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Regulation of Immunoglobulin Isotype Switching and of the Germinal Center Response
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2014. , s. 67
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
immunologi
Identifikatorer
URN: urn:nbn:se:su:diva-106690ISBN: 978-91-7447-942-3 (tryckt)OAI: oai:DiVA.org:su-106690DiVA, id: diva2:738104
Disputation
2014-09-23, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript.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

Tillgänglig från: 2014-09-01 Skapad: 2014-08-15 Senast uppdaterad: 2017-03-08Bibliografiskt granskad
Delarbeten
1. Cyclin-dependent kinases regulate Ig class switching by controlling access of AID to the nucleus
Öppna denna publikation i ny flik eller fönster >>Cyclin-dependent kinases regulate Ig class switching by controlling access of AID to the nucleus
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Immunologi
Forskningsämne
immunologi
Identifikatorer
urn:nbn:se:su:diva-106879 (URN)
Tillgänglig från: 2014-08-26 Skapad: 2014-08-26 Senast uppdaterad: 2014-08-26
2. 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
Öppna denna publikation i ny flik eller fönster >>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
Visa övriga...
2014 (Engelska)Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, nr 9, s. 4732-4738Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Immunologi
Forskningsämne
immunologi
Identifikatorer
urn:nbn:se:su:diva-110180 (URN)10.4049/jimmunol.1401242 (DOI)000344079500047 ()
Anmärkning

AuthorCount:9;

Tillgänglig från: 2015-02-10 Skapad: 2014-12-08 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
3. Type I interferons directly down-regulate BCL-6 in primary and transformed germinal center B cells: Differential regulation in B cell lines derived from endemic or sporadic Burkitt's lymphoma
Öppna denna publikation i ny flik eller fönster >>Type I interferons directly down-regulate BCL-6 in primary and transformed germinal center B cells: Differential regulation in B cell lines derived from endemic or sporadic Burkitt's lymphoma
Visa övriga...
2012 (Engelska)Ingår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 57, nr 3, s. 360-371Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Type I interferons (IFN) exert multiple effects on both the innate and adaptive immune system in addition to their antiviral and antiproliferative activities. Little is known, however about the direct effects of type IFNs on germinal center (GC) B cells, the central components of adaptive B cell responses. We used Burkitt's lymphoma (BL) lines, as a model system of normal human GC B cells, to examine the effect of type I IFNs on the expression of BCL-6, the major regulator of the GC reaction. We show that type I IFNs, but not IFN gamma, IL-2 and TNF alpha rapidly down-regulate BCL-6 protein and mRNA expression, in cell lines derived from endemic, but not from sporadic BL. IFN alpha-induced down-regulation is specific for BCL-6, independent of Epstein-Barr virus and is not accompanied by IRF-4 up-regulation. IFN alpha-induced BCL-6 mRNA down-regulation does not require de novo protein synthesis and is specifically inhibited by piceatannol. The proteasome inhibitor mG132 non-specifically prevents, while inhibitors of alternate type I IFN signaling pathways do not inhibit IFNa-induced BCL-6 protein downregulation. We validate our results with showing that IFN alpha rapidly down-regulates BCL-6 mRNA in purified mouse normal GC B cells. Our results identify type I IFNs as the first group of cytokines that can down-regulate BCL-6 expression directly in GC B cells.

Nyckelord
Type I interferons, BCL-6, Burkitt's lymphoma
Nationell ämneskategori
Immunologi
Forskningsämne
immunologi
Identifikatorer
urn:nbn:se:su:diva-77001 (URN)10.1016/j.cyto.2011.12.001 (DOI)000300868000008 ()
Anmärkning

12

Tillgänglig från: 2012-05-28 Skapad: 2012-05-28 Senast uppdaterad: 2017-12-07Bibliografiskt granskad

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He, Minghui
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Institutionen för molekylär biovetenskap, Wenner-Grens institut
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