AB0128 P-Selectin Absence Triggers A Lupus-like Syndrome in Mice
Authors: R. González-Tajuelo, A. Pérez-Frías, J. Silván, M. de la Fuente-Fernández, E. Vicente, S. Castañeda, C. Gamallo, A. Urzainqui
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Selectins regulate the tethering and rolling of leukocytes before their extravasation. P-Selectin/PSGL-1 interaction is involved in the generation of regulatory T cells<sup>1</sup> and <i>Psgl-1</i><sup>–/–</sup> mice have altered the colonic lamina propria tolerance/immunity balance<sup>2</sup> and spontaneously develop an autoimmune syndrome similar to human scleroderma<sup>3</sup>. Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies, immune complexes deposition, complement activation and polyclonal expansion of autorreactive lymphocytes<sup>4,5</sup>. <h3>Objectives</h3> To characterize the development and progression of a lupus-like syndrome in P-Selectin KO (<i>P-sel</i><sup>–/–</sup>) mice and to analyze P-Selectin expression in skin biopsies of lupus patients. <h3>Methods</h3> Mice skin and internal organs were analyzed histologically. Deposition of Immune complexes was determined by immunohistochemistry (IHQ). Levels of serum autoantibodies were quantified by ELISA. Peripheral blood leukocytes and splenocytes were analyzed by flow cytometry. UVB radiation (0.306 J/cm<sup>2</sup>) was performed to 3 month-old WT and <i>P-Sel</i><sup>–/–</sup> mice every other day for a week. The expression of P-Selectin in skin biopsies from healthy controls and lupus patients was assessed by IHQ. <h3>Results</h3> <i>P-Sel</i><sup>–/–</sup> mice showed skin alterations characteristic of lupus prone mice. Lupus-like pathogenesis was characterized by deposition of immune complexes in the dermoepidermal junction and renal glomeruli and the presence of anti-dsDNA and anti-Sm autoantibodies in the serum. The histological analysis revealed immune infiltration of the skin, kidney and lung, and tissue structural alterations such as renal infarcts and nonspecific interstitial pneumonia. We found a reduction in the IL-10 producing PBLs, and splenic T cells showed a more effector phenotype. More important, skin biopsies of lupus patients did not show increased expression of P-Selectin, as described for other inflammatory diseases, and the number of vessels expressing P-Selectin was reduced. <h3>Conclusions</h3> P-Selectin deficiency leads to a lupus-like syndrome similar to established lupus mouse models. Additionally, we found imbalanced regulatory/proinflammatory leukocytes ratio in peripheral blood and spleen. These results reaffirm the notion that the PSGL-1/P-Selectin axis is crucial for maintaining immune system homeostasis and preventing autoimmunity. <h3>References</h3> Urzainqui A, Martínez del Hoyo G, Lamana A, et al. Functional role of P-selectin glycoprotein ligand 1/P-selectin interaction in the generation of tolerogenic dendritic cells. J Immunol. 2007;179:7457–65. Nuñez-Andrade N, Lamana A, Sancho D, et al. P-selectin glycoprotein ligand-1 modulates immune inflammatory responses in the enteric lamina propria. J Pathol 2011;224:212–21. Pérez-Frías A, González-Tajuelo R, Núñez-Andrade N, et al. Development of an autoimmune syndrome affecting the skin and internal organs in p-selectin glycoprotein ligand 1 leukocyte receptor-deficient mice. Arthritis Rheumatol 2014;66:3178–89. Bignon A, Gaudin F, Hémon P, et al. Ccr1 inhibition ameliorates the progression of lupus nephritis in nzb/w mice. J Immunol 2014;192:886–96. Lichtnekert J, Rupanagudi K, Kulkarni O, et al. Activated protein c attenuates systemic lupus erythematosus and lupus nephritis in mrl-fas(lpr) mice. J Immunol 2011;187:3413–21. <h3>Disclosure of Interest</h3> None declared