Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans

Meyers, Greta; Ng, Yen-Shing; Bannock, Jason M.; Lavoie, Aubert; Walter, Jolán E.; Notarangelo, Luigi D.; Kılıç, Sara Şebnem; Aksu, Güzide; Debré, Marianne; Rieux-Laucat, Frédéric; Conley, Mary Ellen; Cunningham‐Rundles, Charlotte; Durandy, Anne; Meffre, Eric

doi:10.1073/pnas.1102600108

Cited by 122 publications

(164 citation statements)

References 52 publications

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“…The molecular or cellular basis for this novel phenotype of UNG deficiency, and whether the C57BL/6 background has any incidence, is unknown. It is suggestive that the presence of circulating autoantibodies in AID-deficient mice and patients was recently found to be a consequence of a defect in B cell tolerance (43,44). The mechanism by which AID contributes to B cell tolerance is unknown, but our results suggest the possibility that UNG can be part of this pathway and warrants further investigation.…”

Section: Discussionmentioning

confidence: 83%

Separation of Function between Isotype Switching and Affinity Maturation In Vivo during Acute Immune Responses and Circulating Autoantibodies in UNG-Deficient Mice

Zahn

Daugan

Safavi

et al. 2013

The Journal of Immunology

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Activation-induced deaminase converts deoxycytidine to deoxyuridine at the Ig loci. Complementary pathways, initiated by the uracil-DNA glycosylase (UNG) or the mismatch repair factor MSH2/MSH6, must process the deoxyuridine to initiate class-switch recombination (CSR) and somatic hypermutation. UNG deficiency most severely reduces CSR efficiency and only modestly affects the somatic hypermutation spectrum in vitro. This would predict isotype-switching deficiency but normal affinity maturation in Ung−/− mice in vivo, but this has not been tested. Moreover, puzzling differences in the amount of circulating Ig between UNG-deficient humans and mice make it unclear to what extent MSH2/MSH6 can complement for UNG in vivo. We find that Ab affinity maturation is indeed unaffected in Ung−/− mice, even allowing IgM responses with higher than normal affinity. Ung−/− mice display normal to only moderately reduced basal levels of most circulating Ig subclasses and gut-associated IgA, which are elicited in response to chronically available environmental Ag. In contrast, their ability to produce switched Ig in response to immunization or vesicular stomatitis virus infection is strongly impaired. Our results uncover a specific need for UNG in CSR for timely and efficient acute Ab responses in vivo. Furthermore, Ung−/− mice provide a novel model for separating isotype switching and affinity maturation during acute (but not chronic) Ab responses, which could be useful for dissecting their relative contribution to some infections. Interestingly, Ung−/− mice present with circulating autoantibodies, suggesting that UNG may impinge on tolerance.

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Section: Discussionmentioning

confidence: 83%

Separation of Function between Isotype Switching and Affinity Maturation In Vivo during Acute Immune Responses and Circulating Autoantibodies in UNG-Deficient Mice

Zahn

Daugan

Safavi

et al. 2013

The Journal of Immunology

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“…2 and 4B). Significantly, a comparable role for the orthologous AICDA gene in human B-cell tolerance has been discovered by Meyers and colleagues (41).…”

Section: Discussionmentioning

confidence: 93%

Activation-induced cytidine deaminase mediates central tolerance in B cells

Kuraoka

Holl

Liao

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

123

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The Aicda gene product, activation-induced cytidine deaminase (AID), initiates somatic hypermutation, class-switch recombination, and gene conversion of Ig genes by the deamination of deoxycytidine, followed by error-prone mismatch-or base-excision DNA repair. These processes are crucial for the generation of genetically diverse, high affinity antibody and robust humoral immunity, but exact significant genetic damage and promote cell death. In mice, physiologically significant AID expression was thought to be restricted to antigen-activated, mature B cells in germinal centers. We now demonstrate that low levels of AID in bone marrow immature and transitional B cells suppress the development of autoreactivity. Aicda −/− mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature and transitional B cells. In vitro, AID deficient immature/transitional B cells are significantly more resistant to anti-IgM-induced apoptosis than their normal counterparts. Thus, early AID expression plays a fundamental and unanticipated role in purging selfreactive immature and transitional B cells during their maturation in the bone marrow.Aicda-knockout mice | B-cell development | B-cell tolerance | competitive hematopoietic reconstitution | lymphopoiesis

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“…17 We hypothesize that the non-CpG breaks in MCL might occur in immature/transitional 1 (T1) stage B cells, where AID is expressed at an intermediate level [18][19][20][21][22] (Figure 1B), presumably in conjunction with receptor editing. [22][23][24] This would explain their preference for WGCW motifs Figures 1 and 2). ʈNon-V(D)J break between JH4 and JH5 (see supplemental Figure 1).…”

Section: Resultsmentioning

confidence: 99%

IgH partner breakpoint sequences provide evidence that AID initiates t(11;14) and t(8;14) chromosomal breaks in mantle cell and Burkitt lymphomas

Greisman

Tsai

et al. 2012

Blood

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Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans

Cited by 122 publications

References 52 publications

Separation of Function between Isotype Switching and Affinity Maturation In Vivo during Acute Immune Responses and Circulating Autoantibodies in UNG-Deficient Mice

Separation of Function between Isotype Switching and Affinity Maturation In Vivo during Acute Immune Responses and Circulating Autoantibodies in UNG-Deficient Mice

Activation-induced cytidine deaminase mediates central tolerance in B cells

IgH partner breakpoint sequences provide evidence that AID initiates t(11;14) and t(8;14) chromosomal breaks in mantle cell and Burkitt lymphomas

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