Background Selectins regulate the tethering and rolling of leukocytes before their extravasation. P-Selectin/PSGL-1 interaction is involved in the generation of regulatory T cells1 and Psgl-1–/– mice have altered the colonic lamina propria tolerance/immunity balance2 and spontaneously develop an autoimmune syndrome similar to human scleroderma3. Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies, immune complexes deposition, complement activation and polyclonal expansion of autorreactive lymphocytes4,5.
Objectives To characterize the development and progression of a lupus-like syndrome in P-Selectin KO (P-sel–/–) mice and to analyze P-Selectin expression in skin biopsies of lupus patients.
Methods 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/cm2) was performed to 3 month-old WT and P-Sel–/– 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.
Results P-Sel–/– 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.
Conclusions 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.
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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.
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Disclosure of Interest None declared
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