OBJECTIVE:Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS.METHODS:Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined.RESULTS:As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS.CONCLUSION:This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.

Patients with sporadic early-onset granulomatous arthritis are clinically identical to Blau syndrome, but without the family history. Blau syndrome is an autosomal dominant inherited disease and is known to be caused by mutations in the CARD15 gene (also called NOD2). We investigated the hypothesis that an individual with sporadic early onset granulomatous arthritis may have a Blau syndrome mutation in CARD15/NOD2. Our patient's genomic DNA isolated from a buccal swab sample was subjected to amplification to include the region of exon 4 from the CARD15/NOD2 gene that contains known mutations that cause Blau syndrome. This region was screened for mutations by direct DNA sequencing in both directions. One of the mutations in CARD15/NOD2 attributed to Blau syndrome was found in the DNA sample. The nucleotide change encodes an amino acid substitution from arginine to tryptophan at position 334 of the protein. This mutation has been found in some Blau syndrome pedigrees reported in the literature. These data suggest that sporadic granulomatous arthritis may in fact be the sporadic form of Blau syndrome, but arising from a spontaneous neomutation. This would explain the profound clinical identity and the lack of disease history in the parents.

Transactivation of the DNA-binding proteins nuclear factor-kappa B (NF-kappa B) and activator protein (AP)-1 by de novo oxyradical generation is a stereotypic redox-sensitive process during hypoxic stress of the liver. Systemic trauma is associated with splanchnic hypoxia-reoxygenation (H/R) followed by intraportal gram-negative bacteremia, which collectively have been implicated in posttraumatic liver dysfunction and multiple organ damage. We hypothesized that hypoxic stress of the liver before stimulation by Escherichia coli serotype O55:B5 (EC) amplifies oxyradical-mediated transactivation of NF-kappa B and AP-1 as well as cytokine production compared with noninfectious H/R or gram-negative sepsis without prior hypoxia. Livers from Sprague-Dawley rats underwent perfusion for 180 min with or without 0.5 h of hypoxia (perfusate PO(2), 40 +/- 5 mmHg) followed by reoxygenation and infection with 10(9) EC or 0.9% NaCl infusion. In H/R + EC livers, nuclear translocation of NF-kappa B and AP-1 was unexpectedly reduced in gel shift assays vs. normoxic EC controls, as were perfusate TNF-alpha and IL-1 beta levels. Preceding hypoxic stress paradoxically increased postbacteremic reduced-to-oxidized glutathione ratios plus nuclear localization of I kappa B alpha and phospho-I kappa B alpha, but not JunB/FosB profiles. Notably, xanthine oxidase inhibition increased transactivation as well as cytokine production in H/R + EC livers. Thus brief hypoxic stress of the liver before intraportal gram-negative bacteremia potently suppresses activation of canonical redox-sensitive transcription factors and production of inflammatory cytokines by mechanisms including xanthine oxidase-induced oxyradicals functioning in an anti-inflammatory signaling role. These results suggest a novel multifunctionality of oxyradicals in decoupling hepatic transcriptional activity and cytokine biosynthesis early in the posttraumatic milieu.