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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901548v1 183/5/3237    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kuraoka, M. Articles by Ueda, Y. PubMed PubMed Citation Articles by Kuraoka, M. Articles by Ueda, Y.

Activation-Induced Cytidine Deaminase Expression and Activity in the Absence of Germinal Centers: Insights into Hyper-IgM Syndrome¹

Masayuki Kuraoka^*, Dongmei Liao^*, Kaiyong Yang^*, Sallie D. Allgood, Marc C. Levesque, Garnett Kelsoe^2,* and Yoshihiro Ueda^*

^* Department of Immunology and Department of Medicine, Duke University, Durham, NC 27710

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Bill and Melinda Gates Foundation and National Institutes of Health Grants AI024335, AI056363 (to G.K.), and AI066106 (to M.L.).

² Address correspondence and reprint requests to Dr. Garnett Kelsoe, Department of Immunology, Duke University, Durham, NC 27710. E-mail address: ghkelsoe{at}duke.edu

³ Abbreviations used in this paper: SHM, somatic hypermutation; AID, activation-induced cytidine deaminase; AMuLV, Abelson murine leukemia virus; BL/6, C57BL/6; BM, bone marrow; CGG, chicken -globulin; CSR, class-switch recombination; GC, germinal center; HIGM1, type-1 hyper IgM syndrome; im/T1, immature/transitional 1; MF, mature follicular; MZ, marginal zone; NIP, (4-hydroxy-5-iodo-3-nitrophenyl)acetyl; NP, (3-hydroxy-4-nitrophenyl)acetyl; PP, Peyer’s patch; T_d, T cell-dependent; T_i, T cell-independent; T2, transitional 2.

⁴ The online version of this article contains supplemental material.