1. Översiktlig projektbeskrivning

Engelsk titel

IMMUNE PERTURBATIONS AND INFECTIONS IN CARDIOVASCULAR DISEASE.

Sammanfattning av projektet

Bakgrund
Att vi drabbas av hjärt-kärlsjukdomar beror på en kroniskt låg-gradig inflammation i blodkärlen. Vad denna inflammation beror på är inte klarlagt men vår grupp har visat att störning av immunaktiveringen spelar roll genom att vara ”kroniskt aktiverat”. Denna kroniska aktivering leder till förändringar i blodkärlet och därmed åderförkalkning. Olika typer av infektioner har också betydelse vid åderförkalkning. Luftvägsbakterien Chlamydophila pneumoniae tar sig ut i våra blodkärl och skapar en kronisk infektion i blodcirkulationen. Bakterien aktiverar olika typer av immunceller och det finns många studier som visar ett en förhöjd risk för insjuknande i hjärt-kärlsjukdom om man är infekterad. Vår grupp har bland annat funnit att denna bakterie aktiverar blodplättar till att bilda blodproppar och oxidera kolesterol.

Syfte
Detta projekt syftar till att ta reda på om en störd immunaktivering vid hjärt-kärlsjukdom beror på infektion av Chlamydophila pneumoniae. Dessutom ska vi undersöka om Chlamydophila infektioner och blodplättsaktivering i blodkärlen kan orsaka inflammation åderförkalkning.

Arbetsplan
För att besvara dessa frågeställningar samlar vi in blodprover från patienter med kranskärlssjukdom. I dessa blodprover mäter vi olika ”markörer” för att få svar på hur aktiverade immunförsvarcellerna och blodplättarna är och vad det i sin tur beror på. Vi kommer dessutom att göra grundforskningsstudier för att ta reda på hur bakterien aktiverar blodplättar och andra inflammatoriska celler.

Betydelse
Detta projekt syftar till att finna olika typer av immunologiska riskmarkörer till hjärt-kärlsjukdom. Därmed kan det bli möjligt att göra en ”immunologisk riskbedömning” för hjärt-kärlsjukdom och sätta in en effektiv behandling. Genom att i detalj ta reda på hur immunförsvaret aktiveras kan man dessutom förhindra den kroniska aktivering och därmed undvika nytt insjuknande.

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva ämnesområdet

Inlagda MeSH-termer

Cardiovascular Diseases

Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.

Bacterial Infections and Mycoses

Infections caused by bacteria and fungi, general, specified, or unspecified.

Projektets delaktighet i utbildning

Avhandling
D-uppsats / Magisterexamen
C-uppsats / Kandidatexamen
ST-läkarutbildning
Annan utbildning
Ej del i utbildning

3. Processen och projektets redovisning

Pågående aktiviteter

Planering och förberedelse före datainsamling
Datainsamling pågår
Analys av insamlade data pågår
Författande av skriftlig redovisning / publikation pågår
En eller flera publikationer från projektet är publicerade
Slutfört och inget mer görs inom ramen för detta projekt

Projektstart (när planeringen påbörjas och börjar dokumenteras skriftligt)

2009-01-01

4. Detaljerad projektbeskrivning

Bakgrundsbeskrivning

Background
The atherosclerotic disease involves a chronic low-grade inflammation. An excessive production of pro-inflammatory T helper(h)1 cytokines like interferon (IFN)- and tumor necrosis factor (TNF)- , is considered to drive the development towards plaque rupture and thrombosis. Activated T cells, mainly of the Th1 type, and macrophages are frequently found in so-called high-risk lesions (Jonasson et al 2003, Nijm et al 2005).
In peripheral blood of coronary artery disease (CAD) patients, the levels of inflammatory markers are increased and the compartment of activated T helper cells is expanded. In addition, the circulating levels of matrix-degrading enzymes, like MMP are elevated in patients with clinically unstable forms of CAD (Nilsson et al 2006). MMP are produced by a number of cell types in the circulation, including platelets, macrophages and neutrophils. Altogether, there is evidence for an association between enhanced Th1 activity and plaque instability in patients with CAD.
Besides an increased CD4+ T cell activation, we have demonstrated an altered T cell homeostasis involving the CD8+ population in peripheral blood of stable CAD patients compared to healthy age- and gender-matched controls. CD8+ T cells are mainly regarded as cytotoxic effector cells but recently, a subset of CD8+CD56+ T suppressor cells (Ts cells) with anti-inflammatory effects was identified. Preliminary studies by Jonasson et al have shown that the proportion of circulating CD8+CD56+ T cells is significantly lower in patients with CAD compared to healthy controls and that this difference is particularly pronounced in patients with unstable CAD. In addition, preliminary data indicate an increased proportion of apoptotic CD8+CD56+ T cells in peripheral blood of CAD patients compared to controls (1.3 vs 5.1 %).
Natural killer (NK) cells are lymphocytes with important functions, both as non-MHC-restricted cytotoxic cells and as suppressor cells. New findings show a significant reduction of NK cells and NK cell activity in CAD patients compared with controls (Jonasson et al 2005) Furthermore, the rate of spontaneous NK cell apoptosis is significantly increased in the CAD patients (Li et al 2008).
Cumulative evidence supports an association of C. pneumoniae with atherosclerosis and the biological plausibility that it contributes to the inflammatory activity in the plaque. Among middle-aged subjects, C. pneumoniae seropositivity is common. However, the infection often resides in a chronic form while the frequency of active infection in the population is reported to be low. C. pneumoniae infects T cells and both CD4+ and CD8+ T cells contribute to protection, mainly through their secretion of cytokines. Our results show that this bacteria stimulates platelet aggregation, secretion, ROS production and LDL oxidation, and thereby play an important role in both atherogensis and thrombosis (Kälvegren et al 2003, 2005, 2007, 2008). Furthermore, our research shows that platelets express active Toll-like receptor 2 (TLR2) and that this receptor mediates the C. pneumoniae-induced platelet activation.

Syfte

The general aim is to study the perturbed immune system in patients with CAD and to investigate its possible causes and clinical consequences.
Specific aims are to examine:
←ex vivo if the immune perturbations in CAD are associated with a failure to suppress T cell activity.
←whether these immune perturbations in CAD patients are linked to Chlamydophila pneumoniae infection.
←if the production of metalloproteinases (MMP) from platelets is increased in CAD patients and has a role in cardiovascular disease.
←if TLR2 expression on platelets is connected to CAD and to continue the in vitro studies on the TLR2- associated signalling pathways in platelets.
←the role of bacteria-platelet interaction in innate immunity and atherosclerosis.

Frågeställning / Hypoteser

←The failure to suppress Th1 activity is associated with unstable forms of CAD.
←The failure to suppress Th1 activity increase the possibility of active C. pneumoniae infection in CAD patients thereby providing a link between C. pneumoniae infection and plaque instability.
←One reason behind increased serum MMP in patients with CAD is increased secretion of MMP from platelets. MMP secreted from platelets can stimulate atherogenesis.
←Platelets express unique TLR associated signalling pathways and TLRs on platelets have a significant role in innate immunity and in atherosclerosis.
←Increased platelet activation due to bacteria can contribute to atherosclerosis.

Metod: Gruppindelning

(I) patients (< 75 years) admitted to hospital with a diagnosis of unstable CAD, i.e. unstable angina/non-ST-elevation myocardial infarction, (II) patients (< 75 years) with stable CAD, i.e. no acute events or worsening of symptoms during the last 3 months, (III) age- and gender-matched individuals, clinically healthy and without any pharmacological therapy.

Diskussion

Importance: The immune perturbations in CAD indicate the presence of a chronic immune stimulation and, possibly, an impaired protective immunity or a so-called “immune risk phenotype”. We have earlier shown that an active cytomegalovirus infection is more frequent in patients with CAD compare to controls. C. pneumoniae is another microorganism that has been strongly associated with myocardial infarction although mechanisms or causal relationships are not clarified. However, impaired protective immunity may imply an increased reactivation of C. pneumoniae infection, both in the lesion and systemically, and thereby constitute an increased risk of plaque instability and thrombosis. To become able to target the prevention of plaque instability by immunomodulatory and/or antibiotic therapy, we need a precise characterization of the immune status in atherosclerosis as well as an evaluation of its role in vivo.