Protective Immunity in Atherosclerosis

The immune system is a promising target for novel therapies that are aiming at reducing cardiovascular diseases. Autoimmune responses against modified low density lipoprotein (LDL) are believed to promote development of atherosclerosis. Proinflammatory immune responses can be counterbalanced by immunosuppressive regulatory T cells (Tregs). Immunizations of hypercholesterolemic mice with oxidized LDL or peptides derived from the protein part of LDL, apoB-100, inhibit the development of atherosclerosis. The protective immunity induced by the apoB-100 peptide vaccine aBp210 is associated with an activation of Tregs indicating that specific activation of Tregs could be a promising target in immune modulating therapies. Activation of the inhibitory Fcgamma receptor IIB (FcgammaRIIB) is an additional potential target for immune modulating therapy as hypercholesterolemic mice deficient in FcgammaRIIB have a more aggressive disease development. Antigen presentation is a fundamental step in T cell activation. By investigating the role of antigen presentation in atherosclerosis development new targets for intervention could be provided. Antigen presentation on major histocompatibility complex (MHC) class II is critical in activation of CD4+ T cells whereas CD1d antigen presentation is required for activation of NKT cells. The role of MHC class II antigen presentation in atherosclerosis is complex and was unexpectedly found to be associated with reduced atherosclerosis development, whereas, neointima formation in response to vascular injury was accelerated by CD1d lipid antigen presentation. NKT cells and CD1d could therefore be an additional potential target in immune modulating therapies. Except for novel therapies, new biomarkers to better predict development of acute cardiovascular events are also needed in order to reduce the disease. Low levels of circulating Tregs may be a future predictor for myocardial infarction and stroke

CD8+ T cell activation predominate early immune responses to hypercholesterolemia in Apoe-/- mice

<p>Abstract</p> <p>Background</p> <p>It is well established that adaptive immune responses induced by hypercholesterolemia play an important role in the development of atherosclerosis, but the pathways involved remain to be fully characterized. In the present study we assessed immune responses to hypercholesterolemia induced by feeding <it>Apoe^-/-</it>mice a high-fat diet for 4 or 8 weeks.</p> <p>Results</p> <p>The primary immune response in lymph nodes draining the aortic root was an increased expression of interferon (IFN)-γ in CD8⁺CD28⁺T cells, while an activation of IFN-γ expression in CD4⁺T cells was observed only after 8 weeks of high-fat diet. Contrarily, spleen CD4⁺T cells responded with a higher expression of IL-10. Spleen CD8⁺T cells expressed both IFN-γ and IL-10 and showed enhanced proliferation when exposed to Concanavalin A. Plasma levels of IgG and IgM against oxidized LDL did not change, but the level of apolipoprotein B/IgM immune complexes was increased.</p> <p>Conclusion</p> <p>Hypercholesterolemia leads to unopposed activation of Th1 immune responses in lymph nodes draining atherosclerotic lesions, whereas Th1 activation in the spleen is balanced by a concomitant activation of Th2 cells. The activation of CD8⁺T cells implies that hypercholesterolemia is associated with formation of cell autoantigens.</p

Decreased levels of stem cell factor in subjects with incident coronary events.

It has been proposed that vascular progenitor cells play an important role in vascular repair, but their possible clinical importance in cardiovascular disease has not been fully characterized. Vascular endothelial growth factor A, placental growth factor and stem cell factor (SCF) are three growth factors that are important in recruiting vascular progenitor cells. In this study, we investigated the association between the plasma levels of these growth factors and incident coronary events (CEs)

CD4(+) CD56(+) natural killer T-like cells secreting interferon-γ are associated with incident coronary events.

CD3(+) CD56(+) natural killer T (NKT)-like cells are a subset of T cells characterized by expression of NK receptors and potent antitumour activity. It has also been suggested that they have a role in autoimmune disease, and levels of NKT-like cells are elevated in patients with coronary disease

IL-22 affects smooth muscle cell phenotype and plaque formation in apolipoprotein E knockout mice.

IL-22 is a recently discovered cytokine that belongs to the family of IL-10 related cytokines. It is produced by activated T-cells and innate lymphoid cells and has been suggested to be involved in tissue repair. As both inflammation and repair play important roles in atherosclerosis we investigated if IL-22 deficiency influences the disease process in Apoe(-/-) mice

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Följsamhet i läkemedelsbehandling vid bipolär sjukdom : Testning och produktutvärdering

Examensarbetet görs i samarbete med psykiatriska vårdenheten i Pargas inom projektet TAG i livet (Tillgång, Aktivitet och Gemenskap). Projektets mål är att stöda vuxna och äldre människor till självständighet genom rehabiliterande och resursförstärkande arbetssätt. Det här examensarbetet bygger delvis på ett tidigare examensarbete i vilket det utvecklades en uppföljningskalender för att motivera patienter med bipolär sjukdom till följsamhet i läkemedelsbehandling. I det här examensarbetet utförs en testning och utvärdering av uppföljningskalendern. Syftet är att utvärdera uppföljningskalendern som motivationsskapare till följsamhet i läkemedelsbehandling för patienter med bipolär sjukdom. Tanken är också att examensarbetet bidrar till utvecklande av vårdarbete och främjande av hälsa hos bipolära patienter. Uppföljningskalendern testades av patienter med bipolär sjukdom (n=3). För utvärderingen utvecklades det en enkät med frågor åt sjukskötare som samarbetat med de patienter som testat uppföljningskalendern. Patienterna använde kalendern dagligen och två av dem bedömdes ha klarat av användningen bra och en patient mycket dåligt. Kalendern bedömdes inte ha påverkat på uppföljningen av medicineringen för patienterna under avdelningsvården och ingen förändring i patienternas medicinintag hade upptäckts. Några kommentarer och förbättringsförslag framkom. Eftersom kalendern fylldes i regelbundet av patienterna, kan det antas att användningen inte var svår. Med tanke på antalet deltagare kan det ändå inte dras generaliserbara slutsatser, endast antaganden. Ytterligare utvärdering behövs för att kunna dra tillförlitliga slutsatser.Tämä opinnäytetyö tehdään yhteistyössä Paraisten psykiatrisen hoitoyksikön kanssa osana projektia, OTE- elämästä (Omaehtoisen Toiminnan Edistäminen). Projektin tavoitteena on tukea aikuisten ja iäkkäämpien ihmisten itsenäisyyttä kuntoutuksen ja voimavaroja vahvistavan työtavan avulla. Tämä opinnäytetyö pohjautuu osittain aikaisempaan opinnäytetyöhön jossa kehitettiin seurantakalenteri motivoimaan kaksisuuntaista mielialahäiriötä sairastavia potilaita lääkehoitoon sitoutumisessa. Tässä opinnäytetyössä tehdään seurantakalenterin testaus ja arviointi. Tavoitteena on arvioida seurantakalenteria motivaation luojana kaksisuuntaista mielialahäiriötä sairastavien lääkehoitoon sitoutumisessa. Ajatuksena on myös, että opinnäytetyö myötävaikuttaa hoitotyön kehittämiseen ja kaksisuuntaista mielialahäiriötä sairastavien terveyden edistämiseen. Seurantakalenterin testaus tehtiin kaksisuuntaista mielialahäiriötä sairastavien potilaiden kanssa (n=3). Arviointia varten kehitettiin kyselylomake, joka sisälsi kysymyksiä niille sairaanhoitajille, jotka olivat toimineet yhteistyössä kalenteria kokeilleiden potilaiden kanssa. Potilaat käyttivät kalenteria päivittäin ja kahden heistä arvioitiin hallinneen kalenterin käyttö hyvin ja yhden erittäin huonosti. Kalenterin ei arvioitu vaikuttaneen lääkehoidon seurantaan osastohoidon aikana, eikä lääkkeiden ottamiseen liittyen huomattu eroja potilaissa. Muutamia kommentteja ja parannusehdotuksia annettiin. Koska potilaat käyttivät kalenteria päivittäin, voidaan olettaa, ettei sen käyttö tuottanut vaikeuksia. Osallistujien määrään viitaten ei kuitenkaan voida tehdä yleistäviä johtopäätöksiä, ainoastaan olettamuksia. Lisäarviointia tarvitaan luotettavien johtopäätösten tekemiseksi.This Bachelor´s thesis is done in cooperation with the psychiatric unit in Pargas in the frames of the project “TAG i livet”. The aim of the project is to support adult and elderly people to independence through rehabilitation and resource enhancement. This thesis work is partly based on an earlier thesis work in which a calendar to motivate patients with bipolar disorder to adherence in the intake of medication was done. This thesis is about evaluating and testing the calendar. The aim of this work is to establish if the calendar has worked as a source of motivation for patients with bipolar disorder and to develop and promote the health of patients with bipolar disorder. The calendar was tested on patients with bipolar disorder (n=3). For the evaluation of the calendar, a questionnaire was developed; aimed for the nurses working with the patients who have been using the calendar. The patients used the calendar daily and two of them managed it well and one really poorly. It was established that during hospitalized care, no effect of the calendar could be found and the intake of medication was not noticed to be affected. Some comments and ideas for development of the calendar were given. It can be assumed that the calendar was not difficult to use because the patients used it regularly. Due to the small amount of participants no general conclusions can be made, only assumptions. Further evaluations needs to me done to establish any valid conclusions