Objective. To define and characterize the progression of the spontaneous autoimmune disease that develops in mice in the absence of the leukocyte adhesion receptor P-selectin glycoprotein ligand 1 (PSGL-1).Methods. Skin-resident immune cells from PSGL-1-deficient mice and C57BL/6 control mice of different ages were isolated and analyzed by flow cytometry. Biochemical parameters were analyzed in mouse serum and urine, and the presence of serum autoantibodies was investigated. Skin and internal organs were extracted, and their structure was analyzed histologically.Results. Skin-resident innate and adaptive immune cells from PSGL-1 ؊/؊ mice had a proinflammatory phenotype with an imbalanced T effector cell:Treg cell ratio. Sera from PSGL-1 ؊/؊ mice had circulating autoantibodies commonly detected in connective tissuerelated human autoimmune diseases. Biochemical and histologic analysis of skin and internal organs revealed skin fibrosis and structural and functional abnormalities in the lungs and kidneys. Furthermore, PSGL-1 ؊/؊ mice exhibited vascular alterations, showing loss of dermal vessels, small vessel medial layer remodeling in the lungs and kidneys, and ischemic processes in the kidney that promote renal infarcts.Conclusion. Our study demonstrates that immune system overactivation due to PSGL-1 deficiency triggers an autoimmune syndrome with characteristics similar to systemic sclerosis, including skin fibrosis, vascular alterations, and systemic organ involvement. These results suggest that PSGL-1 expression contributes to the maintenance of the homeostasis of the immune system and could act as a barrier for autoimmunity in mice.
Systemic sclerosis (SSc) is an autoimmune disorder with high morbidity and mortality, is difficult to diagnose early, and has no curative treatment. PSGL-1 is a leukocyte receptor whose deficiency in mice promotes an SSc-like disease. ADAM8, a metalloprotease that cleaves PSGL-1, is implicated in inflammatory processes. Our goal was to evaluate whether PSGL-1 and ADAM8 contribute to the pathogenesis of human SSc. We found that patients with SSc presented increased PSGL-1 expression on monocytes, dendritic cells, and T cells and decreased expression of PSGL-1 on B cells. PSGL-1 on monocytes from SSc patients failed to induce Syk phosphorylation or IL-10 production after interaction with P-selectin. Up to 60% of the IL-10-producing B cells expressed PSGL-1, pointing to a regulatory role for PSGL-1 in B cells, and PSGL-1 B cells from SSc patients had decreased IL-10 production. ADAM8 expression was increased on antigen-presenting cells and T lymphocytes of SSc patients. Patients treated with calcium antagonists had lower levels of ADAM8 on APCs and T lymphocytes. Multivariate analysis indicated that the high percentage of ADAM8-expressing plasmacytoid dendritic cells discriminated patients from healthy donors. High PSGL-1 expression on dendritic cells was associated with the presence of interstitial lung disease.
Mice deficient in P-Selectin presented altered immunity/tolerance balance. We have observed that the absence of P-Selectin promotes splenomegaly with reduced naïve T cell population, elevated activated/effector T cell subset, increased germinal center B and Tfh populations and high production of autoreactive antibodies. Moreover, 1.5-3-month-old P-selectin KO mice showed reduced IL-10-producing leukocytes in blood and a slightly reduced Treg population in the skin. With aging and, coinciding with disease severity, there is an increase in the IL17+ circulating and dermal T cell subpopulations and reduction of dermal Treg. As a consequence, P-Selectin deficient mice developed a progressive autoimmune syndrome showing skin alterations characteristic of lupus prone mice and elevated circulating autoantibodies, including anti-dsDNA. Similar to human SLE, disease pathogenesis was characterized by deposition of immune complexes in the dermoepidermal junction and renal glomeruli, and a complex pattern of autoantibodies. More important, skin biopsies of cutaneous lupus erythematosus 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.
Background Previous studies in our lab have established that PSGL-1 signaling in human monocyte-derived dendritic (DC) cells induces a tolerogenic program that enables them to promote the differentiation of naïve T cells to T regulatory cells (Treg). We have also found that PSGL-1 modulates the immune inflammatory response in the murine enteric lamina propria, indicating that this adhesion receptor plays a role in the control of peripheral tolerance, acting as a tolerogenic receptor. Objectives To study the spontaneous disease developed in PSGL-1 deficient mice and and analyze its evolution with aging Methods Inmunological study of skin infiltrate, Serological analysis and histological studies of skin, lungs and kidney of C57/Bl6 WT and PSGL-1 deficient mice Results we have observed that 30% of PSGL-1 deficient mice at the age of 3 months present skin ulcers in their back that get more severe as the animals get older. The immunological studies show an inflammatory environment in the skin of the PSGL-1 KO mice, with activated and pro-inflammatory DC and macrophage populations, increased populations of granulocytes and B lymphocytes and increased Teff/Treg ratio. In addition, these animals cannot maintain the back legs extended, suggesting muscle weakness, and do not gain weight after the age of 1 year, probably due to intestinal absorption problems. The serum analysis shows the presence of connective tissue disease-related autoantibodies that accumulate as the mice get old. By histological studies we have found that the skin of PSGL-1 deficient mice is altered, with loss of the fat layer and thickening of the dermis by collagen accumulation, a major criterion supporting a diagnosis of Scleroderma. We have also found that the old PSGL-1 deficient mice have infiltrating leukocytes in the lungs and in the kidneys, indicating systemic autoimmune disease. Conclusions All these data indicate that PSGL-1 has an important role in maintaining the homeostasis of the immune system and controlling the development of systemic sclerosis Disclosure of Interest None Declared
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