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A Novel Mouse Model for the Hyper-IgM Syndrome: A Spontaneous Activation-Induced Cytidine Deaminase Mutation Leading to Complete Loss of Ig Class Switching and Reduced Somatic Hypermutation
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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2014 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 9, 4732-4738 p.Article in journal (Refereed) Published
Abstract [en]

We describe a spontaneously derived mouse line that completely failed to induce Ig class switching in vitro and in vivo. The mice inherited abolished IgG serum titers in a recessive manner caused by a spontaneous G -> A transition mutation in codon 112 of the aicda gene, leading to an arginine to histidine replacement (AID(R112H)). Ig class switching was completely reconstituted by expressing wild-type AID. Mice homozygous for AID(R112H) had peripheral B cell hyperplasia and large germinal centers in the absence of Ag challenge. Immunization with SRBCs elicited an Ag-specific IgG1 response in wild-type mice, whereas AID(R112H) mice failed to produce IgG1 and had reduced somatic hypermutation. The phenotype recapitulates the human hyper-IgM (HIGM) syndrome that is caused by point mutations in the orthologous gene in humans, and the AID(R112H) mutation is frequently found in HIGM patients. The AID(R112H) mouse model for HIGM provides a powerful and more precise tool than conventional knockout strategies.

Place, publisher, year, edition, pages
2014. Vol. 193, no 9, 4732-4738 p.
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-110180DOI: 10.4049/jimmunol.1401242ISI: 000344079500047OAI: oai:DiVA.org:su-110180DiVA: diva2:787506
Note

AuthorCount:9;

Available from: 2015-02-10 Created: 2014-12-08 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Regulation of Immunoglobulin Isotype Switching and of the Germinal Center Response
Open this publication in new window or tab >>Regulation of Immunoglobulin Isotype Switching and of the Germinal Center Response
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

After stimulation, B cells can undergo two types of genetic alteration in their immunoglobulin (Ig) genes: somatic hypermutation and class switch recombination (CSR), both of which are initiated by activation-induced cytidine deaminase (AID).

Although class switching requires cell proliferation, the mechanism is partly unknown. In Study I, analysis of the cell cycle distribution of newly switched cells showed that majority of the IgG1+ cells were in the S/G2/M phases, suggesting that switching ended in the late G1 or early S phase. Subsequent experiments with roscovitine treatment showed that Ig switching reduced dramatically upon the inhibition of CDK activity, suggesting the involvement of CDK during CSR. Interestingly the association of AID to the S region was compromised, while the expression levels of aicda, ung and germline transcripts were unchanged upon inhibition. This is probably due to the reduced accumulation of AID in the nucleus. In  study II, we identified a mouse strain with a spontaneous point mutation in AID, leading to an amino acid substitution of arginine 112 by histidine. In this work, we aimed at establishing a mouse model for type II hyper IgM syndrome. We found that both CSR and somatic hypermutation was completely abolished in the mutant B cells, indicating that R112 is essential for AID function. The mutant mice were characterized by big germinal centers even before immunization, and they had an elevated total B cell population with a relatively lower percentage of plasma cells, indicating that B cell differentiation is halted in these mice. In Study III, we analyzed how BCL6 was influenced by type I interferons (IFNs). We found that IFN-α down-regulated BCL6 mRNA in a JAK/STAT-dependent way and promoted BCL6 protein degradation in the germinal center-derived cell lines. Similar result was found also in primary germinal center B cells. This suggests a mechanism for the impact of the innate immune response on the adaptive immune response.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2014. 67 p.
National Category
Biological Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-106690 (URN)978-91-7447-942-3 (ISBN)
Public defence
2014-09-23, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
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Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 2: Accepted.

Available from: 2014-09-01 Created: 2014-08-15 Last updated: 2017-03-08Bibliographically approved

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