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.

Association of interleukin 23 receptor gene with sarcoidosis.

Interleukin 23 receptor (IL23R) gene has been reported as a genetic factor strongly associated with inflammatory bowel disease, psoriasis, and ankylosing spondylitis. We investigated the association between IL23R gene single nucleotide polymorphisms (SNPs) and susceptibility to sarcoidosis, including the clinical manifestation of uveitis. Ninety-one sarcoidosis subjects (58 with and 33 without uveitis) and 104 healthy controls were genotyped for eleven IL23R SNPs. DNA was amplified using specific PCR primers and genotyped by denaturing HPLC and/or direct DNA sequencing. Case-control frequency comparisons were analyzed using Chi square test. Three IL23R SNPs, rs7517847 (intron 6), rs11465804 (intron 8), and rs11209026 (exon 9, c.1142G>A, p.Arg381Gln) were associated with sarcoidosis in our population (p<0.05): rs7517847 showed increased frequencies in sarcoidosis compared to controls, but rs11465804 and rs11209026 were decreased. Two of these SNPs were associated with the uveitis subgroup compared to controls: rs11465804 (0.9% vs. 7.2%, OR=0.11, P=0.013) and rs11209026 (1.8% vs. 7.3%, OR=0.23, P=0.038). This finding indicates the association of IL23R polymorphism with sarcoidosis, especially with sarcoid uveitis. IL23R may be a common susceptibility gene shared by several autoimmune disorders including inflammatory bowel disease, psoriasis, and ankylosing spondylitis and sarcoid uveitis.

Killer cell immunoglobulin-like receptors in HLA-B27-associated acute anterior uveitis, with and without axial spondyloarthropathy.

PURPOSE: To determine associations between polymorphic genes that encode KIRs and their HLA class I ligands in patients with HLA-B27-associated acute anterior uveitis (AAU), with and without axial spondyloarthropathy (axial SpA). METHODS: Molecular DNA typing methods were used to define the frequencies of variable KIR genes and their relevant HLA class I ligands in HLA-B27(+) (B27(+)) Caucasian subjects with AAU and 429 healthy Caucasian control subjects. The patients were evaluated for axial SpA based on their histories using published criteria. RESULTS: Of 143 Caucasian subjects with AAU, 71 (49.6%) had features of axial SpA. The only difference between cases and controls in KIR gene frequencies was a trend toward fewer activating KIRs in subjects with AAU with axial SpA, which reached statistical significance for 2DS5 (P = 0.025, corrected P [P(c)] = 0.05; odds ratio [OR], 0.48; 95% CI, 0.25-0.90). The 3DL1+Bw4(T80) combination implicated in weak inhibition was more frequent in subjects with AAU than in control subjects (P = 2.73 x 10(-28), P(c) = 8.2 x 10(-27); OR, 13.5; 95% CI, 7.73-23.68). The 2DL1+HLA-C2 combination was decreased in subjects with axial SpA compared with subjects with AAU without axial SpA (P = 0.022; P(c) = NS; OR, 0.43; 95% CI, 0.21-0.88). CONCLUSIONS: Evidence was found of a role for KIR-HLA combinations that trigger weaker inhibition in subjects with AAU. Furthermore, there was a trend toward fewer KIR3DS1, -2DS1, and -2DS5 in AAU patients with axial SpA, which have been implicated in NK cell activation. HLA-B27(+) without KIR2DS3 (and -2DS1 and -3DS1) may fail to trigger an early NK cell response to clear antigenic stimuli, which may in part contribute to disease pathogenesis.

Incomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigree.

Pediatric granulomatous arthritis (PGA) has been associated with 12 different substitutions in the NOD2 gene thus far. We report a case of PGA in a 6-year-old girl with the NOD2 E383K gene substitution. Genotype analysis of the patient's family members revealed that her affected paternal aunt, as well as her asymptomatic father and 3 younger siblings, were heterozygous for the E383K substitution. The patient's mother did not have a NOD2 mutation. This is the first report of a pedigree in which 4 asymptomatic members carry the E383K substitution in NOD2, as well as the first observation of an asymptomatic carrier state for any of the NOD2 "Blau mutations."

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.