Susanna Kullberg

Bakgrund: There is no cure for sarcoidosis, an inflammatory disease that can affect any organ but most commonly the lungs. Some experience a resolving, and others develop a chronic disease, e.g. pulmonary fibrosis, heart failure when there is cardiac involvement. Little is known about how to identify individuals at risk of poor outcomes. Despite treatment with 1st line corticosteroids, 2nd line cytotoxic agents and 3rd line tumour necrosis factor alpha inhibitors, many patients deteriorate. CD4+ T-cells accumulate in the lungs and release inflammatory cytokines. The heterogeneity of the disease is associated with genetic variants including HLA DRB1-alleles and signaling pathways, e.g expression of T-cell receptor segments and cytokines, but the understanding of mechanisms behind differences in disease course is incomplete. Increasing evidence indicate that other immune cells besides T-cells, for instance B-cells as important and B-cell targeted therapy proved successful in some patients but it is unclear whether a special phenotype is responsive. Målsättning: To identify biomarkers/predictors for 1) disease course 2) treatment response Arbetsplan: The majority of data is collected during routine diagnostic and follow-up visits for patients with sarcoidosis. Almost all individuals continue their care at our outpatient clinic, thus there will be long-term data on disease course. The bronchoalveolar fluid from bronchoscopy is sufficient for diagnostic and research analyses. Extra blood samples are taken at first and follow-up visits. Some patients will undergo two additional bronchoscopies, before and after treatment. A broad set of immune cells and cytokines, focusing on B- and T-cell homeostasis will be investigated by spectral flow cytometry, Olink, Luminex and ELISA. The results will be correlated to genotype focusing on HLA-DRB1* alleles, disease course and outcomes from treatment. A special attention will be drawn towards B-cell homeostasis and its correlation with treatment outcomes. Betydelse: By comparing the inflammation in blood and lung at a molecular level with disease course, genotype and treatment outcomes, I hope to identify biomarkers/predictors for disease course and treatment response and whether a special phenotype may benefit from B-cell targeted therapy, enabeling early individualized therapy. The results may also lead to identification of new targets for therapy.

Bakgrund: There is no cure for sarcoidosis, an inflammatory disease that can affect any organ but most commonly the lungs. Some experience a resolving, and others develop a chronic disease, e.g. pulmonary fibrosis, heart failure when there is cardiac involvement. Little is known about how to identify individuals at risk of poor outcomes. Despite treatment with 1st line corticosteroids, 2nd line cytotoxic agents and 3rd line tumour necrosis factor alpha inhibitors, many patients deteriorate. CD4+ T-cells accumulate in the lungs and release inflammatory cytokines. The heterogeneity of the disease is associated with genetic variants including HLA DRB1-alleles and signaling pathways, e.g expression of T-cell receptor segments and cytokines, but the understanding of mechanisms behind differences in disease course is incomplete. Increasing evidence indicate that other immune cells besides T-cells, for instance B-cells as important and B-cell targeted therapy proved successful in some patients but it is unclear whether a special phenotype is responsive. Målsättning: To identify biomarkers/predictors for 1) disease course 2) treatment response Arbetsplan: The majority of data is collected during routine diagnostic and follow-up visits for patients with sarcoidosis. Almost all individuals continue their care at our outpatient clinic, thus there will be long-term data on disease course. The bronchoalveolar fluid from bronchoscopy is sufficient for diagnostic and research analysis. Extra blood samples are taken at first and follow-up visits. Some patients will undergo two additional bronchoscopies, before and after treatment. A broad set of immune cells and cytokines, focusing on B- and T-cell homeostasis will be investigated by spectral flow cytometry, Olink, Luminex and ELISA. The results will be correlated to genotype focusing on HLA-DRB1* alleles, disease course and outcomes from treatment. A special attention will be drawn towards B-cell homeostasis and its correlation with treatment outcomes. Betydelse: By comparing the inflammation in blood and lung at a molecular level with disease course, genotype and treatment outcomes, I hope to identify biomarkers/predictors for disease course and treatment response, and whether a special phenotype may benefit from B-cell targeted therapy, enabeling early individualized therapy. The results may also lead to identification of new targets for therapy.

The goal of this application is to resolve the aetiology of the inflammatory disease sarcoidosis and to identify clinically relevant markers for improved diagnosis and prognosis. Today, around 16.000 individuals in Sweden live with sarcoidosis, with about 1.200 to 1.500 new patients added yearly. Patients usually suffer from airway problems but also experience more general symptoms like fatigue. In fact, symptoms vary from patient to patient, depending on which organs are engaged. There is no specific treatment and oral steroids that are usually applied have well-known and severe side effects. Hopefully, our studies may point out new targets for treatments.Studies of the immune system indicated the existence of specific antigens and in collaboration with prof A Fontenot, Denver, we recently identified such a candidate antigen, ie. an enzyme found in the fungus Aspergillus Nidulans (published in J Exp Med). We are now studying the functional aspects of this fungus.Our group is well-established also internationally, e.g. the applicant served for 10 years as General Secretary of WASOG, the international organization for sarcoidosis research. Moreover, we were invited to publish reviews in NEJM (N Engl J Med. 2021) and Nature (Nat Rev Dis Primers 2019), showing our excellent reputation in this field. We continue to search for new antigens, applying various techniques. This setup might be valuable also in other inflammatory diseases that involve specific antigens.