51. |
- Holmdahl, Rikard
(author)
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IL-21 and autoimmune disease - hypothesis and reality?
- 2008
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In: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 38:7, s. 1800-1802
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Journal article (peer-reviewed)abstract
- Previous data have indicated that IL-21 and/or IL-21R are crucial for the differentiation of naïve T cells into Th17 cells and also play a key role in the development of autoimmune disease. Given this, IL-21 and/or IL-21R are potential targets for therapy of such diseases; however, a study in this issue of the European Journal of Immunology, provides a new twist in the story as it is now shown that IL-21 and/or IL-21R play no role in Th17 development or autoimmune inflammatory disease. The reasons for these contradictory data are discussed in this Commentary.See accompanying article: http://dx.doi.org/10.1002/eji.200838511.
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52. |
- Hässler, Signe, et al.
(author)
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Increased antigen presenting cell-mediated T cell activation in mice and patients without the autoimmune regulator
- 2006
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In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 36:2, s. 305-317
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Journal article (peer-reviewed)abstract
- Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire(-/-) dendritic cells (DC) activate naive T cells more efficiently than do Aire(+/+) DC. Expression array analyses of Aire(-/-) DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire(-/-) DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire(-/-) DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire(-/-) DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire(-/-) mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.
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53. |
- Isaksson, Magnus, et al.
(author)
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Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE
- 2009
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In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 39:10, s. 2925-2935
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Journal article (peer-reviewed)abstract
- EAE, an animal model for MS, is a Th17 and Th1-cell-mediated autoimmune disease, but the mechanisms leading to priming of encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. To investigate the role of plasmacytoid DC (pDC) in the initiation of autoimmune Th17- and Th1-cell responses and EAE, we depleted pDC with anti-pDC Ag-1 (anti-PDCA1) mAb prior to immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG). pDC-depleted mice developed less severe clinical and histopathological signs of EAE than control mice, which demonstrates a promoting role for pDC in the initiation of EAE. The levels of type I IFN were much lower in the sera from anti-PDCA1-treated mice. However, neutralization of type I IFN ameliorated the early phase of EAE but did not alter the severity of disease. Thus, only a minor part of the EAE-promoting effect of pDC appears to be mediated by IFN-alpha/beta secretion. The numbers of MOG-specific Th17 cells, but not Th1 cells, were lower in spleen from anti-PDCA1-treated mice compared with controls. In contrast, pDC depletion a week after MOG immunization resulted in more severe clinical signs of EAE. In conclusion, we demonstrate that pDC promote initiation of MOG-induced Th17-cell responses and EAE.
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54. |
- Jenkinson, William E., et al.
(author)
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Chemokine receptor expression defines heterogeneity in the earliest thymic migrants
- 2007
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In: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 37:8, s. 2090-2096
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Journal article (peer-reviewed)abstract
- Chemokine signaling has been implicated in directing colonization of the fetal thymus by hematopoietic precursors. However, the patterns of expression of the chemokine receptors responsible for directing thymic colonization by the earliest thymic migrants remain unknown. We have identified heterogeneity within the earliest thymus seeding cells based on chemokine receptor expression. By analyzing the first wave of progenitors to colonize the thymus at E12 of gestation, we show that multiple chemokine receptors are expressed by T-lymphoid precursors present within perithymic mesenchyme, while expression of chemokine ligands is limited to CCL21, CCL25 and CXCL12, which are located in distinct epithelial and mesenchymal compartments of the thymic/parathyroid anlagen. Collectively, these results identify multiple populations of T-lymphoid precursors colonizing the fetal thymus and provide evidence for several potential pathways mediating migration of precursors into the embryonic thymus.
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55. |
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56. |
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57. |
- Kutty Selva, Nandakumar, et al.
(author)
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Endoglycosidase treatment abrogates IgG arthritogenicity: Importance of IgG glycosylation in arthritis.
- 2007
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In: European Journal of Immunology. - Weinheim : Wiley. - 1521-4141 .- 0014-2980. ; 37:10, s. 2973-2982
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Journal article (peer-reviewed)abstract
- The glycosylation status of IgG has been implicated in the pathology of rheumatoid arthritis. Earlier, we reported the identification of a novel secreted endo-beta-N-acetylglucosaminidase (EndoS), secreted by Streptococcus pyogenes that specifically hydrolyzes the beta-1,4-di-N-acetylchitobiose core of the asparagine-linked glycan of human IgG. Here, we analyzed the arthritogenicity of EndoS-treated collagen type II (CII) -specific mouse mAb in vivo. Endoglycosidase treatment of the antibodies inhibited the induction of arthritis in (BALB/c x B10.Q) F1 mice and induced a milder arthritis in B10.RIII mice as compared with the severe arthritis induced by non-treated antibodies. Furthermore, EndoS treatment did not affect the binding of IgG to CII and their ability to activate complement, but it resulted in reduced IgG binding to Fc gamma R and disturbed the formation of stable immune complexes. Hence, the asparagine-linked glycan on IgG plays a crucial role in the development of arthritis.
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58. |
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59. |
- Licence, S, et al.
(author)
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The VpreB1 enhancer drives developmental stage-specific gene expression in vivo
- 2003
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In: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 33:4, s. 1117-1126
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Journal article (peer-reviewed)abstract
- In adult mice, the VpreB genes are expressed in bone marrow progenitor (pro-) and precursor (pre-) B cells. As part of the pre-B cell receptor, the proteins are crucial for the proliferation of these cells and consequently normal B lymphocyte development. Using cell lines, we identified a lineage- and developmental-stage-specific VpreB1 enhancer. Here, we analyze its specificity in vivo by generating transgenic mice in which expression of a reporter gene (human CD122) is regulated by the VpreB1 enhancer in the context of its own promoter. All transgenic lines expressed the reporter gene in the bone marrow in a copy number-independent manner, whereas expression levels were integration site-dependent. While the enhancer is not tissue specific, within the B cell lineage the expression pattern of human CID122 mimicked that of endogenous VpreB1. Thus, low levels were detected in pro-B cells, high levels in pre-BI and slightly lower levels in pre-BII cells; no expression was detected in immature/mature B cells. Furthermore, when in vitro cultured transgenic pre-B cells differentiated into immature B cells there was concomitant down-regulation of human CD122 and endogenous VpreB1. Thus the VpreB1 enhancer is sufficient to ensure developmental stage-specific expression of a reporter gene in B lymphocytes in vivo.
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60. |
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