Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

Aisha V Sauer; Immacolata Brigida; Nicola Carriglio; Raisa Jofra Hernandez; Samantha Scaramuzza; Daniela Clavenna; Francesca Sanvito; Pietro L Poliani; Nicola Gagliani; Filippo Carlucci; Antonella Tabucchi; Maria Grazia Roncarolo; Elisabetta Traggiai; Anna Villa; Alessandro Aiuti

doi:10.1182/blood-2011-07-366781

Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

Standard

Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. / Sauer, Aisha V; Brigida, Immacolata; Carriglio, Nicola; Hernandez, Raisa Jofra; Scaramuzza, Samantha; Clavenna, Daniela; Sanvito, Francesca; Poliani, Pietro L; Gagliani, Nicola; Carlucci, Filippo; Tabucchi, Antonella; Roncarolo, Maria Grazia; Traggiai, Elisabetta; Villa, Anna; Aiuti, Alessandro.

In: BLOOD, Vol. 119, No. 6, 09.02.2012, p. 1428-39.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sauer, AV, Brigida, I, Carriglio, N, Hernandez, RJ, Scaramuzza, S, Clavenna, D, Sanvito, F, Poliani, PL, Gagliani, N, Carlucci, F, Tabucchi, A, Roncarolo, MG, Traggiai, E, Villa, A & Aiuti, A 2012, 'Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID', BLOOD, vol. 119, no. 6, pp. 1428-39. https://doi.org/10.1182/blood-2011-07-366781

APA

Sauer, A. V., Brigida, I., Carriglio, N., Hernandez, R. J., Scaramuzza, S., Clavenna, D., Sanvito, F., Poliani, P. L., Gagliani, N., Carlucci, F., Tabucchi, A., Roncarolo, M. G., Traggiai, E., Villa, A., & Aiuti, A. (2012). Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. BLOOD, 119(6), 1428-39. https://doi.org/10.1182/blood-2011-07-366781

Vancouver

Sauer AV, Brigida I, Carriglio N, Hernandez RJ, Scaramuzza S, Clavenna D et al. Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. BLOOD. 2012 Feb 9;119(6):1428-39. https://doi.org/10.1182/blood-2011-07-366781

Bibtex

@article{01a1782fa61141c98727571f0ebce174,

title = "Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID",

abstract = "Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)-mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA-treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA(-/-) Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA-treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA-treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID.",

keywords = "5'-Nucleotidase, Adenosine, Adenosine Deaminase, Adolescent, Adult, Agammaglobulinemia, Animals, Antigens, CD, Apyrase, Autoantibodies, Child, Child, Preschool, Female, Forkhead Transcription Factors, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Humans, Hypothyroidism, Immunohistochemistry, Infant, Male, Mice, Mice, Knockout, Polyethylene Glycols, Severe Combined Immunodeficiency, T-Lymphocytes, Regulatory, Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't",

author = "Sauer, {Aisha V} and Immacolata Brigida and Nicola Carriglio and Hernandez, {Raisa Jofra} and Samantha Scaramuzza and Daniela Clavenna and Francesca Sanvito and Poliani, {Pietro L} and Nicola Gagliani and Filippo Carlucci and Antonella Tabucchi and Roncarolo, {Maria Grazia} and Elisabetta Traggiai and Anna Villa and Alessandro Aiuti",

year = "2012",

month = feb,

day = "9",

doi = "10.1182/blood-2011-07-366781",

language = "English",

volume = "119",

pages = "1428--39",

journal = "BLOOD",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "6",

}

RIS

TY - JOUR

T1 - Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

AU - Sauer, Aisha V

AU - Brigida, Immacolata

AU - Carriglio, Nicola

AU - Hernandez, Raisa Jofra

AU - Scaramuzza, Samantha

AU - Clavenna, Daniela

AU - Sanvito, Francesca

AU - Poliani, Pietro L

AU - Gagliani, Nicola

AU - Carlucci, Filippo

AU - Tabucchi, Antonella

AU - Roncarolo, Maria Grazia

AU - Traggiai, Elisabetta

AU - Villa, Anna

AU - Aiuti, Alessandro

PY - 2012/2/9

Y1 - 2012/2/9

N2 - Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)-mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA-treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA(-/-) Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA-treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA-treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID.

AB - Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)-mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA-treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA(-/-) Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA-treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA-treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID.

KW - 5'-Nucleotidase

KW - Adenosine

KW - Adenosine Deaminase

KW - Adolescent

KW - Adult

KW - Agammaglobulinemia

KW - Animals

KW - Antigens, CD

KW - Apyrase

KW - Autoantibodies

KW - Child

KW - Child, Preschool

KW - Female

KW - Forkhead Transcription Factors

KW - Genetic Therapy

KW - Hematopoietic Stem Cell Transplantation

KW - Humans

KW - Hypothyroidism

KW - Immunohistochemistry

KW - Infant

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Polyethylene Glycols

KW - Severe Combined Immunodeficiency

KW - T-Lymphocytes, Regulatory

KW - Clinical Trial

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1182/blood-2011-07-366781

DO - 10.1182/blood-2011-07-366781

M3 - SCORING: Journal article

C2 - 22184407

VL - 119

SP - 1428

EP - 1439

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 6

ER -