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Contribution of autoallergy to the pathogenesis in the NOD mice
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi. (Kristina Lejon)
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi. (Kristina Lejon)
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi. (Kristina Lejon)ORCID-id: 0000-0001-5025-6539
2015 (Engelska)Ingår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 48, nr 5, s. 298-304Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2015. Vol. 48, nr 5, s. 298-304
Nyckelord [en]
Autoallergy, B lymphocytes, IgE, NOD mouse, Type 1 diabetes
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-102419DOI: 10.3109/08916934.2015.1016220ISI: 000359797600004PubMedID: 25707684Scopus ID: 2-s2.0-84942801374OAI: oai:DiVA.org:umu-102419DiVA, id: diva2:807792
Tillgänglig från: 2015-04-24 Skapad: 2015-04-24 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Ingår i avhandling
1. Anomalies in humoral immunity in the NOD mouse: contribution to the progression of type 1 diabetes
Öppna denna publikation i ny flik eller fönster >>Anomalies in humoral immunity in the NOD mouse: contribution to the progression of type 1 diabetes
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2016. s. 57
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1834
Nyckelord
Type 1 Diabetes, NOD mouse, B cells, IgE, TACI, BAFF
Nationell ämneskategori
Immunologi inom det medicinska området
Forskningsämne
immunologi
Identifikatorer
urn:nbn:se:umu:diva-125001 (URN)978-91-7601-542-1 (ISBN)
Externt samarbete:
Disputation
2016-09-30, Salen - byggnad 6D, R0_A5, Målpunkt R, Umeå University, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-09-09 Skapad: 2016-09-01 Senast uppdaterad: 2022-10-03Bibliografiskt granskad

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Thyagarajan, RadhaBanday, ViqarLejon, Kristina

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