Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 125, Issue 1, Pages 209-216Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2009.10.023
Keywords
Immunodeficiency; V(D)J recombination; Omenn syndrome; regulatory T cells; FOXP3; anergy and tolerance; thymus and the development of lymphocytes
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Funding
- Italian Telethon Foundation
- Fondazione Cariplo
- EU [201461]
- PRIN [2007ACZMMZ_005]
- Telethon [GGP07241]
- FIRB/MIUR [RBIN04CHXT]
- Ministero della Salute RF2007 Giovani Ricercatori Grant
- Manton Foundation
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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(+) CD25(high) peripheral blood T cells in 2 of these patients. Results: We have observed that CD4(+)CD25(high)T 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. (J Allergy Clin Immunol 2010;125:209-16.)
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