| 1. |
- Mantani, Polyxeni, et al.
(author)
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Circulating CD40(+) and CD86(+) B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke
- 2014
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 34:1, s. 211-218
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Journal article (peer-reviewed)abstract
- Objective-Accumulating evidence shows that immune cells play an important role in atherosclerosis. Most attention has focused on the role of different T cell subsets, whereas the possible involvement of B cells has been less studied. In this study, we assessed the association of 2 different B cell subsets, CD19(+)CD40(+) and CD19(+)CD86(+) B cells, with risk for development of acute cardiovascular events. Approach and Results-The prospective study included 700 subjects randomly selected from the cardiovascular cohort of the Malmo Diet and Cancer study. Mononuclear leukocytes, stored at -140 degrees C at the baseline investigation in 1991-1994, were thawed and B cell subsets analyzed by flow cytometry. Cytokine release from CD3/CD28-stimulated mononuclear leukocytes was measured with multiplex ELISA. Baseline carotid intima-media thickness and stenosis were assessed by ultrasonography, and clinical events were monitored through validated national registers during a median/mean follow-up time of 15 years. The subjects in the highest tertile of CD19(+)CD40(+) B cells had a significantly lower risk of incident stroke after adjustment for other risk factors. In contrast, CD19(+)CD86(+) B cells were associated with higher risk for development of a stroke event and increased release of proinflammatory cytokines from mononuclear leukocytes. Conclusions-These observations provide evidence for an involvement of B cells in the incidence of stroke and suggest that both pathogenic and protective B cell subsets exist.
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| 2. |
- Mantani, Polyxeni
(author)
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IL-25 and B cells in atherosclerosis
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Atherosclerosis is a chronic inflammatory disease of medium and large vessels of the body which is mainly characterized by the formation of lipid rich plaques within the arterial tissue. It is the most common cause of cardiovascular disease leading to clinical manifestations of coronary artery and cerebrovascular disease. Immune responses targeting modified low density lipoprotein (LDL) play an important role in atherosclerosis. Moreover, Th1 immune responses have inextricably been associated with disease progression while the role of Th17 and Th2 related immune responses is less clear. In the present work we report that different B cell subsets could potentially be used as biomarkers for the prediction of future stroke events. Specifically, our findings demonstrate an association between high levels of CD19+CD40+ cells and a decreased risk of stroke while high levels of CD19+CD86+ B cells were associated with an increased risk. Another main focus was the investigation of the role of IL-25 in atherosclerosis. In order to tackle this, the cytokine was both administered and blocked in hypercholesterolaemic apoE-/- mice. Interestingly, an atheroprotective effect of the cytokine was observed. Regarding exogenous IL-25 administration, the proposed mechanism of atheroprotection implicates the increase of IgM antibodies targeting phosphorylcholine (PC), a major epitope on oxidized LDL (oxLDL) via innate lymphoid cell type 2 (ILC2)-derived IL-5. We suggest that the essential trigger for this mechanism is the expansion of ILC2s. Additionally, blockade of endogenous IL-25 at the onset of atherosclerosis led to increased plaque formation of unstable phenotype, accompanied by a Th1/Th17 shift of the cytokine balance in the spleen of the mice. The above mentioned findings suggest that signaling through IL-25 during early plaque formation possibly regulates protective immune mechanisms and that disruption of that signaling leads to the dominance of pro-inflammatory immune responses. Due to the atheroprotective effect of IL-25 in mice we also investigated its effect on human peripheral blood mononuclear cells (hPBMCs). IL-25 was shown to dampen Th17 and Th1-related immune responses in hPBMCs while in the presence of oxLDL it dampens Th1 and promotes Th2-related immune responses. The above mentioned findings indicate that IL-25 could potentially have a protective role in human atherosclerosis.
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| 3. |
- Mantani, Polyxeni, et al.
(author)
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IL-25 Inhibits Atherosclerosis Development in Apolipoprotein E Deficient Mice
- 2015
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:1
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Journal article (peer-reviewed)abstract
- Objective IL-25 has been implicated in the initiation of type 2 immunity and in the protection against autoimmune inflammatory diseases. Recent studies have identified the novel innate lymphoid type 2 cells (ILC2s) as an IL-25 target cell population. The purpose of this study was to evaluate if IL-25 has any influence on atherosclerosis development in mice. Methods and Results Administration of 1 mu g IL-25 per day for one week to atherosclerosis-prone apolipoprotein (apo) E deficient mice, had limited effect on the frequency of T cell populations, but resulted in a large expansion of ILC2s in the spleen. The expansion was accompanied by increased levels of anti-phosphorylcholine (PC) natural IgM antibodies in plasma and elevated levels of IL-5 in plasma and spleen. Transfer of ILC2s to apoE deficient mice elevated the natural antibody-producing B1a cell population in the spleen. Treatment of apoE/Rag-1 deficient mice with IL-25 was also associated with extensive expansion of splenic ILC2s and increased plasma IL-5, suggesting ILC2s to be the source of IL-5. Administration of IL-25 in IL-5 deficient mice resulted in an expanded ILC2 population, but did not stimulate generation of anti-PC IgM, indicating that IL-5 is not required for ILC2 expansion but for the downstream production of natural antibodies. Additionally, administration of 1 mu g IL-25 per day for 4 weeks in apoE deficient mice reduced atherosclerosis in the aorta both during initiation and progression of the disease. Conclusions The present findings demonstrate that IL-25 has a protective role in atherosclerosis mediated by innate responses, including ILC2 expansion, increased IL-5 secretion, B1a expansion and natural anti-PC IgM generation, rather than adaptive Th2 responses.
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| 4. |
- Mantani, Polyxeni T, et al.
(author)
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ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions
- 2019
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In: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 20
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Journal article (peer-reviewed)abstract
- BACKGROUND: Expansion of type 2 innate lymphoid cells (ILC2s) in hypercholesterolaemic mice protects against atherosclerosis while different ILC2 subsets have been described (natural, inflammatory) based on their suppression of tumorigenicity 2 (ST2) and killer-cell lectin like receptor G1 (KLRG1) expression. The aim of the current study is to characterize the interleukin 25 (IL25)-induced splenic ILC2 population (Lin-CD45+IL17RB+ICOS+IL7raintermediate) and address its direct role in experimental atherosclerosis by its adoptive transfer to hypercholesterolaemic apolipoprotein E deficient (apoE-/-) mice.RESULTS: Immunomagnetically enriched, FACS-sorted ILC2s from the spleens of IL-25 treated apoE-/- mice were stained for KLRG1 and ST2 directly upon cell obtainment or in vitro cell expansion for flow cytometric analysis. IL25-induced splenic ILC2s express high levels of both KLRG1 and ST2. However, both markers are downregulated upon in vitro cell expansion. In vitro expanded splenic ILC2s were intraperitoneally transferred to apoE-/- recipients on high fat diet. ApoE-/- mice that received in vitro expanded splenic ILC2s had decreased lipid content in subvalvular heart and brachiocephalic artery (BCA) plaques accompanied by increased peritoneal B1 cells, activated eosinophils and alternatively activated macrophages (AAMs) as well as anti-phosphorylcholine (PC) immunoglobulin (Ig) M in plasma.CONCLUSIONS: With the current data we designate the IL25-induced ILC2 population to decrease the lipid content of atherosclerotic lesions in apoE-/- mice and we directly link the induction of B1 cells and the atheroprotective anti-PC IgM antibodies with ILC2s.
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| 5. |
- Mantani, Polyxeni T., et al.
(author)
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Interleukin-25 (IL-25) has a protective role in atherosclerosis development in the aortic arch in mice
- 2018
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In: Journal of Biological Chemistry. - 0021-9258. ; 293:18, s. 6791-6801
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Journal article (peer-reviewed)abstract
- Atherosclerosis is a chronic inflammatory disease characterized by the entrapment of apolipoprotein B– containing lipoproteins in the arterial intima, leading to local inflammation. T helper (Th) cell 1–mediated immune responses have been associated with atherosclerosis, and the cytokine interleukin-25 (IL-25 or IL-17E) has been reported to potentially regulate Th1 cell– and Th17 cell–related immune responses. In this study, we evaluated the effects of complete IL-25 deficiency or of a temporal IL-25 blockade on atherosclerosis development in apolipoprotein E– deficient (Apoe/) mice. Mice deficient in both apolipoprotein E and IL-25 (Apoe//IL-25/) had more Th1 cells in the spleen, along with elevated plasma levels of IL-17 and an increased release of splenic interferon- (INF-). In support of this observation, a 4-week-long treatment of young Apoe/ mice (at 10 –14 weeks of age) with an IL-25– blocking antibody increased the release of Th1/Th17-associated cytokines in the spleen. In both mouse models, these findings were associated with increased atherosclerotic plaque formation in the aortic arch. We conclude that complete IL-25 deficiency and a temporal IL-25 blockade during early plaque development aggravate atherosclerosis development in the aortic arch of Apoe/ mice, accompanied by an increase in Th1/Th17-mediated immune responses. Our finding that endogenous IL-25 has an atheroprotective role in the murine aortic arch has potential implications for atherosclerosis development and management in humans.
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| 6. |
- Mantani, Polyxeni T., et al.
(author)
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Interleukin-25 reduces Th17 cells and inflammatory responses in human peripheral blood mononuclear cells
- 2018
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In: Human Immunology. - : Elsevier BV. - 0198-8859. ; 79:9, s. 685-692
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Journal article (peer-reviewed)abstract
- Background: The absence of interleukin-25 (IL-25) favors the induction of Th1 and Th17 immune responses in mice. Th1 immune responses have been associated with the pathology of atherosclerosis, a lipid and inflammation driven disease of the arterial wall. Purpose of research: To evaluate the effect of IL-25 on human peripheral blood mononuclear cells (hPBMCs) in the presence and absence of oxidized low density lipoprotein (oxLDL), a key player in atherosclerosis development. Principal results: Human PBMCs were incubated with recombinant human IL-25 (rhIL-25) in the presence and absence of oxLDL and analyzed with flow cytometry while cytokine secretion was measured in cell culture supernatants. The IL-25 receptor, IL-17RB, was mostly expressed on T cells. Incubation of hPBMCs with IL-25 reduced the frequency of Th17 cells. Furthermore, IL-25 inhibited the release of the Th17-inducing cytokine IL-6 from dendritic cells isolated from hPBMCs indicating that the IL-25 mediated Th17 suppression may be indirect. Moreover, IL-25 reduced the secretion of the proinflammatory cytokine IFNγ from hPBMCs. OxLDL decreased IFNγ release from hPBMCs regardless of the presence or absence of IL-25. Conclusions: IL-25 reduces Th1 and Th17 immune responses in hPBMCs raising the interesting possibility that IL-25 could have a protective role in human atherosclerosis.
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| 7. |
- Rattik, Sara, et al.
(author)
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B cells treated with CTB-p210 acquire a regulatory phenotype in vitro and reduce atherosclerosis in apolipoprotein E deficient mice
- 2018
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In: Vascular Pharmacology. - : Elsevier BV. - 1537-1891. ; 111, s. 54-61
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Journal article (peer-reviewed)abstract
- Objective: Intranasal immunization with a fusion protein of the ApoB100-derived peptide p210 and the cholera toxin B subunit (CTB-p210) has previously been shown to induce mucosal tolerance and reduce atherosclerosis development, but the exact mode of action remains to be elucidated. Recent studies have indicated an important role for B cells in mucosal tolerance, in particular by induction of regulatory B (Bregs) and T cells (Tregs). In this study, we aimed to investigate if transfer of B cells pulsed with CTB-p210 can protect against atherosclerosis. Method and results: First, we studied if CTB-p210 can induce Bregs and Tregs in vitro. After pulsing B cells from Apob(tm2gy)ldlr(-/-) or Apoe(-/-) mice with CTB-p210 for 1 h and co-culturing them with naive T cells for 48 h, we observed increased expression of membrane bound TGF beta/latency-associated peptide (mTGF beta/LAP) on B cells and an increased proportion of CD25(hi)FoxP3(+) Tregs. Adoptive transfer of B cells pulsed with CTB-p210 into high-fat diet-fed Apoe(-/-) mice at 8, 10 and 12 weeks of age, reduced the plaque area in the aorta at 20 weeks of age as compared with control-treated (CTB-pOVA treated B cells or PBS) mice. Moreover, mice receiving p210-CTB treated B cells had increased levels of anti-p210 IgG antibodies. Conclusion: Our observations suggest that CTB-p210 pulsed B cells acquire a regulatory phenotype and induce Tregs in vitro. Adoptive transfer of CTB-p210, but not control-treated, B cells into Apoe(-/-) mice decreased atherosclerosis development.
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