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An Activation-Induced Cytidine Deaminase-Independent Mechanism of Secondary V_H Gene Rearrangement in Preimmune Human B Cells¹

Nancy S. Longo^2,*, Gabrielle J. Grundy, Jisoo Lee^*, Martin Gellert and Peter E. Lipsky^*

^* Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases and Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

V_H replacement is a form of IgH chain receptor editing that is believed to be mediated by recombinase cleavage at cryptic recombination signal sequences (cRSS) embedded in V_H genes. Whereas there are several reports of V_H replacement in primary and transformed human B cells and murine models, it remains unclear whether V_H replacement contributes to the normal human B cell repertoire. We identified V_HV_H(D)J_H compound rearrangements from fetal liver, fetal bone marrow, and naive peripheral blood, all of which involved invading and recipient V_H4 genes that contain a cryptic heptamer, a 13-bp spacer, and nonamer in the 5' portion of framework region 3. Surprisingly, all pseudohybrid joins lacked the molecular processing associated with typical V_H(D)J_H recombination or nonhomologous end joining. Although inefficient compared with a canonical recombination signal sequences, the V_H4 cRSS was a significantly better substrate for in vitro RAG-mediated cleavage than the V_H3 cRSS. It has been suggested that activation-induced cytidine deamination (AICDA) may contribute to V_H replacement. However, we found similar secondary rearrangements using V_H4 genes in AICDA-deficient human B cells. The data suggest that V_H4 replacement in preimmune human B cells is mediated by an AICDA-independent mechanism resulting from inefficient but selective RAG activity.

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 research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases intramural research programs of the National Institutes of Health, Bethesda, MD.

² Address correspondence and reprint requests to Dr. Peter E. Lipsky, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 6D47C, Bethesda, MD 20892-1560. E-mail address: peterlipsky{at}comcast.net

³ Abbreviations used in this paper: RSS, recombination signal sequence; AICDA, activation-induced cytidine deaminase; cRSS, cryptic RSS; FR, framework region; HMG, high mobility group; HMGB1, HMG box 1; IGMT, ImMunoGeneTics; NS, nonspecific; SHM, somatic hypermutation; X-HIgM, X-linked hyper-IgM.

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