Genetic background and disease markers in Sarcoidosis

There are approximately 2000 new cases of sarcoidosis in Sweden yearly, and the peak incidence is in adults less than 40 years of age. The disease has a substantial impact on patients' health status and quality of life, particularly for female patients who generally experience more symptoms.

In Sweden, more than half of the patients develop a disease with more than two years duration, and pulmonary fibrosis develops in 20-25% of the patients, with subsequent mortality rates of 1-5 %, usually due to severe pulmonary complications, myocardial involvement, or central nervous system involvement.


To characterise the genetic background and to identify specific disease markers in sarcoidosis.

Previous results and work plan

There is a significant genetic influence in sarcoidosis. Specific HLA alleles associate with an increased risk for sarcoidosis, and we have previously shown a strong association between HLA-DRB1*03 (also called DR3 or DR17) and good prognosis, and between HLA-DRB1*14 and DRB1*15 with chronic disease. We also found that HLA class I alleles could influence the disease course, and we identified certain HLA allele-combinations to be strongly associated with persistent disease (A*03,B*07,DRB1*15) or with good prognosis (A*01,B*08,DRB1*03), respectively (1). Other genes of interest include chemokine receptor 2 (CCR2), which recently was found to associate with a subgroup of sarcoidosis i.e. Löfgren´s syndrome.

Our plan is to identify other sarcoidosis associated genes. For this reason we have collected DNA from an exceptionally large number of patients (>800 patients). All our patients are carefully characterized clinically and furthermore already HLA-typed, giving us the possibility to subgroup patients which will increase the chance to unmask phenotype-specific genetic associations. Our materials include >300 patients with Löfgren´s syndrome (2), generally with a good prognosis (3), which altogether gives us a unique possibility to identify genes associated with resolution of disease or with progression of inflammation and development of fibrosis. Our large patient material gives us a chance to understand the role also of HLA alleles that are less frequent. Moreover, we will be able to investigate associations between certain HLA alleles and distinct clinical manifestations of the disease such as uveitis, skin sarcoidosis, heart manifestations etc. Such patient groups are clinically important, as they may suffer severely from the disease if untreated.

We also search for biomarkers, and in our proteomic approach, we have analyzed protein expression in BAL fluid (4). We recently used state-of-the-art proteomics technology (DIGE) to quantify alterations in BAL fluid protein expression of sarcoidosis patients as compared to healthy controls. Several putative biomarkers for sarcoidosis were identified (5).

Earlier studies showed that following injection of non-viable autologous BAL cells into the skin of sarcoidosis patients, but not controls, granulomas were formed. Thus, BAL cells (alveolar macrophages) may harbour in their membranes a factor capable of inducing granulomas in sarcoidosis patients ("granulomagenic factor"), which could include sarcoidosis specific antigens. We are now using newly developed techniques to identify membrane-associated proteins of BAL cells with such a capacity to induce granuloma formation, and possibly containing a sarcoidosis specific antigen.

Clinical relevance

Our studies may reveal gene associations that can improve our understanding of the exaggerated sarcoid inflammatory reaction. Our studies may also result in a more thorough clinical deliniation of patient subgroups, which is of importance for improved clinical management of these patients. We also search to identify biomarkers of disease, and markers of importance for resolution of inflammation and/or progression of inflammation and fibrosis development, that could become targets of future immunotherapies.



Telefon:08-517 751 17

Enhet:Forskargrupp J Grunewald