Insights in to the pathogenesis of axial spondyloarthropathy based on gene expression profiles.

INTRODUCTION: Axial spondyloarthropathy (SpA) is a group of inflammatory diseases, with ankylosing spondylitis as the prototype. SpA affects the axial skeleton, entheses, joints and, at times, the eyes. This study tested the hypothesis that SpA is characterized by a distinct pattern of gene expression in peripheral blood of affected individuals compared with healthy controls. METHODS: High-density, human GeneChip probe arrays were used to profile mRNA of peripheral blood cells from 18 subjects with SpA and 25 normal individuals. Samples were processed as two separate sets at different times (11 SpA + 12 control subjects in primary set (Set 1); 7 SpA+ 13 control subjects in the validation set (Set 2)). Blood samples were taken at a time when patients were not receiving systemic immunomodulatory therapy. Differential expression was defined as a 1.5-fold change with a q value < 5%. Gene ontology and pathway information were also studied. RESULTS: Signals from 134 probe sets (representing 95 known and 12 unknown gene transcripts) were consistently different from controls in both Sets 1 and 2. Included among these were transcripts for a group of 20 genes, such as interleukin-1 (IL-1) receptors 1 and 2, Nod-like receptor family, pyrin domain containing 2 (NLRP2), secretory leukocyte peptidase inhibitor (SLPI), secreted protein acidic and rich in cysteine (SPARC), and triggering receptor expressed on myeloid cells 1 (TREM-1) that are clearly related to the immune or inflammatory response and a group of 4 transcripts that have a strong role in bone remodeling. CONCLUSIONS: Our observations are the first to implicate SPARC, SLPI, and NLRP2, a component of the innate immune system, in the pathogenesis of SpA. Our results also indicate a possible role for IL-1 and its receptors in SpA. In accord with the bone pathology component of SpA, we also found that expression levels of transcripts reflecting bone remodeling factors are also distinguishable in peripheral blood from patients with SpA versus controls. These results confirm some previously identified biomarkers implicated in the pathogenesis of SpA and also point to novel mediators in this disease.

Hypothesis: sarcoidosis is a STAT1-mediated disease.

Immunologic pathways involved in sarcoidosis pathogenesis are largely unknown. We hypothesized that patients with sarcoidosis have characteristic mRNA profiles. Microarray analysis of gene expression was done on peripheral blood (12 patients, 12 controls), lung (6 patients, 6 controls) and lymph node (8 patients, 5 controls). Comparing peripheral blood from patients with sarcoidosis to controls, 872 transcripts were upregulated and 1039 were downregulated at >1.5-fold change and a significant q value. Several transcripts associated with interferon and STAT1 were upregulated. Lung and lymph node analyses also showed dramatic increases in STAT1 and STAT1-regulated chemokines. Granulomas in lymph nodes of patients with sarcoidosis expressed abundant STAT1 and phosphorylated STAT1. STAT1 might play an important role in sarcoidosis. This novel hypothesis unites seemingly disparate observations with regard to sarcoidosis including implication of a casual role for interferons, a suspected infectious trigger, T(H)1 predominating lymphocytes in bronchoalveolar lavage, and the association with hypercalcemia.