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Anomalies in humoral immunity in the NOD mouse: contribution to the progression of type 1 diabetes
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The non-obese diabetic (NOD) mouse is widely used model Type 1 diabetes (T1D), a chronic inflammatory disease characterized by destruction of the insulin producing β cells in the islets of Langerhans by immune cells. The classical symptoms include increased glucose levels in urine and blood, frequent urination and enhanced thirst. The disease has a strong genetic component and is also influenced by the environment. NOD mice develop T1D spontaneously. The disease occurs in two phases; insulitis - the infiltration of immune cells in the islets of Langerhans and overt diabetes caused by the destruction of insulin producing β cells. Several disease associated gene regions or loci [termed insulin dependent diabetes (Idd) loci] have been associated with T1D development. Although, T1D is recognized as a T cell mediated disease in both mouse and man, many studies have shown the importance of B cells in the pathogenesis of the disease. Autoantibodies appear prior to islet infiltration and several molecular and cellular events precede this beta-cell autoimmunity. Although the pathogenesis of T1D is well characterized, less is known about the environmental and immunological factors that trigger the disease.

In this thesis, we studied the contribution of B cell anomalies to the skewed immune response observed in the NOD mouse. In our studies covered in the thesis we observed that NOD mice display enhanced IgE in the serum already at one week of age. In addition, upon treatment of pre-diabetic NOD mice with anti-IgE antibodies, diabetes incidence was delayed. We hypothesize that the presence of IgE in the system may be explained due to enhanced class switching. Antibody feedback however, is an essential component of the immune response and can lead to either enhanced or dampened responses. Thus, increased IgE may provide positive feedback that might sustain an immune response. We also aimed to analyze the biological consequence of this feature. In vitro stimulation of B cells by the TACI ligand APRIL resulted in enhanced plasma cell differentiation accompanied with increased class switching and IgG production. In addition, TACI+ cells were observed in NOD germinal centers facilitating increased BAFF uptake and subsequent escape of low affinity antibody producing clones. NOD mice elicited an enhanced and prolonged immune response towards T-dependent antigens such as hen-egg lysozyme (HEL). Serum HEL-specific IgG level was significantly increased and was predominantly of the IgG1 isotype. Immunofluorescence analysis of NOD spleen revealed the presence of spontaneous germinal centers which others have perceived to provide a ready niche for the entry of naïve B cells that encountered novel antigen. Adoptive transfer experiments of purified B and T cells from NOD into NOD.Rag2-/- (NOD-RAG) mice illustrated the importance of B cell intrinsic defects in the reproduction of the original phenotype as observed in NOD.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 57 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1834
Keyword [en]
Type 1 Diabetes, NOD mouse, B cells, IgE, TACI, BAFF
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-125001ISBN: 978-91-7601-542-1OAI: oai:DiVA.org:umu-125001DiVA: diva2:957389
Public defence
2016-09-30, Salen - byggnad 6D, R0_A5, Målpunkt R, Umeå University, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-09-09 Created: 2016-09-01 Last updated: 2016-09-09Bibliographically approved
List of papers
1. Contribution of autoallergy to the pathogenesis in the NOD mice
Open this publication in new window or tab >>Contribution of autoallergy to the pathogenesis in the NOD mice
2015 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 48, no 5, 298-304 p.Article in journal (Refereed) Published
Abstract [en]

The immunoglobulin isotype IgE is commonly associated with allergy. However, its involvement in autoimmune disease in general, and Type 1 diabetes (T1D) in particular, is still not completely clarified, nonetheless IgE has been observed in patients with T1D. In this article, we aimed to elucidate the contribution of IgE in the pathogenesis of the disease in a spontaneous model for T1D, i.e. the NOD mouse. We observed increased levels of IgE in splenic, lymph node and peripheral blood B cells in the NOD mice compared to the control C57BL/6 (B6) mice. No correlation was found between the IgE levels on B cells and those in the sera of these mice, indicating a B cell intrinsic property mediating IgE capture in NOD. Functionally, the B cells from NOD were similar to B6 in rescuing the IgE-mediated immune response via the low affinity receptor CD23 in a transgenic adoptive transfer system. However, the involvement of IgE in diabetes development was clearly demonstrated, as treatment with anti-IgE antibodies delayed the incidence of the diabetes in the NOD mice compared to the PBS treated group. Pancreas sections from a 13-week-old NOD revealed the presence of tertiary lymphoid structures with T cells, B cells, germinal centers and IgE suggesting the presence of autoantigen specific IgE. Our study provides an insight to the commonly overlooked immunoglobulin IgE and its potential role in autoimmunity.

Keyword
Autoallergy, B lymphocytes, IgE, NOD mouse, Type 1 diabetes
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-102419 (URN)10.3109/08916934.2015.1016220 (DOI)000359797600004 ()25707684 (PubMedID)
Available from: 2015-04-24 Created: 2015-04-24 Last updated: 2016-09-01Bibliographically approved
2. Increased expression of TACI on NOD B cells results in germinal centre reaction anomalies, enhanced plasma cell differentiation and immunoglobulin production
Open this publication in new window or tab >>Increased expression of TACI on NOD B cells results in germinal centre reaction anomalies, enhanced plasma cell differentiation and immunoglobulin production
2016 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567Article in journal (Refereed) Epub ahead of print
Abstract [en]

B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic (NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACIhigh-expressing B cells compared with C57BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) trait was confirmed using double congenic NOD.B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand (APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch. Hence, the functional consequence of the up-regulation of TACI on NOD B cells was analysed both in vitro and in vivo. NOD B cells stimulated with APRIL showed an enhanced plasma cell differentiation and class switch to IgG and IgA compared with B cells from C57BL/6 mice. Moreover, flow cytometry analyses revealed that germinal centre B cells in NOD failed to down-regulate TACI. Availability of the TACI ligand B-cell activating factor (BAFF) has been shown to be a limiting factor in the germinal centre reaction. In line with this, upon immunization with 4-hydroxy-3-nitrophenylacetyl hapten-conjugated hen egg lysozyme, NOD mice produced higher titres of low-affinity antibodies compared with C57BL/6 mice. This observation was supported by the detection of increased levels of BAFF in NOD germinal centres after immunization compared with C57BL/6 by immunofluorescence. Our results support the hypothesis that increased TACI expression on NOD B cells contributes to the pathogenesis of type 1 diabetes in the NOD mouse.

Keyword
affinity maturation, B cells, B-cell activating factor, non-obese diabetic mouse, transmembrane activat or, calcium modulator and cyclophilin ligand interactor
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-119452 (URN)10.1111/imm.12651 (DOI)
External cooperation:
Note

Originally published in thesis in manuscript form with the title: Increased expression of TACI in the NOD mouse results in enhanced plasma cell differentiation and immunoglobulin production

Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2016-09-09
3. B cell intrinsic defects lead to enhanced immune response in the NOD mice
Open this publication in new window or tab >>B cell intrinsic defects lead to enhanced immune response in the NOD mice
(English)Manuscript (preprint) (Other academic)
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-119453 (URN)
External cooperation:
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2016-09-08

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