3 research outputs found
Sarcoidosis : expression of cell regulatory markers and the influence of patient phenotype on bronchoalveolar lavage cell differential counts
Sarcoidosis is a systemic inflammatory disease that can affect almost any organ,
but the respiratory system is affected in more than 90% of the cases. To elicit an
immune response, an antigen(s) is processed by antigen-presenting cells (APCs),
e.g. alveolar macrophages (AMs), and is presented in association with HLAmolecules
to specific T cells, using their T cell receptor (TCR). In sarcoidosis, this
interaction between the innate and adaptive immune system leads to an exaggerated
immune response and formation of non-caseating granulomas in affected organs.
The causative antigen remains elusive. To generate the sarcoid inflammatory
process, the genetic background as well as exposure for antigens, endogenous or
exogenous, is it of importance. Clinically, sarcoidosis patients can be divided into
two major groups, i.e. patients with Löfgren’s syndrome (LS) or with non-Löfgren’s
syndrome (non-LS). LS is a clinically distinct and well-defined phenotype that is
characterized by an acute onset and is associated with specific HLA molecules,
i.e. HLA-DRB1*03. In most of the LS patients, the disease resolves within two
years. On the other hand, non-LS patients constitute a heterogeneous group and
are prone to develop a chronic disease course.
Collecting cells from the deep lung compartment via bronchoalveolar lavage (BAL)
enabled many researchers to explore immunological mechanisms in the alveolar
space. In a healthy individual, BAL fluid (BALF) are mainly macrophages, some
lymphocytes, and fewer neutrophils, and eosinophils; basophils and mast cells are
rare. BALF from sarcoidosis patients contains an increased number of all these
cell types, especially lymphocytes.
The first two studies (I, II) aimed to shed some light on the expression of cell regulatory
markers in LS and non-LS patients. Macrophages are classically subdivided
into two major subtypes, i.e. M1 – known as proinflammatory macrophages – and
M2 – known as remodeling macrophages. We found in the first study (I) reduced
gene expression of toll-like receptor 2 (TLR2: M1 associated marker) – mainly
in LS patients – and increased expression of CCL18 (M2 associated marker) in
AM of sarcoidosis patients. This finding could indicate a shift toward M2-like
macrophages in sarcoidosis. The reduced TLR2 expression in LS patients might
allow for a more effective immune response leading to resolution of granulomas.
The CCL18 chemokine is known to act as T cell chemoattractant and can also
induce collagen production in fibroblasts. Hence, the increased expression of
CCL18 in AM of patients might attract T cells to the lung in the early stages of
the disease and exhibit a profibrotic role in more advanced disease. The second
study (II) explored the expression of specific transcription factors/nuclear receptors
known to have regulatory roles in inflammatory diseases, i.e. the peroxisome
proliferator-activated receptors (PPARs): PPARα, PPARβ/δ and PPARγ. Compared
to LS patients, PPARα expression was downregulated in BALF and blood CD4+
and CD8+ T cells in non-LS patients. Thus, CCL18 and PPARα could be used as
biomarkers and might help in identifying patients at increased risk of developing
more advanced lung disease.
The third study (III) aimed to explore the influence of patient phenotypes on BALF
cell differential counts. We found that genetic variants associated with risk of LS
and clustered in the extended MHC region were associated with the quantitative
levels of BALF macrophages, lymphocytes, and neutrophils. Genetic variants
associated with non-LS and located in the MHC II region associated with the
quantitative levels of BALF macrophages only. In addition, these genetic variants
exhibit regulatory effects on other genes in the lung, blood, T cells, B cells, macrophages
and neutrophils.
The fourth study (IV) aimed to utilize data from a BALF registry of pulmonary
sarcoidosis patients (LS and non-LS) to identify BALF cells that could predict
disease severity (defined as advanced chest radiographs, reduced pulmonary
function, or necessity for treatment) and/or chronicity (non-resolving course after
two years). Compared with LS-resolving patients, LS-chronic patients exhibited
higher BALF lymphocytes, neutrophils, and eosinophils. Additionally, in newly
diagnosed LS patients, increased BALF neutrophils and basophils were more likely
to associate with more severe disease; and increased BALF lymphocytes count
was more likely to associate with a chronic disease course. In non-LS patients,
increased BALF mast cells associated with a more severe and a chronic (nonresolving)
disease, and increased BALF lymphocytes, neutrophils, eosinophils,
and basophils associated with a more severe disease.
In summary, searching for biomarkers, we identified two possible markers for
severe and/or chronic disease, i.e. PPARα and CCL18. In study III and IV, we
showed that genetic variants associated with LS and non-LS can influence BALF
cell counts and that increased BALF neutrophils, eosinophils, lymphocytes,
basophils and notably mast cells have prognostic implication in newly diagnosed
sarcoidosis patients