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- Hässler, Signe, et al.
(författare)
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Aire deficiency causes increased susceptibility to streptozotocin-induced murine type 1 diabetes
- 2008
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 67:6, s. 569-580
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Tidskriftsartikel (refereegranskat)abstract
- Aire-deficient mice are a model of the human monogenic disorder autoimmune polyendocrine syndrome type I (APS I) characterized by a progressive autoimmune destruction of multiple endocrine glands such as the adrenal cortex, the parathyroids and the beta-cells of the pancreas. The disease is caused by mutations in the autoimmune regulator (AIRE) gene, a putative transcription factor expressed in thymic medullary epithelial cells and in antigen-presenting cells of the myeloid lineage in peripheral lymphoid organs. As Aire(-/-) mice do not spontaneously develop endocrinopathies, we wanted to evaluate the autoimmune multiple low-dose streptozotocin (MLDSTZ) diabetes model in Aire(-/-) mice. Surprisingly, Aire heterozygote mice were most susceptible to MLDSTZ-induced diabetes, whereas Aire(-/-) mice displayed an intermediate sensitivity to diabetes. Furthermore, Aire(-/-) macrophages produced higher levels of TNF-alpha and lower levels of IL-10 following streptozotocin stimulation, and Aire(-/-) mice developed a higher frequency of islet cells autoantibodies as a sign of increased activation. However, the number of islet infiltrating F4/80(+) Aire(-/-) macrophages was significantly decreased which was attributed to an increased susceptibility to streptozotocin cytotoxicity of Aire(-/-) macrophages. In conclusion, Aire(-/-) macrophages display an increased activation after STZ stimuli, but suffer from increased susceptibility to STZ cytotoxicity. These results support an important function of Aire in the control of peripheral tolerance through myeloid antigen-presenting cells.
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- Ahlén Bergman, Emma, et al.
(författare)
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Epigenetic methylation profiles of CD4 T cell signature loci from patients with urinary bladder cancer
- 2017
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Ingår i: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 86:4, s. 264-264
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Urinary bladder cancer (UBC) is one of the most frequent cancer diseases with 380 000 new cases diagnosed worldwide and about 150 000 deaths yearly. To dissect the role of T helper (Th) cell responses in UBC we investigate the T helper cell subpopulations; Th1, Th2, Th17 and T regulatory cells (Tregs) and their lineage commitment in draining (sentinel) and non-draining lymph nodes and blood from patients subjected to transurethral resection of the bladder (TUR-B) and/or Cystectomy. By analyzing methylation in signature genes IFNG, IL13, IL17a and FOXP3 we measure the epigenetic stability of these T helper cells.In most patients IFNG is more demethylated in sentinel nodes compared to non-sentinel nodes and blood, suggesting a Th1 activation in nodes in contact with the tumor. Aside from that, the distribution of subpopulations in all tissues investigated is highly variable in between patients. All subsets are represented, although there seem to be no or little Th17 cells in nodes. After neoadjuvant treatment (given in between the TUR-B and cystectomy) a temporary increase in methylation of IFNG locus is seen in blood, which could suggest a translocation of activated Th cells from the blood to the tumor area, but also de novo synthesis of Th cells.By analyzing the intra-patient variations in distribution and relative amount of Th cell subpopulations in blood and sentinel nodes we hope to draw conclusions on differences in outcome. The long-term goal is to be able to identify which patients could respond well to immune modulatory treatments.
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- Arkestal, Kurt, et al.
(författare)
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CCR2 upregulated on peripheral T cells in osteoarthritis but not in bone marrow
- 2018
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Ingår i: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 88:6
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Tidskriftsartikel (refereegranskat)abstract
- Osteoarthritis (OA) is a condition affecting millions of patients around the world, causing pain and disability and often resulting in joint replacement surgery. The aetiology of OA has long been attributed to mechanical wear mainly due to the increased prevalence of OA in load bearing joints among older patients. However, recent studies reveal a complex molecular disease causality in which inflammation, nutritional deficit and angiogenesis lead to the destruction of the joint structure. The aim of this study was to examine chemokine receptor expression in peripheral blood and bone marrow in OA patients. We devised a protocol for extracting healthy bone marrow from patients undergoing hip arthroplasty due to coxarthrosis. Flow cytometry was used to determine the expression of 18 chemokine receptors on CD4 and CD8 T cells from bone marrow and blood from 7 osteoarthritis patients and peripheral blood from 9 healthy controls. We found a significantly increased fraction of CCR2 expressing CD4 and CD8 T cell in peripheral blood compared to healthy controls. Also, there was a significant decrease in CXCR3 (Th1) (P < 0.01) expressing T cells in peripheral blood from OA patients. Finally, multivariate analysis was used to separate T cell profiles from healthy controls and OA patients and demonstrate that the divergence of chemokine receptor expression occurs in the mature T cell subsets. In conclusion, we find increased CCR2 expression in peripheral blood from OA patients that possibly may be targeted in future clinical studies.
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- Krantz, David, et al.
(författare)
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IL-16 processing in sentinel node regulatory T cells is a factor in bladder cancer immunity
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 92:6
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Tidskriftsartikel (refereegranskat)abstract
- In the effort of developing new immunotherapies, the sentinel node (SN) has proven a promising source from which to harness an effective antitumour T cell response. However, tumour immune escape, a process in which regulatory T cells (Tregs) play a central role, remains a major limiting factor. Therefore, there is a clear need to increase the knowledge of Treg function and signalling in sentinel nodes. Here, we set out to explore whether the proteome in SN-resident T cells is altered by the tumour and to identify key proteins in SN T cell signalling, focusing on Tregs. Five patients with muscle-invasive urothelial bladder cancer were prospectively included. Mass spectrometry was performed on two patients, with validation and functional studies being performed on three additional patients and four healthy donors. At cystectomy, SN, non-SN lymph nodes and peripheral blood samples were collected from the patients and T cell subsets isolated through flow cytometry before downstream experiments. Proteomic analysis indicated that growth and immune signalling pathways are upregulated in SN-resident Tregs. Furthermore, centrality analysis identified the cytokine IL-16 to be central in the SN-Treg signalling network. We show that tumour-released factors, through activating caspase-3, increase Treg IL-16 processing into bioactive forms, reinforcing Treg suppressive capacity. In conclusion, we provide evidence that Tregs exposed to secreted factors from bladder tumours show increased immune and growth signalling and altered IL-16 processing which translates to enhanced Treg suppressive function, indicating altered IL-16 signalling as a novel tumour immune escape mechanism.
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- Zhang, Lu, et al.
(författare)
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Immune responses against Human Papilloma virus in draining lymph nodes from patients with penile cancer
- 2017
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Ingår i: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 86:4, s. 339-339
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Human papillomavirus (HPV) is a DNA virus which accounts for 5.2% of all cancers worldwide and is a well‐known cause of cervical, vulvar, head and neck cancer, but studies on penile cancer (PC) are rare. There are more than 170 HPV strains, where HPV16 is the main strain accounting for 94.7% of all PCs. Additional studies have detected HPV DNA in both primary tumors and metastases, indicating the potential role of HPV in tumor progression. We have investigated immune responses against autologous tumor‐extract in draining lymph nodes (LNs) in colon and urinary bladder cancer. There are several indications that HPV associated malignancies eliciting a virus‐antigen‐specific immune response. HPV E6 and E7 as oncogenes are widely studied in HPV associated cancer. A study comparing different HPV antigen‐specific T cell efficiency in killing autologous HPV positive tumor cells in cervical cancer patients, suggests that L1‐specific CD8+ cytotoxic T lymphocytes (CTLs) are equally effective as E7‐specific CD8+ CTLs. We set out to evaluate immune responses in LNs from PC patients against the HPV vaccine Gardasil (L1). In this study, nearly half of the PC patients were detected as HPV positive by PCR. Phenotypes of the lymphocytes from LNs were characterized. We used FASCIA to investigate lymphocyte responses towards tumor‐extract and Gardasil in LNs, found a good response towards Gardasil among HPV‐positive patients but not in HPV‐negative patients. A dose dependent reactivity was observed. Strategies using HPV L1 proteins as antigens may be useful for adoptive T cell therapy of patients with PC.
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| 9. |
- Zirakzadeh, A. Ali, et al.
(författare)
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Tumour-associated B cells in urothelial urinary bladder cancer
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 91:2
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Tidskriftsartikel (refereegranskat)abstract
- Tumour infiltrating B cells and CD38+ plasma cells have been correlated with survival in different malignancies but their role in urinary bladder cancer is unclear. IL-10 is a multifunctional cytokine with both anti-inflammatory and immunostimulatory properties, that can be released by regulatory B cells (Bregs). We have stained paraffin-embedded tumour sections from 31 patients with invasive urothelial urinary bladder cancer with respect to CD20+ B cells, CD38+ cells, IL-10-expressing cells, IgG, C1q and C3a and analysed the impact of these markers on survival. Interestingly, we observe tumour-associated CD20+ B cells forming follicle-like structures in tumours of some patients. We demonstrate that follicle-like structures, tumour-associated CD38+ cells, IL-10 produced by non-B cells, tumour infiltrating IgG and activation of the complement system, may associate to longer survival of urinary bladder cancer patients. IL-10 expression by tumour-associated Bregs may instead negatively affect prognosis. More research is needed to fully understand the role of B cells and IL-10 in urinary bladder cancer.
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