Defect of regulatory T cells in patients with Omenn syndrome

doi:10.1016/j.jaci.2009.10.023

Journal of Allergy and Clinical Immunology

Volume 125, Issue 1, January 2010, Pages 209-216

https://doi.org/10.1016/j.jaci.2009.10.023 Get rights and content

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^highT 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.

Section snippets

Patients

Eight patients with RAG1 defects and 1 patient with a RAG2 defect previously described (patient 5¹²) were included in this study. The clinical, immunologic, and molecular features of the patients, consistent with OS, are outlined in Table I, Table II. Briefly, patient 1 was a boy who presented in the first days of life with erythrodermia, lymphadenopathy, spleen, and liver enlargement. Laboratory analysis showed leukocytosis (59 × 10³ cells/μL) with marked eosinophilia (40 × 10³ cells/μL) and

Phenotypic characterization of FOXP3⁺ cells in the peripheral blood of patients with OS

We analyzed CD4⁺ CD25⁺ FOXP3⁺ T cells from the peripheral blood of 4 patients with OS caused by mutations in the RAG1 gene (Table I). The percentage of FOXP3⁺ cells among the CD4⁺CD25⁺ cells were in the normal range for patients 1, 2, and 4, whereas in patient 3, this subset was markedly increased (Fig 1, A). Quantitative analysis of the absolute number of CD4⁺ FOXP3⁺ cells showed broad variability in these patients (Fig 1, B). Interestingly, the 2 patients (patients 1 and 2) displaying the

Discussion

In this article, we demonstrate that patients with OS have a variable number of circulating FOXP3⁺ T lymphocytes. However, at variance from what was observed in normal individuals, circulating FOXP3⁺ cells in patients with OS coexpress activation markers and fail to suppress proliferation of allogenic activated CD4⁺ T cells. OS is characterized by a profound impairment of T lymphocyte generation and abnormalities in the mechanisms that govern central tolerance. In this context, it is likely

References (30)

H.D. Ochs et al.
Combined immunodeficiency and reticuloendotheliosis with eosinophilia
J Pediatr
(1974)
E. Ozcan et al.
Primary immune deficiencies with aberrant IgE production
J Allergy Clin Immunol
(2008)
S. Signorini et al.
Intrathymic restriction and peripheral expansion of the T-cell repertoire in Omenn syndrome
Blood
(1999)
A. Villa et al.
V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations
Blood
(2001)
A. Villa et al.
Omenn syndrome: inflammation in leaky severe combined immunodeficiency
J Allergy Clin Immunol
(2008)
P. Matangkasombut et al.
Lack of iNKT cells in patients with combined immune deficiency due to hypomorphic RAG mutations
Blood
(2008)
S. Sakaguchi et al.
Regulatory T cells and immune tolerance
Cell
(2008)
R. Bacchetta et al.
Role of regulatory T cells and FOXP3 in human diseases
J Allergy Clin Immunol
(2007)
T.A. Chatila
Role of regulatory T cells in human diseases
J Allergy Clin Immunol
(2005)
M. Miyara et al.
Functional delineation and differentiation dynamics of human CD4 + T cells expressing the FoxP3 transcription factor
Immunity
(2009)

K.R. Ryan et al.

CD4 + CD25 + T-regulatory cells are decreased in patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy

J Allergy Clin Immunol

(2005)

P.L. Poliani et al.

Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome

Blood

(2009)

G.S. Omenn

Familial reticuloendotheliosis with eosinophilia

N Engl J Med

(1965)

G. de Saint Basile et al.

X-linked immunodeficiencies: clues to genes involved in T- and B-cell differentiation

Immunol Today

(1991)

D. Brugnoni et al.

In vitro cell death of activated lymphocytes in Omenn's syndrome

Eur J Immunol

(1997)

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: This work was supported by grants from the Italian Telethon Foundation to A.V., from Fondazione Cariplo (Nobel project to A.V., and L.D.N./R.B.), Fondazione Cariplo to A.V. and P.L.P., EU grant FP7 HLH-cure (project n. 201461), PRIN 2007 n. 2007ACZMMZ_005, Telethon GGP07241 to R.B., grant FIRB/MIUR (n. RBIN04CHXT) to P.V., Ministero della Salute RF2007 Giovani Ricercatori Grant to C.S., and the Manton Foundation to L.D.N.

: Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

^∗: These authors share senior authorship of this work.

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Immune deficiencies, infection, and systemic immune disordersDefect of regulatory T cells in patients with Omenn syndrome

Background

Objective

Methods

Results

Conclusion

Section snippets

Patients

Phenotypic characterization of FOXP3+ cells in the peripheral blood of patients with OS

Discussion

J Pediatr

J Allergy Clin Immunol

Blood

Blood

J Allergy Clin Immunol

Blood

Cell

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunity

J Allergy Clin Immunol

Blood

Familial reticuloendotheliosis with eosinophilia

N Engl J Med

X-linked immunodeficiencies: clues to genes involved in T- and B-cell differentiation

Immunol Today

In vitro cell death of activated lymphocytes in Omenn's syndrome

Eur J Immunol

Immune deficiencies, infection, and systemic immune disorders
Defect of regulatory T cells in patients with Omenn syndrome

Phenotypic characterization of FOXP3⁺ cells in the peripheral blood of patients with OS