Journal of Clinical Immunology

, Volume 25, Issue 4, pp 321–328 | Cite as

No Indication for a Defect in Toll-Like Receptor Signaling in Patients with Hyper-IgE Syndrome

  • E. D. Renner
  • I. Pawlita
  • F. Hoffmann
  • V. Hornung
  • D. Hartl
  • M. Albert
  • A. Jansson
  • S. Endres
  • G. Hartmann
  • B. H. Belohradsky
  • S. RothenfusserEmail author


Hyper-IgE syndrome is a rare primary immunodeficiency of unknown etiology characterized by recurrent infections of the skin and respiratory system, chronic eczema, elevated total serum IgE, and a variety of associated skeletal symptoms. Recent reports about susceptibility to pyogenic bacterial infections and high IgE levels in patients and animals with defects in toll-like receptor (TLR) signaling pathways prompted us to search for TLR signaling defects as an underlying cause of hyper-IgE syndrome. Blood samples from six patients with hyper-IgE syndrome were analyzed for serum cytokine levels, intracellular cytokine production in T cells after stimulation with PMA/ionomycin, and cytokine production from peripheral blood mononuclear cells stimulated by TLR ligands and bacterial products including LPS (TLR4), peptidoglycan (TLR2), PolyIC (TLR3), R848 (TLR7/8), CpG-A, and CpG-B (TLR9), zymosan and heat killed Listeria monocytogenes. All results were compared to data from healthy controls. A reduction in IFN-γ, IL-2, and TNF-α producing T cells after PMA stimulation suggested a reduced inflammatory T cell response in patients with hyper-IgE syndrome. Increased serum levels of IL-5 indicated a concomitant Th2 shift. However, normal production of cytokines (TNF-α, IL-6, IL-10, IFN-α, IP-10) and upregulation of CD86 on B cells and monocytes after TLR stimulation made a defect in TLR signaling pathways highly unlikely. In summary, our data confirmed an imbalance in T cell responses of patients with hyper-IgE syndrome as previously described but showed no indication for an underlying defect in toll-like receptor signaling.

Key Words

Hyper-IgE syndrome toll-like receptor signaling cytokine pattern interferon-γ interleukin-4 innate immunity 



peripheral blood mononuclear cells; IRAK, IL-1-receptor-associated kinase; MyD88, myeloid differentiation factor 88; IP-10, γ-interferon inducible protein 10; NFκ-B, nuclear factor kappa B; ODN, oligodeoxynucleotide; IRF, interferon regulatory factor; PMA, phorbol 12-myristate 13-acetate.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O’Connell AC, Puck JM: Hyper-IgE syndrome with recurrent infections—An autosomal dominant multisystem disorder. N Engl J Med 340:692–702, 1999CrossRefPubMedGoogle Scholar
  2. 2.
    Erlewyn-Lajeunesse MD: Hyperimmunoglobulin-E syndrome with recurrent infection: A review of current opinion and treatment. Pediatr Allergy Immunol 11:133–141, 2000CrossRefPubMedGoogle Scholar
  3. 3.
    Belohradsky BH, Daumling S, Kiess W, Griscelli C: [The hyper-IgE-syndrome (Buckley- or Job-syndrome)]. Ergeb Inn Med Kinderheilkd 55:1–39, 1987PubMedGoogle Scholar
  4. 4.
    Buckley RH: The hyper-IgE syndrome. Clin Rev Allergy Immunol 20:139–154, 2001CrossRefPubMedGoogle Scholar
  5. 5.
    Grimbacher B, Dutra AS, Holland SM, Fischer RE, Pao M, Gallin JI, Puck JM: Analphoid marker chromosome in a patient with hyper-IgE syndrome, autism, and mild mental retardation. Genet Med 1:213–218, 1999PubMedGoogle Scholar
  6. 6.
    Grimbacher B, Schaffer AA, Holland SM, Davis J, Gallin JI, Malech HL, Atkinson TP, Belohradsky BH, Buckley RH, Cossu F, Espanol T, Garty BZ, Matamoros N, Myers LA, Nelson RP, Ochs HD, Renner ED, Wellinghausen N, Puck JM: Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 65:735–744, 1999CrossRefPubMedGoogle Scholar
  7. 7.
    Hill HR, Ochs HD, Quie PG, Clark RA, Pabst HF, Klebanoff SJ, Wedgwood RJ: Defect in neutrophil granulocyte chemotaxis in Job’s syndrome of recurrent cold staphylococcal abscesses. Lancet 2:617–619, 1974CrossRefPubMedGoogle Scholar
  8. 8.
    Hill HR, Quie PG: Raised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections. Lancet 1:183–187, 1974CrossRefPubMedGoogle Scholar
  9. 9.
    Donabedian H, Gallin JI: Two inhibitors of neutrophil chemotaxis are produced by hyperimmunoglobulin E recurrent infection syndrome mononuclear cells exposed to heat-killed staphylococci. Infect Immun 40:1030–1037, 1983PubMedGoogle Scholar
  10. 10.
    Borges WG, Augustine NH, Hill HR: Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome. J Pediatr 136:176–180, 2000PubMedGoogle Scholar
  11. 11.
    Vercelli D, Jabara HH, Cunningham-Rundles C, Abrams JS, Lewis DB, Meyer J, Schneider LC, Leung DY, Geha RS: Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE syndrome. J Clin Invest 85:1666–1671, 1990PubMedGoogle Scholar
  12. 12.
    Ito R, Mori M, Katakura S, Kobayashi N, Naruto T, Osamura Y, Aihara Y, Yokota S: Selective insufficiency of IFN-gamma secretion in patients with hyper-IgE syndrome. Allergy 58:329–336, 2003CrossRefPubMedGoogle Scholar
  13. 13.
    Ohga S, Nomura A, Ihara K, Takahata Y, Suga N, Akeda H, Shibata R, Okamura J, Kinukawa N, Hara T: Cytokine imbalance in hyper-IgE syndrome: Reduced expression of transforming growth factor beta and interferon gamma genes in circulating activated T cells. Br J Haematol 121:324–331, 2003CrossRefPubMedGoogle Scholar
  14. 14.
    Chehimi J, Elder M, Greene J, Noroski L, Stiehm ER, Winkelstein JA, Sullivan KE: Cytokine and chemokine dysregulation in hyper-IgE syndrome. Clin Immunol 100:49–56, 2001CrossRefPubMedGoogle Scholar
  15. 15.
    Martinez AM, Montoya CJ, Rugeles MT, Franco JL, Patino PJ: Abnormal expression of CD54 in mixed reactions of mononuclear cells from hyper-IgE syndrome patients. Mem Inst Oswaldo Cruz 99:159–165, 2004PubMedGoogle Scholar
  16. 16.
    Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. 5:987–995, 2004Google Scholar
  17. 17.
    Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 4:499–511, 2004PubMedGoogle Scholar
  18. 18.
    Cook DN, Pisetsky DS, Schwartz DA: Toll-like receptors in the pathogenesis of human disease. 5:975–979, 2004Google Scholar
  19. 19.
    Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R: Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2:947–950, 2001CrossRefPubMedGoogle Scholar
  20. 20.
    Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, Lowry SF: Humanvadjust toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 186:1522–1525, 2002CrossRefPubMedGoogle Scholar
  21. 21.
    Takeuchi O, Hoshino K, Akira S: Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 165:5392–5396, 2000PubMedGoogle Scholar
  22. 22.
    Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA: A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 68:6398–6401, 2000CrossRefPubMedGoogle Scholar
  23. 23.
    Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL: Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299:2076–2079, 2003CrossRefPubMedGoogle Scholar
  24. 24.
    Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M, Bergmann M, Davis J, Belohradsky BH, Grimbacher B: Autosomal recessive hyperimmunoglobulin E syndrome: A distinct disease entity. J Pediatr 144:93–99, 2004CrossRefPubMedGoogle Scholar
  25. 25.
    Rothenfusser S, Hornung V, Ayyoub M, Britsch S, Towarowski A, Krug A, Sarris A, Lubenow N, Speiser D, Endres S, Hartmann G: CpG-A and CpG-B oligonucleotides differentially enhance human peptide-specific primary and memory CD8+ T-cell responses in vitro. Blood 103:2162–2169, 2004CrossRefPubMedGoogle Scholar
  26. 26.
    Simon D, Braathen LR, Simon HU: Eosinophils and atopic dermatitis. Allergy 59:561–570, 2004CrossRefPubMedGoogle Scholar
  27. 27.
    Chamlin SL, McCalmont TH, Cunningham BB, Esterly NB, Lai CH, Mallory SB, Mancini AJ, Tamburro J, Frieden IJ: Cutaneous manifestations of hyper-IgE syndrome in infants and children. J Pediatr 141:572–575, 2002CrossRefPubMedGoogle Scholar
  28. 28.
    Del Prete G, Tiri A, Maggi E, De Carli M, Macchia D, Parronchi P, Rossi ME, Pietrogrande MC, Ricci M, Romagnani S: Defective in vitro production of gamma-interferon and tumor necrosis factor-alpha by circulating T cells from patients with the hyper-immunoglobulin E syndrome. J Clin Invest 84:1830–1835, 1989PubMedGoogle Scholar
  29. 29.
    Gudmundsson KO, Sigurjonsson OE, Gudmundsson S, Goldblatt D, Weemaes CM, Haraldsson A: Increased expression of interleukin-13 but not interleukin-4 in CD4+ cells from patients with the hyper-IgE syndrome. Clin Exp Immunol 128:532–537, 2002CrossRefPubMedGoogle Scholar
  30. 30.
    Geha RS, Jabara HH, Brodeur SR: The regulation of immunoglobulin E class-switch recombination. Nat Rev Immunol 3:721–732, 2003CrossRefPubMedGoogle Scholar
  31. 31.
    Roeder A, Kirschning CJ, Rupec RA, Schaller M, Korting HC: Toll-like receptors and innate antifungal responses. Trends Microbiol 12:44–49, 2004CrossRefPubMedGoogle Scholar
  32. 32.
    Picard C, Casanova JL: Inherited disorders of cytokines. Curr Opin Pediatr 16:648–658, 2004CrossRefPubMedGoogle Scholar
  33. 33.
    Puel A, Picard C, Ku CL, Smahi A, Casanova JL: Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol 16:34–41, 2004CrossRefPubMedGoogle Scholar
  34. 34.
    Gennery AR, Flood TJ, Abinun M, Cant AJ: Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant 25:1303–1305, 2000CrossRefPubMedGoogle Scholar
  35. 35.
    Cookson W: The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat Rev Immunol 4:978–988, 2004CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • E. D. Renner
    • 1
    • 3
  • I. Pawlita
    • 1
  • F. Hoffmann
    • 1
  • V. Hornung
    • 2
  • D. Hartl
    • 1
  • M. Albert
    • 1
  • A. Jansson
    • 1
  • S. Endres
    • 2
  • G. Hartmann
    • 2
  • B. H. Belohradsky
    • 1
  • S. Rothenfusser
    • 2
    • 4
    • 5
    Email author
  1. 1.University Children’s Hospital, Dr. von Haunersches Kinderspital, Ludwig-Maximilians-UniversityMunichGermany
  2. 2.Department of Internal Medicine, Division of Clinical PharmacologyLudwig-Maximilians-UniversityMunichGermany
  3. 3.Department of PediatricsUniversity of Washington School of MedicineSeattleWashington
  4. 4.Division of Infectious Diseases and ImmunologyUniversity of Massachusetts Medical SchoolWorcester
  5. 5.Division of Infectious Diseases & ImmunologyUniversity of Massachusetts Medical SchoolWorcester

Personalised recommendations