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Thyagarajan, Radha
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Banday, V. S., Thyagarajan, R. & Lejon, K. (2017). Contribution of both B cell intrinsic alterations as well as non-hematopoietic derived factors in the enhanced immune response of the NOD mouse. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 252-252
Öppna denna publikation i ny flik eller fönster >>Contribution of both B cell intrinsic alterations as well as non-hematopoietic derived factors in the enhanced immune response of the NOD mouse
2017 (Engelska)Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, nr 4, s. 252-252Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
WILEY, 2017
Nationell ämneskategori
Immunologi
Identifikatorer
urn:nbn:se:umu:diva-140890 (URN)10.1111/sji.12587 (DOI)000411865200015 ()
Konferens
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Anmärkning

Meeting Abstract: A-31163

Tillgänglig från: 2017-11-21 Skapad: 2017-11-21 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Banday, V. S., Thyagarajan, R. & Lejon, K. (2017). Contribution of both B-cell intrinsic alterations as well as non-hematopoietic-derived factors in the enhanced immune response of the NOD mouse. Autoimmunity, 50(6), 363-369
Öppna denna publikation i ny flik eller fönster >>Contribution of both B-cell intrinsic alterations as well as non-hematopoietic-derived factors in the enhanced immune response of the NOD mouse
2017 (Engelska)Ingår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, nr 6, s. 363-369Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The underlying cellular and molecular mechanism for the development of Type 1 diabetes is still to be fully revealed. We have previously demonstrated that the NOD mouse, a model for Type 1 diabetes, display a prolonged and enhanced immune response to both self and non-self-antigens. The molecular explanation for this defect however, has not been determined. In this study we immunized NOD and C57BL/6 (B6) with the conventional antigen i.e. hen egg lysozyme (HEL) and analyzed B cell activation, germinal center reaction and antibody clearance. Corroborating our previous observations NOD mice responded robustly to a single immunization of HEL. Immunofluorescence analysis of the spleen revealed an increased number of germinal centers in unimmunized NOD compared to B6. However, post immunization germinal center numbers were similar in NOD and B6. NOD mice showed lower response to BCR stimulation with anti-IgM, in particular at lower concentrations of anti-IgM. Antibody clearance in vivo did not differ between the strains. To determine the cell type that is responsible for the prolonged and enhance immune response, we reconstituted NOD-RAGs with cells from primed donors in different combinations. NOD B cells were required to reproduce the phenotype; however the non-lymphoid compartment of NOD origin also played a role. Based on our results we propose that preexisting GCs in the NOD promote the robust response and alteration in the BCR signaling could promote survival of stimulated cells. Overall, this mechanism could in turn also contribute to the activation and maintenance of autoreactive B cells in the NOD mouse.

Ort, förlag, år, upplaga, sidor
TAYLOR & FRANCIS LTD, 2017
Nyckelord
Type 1 diabetes, immune response, NOD mouse, B lymphocytes, hen egg lysozyme
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-140061 (URN)10.1080/08916934.2017.1344977 (DOI)000410935800004 ()28686488 (PubMedID)
Tillgänglig från: 2017-09-29 Skapad: 2017-09-29 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Thyagarajan, R. (2016). Anomalies in humoral immunity in the NOD mouse: contribution to the progression of type 1 diabetes. (Doctoral dissertation). Umeå: Umeå University
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: 2018-06-07Bibliografiskt granskad
Banday, V. S., Thyagarajan, R., Sundström, M. & Lejon, K. (2016). Increased expression of TACI on NOD B cells results in germinal centre reaction anomalies, enhanced plasma cell differentiation and immunoglobulin production. Immunology, 149(3), 297-305
Öppna denna publikation i ny flik eller fönster >>Increased expression of TACI on NOD B cells results in germinal centre reaction anomalies, enhanced plasma cell differentiation and immunoglobulin production
2016 (Engelska)Ingår i: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 149, nr 3, s. 297-305Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
affinity maturation, B cells, B-cell activating factor, non-obese diabetic mouse, transmembrane activat or, calcium modulator and cyclophilin ligand interactor
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-119452 (URN)10.1111/imm.12651 (DOI)000387360300005 ()27444337 (PubMedID)
Anmärkning

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

Tillgänglig från: 2016-04-19 Skapad: 2016-04-19 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Thyagarajan, R., Banday, V., Ding, Z. & Lejon, K. (2015). Contribution of autoallergy to the pathogenesis in the NOD mice. Autoimmunity, 48(5), 298-304
Öppna denna publikation i ny flik eller fönster >>Contribution of autoallergy to the pathogenesis in the NOD mice
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.

Nyckelord
Autoallergy, B lymphocytes, IgE, NOD mouse, Type 1 diabetes
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-102419 (URN)10.3109/08916934.2015.1016220 (DOI)000359797600004 ()25707684 (PubMedID)
Tillgänglig från: 2015-04-24 Skapad: 2015-04-24 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Thyagarajan, R. & Lejon, K. (2014). B Cells and IgE in Type 1 Diabetes. Paper presented at 42nd Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), JUN 11-14, 2014, Reykjavik, ICELAND. Scandinavian Journal of Immunology, 79(6), 452-452
Öppna denna publikation i ny flik eller fönster >>B Cells and IgE in Type 1 Diabetes
2014 (Engelska)Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, nr 6, s. 452-452Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-91214 (URN)000337588500074 ()
Konferens
42nd Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), JUN 11-14, 2014, Reykjavik, ICELAND
Tillgänglig från: 2014-07-21 Skapad: 2014-07-21 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Banday, V. S., Thyagarajan, R. & Lejon, K.B cell intrinsic defects lead to enhanced immune response in the NOD mice.
Öppna denna publikation i ny flik eller fönster >>B cell intrinsic defects lead to enhanced immune response in the NOD mice
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-119453 (URN)
Externt samarbete:
Tillgänglig från: 2016-04-19 Skapad: 2016-04-19 Senast uppdaterad: 2018-06-07
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