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.