liu, Steven Holland, Jonathan M J Derry

Affiliation

¹ Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland 20892, USA. [email protected]

PMID: 15578091
PMCID: PMC529497
DOI: 10.1172/JCI21345

Abstract

Hypomorphic mutations in the zinc finger domain of NF-kappaB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-kappaB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-kappaB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-kappaB activation and candidate factors that may be necessary for CSR and SHM in B cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
B-Lymphocytes / cytology
B-Lymphocytes / physiology*
CD40 Antigens / metabolism*
Carrier Proteins / genetics*
Carrier Proteins / immunology*
Cell Differentiation / physiology*
Child, Preschool
Cytidine Deaminase
Cytosine Deaminase / genetics
Cytosine Deaminase / metabolism
Ectodermal Dysplasia / genetics
Ectodermal Dysplasia / immunology
Gene Expression Regulation
Humans
Hypergammaglobulinemia / genetics
Hypergammaglobulinemia / immunology
I-kappa B Kinase
Immunoglobulin Class Switching / genetics
Immunoglobulins / blood
Interleukin-4 / metabolism
Molecular Sequence Data
Mutation*
NF-kappa B / immunology
Proto-Oncogene Proteins c-rel / genetics
Proto-Oncogene Proteins c-rel / immunology*
Somatic Hypermutation, Immunoglobulin / genetics
Syndrome

Substances

CD40 Antigens
Carrier Proteins
IKBKG protein, human
Immunoglobulins
NF-kappa B
Proto-Oncogene Proteins c-rel
Interleukin-4
I-kappa B Kinase
AICDA (activation-induced cytidine deaminase)
Cytosine Deaminase
Cytidine Deaminase