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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.
AuthorsMasayuki Kuraoka, Dongmei Liao, Kaiyong Yang, Sallie D Allgood, Marc C Levesque, Garnett Kelsoe, Yoshihiro Ueda
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 5 Pg. 3237-48 (Sep 01 2009) ISSN: 1550-6606 [Electronic] United States
PMID19667096 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Receptors, Antigen, B-Cell
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase
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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