Defect of regulatory T cells in patients with Omenn syndrome.
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.


CONCLUSIONS
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.
Cassani
Barbara
B
Fondazione Humanitas per la Ricerca, Rozzano (MI), Italy.
Poliani
Pietro Luigi
PL
Moratto
Daniele
D
Sobacchi
Cristina
C
Marrella
Veronica
V
Imperatori
Laura
L
Vairo
Donatella
D
Plebani
Alessandro
A
Giliani
Silvia
S
Vezzoni
Paolo
P
Facchetti
Fabio
F
Porta
Fulvio
F
Notarangelo
Luigi D
LD
Villa
Anna
A
Badolato
Raffaele
R
D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology*; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D053645:Interleukin-2 Receptor alpha Subunit; C064658:RAG-1 protein