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Journal of Clinical Immunology

, Volume 35, Issue 3, pp 264–272 | Cite as

Long-Term Follow-up of STAT5B Deficiency in Three Argentinian Patients: Clinical and Immunological Features

  • Liliana Bezrodnik
  • Daniela Di Giovanni
  • María Soledad Caldirola
  • María Esnaola AzcoitiEmail author
  • Troy Torgerson
  • María Isabel Gaillard
Original Research

Abstract

The signal transducer and activator of transcription (STAT) family of proteins regulate gene transcription in response to a variety of cytokines. STAT5B, in particular, plays an important role in T cells, where it is a key mediator of interleukin-2 (IL-2) induced responses. STAT5B deficiency causes a rare autosomal recessive disorder reported in only a handful of individuals. There are currently ten published cases of STAT5B deficiency, four of which are Argentinians.

Aim

This is a report of more than 10 years follow up of the clinical and immunological features of three Argentinian STAT5B deficient patients.

Conclusion

More than a decade of follow-up demonstrates that STAT5B deficiency is associated with various clinical pathologies that cause significant morbidity. Early diagnosis is critical for the prevention and improvement of clinical outcomes for STAT5B deficient patients.

Keywords

Stat5B primary immunodeficiency growth hormone lymphocytic interstitial pneumonitis dysregulatory syndrome regulatory T cells 

References

  1. 1.
    Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr. 2013;25(6):708–14.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lin JX, Leonard WJ. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene. 2000;19(21):2566–76.CrossRefPubMedGoogle Scholar
  3. 3.
    Chatila TA. Regulatory T cells: key players in tolerance and autoimmunity. Endocrinol Metab Clin North Am. 2009;38(2):265–72. vii.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Antov A et al. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol. 2003;171(7):3435–41.CrossRefPubMedGoogle Scholar
  5. 5.
    Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120(4):744–50. quiz 751–2.CrossRefPubMedGoogle Scholar
  6. 6.
    Bernasconi A et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics. 2006;118(5):e1584–92.CrossRefPubMedGoogle Scholar
  7. 7.
    Cavallo MC, Llugdar J, Lozano NA, Pacoricona DL, Lozano A. Inmunodeficiencia primaria con deficit de crecimiento: rol de STAT5b. CIMEL. 2006;11:96–100.Google Scholar
  8. 8.
    Hwa V et al. Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. Horm Res. 2007;68(5):218–24.CrossRefPubMedGoogle Scholar
  9. 9.
    Hwa V et al. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b. J Clin Endocrinol Metab. 2005;90(7):4260–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Kofoed EM et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349(12):1139–47.CrossRefPubMedGoogle Scholar
  11. 11.
    Pugliese-Pires PN et al. A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings. Eur J Endocrinol. 2010;163(2):349–55.CrossRefPubMedGoogle Scholar
  12. 12.
    Scaglia PA et al. A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease. J Clin Endocrinol Metab. 2012;97(5):E830–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Vidarsdottir S et al. Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J Clin Endocrinol Metab. 2006;91(9):3482–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Kanai T, Jenks J, Nadeau KC. The STAT5b pathway defect and autoimmunity. Front Immunol. 2012;14(3):234.Google Scholar
  15. 15.
    Cohen AC et al. Cutting edge: decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency. J Immunol. 2006;177(5):2770–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Casanova JL, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity. 2012;36(4):515–28.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Udy GB et al. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A. 1997;94(14):7239–44.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ayling RM et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet. 1997;16(1):13–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Duquesnoy P et al. A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization. EMBO J. 1994;13(6):1386–95.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Yao Z et al. Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci U S A. 2006;103(4):1000–5.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Burchill MA et al. Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells. J Immunol. 2003;171(11):5853–64.CrossRefPubMedGoogle Scholar
  22. 22.
    Yao Z et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood. 2007;109(10):4368–75.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Murawski MR et al. Upregulation of Foxp3 expression in mouse and human Treg is IL-2/STAT5 dependent: implications for the NOD STAT5B mutation in diabetes pathogenesis. Ann N Y Acad Sci. 2006;1079:198–204.CrossRefPubMedGoogle Scholar
  24. 24.
    Bezrodnik L et al. Follicular bronchiolitis as phenotype associated with Cd25 Deficiency. Clin Exp Immunol. 2014;175:227–34.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocvronophaty, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol. 2007;119:482.CrossRefPubMedGoogle Scholar
  26. 26.
    Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini Mannurita S, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immun. 2013;146:248–61.CrossRefGoogle Scholar
  27. 27.
    Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci. 1997;94(7):3168–71.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Imada K et al. Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J Exp Med. 1998;188(11):2067–74.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Behbod F et al. Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells. J Immunol. 2003;171(8):3919–27.CrossRefPubMedGoogle Scholar
  30. 30.
    Jenks JA et al. Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells. Clin Immunol. 2013;148(2):227–36.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Goetz CA et al. STAT5 activation underlies IL7 receptor-dependent B cell development. J Immunol. 2004;172(8):4770–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Dorner T et al. Abnormalities of B cell subsets in patients with systemic lupus erythematosus. J Immunol Methods. 2011;363(2):187–97.CrossRefPubMedGoogle Scholar
  33. 33.
    Snow JW et al. Bone marrow transplant completely rescues hematolymphoid defects in STAT5A/5B-deficient mice. Exp Hematol. 2003;31(12):1247–52.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Liliana Bezrodnik
    • 1
  • Daniela Di Giovanni
    • 1
  • María Soledad Caldirola
    • 1
  • María Esnaola Azcoiti
    • 1
    Email author
  • Troy Torgerson
    • 2
    • 3
    • 4
  • María Isabel Gaillard
    • 1
  1. 1.“Dr. Ricardo Gutiérrez” Children’s HospitalCapital FederalArgentina
  2. 2.Seattle Children’s Research InstituteSeattleUSA
  3. 3.Department of PediatricsUniversity of Washington School of MedicineSeattleUSA
  4. 4.Immunology Diagnostic Laboratory within the Center for Immunity and Immunotherapies at Seattle Childrens Research InstituteSeattleUSA

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