Introduction

Sarcoidosis is an inflammatory systemic disorder. The lungs and lymph nodes are most commonly affected, but any organ may be involved, resulting in organ function impairment and sometimes failure (e.g. respiratory insufficiency). The disease can be self-limiting, seen mostly in patients with the clinical phenotype Löfgren´s syndrome and characterized by an acute onset, but many patients (commonly patients with non-Löfgrens syndrome, usually with a more insidious onset) experience a chronic course despite treatment. The exact nature and order of immunological events leading to formation of non-necrotizing granulomas, a pathological hallmark of the disease, remains unknown. It has been established, though, that both genetic factors and a dysregulated immune system characterized by a T-cell alveolitis are involved. Available data suggests that a triggering antigen is presented by human leukocyte antigen (HLA) class II molecules leading to an accumulation of CD4+ T-cells, increased cell concentration in the lungs and production of proinflammatory cytokines1. TNF-α is regarded as crucial for granuloma formation and the release from alveolar macrophages is higher in patients with active disease2,3. T regulatory cells (Tregs) normally dampen the release of proinflammatory cytokines and thereby have the potential to control and terminate immune responses4. The exaggerated inflammatory response in sarcoidosis has, at least partly, been explained by a reduced function and/ or frequency of Tregs in bronchoalveolar fluid (BALF) and blood as well as a decreased expression of the Treg-specific transcription factor FoxP3, which is essential for their function5,6.
An increased cell concentration, accumulation of CD4+ T-cells, and a CD4/CD8 ratio exceeding 3.5 in BALF strongly support the diagnosis of sarcoidosis 7. However, evidence indicates that not only the CD4+ T-cells, but also other cell types, are of importance for the sarcoid inflammation. Upon stimulation, CD8+ T-cells from blood and especially from BALF from patients with sarcoidosis have a higher capacity to produce interferon γ (IFN-γ) as compared to CD4+ T-cells8. In a more recent study, blood CD8+ T-cells were demonstrated to have a higher cytotoxic capacity compared to healthy controls9. It is generally held that macrophages are the main source of TNF- α10,11, but also other cells, e.g. CD4+ and CD8+ T-cells as well as mast cells can produce TNF- α8,12-14. Furthermore, the number of mast cells is higher in patients with sarcoidosis compared to healthy controls, and they are activated and more numerous in patients with high inflammatory activity and a more severe disease course15-19.
There are no sarcoidosis-specific treatments. Patients in need of treatment are eligible for third-line therapy with TNF- α inhibitors when first-and second-line therapy (mostly corticosteroids and/or methotrexate and azathioprine) have failed or when contraindications are present. Several TNF- α inhibitors are available, but infliximab seems superior20,21. However, roughly 20 % of patients receiving TNF-α inhibitors do not seem to benefit from treatment at all, and the optimal dose and treatment duration is not established. The risk of relapse is high after cessation of therapy as at least half of the patients are reported to relapse after treatment discontinuation20-22. A few studies have investigated how TNF- α inhibition interferes in the sarcoid inflammation23,24,25,26,27. Notably, despite that immune cells in the lung differ considerably from those in blood, and that T-cell activation in sarcoidosis is compartmentalized, with lung T-cells disclosing a higher level of activity compared to blood28-32, so far no one investigated the effect of treatment on the local lung inflammation. Insight into the influence of infliximab on lung immune cells may provide clues to what drives inflammation in sarcoidosis and how inhibition of TNF-α interferes with this process. Therefore, the current study was undertaken to analyse the effect of TNF- α inhibition on lung immune cells, by performing bronchoscopy with BAL in close adjacent to start of treatment and after six months of infliximab therapy.