Activation-induced cytidine deaminase expression and activity in the absence of germinal centers: insights into hyper-IgM syndrome.
Abstract |
Somatic hypermutation normally occurs as a consequence of the expression of activation-induced cytidine deaminase (AID) by Ag-activated, mature B cells during T cell-dependent germinal center responses. Nonetheless, despite their inability to express CD154 and initiate GC responses, patients with type 1 hyper-IgM syndrome ( HIGM1) support populations of IgM(+) IgD(+)CD27(+) B cells that express mutated Ig genes. The origin of these mutated B cells is unknown; the IgM(+) IgD(+)CD27(+) cells do not express AID and appear to acquire mutations independent of stringent selection by Ag. Here, we demonstrate that immature/transitional 1 B cells from the bone marrow of CD154-deficient mice express AID and acquire Ig mutations that lack the hallmarks of antigenic selection via BCR signaling. Comparable levels of AID expression was found in developmentally immature B cells recovered from murine fetal liver and from human immature/transitional 1 B cells recovered from umbilical cord blood. AID expression in human fetal liver was also robust, approaching that of human tonsil tissue and the human germinal center B cell line, Ramos. These observations led us to conclude that AID expression in developing human B cells is the origin of the mutated IgM(+) IgD(+)CD27(+) B cells present in HIGM1 patients, and we propose that both mice and humans share a latent, AID-dependent pathway for the preimmune diversification of B lymphocytes that is more prominent in chicken, sheep, and rabbits.
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Authors | Masayuki Kuraoka, Dongmei Liao, Kaiyong Yang, Sallie D Allgood, Marc C Levesque, Garnett Kelsoe, Yoshihiro Ueda |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 183
Issue 5
Pg. 3237-48
(Sep 01 2009)
ISSN: 1550-6606 [Electronic] United States |
PMID | 19667096
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Receptors, Antigen, B-Cell
- AICDA (activation-induced cytidine deaminase)
- Cytidine Deaminase
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Topics |
- Animals
- B-Lymphocyte Subsets
(enzymology, immunology, pathology)
- Bone Marrow Cells
(enzymology, immunology, pathology)
- Cell Line, Transformed
- Cell Line, Tumor
- Cytidine Deaminase
(biosynthesis, genetics, metabolism)
- Female
- Gene Expression Regulation, Developmental
(immunology)
- Gene Rearrangement, B-Lymphocyte
(genetics)
- Germinal Center
(enzymology, immunology, pathology)
- Humans
- Hyper-IgM Immunodeficiency Syndrome
(enzymology, genetics, immunology)
- Immunophenotyping
- Lymphocyte Activation
(genetics, immunology)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Molecular Sequence Data
- Receptors, Antigen, B-Cell
(deficiency, genetics)
- Signal Transduction
(genetics, immunology)
- Somatic Hypermutation, Immunoglobulin
(genetics)
- Stem Cells
(enzymology, immunology, pathology)
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