SAT0249 Novel cytotoxic T cell epitope in brucellosis-induced murine spondyloarthropathy
Authors: V. Adarichev, E.T. Lyons, D. Magnani, T.S. Forde, G.A. Splitter
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Brucellosis is one of the most common bacterial zoonosis and causes significant human morbidity worldwide<sup>1</sup>. Osteoarticular complications are the most frequent clinical manifestations in patients<sup>2,3</sup>. However, pathophysiological and immune mechanisms of brucellosis remain poorly characterized. <h3>Objectives</h3> The goal of the study was to establish a murine model for human Brucellosis to better understanding the immune mechanisms of association between Brucellosis and spondyloarthropathy (SpA). <h3>Methods</h3> BALB/c mice were infected intraperitoneally with 10<sup>6</sup>–10<sup>8</sup> CFU of the virulent bioluminescent <i>B. melitensis</i> strain GR023 or <i>B. abortus</i> vaccine strain S19<sup>4,5</sup>. Bacterial dissemination was monitored using biophotonic imaging and immunohistochemistry (IHC). Histopathology slides of axial skeleton, paws, spleen, and liver were IHC stained for IBA-1 marker and Brucella. <h3>Results</h3> <i>In vivo</i> biophotonic imaging showed accumulation of <i>B.melitensis</i> in paws and knees, while the strongest signal was detected in the tail that reproduce the distribution of vertebrae. Upon IHC staining, bacteria were found in the spleen, liver, and in bone marrow. Three weeks post-infection, bacteria-infected cells were not found in the peridiscal space or in the joint cavity, but were located in the subchondral bone of peripheral joints and vertebrae. At 26 weeks post-infection, spleen and bone marrow were negative for IHC staining, and liver showed a weak rare staining. Despite the general absence of infection at this time point, mice developed arthritis in ankle joints and spondylolisthesis. We found that immunodominant <i>Brucella</i>-derived peptide from methionine sulfoxide reductase is presented to cytotoxic T cells by murine macrophages in the context of MHC class I molecule. Homologous mouse/host protein carries a sequence that is 100% identical to Brucella epitope. <i>In silico</i> prediction analysis indicates that the epitope is able to bind to human HLA-B*2705 class I molecule that is strongly associated with human SpA. <h3>Conclusions</h3> Arthritis was not associated with acute <i>Brucella</i> infection in this murine model. Inflammation in joints and changes in skeleton were found weeks after the bacteria were cleared from tissues. Murine Brucellosis demonstrated features that are typical to reactive arthritis. Our data provide support for brucellosis-induced SpA as a reactive arthritis-type disease with a potential involvement of cytotoxic T cells. <h3>References</h3> Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis 6, 91-99, (2006). Turan H, Serefhanoglu K, Karadeli E, Togan T, Arslan H. Osteoarticular involvement among 202 brucellosis cases identified in Central Anatolia region of Turkey. Intern Med 50, 421-428, (2011). Lifeso RM, Harder E, McCorkell SJ. Spinal brucellosis. J Bone Joint Surg Br 67, 345-351, (1985). Magnani DM, Harms JS, Durward MA, Splitter GA. Nondividing but metabolically active gamma-irradiated Brucella melitensis is protective against virulent B. melitensis challenge in mice. Infect Immun 77, 5181-5189, (2009). Ko J, Gendron-Fitzpatrick A, Splitter GA. Susceptibility of IFN regulatory factor-1 and IFN consensus sequence binding protein-deficient mice to brucellosis. J Immunol 168, 2433-2440, (2002). <h3>Disclosure of Interest</h3> None Declared