986 - Dysregulation of Pyrin, the Familial Mediterranean Fever Protein, Exacerbates Endotoxin-Induced Uveitis in Mice

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Holly L. Rosenzweig1, Jenna S. Clowers2, Jordan Allensworth1, Emily E. Vance1, Stephen R. Planck1, Michael P. Davey2, Jae Jin Chae3, Daniel L. Kastner4 and James T. Rosenbaum1, 1Oregon Health & Science University, Portland, OR, 2Veterans Affairs Medical Center, Portland, OR, 3Medical Genetics Branch, National Human Genome Research Institute, MD, 4National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
Presentation Number: 986

Background/Purpose:  Mutation of pyrin (encoded by the gene MEFV) is the cause of the recessively inherited autoinflammatory disorder, familial Mediterranean fever (FMF).  Pyrin is involved in regulation of inflammasome activation and IL-1β production. Given the importance of IL-1β in disease and the association of uveitis with systemic autoinflammatory disorders linked with pyrin, we sought to elucidate the functional consequences of the pathogenic, variant V726A, on the onset and severity of uveitis in mice.

Method:  Knock-in (KI) mice containing the V726A mutation or littermate controls (S129SV background) were observed without intervention or were administered an intravitreal injection of 250 ng lipopolysaccharide (LPS) in one eye and saline in the contralateral eye. Ocular inflammation was assessed histologically using a scoring system. Granulocyte populations in the blood and uveitic eye tissue were quantified by flow cytometry and immunofluorescence.  Arthritis was assessed histologically and by whole body, near-infrared fluorescence imaging of inflamed regions labeled by with ProSense.  Multi-plex ELISA was performed to quantify cytokine levels in uveitic eye tissue. 

Result:  Akin to patients with FMF, carriers with 2 copies of the mutation (i.e. KI mice) exhibit granulocytosis and arthritis that coincided with conjunctivitis. While the MEFV mutation did not predispose to spontaneous onset of uveitis, it did render KI mice markedly sensitive to LPS-induced uveitis as these mice developed an extensive pan-uveitis that was significantly worse that litter-mate controls.  Interestingly, a pathergy response was observed in saline-injected KI controls.  Ocular inflammation was characterized by infiltration predominantly of neutrophils and eosinophils that coincided with dilated blood vessels and hemorrhaging within the retina.  Analysis of cytokine levels in uveitic eye tissue homogenates revealed a significant increase in IL-1β production compared to litter-mate controls.

Conclusion:  Our data provide insight into how dysregulation of pyrin might influence intraocular inflammatory responses, and thereby result in more severe uveitis following an environmental trigger such as LPS.


Keywords: familial Mediterranean fever, inflammatory arthritis and interleukins (IL)

Disclosure: H. L. Rosenzweig, None; J. S. Clowers, None; J. Allensworth, None; E. E. Vance, None; S. R. Planck, None; M. P. Davey, None; J. J. Chae, None; D. L. Kastner, None; J. T. Rosenbaum, Abbott Immunology Pharmaceuticals, 5, Regeneron, 5, Amgen, 5, Genentech and Biogen IDEC Inc., 2, Xoma Corporation , 5, Novartis Pharmaceutical Corporation, 2, Pfizer Inc, 5 .