Background: Omenn syndrome (OS) is an autosomal-recessive disorder characterized by severe immunodeficiency and T-cell-mediated autoimmunity. The disease is caused by hypomorphic mutations in recombination-activating genes that hamper the process of Variable (V) Diversity (D) Joining (J) recombination, leading to the generation of autoreactive T cells. We have previously shown that in OS the expression of autoimmune regulator, a key factor governing central tolerance, is markedly reduced. Objective: Here, we have addressed the role of peripheral tolerance in the disease pathogenesis. Methods: We have analyzed forkhead box protein P3 (FOXP3) expression in peripheral blood T cells of 4 patients with OS and in lymphoid organs of 8 patients with OS and have tested the suppressive activity of sorted CD4+ CD25high peripheral blood T cells in 2 of these patients. Results: We have observed that CD4+CD25highT cells isolated ex vivo from patients with OS failed to suppress proliferation of autologous or allogenic CD4+ responder T cells. Moreover, despite individual variability in the fraction of circulating FOXP3+ CD4 cells in patients with OS, the immunohistochemical analysis of FOXP3 expression in lymph nodes and thymus of patients with OS demonstrated a severe reduction of this cell subset compared with control tissues. Conclusion: Overall, these results suggest a defect of regulatory T cells in OS leading to a breakdown of peripheral tolerance, which may actively concur to the development of autoimmune manifestations in the disease.

Defect of regulatory T cells in patients with Omenn syndrome / B. Cassani, L. Poliani, D. Moratto, C. Sobacchi, V. Marrella, L. Imperatori, D. Vairo, A. Plebani, S. Giliani, F. Facchetti, F. Porta, L.D. Notarangelo, A.V.A.R. Badolato. - In: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. - ISSN 0091-6749. - 125:1(2010), pp. 209-216. [10.1016/j.jaci.2009.10.023]

Defect of regulatory T cells in patients with Omenn syndrome

B. Cassani;F. Facchetti;
2010

Abstract

Background: Omenn syndrome (OS) is an autosomal-recessive disorder characterized by severe immunodeficiency and T-cell-mediated autoimmunity. The disease is caused by hypomorphic mutations in recombination-activating genes that hamper the process of Variable (V) Diversity (D) Joining (J) recombination, leading to the generation of autoreactive T cells. We have previously shown that in OS the expression of autoimmune regulator, a key factor governing central tolerance, is markedly reduced. Objective: Here, we have addressed the role of peripheral tolerance in the disease pathogenesis. Methods: We have analyzed forkhead box protein P3 (FOXP3) expression in peripheral blood T cells of 4 patients with OS and in lymphoid organs of 8 patients with OS and have tested the suppressive activity of sorted CD4+ CD25high peripheral blood T cells in 2 of these patients. Results: We have observed that CD4+CD25highT cells isolated ex vivo from patients with OS failed to suppress proliferation of autologous or allogenic CD4+ responder T cells. Moreover, despite individual variability in the fraction of circulating FOXP3+ CD4 cells in patients with OS, the immunohistochemical analysis of FOXP3 expression in lymph nodes and thymus of patients with OS demonstrated a severe reduction of this cell subset compared with control tissues. Conclusion: Overall, these results suggest a defect of regulatory T cells in OS leading to a breakdown of peripheral tolerance, which may actively concur to the development of autoimmune manifestations in the disease.
anergy and tolerance; FOXP3; Immunodeficiency; Omenn syndrome; regulatory T cells; thymus and the development of T lymphocytes; V(D)J recombination
Settore BIO/17 - Istologia
2010
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/921541
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