Relationship between arterial stiffness index, pulse pressure, and magnetic resonance imaging markers of white matter integrity: A UK biobank study

BACKGROUND: Alzheimer’s disease and dementia in general constitute one of the major public health problems of the 21st century. Research in arterial stiffness and pulse pressure (PP) play an important role in the quest to reduce the risk of developing dementia through controlling modifiable risk factors. OBJECTIVE: The aim of the study is to investigate the association between peripheral PP, arterial stiffness index (ASI) and brain integrity, and to discover if ASI is a better predictor of white matter integrity than peripheral PP. MATERIALS AND METHODS: 17,984 participants 63.09 ± 7.31 from the UK Biobank were used for this study. ASI was estimated using infrared light (photoplethysmography) and peripheral PP was calculated by subtracting the diastolic from the systolic brachial blood pressure value. Measure of fractional anisotropy (FA) was obtained from diffusion imaging to estimate white matter microstructural integrity. White matter hyperintensities were segmented from the combined T1 and T2-weighted FLAIR images as a measure of irreversible white matter damage. RESULTS: An important finding is that peripheral PP better predicts white matter integrity when compared to ASI. This finding is consistent until 75 years old. Interestingly, no significant relationship is found between either peripheral PP or ASI and white matter integrity after 75 years old. CONCLUSION: These results suggest that ASI from plethysmography should not be used to estimate cerebrovascular integrity in older adults and further question the relationship between arterial stiffness, blood pressure, and white matter damage after the age of 75 years old

Th1-Like ICOS⁺ Foxp3⁺ T_reg Cells Preferentially Express CXCR3 and Home to β-Islets during Pre-Diabetes in BDC2.5 NOD Mice

<div><p>Type 1 diabetes (T1D) occurs through a breakdown of self-tolerance resulting in the autoimmune destruction of the insulin producing β-islets of the pancreas. A numerical and functional waning of CD4⁺Foxp3⁺ regulatory T (T_reg) cells, prompted by a pancreatic IL-2 deficiency, accompanies Th1 autoimmunity and T1D progression in non-obese diabetic (NOD) mice. Recently, we identified a dominant subset of intra-islet T_reg cells that expresses the ICOS costimulatory receptor and promotes self-tolerance delaying the onset of T1D. ICOS co-stimulation potently enhances IL-2 induced survival and proliferation, and suppressive activity of T_reg cells <i>in situ</i>. Here, we propose an ICOS-dependent mechanism of T_reg cell homing to the β-islets during pre-diabetes in the NOD model via upregulation of the CXCR3 chemokine receptor. The islet-specific ICOS⁺ T_reg cell subset preferentially expresses CXCR3 in the pancreatic lymph nodes (pLN) in response to T_eff cell-mediated pancreatic inflammation, an expression correlating with the onset and magnitude of IFN-γ production by T_eff cells in pancreatic sites. We also reveal that intra-pancreatic APC populations and insulin-producing β, but not α nor δ, islet cells secrete the CXCR3 chemokines, CXCL9, 10 and 11, and selectively promote ICOS⁺CXCR3⁺ T_reg cell chemotaxis <i>in vitro</i>. Strikingly, islet-derived T_reg cells also produce these chemokines suggesting an auto-regulation of homing by this subset. Unlike ICOS^- cells, ICOS⁺ T_reg cells adopt a Th1-like T_reg phenotype while maintaining their suppressive capacity, characterized by expression of T-bet and CXCR3 and production of IFN-γ in the draining pLNs. Finally, <i>in vivo</i> neutralization of IFN-γ blocked T_reg cell CXCR3 upregulation evincing its role in regulating expression of this chemokine receptor by T_reg cells. Thus, CXCR3-mediated trafficking of T_reg cells could represent a mechanism of homeostatic immunoregulation during diabetogeneesis.</p></div

Dépendance aux jeux vidéo

Centre de réadaptation en dépendance Le VirageÉcole primaire alternative des Trois-Sourcesguylaine.sarrazin.crdlevirage16@[email protected] réalisé dans le cadre du cours PHA2415Création d'une vidéo pour sensibiliser sur le sujet de la dépendance aux jeux vidé

Intra-islet T_reg cells reverse T_eff cell-mediated abrogation of chemokine secretion by ß-islet cells.

<p>β-islet cells were isolated from 4-week-old BDC2.5 mice. (A) Expression of CXCR3 chemokines was compared between insulin^<b>+</b> cells and glucagon^<b>+</b> cells, and unstained controls. (B), NOD.TCRα^<b>-/-</b> mice received T_<b>reg</b> or T_<b>eff</b> cells either alone or at the indicated T_<b>reg/</b>T_<b>eff</b> cell ratios. When mice receiving T_<b>eff</b> cells alone became hyperglycemic (>33mmol/L), CXCL10 expression (MFI) in β-islet cells was compared between groups. (C) IFN-γR ΔMFI (ΔMFI was calculated by subtracting the isotype control MFI from IFN-γR antibody MFI) and was compared between β (insulin^<b>+</b>), α (glucagon^<b>+</b>) and δ (somatostatin^<b>+</b>) cells isolated from 4-week-old BDC2.5 mice. (5B, 5C n = 5).</p

IFN-γ regulates CXCR3 expression by ICOS⁺ T_reg cells and their homing to islets.

<p>NOD.TCRα^<b>-/-</b> mice received BDC2.5 CD4^<b>+</b> T cells (7.5X10^<b>5</b>) and, (A) and the percent CXCR3^<b>+</b> and IFN-γR^<b>+</b> cells among total T_<b>reg</b> cells in pancreas and draining LNs was assessed at the indicated times post-transfer. (B) Correlation between percent CXCR3^<b>+</b> and IFN-γR^<b>+</b> in pancreas and draining LN at all points examined. (C) BDC2.5 CD4^<b>+</b> T cells were stimulated with various concentrations of recombinant IFN-γ, and STAT1 phosphorylation was assessed by flow cytometry and compared between ICOS^<b>+</b> and ICOS^<b>-</b> subsets of T_<b>reg</b> cells. (D) NOD.TCRα^<b>-/-</b> mice received T_<b>eff</b> (7.5X10^<b>5</b>) cells and were injected i.p. with either PBS or anti-IFNγ Ab (XMG1.2) on days -1, 1, 3, 5 and 7 post transfer. Mice were sacrificed when the PBS group displayed hyperglycemia (>33mmol/L). Cell suspensions of the pancreatic draining LN were obtained and the percent CXCR3^<b>+</b> among pT_<b>reg</b> cells was compared between groups. (6A, 6B, 6D n = 5. 6C n = 2).</p

Autoreactive T cell-mediated inflammation induces CXCR3 expression by ICOS⁺ T_reg cells prior to T1D onset.

<p>Cell suspensions of pancreas and draining LN from 4 week old (A, B) WT and (B) ICOS^<b>-/-</b> BDC2.5 mice were assessed for the frequency of CXCR3^<b>+</b> cells and levels of CXCR3 expression (MFI) between the ICOS^<b>+</b> and ICOS^<b>-</b> subsets of T_<b>reg</b> cells. (C and D) NOD.TCRα^<b>-/-</b> mice received MACS sorted BDC2.5 CD4^<b>+</b>CD25^<b>+</b> (T_<b>reg</b>, 0.75X10^<b>5</b>) or CD4^<b>+</b>CD25^<b>-</b> (T_<b>eff</b>, 7.5X10^<b>5</b>) cells alone or at the indicated T_<b>reg/</b>T_<b>eff</b> cell ratios. When the T_<b>eff</b> cell recipient mice displayed hyperglycemia (>33mmol/L), mice were sacrificed and expression of IFN-γ by T_<b>eff</b> cells (C) and CXCR3^<b>+</b> percent cells among the ICOS^<b>+</b> T_<b>reg</b> cell subset were assessed. (E) NOD.TCRα^<b>-/-</b> mice received the indicated ratios of FACS-sorted Thy1.2^<b>+</b> T_<b>reg</b> cells to 7.5X10^<b>5</b> BDC2.5 Thy1.1^<b>+</b> CD4^<b>+</b>Foxp3^<b>-</b> T_<b>eff</b> cells. After 14 days, the Thy1.2 (tT_<b>reg</b>) and Thy1.1^<b>+</b> (pT_<b>reg</b>) subsets of ICOS^<b>+</b> T_<b>reg</b> cells were compared for percent CXCR3^<b>+</b> cells. (n = 4, peri LN = pooled axial, brachial and inguinal peripheral lymph nodes).</p

Resident leukocyte subsets in the pancreas express CXCR3-activating chemokines.

<p>NOD.TCRα^<b>-/-</b> mice initially received BDC2.5 CD4^<b>+</b> T cell (7.5X10^<b>5</b>) cells, and then cell suspensions from pancreas, draining pLN and peripheral LN of diabetic mice were examined for expression of CXCL9, CXCL10 and CXCL11 in F4/80^<b>+</b> (A) and CXCL10 in CD11c^<b>+</b> (B) cells was assessed by flow cytometry. (C) NOD.TCRα^<b>-/-</b> mice were transferred with CD4^<b>+</b> T cells in order to induce T1D. Following adoptive transfer, glucose levels were measured daily in order to assess diabetes onset. Pancreatic cell suspensions from recipients were obtained and CXCL10 expression (MFI) was compared among CD11c^<b>+</b> cells from diabetic or non-diabetic recipients, as well as un-transferred (without T cell transfer) NOD.TCRα^<b>-/-</b> mice. (D) NOD.TCRα^<b>-/-</b> mice received T_<b>reg</b> or T_<b>eff</b> cells either alone or at the indicated T_<b>reg/</b>T_<b>eff</b> cell ratios. When mice receiving T_<b>eff</b> cells alone became hyperglycemic (>33mmol/L), CXCL10 levels were assessed by ELISA in supernatants from pancreatic suspensions. (E), F4/80^<b>+</b> and CD11c^<b>+</b> (1X10^<b>6</b>/well) cells were seeded in triplicate in lower chambers, and CD4^<b>+</b> (1X10^<b>6</b>/well) cells in the upper chambers of 24 well Transwell plate. Following a 3 hour incubation period, the percent migrated CXCR3^<b>+</b> cells among ICOS^<b>+</b> T_<b>reg</b> cells was compared between wells containing APCs and media alone (<i>control</i>). Cell suspensions of pancreas and draining LN of 4-week-old BDC2.5 mice were obtained and CXCL10 expression (MFI) was compared (F) between pancreatic T_<b>reg</b> cells and T_<b>eff</b> cells (G), between T_<b>rec</b> cells at sites indicated, and between ICOS^<b>+</b> and ICOS^<b>+</b> T_<b>reg</b> cells within pancreas (H). (4A-4C n = 6, 4D n = 4, 4E n = 2, 4F-4H n = 5).</p