Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as ... more Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation of the high incidence of relapse and fatal outcome of many blood malignancies. In this report we have used Jurkat and Raji cell lines as a model for studies of the NKG2D receptor-ligand system in T-and B cell leukemia/lymphoma. Using real-time quantitative RT-PCR and immunoflow cytometry we show that Jurkat and Raji cells constitutively express mRNA and protein for the stress-inducible NKG2D ligands MICA/B and ULBP1 and 2, and up-regulate the expression in a cell-line specific and stress-specific manner. Furthermore, we revealed by electron microscopy, immunoflow cytometry and western blot that these ligands were expressed and secreted on exosomes, nanometer-sized microvesicles of endosomal origin. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate the in vitro NKG2D receptor-mediated cytotoxicity and thus impair NK-cell function. Interestingly, thermal and oxidative stress enhanced the exosome secretion generating more soluble NKG2D ligands that aggravated the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress, enhancing the release of immunosuppressive exosomes, should be considered when cytostatic and hyperthermal anti-cancer therapies are designed.
The local immune privilege of the fetus is created by the placenta. Fas ligand (FasL) expression ... more The local immune privilege of the fetus is created by the placenta. Fas ligand (FasL) expression in trophoblast has been implied as one of the mechanisms of fetal tolerance. However, the expression of membranal FasL by trophoblast has failed to explain this role of FasL. Two objections can be raised: (1) there have been contradictions considering which trophoblast cells, syncytiotrophoblast (ST) or cytotrophoblast, express FasL; (2) in vivo and in vitro studies have shown that the membranal form of FasL evokes inflammatory response and thus may promote fetal rejection. Using different assays and the FasL-specific antibody G247-4 we demonstrate beyond doubt that in vivo, (1) FasL is produced by and stored in the first trimester human ST only and (2) the human ST lacks surface membranal FasL. Instead, FasL, loaded in microvesicles, is stored in cytoplasmic granules. These results complement the recent in vitro studies of the microvesicular form of FasL secretion by cultured trophoblast cells, and suggest that placental FasL is synthesized by villous ST, stored in microvesicular form and secreted as exosomes. Secretion of the exosome-associated form of FasL may be one mechanism by which the placenta promotes a state of immune privilege. Additionally, FasL expression in Hofbauer cells is also demonstrated.
American Journal of Reproductive Immunology, Mar 11, 2010
Cell communication comprises cell-cell contact, soluble mediators and intercellular nanotubes. Th... more Cell communication comprises cell-cell contact, soluble mediators and intercellular nanotubes. There is, however, another cell-cell communication by released membrane-bound microvesicles that convey cell-cell contact 'by proxy' transporting signals/packages of information from donor to recipient cells locally and/or at a distance. The nanosized exosomes comprise a specialized type of microvesicles generated within multivesicular bodies (MVB) and released upon MVB fusion with the plasma membrane. Exosomes are produced by a variety of immune, epithelial and tumor cells. Upon contact, exosomes transfer molecules that can render new properties and/or reprogram their recipient cells. Recently, it was discovered that the syncytiotrophoblast constitutively and throughout the pregnancy secretes exosomes. The placenta-derived exosomes are immunosuppressive and carry proteins and RNA molecules that in a redundant way influence a number of mechanisms and promote the fetal allograft survival. In this review, we summarize the current knowledge on the nature of placenta-derived exosomes and discuss their role in pregnancy.
Introduction: Systemic sclerosis (SSc) is an autoimmune disorder, which frequently affects the lu... more Introduction: Systemic sclerosis (SSc) is an autoimmune disorder, which frequently affects the lungs, with manifestations of interstitial lung disease (ILD) with lung fibrosis and of pulmonary hypertension. The pathogenesis remains largely unrecognised. Objective: The aim of this study was to elucidate the inflammation in the bronchial mucosa in patients with SSc. Subjects and methods: Twenty-three subjects diagnosed with SSc participated. Twelve of the SSc patients showed signs of ILD, four were smokers and seven were treated with oral corticosteroids. Seventeen non-smoking, age-and sex-matched healthy subjects served as controls. Bronchoscopy was performed to sample endobronchial mucosal biopsies, which were immunohistochemically stained using a panel of antibodies against inflammatory markers. Results: The number of neutrophils was significantly elevated in the submucosa of SSc patients, regardless of ILD, or whether the subject was smoking or using oral corticosteroids. No up-regulation of neutrophil chemoattractants or cytokines was seen in the bronchial epithelium. The signal transduction pathways and adhesion molecule expression tended to be suppressed or unchanged in SSc patients compared with controls. Conclusion: It is concluded that SSc is associated with a chronic neutrophilic inflammation in the bronchial mucosal, with signs of suppressed signal transduction, regardless of the presence of interstitial lung disease.
Human cancers constitutively produce and release endosome-derived nanometer-sized vesicles called... more Human cancers constitutively produce and release endosome-derived nanometer-sized vesicles called exosomes that carry biologically active proteins, messenger and micro RNAs and serve as vehicles of intercellular communication. The tumour exosomes are present in the blood, urine and various malignant effusions such as peritoneal and pleural fluid of cancer patients and can modulate immune cells and responses thus deranging the immune system of cancer patients and giving advantage to the cancer to establish and spread itself. Here, the role of exosomes in the NKG2D receptor-ligand system's interactions is discussed. The activating NK cell receptor NKG2D and its multiple ligands, the MHC class I-related chain (MIC) A/B and the retinoic acid transcript-1/UL-16 binding proteins (RAET1/ULBP) 1-6 comprise a powerful stress-inducible danger detector system that targets infected, inflamed and malignantly transformed cells and plays a decisive role in anti-tumour immune surveillance. Mounting evidence reveals that the MIC-and RAET1/ULBP ligand family members are enriched in the endosomal compartment of various tumour cells and expressed and released into the intercellular space and bodily fluids on exosomes thus preserving their entire molecule, three-dimensional protein structure and biologic activity. The NKG2D ligand-expressing exosomes serve as decoys with a powerful ability to down regulate the cognate receptor and impair the cytotoxic function of NK-, NKT-, gamma/delta-and cytotoxic T cells. This review summarizes recent findings concerning the role of NKG2D receptor-ligand system in cancer with emphasis on regulation of NKG2D ligand expression and the immunosuppressive role of exosomally expressed NKG2D ligands.
... Nilsson, Kenneth. Nagaeva, Olga (Umeå University, Faculty of Medicine, Department of Clinical... more ... Nilsson, Kenneth. Nagaeva, Olga (Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology). Rantapää-Dahlqvist ... type: Manuscript (Other (popular science, discussion, etc.)). Language: English. URI: urn:nbn:se:umu:diva-3374. Permanent link ...
Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, hav... more Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8 + T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8 + T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8 + T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.
Dr. Takeshi Matsunaga (Fig. 1) was born in Japan at the end of the Second World War. His father N... more Dr. Takeshi Matsunaga (Fig. 1) was born in Japan at the end of the Second World War. His father Noboru was a painter. His mother Somi still writes poetry. Takeshi studied biology at Kyoto University and in 1971 moved to the Basle Institute for Immunology, under the direction of Niels K. Jerne. During a short stay in Edinburgh in Anne McLaren's laboratory, he learnt how to fuse two mouse embryos together to generate tetraparental chimeras. This fascinating approach is a powerful and elegant tool to dissociate the cell-autonomous part from the role played by the microenvironment in the determination of a given trait (McLaren 1976). He chose this sophisticated technology to study immunological tolerance (Matsunaga and Simpson 1979; Simpson and Matsunaga 1979; Matsunaga et al. 1980; Simpson et al. 1980). Takeshi then moved to London in 1976, where he continued his work on tolerance together with Elizabeth Simpson. He had the opportunity there to meet the late Peter Medawar. Next he joined Susumu Ohno's laboratory, where the two men reciprocally taught each other immunology and evolution, after which Takeshi became interested in the evolution of the immune system. From then onwards he contributed original ideas, elegant hypotheses (Ohno et al.
Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance induc... more Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF-a inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4 + T helper (h) lymphocytes (ly), CD8 + T cytotoxic (c) ly, CD19 + B ly and CD14 + monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory-and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8 + Tc and CD19 + B ly was significant. Fold change in MC1-5R and IFNc gene expressions correlated significantly in CD8 + Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1b gene expressions correlated significantly in CD4 + Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8 + Tc ly and CD19 + B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8 + Tc ly and CD4 + Th ly point at a central immune modulating function of the melanocortin system in RA.
Purpose: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disord... more Purpose: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet. Methods: Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-seven IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected. Results: Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti-DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not. Conclusions: IgG anti-tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.
Our aim was to test the hypothesis that a combination of markers for Type 1 diabetes (glutamate d... more Our aim was to test the hypothesis that a combination of markers for Type 1 diabetes (glutamate decarboxylase and IA-2 autoantibodies) and for Type 2 diabetes [oral glucose tolerance test (OGTT) and body mass index (BMI)], would predict clinical diabetes in a regional population. A population-based follow-up cohort study. Participants visited the primary health care centre in Lycksele, Sweden in 1988-92. A cohort of 2278 subjects (M/F 1149/1129) who were studied at follow-up in 1998. At base line there were 2314 subjects (M/F 1167/1147) who participated in the Västerbotten Intervention Program on their birthday when turning either 30, 40, 50 or 60 years of age. Main outcome measurements. A clinically diagnosed diabetes at follow-up when the medical records were reviewed for diagnosis of diabetes. At base line, the participants were subjected to a standard OGTT and their BMI determined along with the autoantibodies. At follow-up, 42/2278 (1.8%, 95% CI 1.2-2.3) (M/F 23/19) had developed diabetes: 41 subjects were clinically classified with Type 2 and one with Type 1 diabetes. There was no significant relation between autoantibody levels at base line and diabetes at follow-up. Stepwise multiple logistic regression showed that the odds ratio for developing diabetes was 10.8 (95% CI 6.3-18.9) in subjects in the fourth quartile of BMI (BMI > 27) compared with 7.8 (95% CI 4.8-12.6) in the fourth quartile of 2-h plasma glucose (>7.5 mmol L(-1)) and 7.2 (95% CI 4.8-11.4) in the fourth quartile of the fasting plasma glucose (>5.6 mmol L(-1)). Islet cell autoantibodies did not predict diabetes at follow-up. BMI measured at base line was as effective as 2-h plasma glucose and fasting plasma glucose to predict diabetes in this adult population.
found significant correlations between changes in MCR 1, 3, 5-and change in IL-1β gene levels in ... more found significant correlations between changes in MCR 1, 3, 5-and change in IL-1β gene levels in CD4 + Th ly. Conclusions: Our results point at a responsive melanocortin system in immune cells in RA. Moreover, its regulation seems intimately connected to the disease driving Th1 response, that is IFNγ production by CD8 + Tc ly. Our results are underlined by the recently reported importance of IFNγ producing CD8 + Tc ly in early RA. Thus our findings indicate that the melanocortin pathway lies open to treatment of auto-reactive effector T ly from RA patients with MCR type specific synthetic ligands in vivo or in vitro to induce Treg transformation. Future curative induction of auto-antigen specific immune tolerance in RA may therefore involve the melanocortin system.
American Journal of Reproductive Immunology, Aug 28, 2014
Citation Mincheva-Nilsson L, Baranov V. Placentaderived exosomes and syncytiotrophoblast micropar... more Citation Mincheva-Nilsson L, Baranov V. Placentaderived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success.
Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of di... more Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.
Expert Review of Obstetrics & Gynecology, Sep 1, 2010
ABSTRACT Exosomes are nanosized membrane-bound microvesicles that originate from the endosomal co... more ABSTRACT Exosomes are nanosized membrane-bound microvesicles that originate from the endosomal compartment and convey cell-cell contact `by proxy', transporting signals/packages of information between donor and recipient cells locally and/or at a distance. Exosomes are produced by a variety of immune, epithelial and tumor cells. Upon contact, exosomes transfer molecules that can render new properties and/or reprogram the recipient cells. Recently, it was discovered that the syncytiotrophoblast of human placenta continuously and constitutively secretes exosomes throughout pregnancy. These exosomes, delivered directly in the maternal blood surrounding the chorionic villi of the placenta, are immunosuppressive and pluripotent carrying proteins, mRNA and miRNA that can influence a number of biologic mechanisms and promote the fetal allograft survival. The current knowledge regarding placental exosomes and their role in pregnancy is summarized and discussed in this article.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as ... more Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation of the high incidence of relapse and fatal outcome of many blood malignancies. In this report we have used Jurkat and Raji cell lines as a model for studies of the NKG2D receptor-ligand system in T-and B cell leukemia/lymphoma. Using real-time quantitative RT-PCR and immunoflow cytometry we show that Jurkat and Raji cells constitutively express mRNA and protein for the stress-inducible NKG2D ligands MICA/B and ULBP1 and 2, and up-regulate the expression in a cell-line specific and stress-specific manner. Furthermore, we revealed by electron microscopy, immunoflow cytometry and western blot that these ligands were expressed and secreted on exosomes, nanometer-sized microvesicles of endosomal origin. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate the in vitro NKG2D receptor-mediated cytotoxicity and thus impair NK-cell function. Interestingly, thermal and oxidative stress enhanced the exosome secretion generating more soluble NKG2D ligands that aggravated the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress, enhancing the release of immunosuppressive exosomes, should be considered when cytostatic and hyperthermal anti-cancer therapies are designed.
The local immune privilege of the fetus is created by the placenta. Fas ligand (FasL) expression ... more The local immune privilege of the fetus is created by the placenta. Fas ligand (FasL) expression in trophoblast has been implied as one of the mechanisms of fetal tolerance. However, the expression of membranal FasL by trophoblast has failed to explain this role of FasL. Two objections can be raised: (1) there have been contradictions considering which trophoblast cells, syncytiotrophoblast (ST) or cytotrophoblast, express FasL; (2) in vivo and in vitro studies have shown that the membranal form of FasL evokes inflammatory response and thus may promote fetal rejection. Using different assays and the FasL-specific antibody G247-4 we demonstrate beyond doubt that in vivo, (1) FasL is produced by and stored in the first trimester human ST only and (2) the human ST lacks surface membranal FasL. Instead, FasL, loaded in microvesicles, is stored in cytoplasmic granules. These results complement the recent in vitro studies of the microvesicular form of FasL secretion by cultured trophoblast cells, and suggest that placental FasL is synthesized by villous ST, stored in microvesicular form and secreted as exosomes. Secretion of the exosome-associated form of FasL may be one mechanism by which the placenta promotes a state of immune privilege. Additionally, FasL expression in Hofbauer cells is also demonstrated.
American Journal of Reproductive Immunology, Mar 11, 2010
Cell communication comprises cell-cell contact, soluble mediators and intercellular nanotubes. Th... more Cell communication comprises cell-cell contact, soluble mediators and intercellular nanotubes. There is, however, another cell-cell communication by released membrane-bound microvesicles that convey cell-cell contact 'by proxy' transporting signals/packages of information from donor to recipient cells locally and/or at a distance. The nanosized exosomes comprise a specialized type of microvesicles generated within multivesicular bodies (MVB) and released upon MVB fusion with the plasma membrane. Exosomes are produced by a variety of immune, epithelial and tumor cells. Upon contact, exosomes transfer molecules that can render new properties and/or reprogram their recipient cells. Recently, it was discovered that the syncytiotrophoblast constitutively and throughout the pregnancy secretes exosomes. The placenta-derived exosomes are immunosuppressive and carry proteins and RNA molecules that in a redundant way influence a number of mechanisms and promote the fetal allograft survival. In this review, we summarize the current knowledge on the nature of placenta-derived exosomes and discuss their role in pregnancy.
Introduction: Systemic sclerosis (SSc) is an autoimmune disorder, which frequently affects the lu... more Introduction: Systemic sclerosis (SSc) is an autoimmune disorder, which frequently affects the lungs, with manifestations of interstitial lung disease (ILD) with lung fibrosis and of pulmonary hypertension. The pathogenesis remains largely unrecognised. Objective: The aim of this study was to elucidate the inflammation in the bronchial mucosa in patients with SSc. Subjects and methods: Twenty-three subjects diagnosed with SSc participated. Twelve of the SSc patients showed signs of ILD, four were smokers and seven were treated with oral corticosteroids. Seventeen non-smoking, age-and sex-matched healthy subjects served as controls. Bronchoscopy was performed to sample endobronchial mucosal biopsies, which were immunohistochemically stained using a panel of antibodies against inflammatory markers. Results: The number of neutrophils was significantly elevated in the submucosa of SSc patients, regardless of ILD, or whether the subject was smoking or using oral corticosteroids. No up-regulation of neutrophil chemoattractants or cytokines was seen in the bronchial epithelium. The signal transduction pathways and adhesion molecule expression tended to be suppressed or unchanged in SSc patients compared with controls. Conclusion: It is concluded that SSc is associated with a chronic neutrophilic inflammation in the bronchial mucosal, with signs of suppressed signal transduction, regardless of the presence of interstitial lung disease.
Human cancers constitutively produce and release endosome-derived nanometer-sized vesicles called... more Human cancers constitutively produce and release endosome-derived nanometer-sized vesicles called exosomes that carry biologically active proteins, messenger and micro RNAs and serve as vehicles of intercellular communication. The tumour exosomes are present in the blood, urine and various malignant effusions such as peritoneal and pleural fluid of cancer patients and can modulate immune cells and responses thus deranging the immune system of cancer patients and giving advantage to the cancer to establish and spread itself. Here, the role of exosomes in the NKG2D receptor-ligand system's interactions is discussed. The activating NK cell receptor NKG2D and its multiple ligands, the MHC class I-related chain (MIC) A/B and the retinoic acid transcript-1/UL-16 binding proteins (RAET1/ULBP) 1-6 comprise a powerful stress-inducible danger detector system that targets infected, inflamed and malignantly transformed cells and plays a decisive role in anti-tumour immune surveillance. Mounting evidence reveals that the MIC-and RAET1/ULBP ligand family members are enriched in the endosomal compartment of various tumour cells and expressed and released into the intercellular space and bodily fluids on exosomes thus preserving their entire molecule, three-dimensional protein structure and biologic activity. The NKG2D ligand-expressing exosomes serve as decoys with a powerful ability to down regulate the cognate receptor and impair the cytotoxic function of NK-, NKT-, gamma/delta-and cytotoxic T cells. This review summarizes recent findings concerning the role of NKG2D receptor-ligand system in cancer with emphasis on regulation of NKG2D ligand expression and the immunosuppressive role of exosomally expressed NKG2D ligands.
... Nilsson, Kenneth. Nagaeva, Olga (Umeå University, Faculty of Medicine, Department of Clinical... more ... Nilsson, Kenneth. Nagaeva, Olga (Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology). Rantapää-Dahlqvist ... type: Manuscript (Other (popular science, discussion, etc.)). Language: English. URI: urn:nbn:se:umu:diva-3374. Permanent link ...
Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, hav... more Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8 + T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8 + T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8 + T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.
Dr. Takeshi Matsunaga (Fig. 1) was born in Japan at the end of the Second World War. His father N... more Dr. Takeshi Matsunaga (Fig. 1) was born in Japan at the end of the Second World War. His father Noboru was a painter. His mother Somi still writes poetry. Takeshi studied biology at Kyoto University and in 1971 moved to the Basle Institute for Immunology, under the direction of Niels K. Jerne. During a short stay in Edinburgh in Anne McLaren's laboratory, he learnt how to fuse two mouse embryos together to generate tetraparental chimeras. This fascinating approach is a powerful and elegant tool to dissociate the cell-autonomous part from the role played by the microenvironment in the determination of a given trait (McLaren 1976). He chose this sophisticated technology to study immunological tolerance (Matsunaga and Simpson 1979; Simpson and Matsunaga 1979; Matsunaga et al. 1980; Simpson et al. 1980). Takeshi then moved to London in 1976, where he continued his work on tolerance together with Elizabeth Simpson. He had the opportunity there to meet the late Peter Medawar. Next he joined Susumu Ohno's laboratory, where the two men reciprocally taught each other immunology and evolution, after which Takeshi became interested in the evolution of the immune system. From then onwards he contributed original ideas, elegant hypotheses (Ohno et al.
Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance induc... more Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF-a inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4 + T helper (h) lymphocytes (ly), CD8 + T cytotoxic (c) ly, CD19 + B ly and CD14 + monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory-and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8 + Tc and CD19 + B ly was significant. Fold change in MC1-5R and IFNc gene expressions correlated significantly in CD8 + Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1b gene expressions correlated significantly in CD4 + Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8 + Tc ly and CD19 + B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8 + Tc ly and CD4 + Th ly point at a central immune modulating function of the melanocortin system in RA.
Purpose: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disord... more Purpose: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet. Methods: Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-seven IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected. Results: Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti-DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not. Conclusions: IgG anti-tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.
Our aim was to test the hypothesis that a combination of markers for Type 1 diabetes (glutamate d... more Our aim was to test the hypothesis that a combination of markers for Type 1 diabetes (glutamate decarboxylase and IA-2 autoantibodies) and for Type 2 diabetes [oral glucose tolerance test (OGTT) and body mass index (BMI)], would predict clinical diabetes in a regional population. A population-based follow-up cohort study. Participants visited the primary health care centre in Lycksele, Sweden in 1988-92. A cohort of 2278 subjects (M/F 1149/1129) who were studied at follow-up in 1998. At base line there were 2314 subjects (M/F 1167/1147) who participated in the Västerbotten Intervention Program on their birthday when turning either 30, 40, 50 or 60 years of age. Main outcome measurements. A clinically diagnosed diabetes at follow-up when the medical records were reviewed for diagnosis of diabetes. At base line, the participants were subjected to a standard OGTT and their BMI determined along with the autoantibodies. At follow-up, 42/2278 (1.8%, 95% CI 1.2-2.3) (M/F 23/19) had developed diabetes: 41 subjects were clinically classified with Type 2 and one with Type 1 diabetes. There was no significant relation between autoantibody levels at base line and diabetes at follow-up. Stepwise multiple logistic regression showed that the odds ratio for developing diabetes was 10.8 (95% CI 6.3-18.9) in subjects in the fourth quartile of BMI (BMI > 27) compared with 7.8 (95% CI 4.8-12.6) in the fourth quartile of 2-h plasma glucose (>7.5 mmol L(-1)) and 7.2 (95% CI 4.8-11.4) in the fourth quartile of the fasting plasma glucose (>5.6 mmol L(-1)). Islet cell autoantibodies did not predict diabetes at follow-up. BMI measured at base line was as effective as 2-h plasma glucose and fasting plasma glucose to predict diabetes in this adult population.
found significant correlations between changes in MCR 1, 3, 5-and change in IL-1β gene levels in ... more found significant correlations between changes in MCR 1, 3, 5-and change in IL-1β gene levels in CD4 + Th ly. Conclusions: Our results point at a responsive melanocortin system in immune cells in RA. Moreover, its regulation seems intimately connected to the disease driving Th1 response, that is IFNγ production by CD8 + Tc ly. Our results are underlined by the recently reported importance of IFNγ producing CD8 + Tc ly in early RA. Thus our findings indicate that the melanocortin pathway lies open to treatment of auto-reactive effector T ly from RA patients with MCR type specific synthetic ligands in vivo or in vitro to induce Treg transformation. Future curative induction of auto-antigen specific immune tolerance in RA may therefore involve the melanocortin system.
American Journal of Reproductive Immunology, Aug 28, 2014
Citation Mincheva-Nilsson L, Baranov V. Placentaderived exosomes and syncytiotrophoblast micropar... more Citation Mincheva-Nilsson L, Baranov V. Placentaderived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success.
Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of di... more Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.
Expert Review of Obstetrics & Gynecology, Sep 1, 2010
ABSTRACT Exosomes are nanosized membrane-bound microvesicles that originate from the endosomal co... more ABSTRACT Exosomes are nanosized membrane-bound microvesicles that originate from the endosomal compartment and convey cell-cell contact `by proxy', transporting signals/packages of information between donor and recipient cells locally and/or at a distance. Exosomes are produced by a variety of immune, epithelial and tumor cells. Upon contact, exosomes transfer molecules that can render new properties and/or reprogram the recipient cells. Recently, it was discovered that the syncytiotrophoblast of human placenta continuously and constitutively secretes exosomes throughout pregnancy. These exosomes, delivered directly in the maternal blood surrounding the chorionic villi of the placenta, are immunosuppressive and pluripotent carrying proteins, mRNA and miRNA that can influence a number of biologic mechanisms and promote the fetal allograft survival. The current knowledge regarding placental exosomes and their role in pregnancy is summarized and discussed in this article.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
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