Skip to main content
SpringerLink
Log in

Recent Advances in DOCK8 Immunodeficiency Syndrome

Journal of Clinical Immunology volume 36, pages 441–449 (2016)Cite this article

Abstract

Since the discovery of the genetic basis of DOCK8 immunodeficiency syndrome (DIDS) in 2009, several hundred patients worldwide have been reported, validating and extending the initial clinical descriptions. Importantly, the beneficial role of hematopoietic stem cell transplantation for this disease has emerged, providing impetus for improved diagnosis. Additionally, several groups have further elucidated the biological functions of DOCK8 in the immune system that help explain disease pathogenesis. Here, we summarize these recent developments.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Zhang Y, Su HC, Lenardo MJ. Genomics is rapidly advancing precision medicine for immunological disorders. Nat Immunol. 2015;16(10):1001–4.

    Article  CAS  PubMed  Google Scholar 

  2. Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med. 2009;361(21):2046–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol. 2009;124(6):1289–302.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Su HC, Jing H, Zhang Q. DOCK8 deficiency. Ann N Y Acad Sci. 2011;1246:26–33.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang Q, Davis JC, Dove CG, Su HC. Genetic, clinical, and laboratory markers for DOCK8 immunodeficiency syndrome. Dis Markers. 2010;29(3–4):131–9.

    PubMed  Google Scholar 

  7. Toth B, Pistar Z, Csorba G, Balogh I, Kovacs T, Erdos M, et al. Novel dedicator of cytokinesis 8 mutations identified by multiplex ligation-dependent probe amplification. Eur J Haematol. 2013;91(4):369–75.

    CAS  PubMed  Google Scholar 

  8. Sanal O, Jing H, Ozgur T, Ayvaz D, Strauss-Albee DM, Ersoy-Evans S, et al. Additional diverse findings expand the clinical presentation of DOCK8 deficiency. J Clin Immunol. 2012;32(4):698–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, et al. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. J Allergy Clin Immunol. 2014;133(6):1667–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kienzler AK, van Schouwenburg PA, Taylor J, Marwah I, Sharma RU, Noakes C, et al. Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency without hyper-IgE. Clin Immunol. 2015;163:17–21.

    Article  PubMed  Google Scholar 

  11. Davis BR, Candotti F. Revertant somatic mosaicism in the Wiskott-Aldrich syndrome. Immunol Res. 2009;44(1–3):127–31.

    Article  PubMed  Google Scholar 

  12. Pai SY, de Boer H, Massaad MJ, Chatila TA, Keles S, Jabara HH, et al. Flow cytometry diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency. J Allergy Clin Immunol. 2014.

  13. Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, et al. DOCK8 deficiency: clinical and immunological phenotype and treatment options—a review of 136 patients. J Clin Immunol. 2015;35(2):189–98.

    Article  CAS  PubMed  Google Scholar 

  14. Engelhardt KR, Gertz ME, Keles S, Schaffer AA, Sigmund EC, Glocker C, et al. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2015;136(2):402–12.

    Article  CAS  PubMed  Google Scholar 

  15. Al-Herz W, Ragupathy R, Massaad MJ, Al-Attiyah R, Nanda A, Engelhardt KR, et al. Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait. Clin Immunol. 2012;143(3):266–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Alsum Z, Hawwari A, Alsmadi O, Al-Hissi S, Borrero E, Abu-Staiteh A, et al. Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty five patients. J Clin Immunol. 2013;33(1):55–67.

    Article  CAS  PubMed  Google Scholar 

  17. Chu EY, Freeman AF, Jing H, Cowen EW, Davis J, Su HC, et al. Cutaneous manifestations of DOCK8 deficiency syndrome. Arch Dermatol. 2011;148(1):79–84.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Jouhadi Z, Khadir K, Ailal F, Bouayad K, Nadifi S, Engelhardt KR, et al. Ten-year follow-up of a DOCK8-deficient child with features of systemic lupus erythematosus. Pediatrics. 2014;134(5):e1458–63.

    Article  PubMed  Google Scholar 

  19. Sabry A, Hauk PJ, Jing H, Su HC, Stence NV, Mirsky DM, et al. Vaccine strain varicella-zoster virus-induced central nervous system vasculopathy as the presenting feature of DOCK8 deficiency. J Allergy Clin Immunol. 2014;133(4):1225–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Al Mutairi M, Al-Mousa H, AlSaud B, Hawwari A, AlJoufan M, AlWesaibi A, et al. Grave aortic aneurysmal dilatation in DOCK8 deficiency. Mod Rheumatol. 2013.

  21. Keles S, Jabara HH, Reisli I, McDonald DR, Barlan I, Hanna-Wakim R, et al. Plasmacytoid dendritic cell depletion in DOCK8 deficiency: rescue of severe herpetic infections with IFN-alpha 2b therapy. J Allergy Clin Immunol. 2014;133(6):1753–5.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Papan C, Hagl B, Heinz V, Albert MH, Ehrt O, Sawalle-Belohradsky J, et al. Beneficial IFN-alpha treatment of tumorous herpes simplex blepharoconjunctivitis in dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2014;133(5):1456–8.

    Article  CAS  PubMed  Google Scholar 

  23. Al-Zahrani D, Raddadi A, Massaad M, Keles S, Jabara HH, Chatila TA, et al. Successful interferon-alpha 2b therapy for unremitting warts in a patient with DOCK8 deficiency. Clin Immunol. 2014;153(1):104–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cuellar-Rodriguez J, Freeman AF, Grossman J, Su H, Parta M, Murdock H, et al. Matched related and unrelated donor hematopoietic stem cell transplantation for DOCK8 deficiency. Biol Blood Marrow Transplant. 2015;21(6):1037–45.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gatz SA, Benninghoff U, Schutz C, Schulz A, Honig M, Pannicke U, et al. Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation. Bone Marrow Transplant. 2011;46(4):552–6.

    Article  CAS  PubMed  Google Scholar 

  26. Bittner TC, Pannicke U, Renner ED, Notheis G, Hoffmann F, Belohradsky BH, et al. Successful long-term correction of autosomal recessive hyper-IgE syndrome due to DOCK8 deficiency by hematopoietic stem cell transplantation. Klin Padiatr. 2010;222(6):351–5.

    Article  CAS  PubMed  Google Scholar 

  27. Barlogis V, Galambrun C, Chambost H, Lamoureux-Toth S, Petit P, Stephan JL, et al. Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency. J Allergy Clin Immunol. 2011.

  28. Metin A, Tavil B, Azik F, Azkur D, Ok-Bozkaya I, Kocabas C, et al. Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome. Pediatr Transplant. 2012. doi:10.1111/j.1399-3046.2011.01641.x.

    PubMed  Google Scholar 

  29. Boztug H, Karitnig-Weiss C, Ausserer B, Renner ED, Albert MH, Sawalle-Belohradsky J, et al. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen. Pediatr Hematol Oncol. 2012;29(7):585–94.

    Article  CAS  PubMed  Google Scholar 

  30. Ghosh S, Schuster FR, Fuchs I, Laws HJ, Borkhardt A, Meisel R. Treosulfan-based conditioning in DOCK8 deficiency: complete lympho-hematopoietic reconstitution with minimal toxicity. Clin Immunol. 2012;145(3):259–61.

    Article  CAS  PubMed  Google Scholar 

  31. Ghosh S, Schuster FR, Adams O, Babor F, Borkhardt A, Comoli P, et al. Haploidentical stem cell transplantation in DOCK8 deficiency—successful control of pre-existing severe viremia with a TCRass/CD19-depleted graft and antiviral treatment. Clin Immunol. 2014;152(1–2):111–4.

    Article  CAS  PubMed  Google Scholar 

  32. Al-Mousa H, Hawwari A, Alsum Z. In DOCK8 deficiency donor cell engraftment post-genoidentical hematopoietic stem cell transplantation is possible without conditioning. J Allergy Clin Immunol. 2013.

  33. Happel CS, Stone KD, Freeman AF, Shah NN, Wang A, Lyons JJ, et al. Food allergies can persist after myeloablative hematopoietic stem cell transplantation in dedicator of cytokinesis 8-deficient patients. J Allergy Clin Immunol. 2016.

  34. Azik F, Azkur D, Avci Z, Vezir E, Isik P, Tunc B, et al. Resolution of food-induced anaphylaxis in DOCK8-deficient patients following bone marrow transplantation. Turk J Pediatr. 2015;57(1):112–5.

    PubMed  Google Scholar 

  35. Hagl B, Heinz V, Schlesinger A, Spielberger BD, Sawalle-Belohradsky J, Senn-Rauh M, et al. Key findings to expedite the diagnosis of hyper-IgE syndromes in infants and young children. Pediatr Allergy Immunol. 2016;27(2):177–84.

    Article  PubMed  Google Scholar 

  36. Janssen E, Tsitsikov E, Al-Herz W, Lefranc G, Megarbane A, Dasouki M, et al. Flow cytometry biomarkers distinguish DOCK8 deficiency from severe atopic dermatitis. Clin Immunol. 2014;150(2):220–4.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang Q, Dove CG, Hor JL, Murdock HM, Strauss-Albee DM, Garcia JA, et al. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J Exp Med. 2014;211(13):2549–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Flesch IE, Randall KL, Hollett NA, Di Law H, Miosge LA, Sontani Y, et al. Delayed control of herpes simplex virus infection and impaired CD4(+) T-cell migration to the skin in mouse models of DOCK8 deficiency. Immunol Cell Biol. 2015;93(6):517–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mizesko MC, Banerjee PP, Monaco-Shawver L, Mace EM, Bernal WE, Sawalle-Belohradsky J, et al. Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2013;131(3):840–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ham H, Guerrier S, Kim J, Schoon RA, Anderson EL, Hamann MJ, et al. Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity. J Immunol. 2013;190(7):3661–9.

    Article  CAS  PubMed  Google Scholar 

  41. Harada Y, Tanaka Y, Terasawa M, Pieczyk M, Habiro K, Katakai T, et al. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood. 2012;119(19):4451–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Randall KL, Chan SS, Ma CS, Fung I, Mei Y, Yabas M, et al. DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J Exp Med. 2011;208(11):2305–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lambe T, Crawford G, Johnson AL, Crockford TL, Bouriez-Jones T, Smyth AM, et al. DOCK8 is essential for T-cell survival and the maintenance of CD8(+) T-cell memory. Eur J Immunol. 2011;41(12):3423–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Steinert EM, Schenkel JM, Fraser KA, Beura LK, Manlove LS, Igyarto BZ, et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell. 2015;161(4):737–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Park CO, Kupper TS. The emerging role of resident T cells in protective immunity and inflammatory diseases. Nat Med. 2015;21(7):688–97.

    Article  CAS  PubMed  Google Scholar 

  46. Thome JJ, Yudanin N, Ohmura Y, Kubota M, Grinshpun B, Sathaliyawala T, et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell. 2014;159(4):814–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Crawford G, Enders A, Gileadi U, Stankovic S, Zhang Q, Lambe T, et al. DOCK8 is critical for the survival and function of NKT cells. Blood. 2013;122(12):2052–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Singh AK, Eken A, Fry M, Bettelli E, Oukka M. DOCK8 regulates protective immunity by controlling the function and survival of RORgammat + ILCs. Nat Commun. 2014;5:4603.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Janssen E, Morbach H, Ullas S, Bannock JM, Massad C, Menard L, et al. Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells. J Allergy Clin Immunol. 2014;134(6):1365–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Caracciolo S, Moratto D, Giacomelli M, Negri S, Lougaris V, Porta F, et al. Expansion of CCR4+ activated T cells is associated with memory B cell reduction in DOCK8-deficient patients. Clin Immunol. 2014;152(1–2):164–70.

    Article  CAS  PubMed  Google Scholar 

  51. Kl R, Lambe T, Johnson A, Treanor B, Kucharska E, Domaschenz H, et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nat Immunol. 2009;10(12):1283–91.

    Article  Google Scholar 

  52. aan de Kerk DJ, van Leeuwen EM, Jansen MH, van den Berg JM, Alders M, Vermont CL, et al. Aberrant humoral immune reactivity in DOCK8 deficiency with follicular hyperplasia and nodal plasmacytosis. Clin Immunol. 2013;149(1):25–31.

    Article  Google Scholar 

  53. Krishnaswamy KJ, Singh A, Gowthaman U, et al. Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration. Proc Natl Acad Sci U S A. 2015;112(10):3056–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med. 2012;18(4):538–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ruiz-Garcia R, Lermo-Rojo S, Martinez-Lostao L, Mancebo E, Mora-Diaz S, Paz-Artal E, et al. A case of partial dedicator of cytokinesis 8 deficiency with altered effector phenotype and impaired CD8(+) and natural killer cell cytotoxicity. J Allergy Clin Immunol. 2014;134(1):218–21.

    Article  CAS  PubMed  Google Scholar 

  56. Ruusala A, Aspenstrom P. Isolation and characterisation of DOCK8, a member of the DOCK180-related regulators of cell morphology. FEBS Lett. 2004;572(1–3):159–66.

    Article  CAS  PubMed  Google Scholar 

  57. Ham H, Huynh W, Schoon RA, Vale RD, Billadeau DD. HkRP3 is a microtubule-binding protein regulating lytic granule clustering and NK cell killing. J Immunol. 2015;194(8):3984–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, et al. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol. 2012;13(6):612–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Intramural Research Program, NIH, National Institute of Allergy and Infectious Diseases. Data in Fig. 2 were generated after obtaining written informed consent from the patient on an NIAID IRB-approved research protocol.

Authorship Contributions

Q.Z. and H.C.S. prepared the figures and wrote the manuscript. H.J. performed experiments in Fig. 2.

Author information

Author notes

  1. Qian Zhang

    Present address: Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar

Authors and Affiliations

  1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10CRC, Room 5-3940, 10 Center Dr., MSC 1456, Bethesda, MD, 20892-1456, USA

    Qian Zhang, Huie Jing & Helen C. Su

Authors
  1. Qian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huie Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helen C. Su
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helen C. Su.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Q., Jing, H. & Su, H.C. Recent Advances in DOCK8 Immunodeficiency Syndrome. J Clin Immunol 36, 441–449 (2016). https://doi.org/10.1007/s10875-016-0296-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-016-0296-z

Keywords

search

Navigation