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Holly L. Rosenzweig, Jenna S. Clowers, Maya Lewinsohn, Stephen R. Planck, Jae Jin Chae, Daniel L. Kastner, James T. Rosenbaum; Mutation in Pyrin Predisposes to Uveitis with Clinical Features Akin to Behçet’s Disease. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5269.
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Mutated pyrin (encoded the MEFV gene) is the genetic cause of the inflammatory disorder, familial Mediterranean fever (FMF). Interestingly, mutations in pyrin are prevalent in patients with Behçet’s disease (BD), wherein they are considered genetic susceptibility factors. Pyrin plays a critical regulatory role in IL-1 beta production--a cytokine considered to be a potential therapeutic target in BD and uveitis. The pathogenic variant of pyrin, V726A, results in spontaneous granulocytosis and arthritis in mice. We sought to determine the extent to which mutated pyrin influences ocular inflammation and whether a genetic-environmental interaction has an impact on the spectrum of disease.
Knock-in (KI) mice containing the V726A mutation or littermate controls (S129SV background) were examined in their naïve state or in response to intravitreal administration of 250 ng endotoxin or saline (n = 6-9 mice/treatment/genotype). Ocular inflammation was assessed by histology using a grading system at 24 h post injection. The cellular composition in the circulation and eye tissue was assessed by flow cytometry and immunofluorescence. The presence of amyloidosis was assessed by Congo red stain. Cytokines were measured by ELISA.
Extraocular inflammation sponatneously arose in KI mice, which manifested as extensive blepharitis involving infiltration of polymorphonuclear leukocytes and granulomatous inflammation. Despite the prevalent eyelid inflammation, little intraocular inflammation was observed. However, in response to endotoxin the pyrin mutation markedly intensified uveitis (score of 12.2 +/- 2.1 for WT controls vs 25.4 +/- 0.8 for KI mice, * p<0.05). A robust aggregate of inflammatory polymorphonuclear cells and proteinaceous exudates filled ~90% of the chamber. Unique pathology in the KI mice not observed in WT mice included numerous hemorrhages within all layers of the retina and dilated blood vessels encased with eosinophilic deposits. Although amyloidosis occurs in FMF patients, the uveitic eyes from the KI mice lacked amyloid within the inflamed vessel walls; which is consistent with the presence of a retinal vasculitis akin to the chronic inflammation of blood vessels seen in BD patients. Also analogous to BD, a pathergy response occurred in saline-injected KI mice (score of 10.3 +/- 0,8 in KIs vs 1.3 +/- 0.3 in WT controls, * p<0.05). Analysis of cytokine levels in uveitic V726A eye homogenates revealed a significant exacerbation in IL-1 beta production compared to littermate controls.
These data illuminate a critical role for pyrin in influencing susceptibility to uveitis and support an environmental-genetic interaction that favors development of uveitis akin to that of BD.
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