Cigarette smoking has been linked to risk of disease or to disease phenotype in a number of autoimmune disorders, such as rheumatoid arthritis (RA), multiple sclerosis (MS), SLE and myositis.
The local microenvironment, such as that present in the lung, may determine which antigens are presented, and also direct the alternative fates of effector and regulatory T cell subsets. However, very little is known about the influence of smoking in this regard, and how it may lead to autoimmunity.
Healthy non-smokers, smokers with normal lung function and patients (e.g. MS and RA) will be included. Samples will be obtained from peripheral blood and from the deep airways by means of bronchoscopy with bronchoalveolar lavage (BAL).
Auto-antigenic peptides presented by HLA-DR molecules on BAL cells will be identified by mass spectrometry, followed by screening for T cell responses by e.g. ELISPOT assay and flow cytometry for intracellular cytokines. Characterization of effector and regulatory T cell populations will be performed by intracellular staining for select combinations of cytokines and transcription factors, followed by multicolor flow cytometry. The expression of mRNA and miRNA in immune cells will also be studied by use of custom microarrays.
Our overall aim is to find immune mechanisms induced in the lungs after cigarette smoke exposure, and that may be common for antigen-specific inflammatory diseases initiated in the lungs. The knowledge gained could provide a strong clinical benefit in the form of new therapies targeting specific antigens via immunotherapy, or modulating the balance between T cell subsets with different functions. The identification of new biomarkers could be used as diagnostic, prognostic and activity markers, and may allow for early intervention or new types of individualized treatments.
Senior researcher projects
Macrophage biology and innate immunity regulated by tobacco smoke
Macrophages are the main population of immune cells in the lung and forms the first line of defense against pollutant and external airborne particles, including tobacco smoke, partly due to their phagocytic properties.
Macrophages can detect a range of pathogens and endogenous danger signals trough invariant pattern recognition receptors and are essential regulators of immunity in the lung. In addition, macrophages provide an important link between the innate and adaptive immune system, and have the potential to activate and modulate T cell function trough antigen presentation, display of co-stimulatory molecules, and secretion of cytokines and chemokines.
We are investigating the immunological effects of tobacco smoke on alveolar macrophages, and the role of smoking in the development of autoimmune diseases.
Key pathways in innate immunity including TLR signaling and inflammasome activation are studied, with focus on intracellular signaling, gene expression and cytokine secretion. The role of chromatin remodeling induced by tobacco smoke and its role in transcriptional regulation of cytokines, chemokines and other regulators of the immune response is also investigated.
In addition, we also utilize unbiased approaches to analyze genome-wide DNA-methylation and mRNA expression in alveolar macrophages in order to reveal the regulatory circuits associated with smoking-induced autoimmune and systemic inflammatory diseases. Through this research we hope to define the key inflammatory mechanisms regulated by tobacco smoke exposure, and identify novel pathways involved in the development of inflammatory diseases
Projects Susanna Kullberg
My work can be divided into three parts:
1.Working half-time clinically, one of my main goals is to recruit patients for the studies on antigen and innate immune mechanisms in sarcoidosis as well as for therapeutic studies, i.e. our current study on treatment with TNF-alpha-inhibitors in sarcoidosis.
2.I´m responsible for the examination and perform the bronchoscopies on patients included in the studies on smoking-induced autoimmunity.
3.By studying data regarding smoking-habits, gender, disease manifestations, risk of chronic disease and genetics (HLA alleles), I´m investigating if smoking influences the course of disease and co-varies with other factors. One of the questions I´m trying to answer is whether smoking is connected to increased risk for chronic disease or not, and if so, is women more sensitive to smoking.