Jiri Homolka

Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

RATIONALE Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. OBJECTIVES To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. METHODS Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. MEASUREMENTS AND MAIN RESULTS Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. CONCLUSIONS Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.

Systemic Immune Cell Activation in a Subgroup of Patients with Idiopathic Pulmonary Fibrosis

Background: The prognosis of idiopathic pulmonary fibrosis (IPF/UIP) is poor and its immunopathogenesis is insufficiently understood. Objectives: The aim of our study was to elucidate the compartmentalization of cell activation and the influence of corticosteroid therapy upon this activation in IPF/UIP. We determined the concentrations of proinflammatory cytokines released by bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMNC) in treated and untreated patients with IPF/UIP. We chose tumor necrosis factor-α (TNFα) since it is a cytokine predominantly secreted by cells of the monocyte/macrophage lineage and interleukin-2 (IL-2) exclusively by T lymphocytes. Methods: The release of TNFα and IL-2 by BAL cells and PBMNC was measured in cell culture supernatants of 72 treated and untreated IPF/UIP patients. Additionally, in the blood compartment serological parameters reflecting the monocyte/macrophage and lymphocyte activation, such as neopterin and soluble IL-2 receptor (sIL-2R), were determined. Results: The TNFα release by BAL cells was significantly elevated in both groups compared to controls but did not differ between treated and untreated patients with IPF/UIP. In 7 of 19 untreated patients with IPF, PBMNC were activated and released increased amounts of TNFα. In only 1 of 17 treated patients with IPF, TNFα release by PBMNC could be found. The serum level of neopterin, a marker of cell activation of the monocyte/macrophage lineage did not differ between treated and untreated patients. The BAL lymphocyte and PBMNC IL-2 release was significantly elevated in IPF/UIP patients without therapy compared to controls (p < 0.05). In contrast, no IL-2 release of BAL cells or PBMNC was observed in treated IPF/UIP patients. Lymphocyte activation was furthermore identified in untreated IPF patients by elevated soluble IL-2 receptor serum concentrations (p < 0.0001). Conclusions: Cells of the monocyte/macrophage lineage and T lymphocytes are activated in BAL cells and PBMNC of patients with IPF/UIP. During treatment, the systemic and local activation of T cells is suppressed. BAL macrophages, however, maintain their activated status, which might be the cause for the frequent chronic progression of the disease.