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Hyper-IgE syndrome

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Hyper-IgE syndrome

Presented by Jintana Chataroopwijit, MD.

October28, 2016

Published in: Health & Medicine
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Hyper-IgE syndrome

  1. 1. Hyper-IgE Syndrome Jintana Chataroopwijit 28 October 2016
  2. 2. Group of primary immunodeficiencies Significant elevation of IgE Recurrent skin infections Eczema Pulmonary infection Cur Opin Hematol 2015, 22:12-22
  3. 3. Autosomal dominant hyperIgE syndrome STAT3 deficiency Autosomal recessive hyperIgE syndrome DOCK8 deficiency Other : Tyrosine kinase 2 deficiency
  4. 4. Cur Opin Hematol 2015, 22:12-22
  5. 5. Autosomal dominant hyper-IgE syndrome
  6. 6. First described as "Job's syndrome" in 1966 Bablical Job : smote with sore boil In 1972, extremely high serum IgE level In 2008, known about mutation of STAT3 Immunol Allergy Clin N Am 28(2008) 227-291
  7. 7. Dominant-negative heterogenous mutation in STAT3 STAT3 located at 17q21.31 Mutation mostly in SH2 and DNA binding domains of STAT3 and mostly missense mutations --> single amino acid changes or short in-frame deletion Immunol Allergy Clin N Am 35 (2015) 767-778 Artritis research and therapy 2012 14:228
  8. 8. Current Opinion in Immunology 2014, 28:49-57
  9. 9. Current Opinion in Immunology 2014, 28:49-57
  10. 10. JAK-STAT 2013; 2:e23435 Immunological and somatic phenotypes and associated pathogenesis
  11. 11. Immunol Allergy Clin N Am 28(2008) 227-291
  12. 12. Newborn rash usually first manifestation First month of life : Pustular and eczematoid rash esp. at face and scalp Histology : eosinophilic infiltration Culture : Staphylococcus aureus Boils : cold abcess Immunol Allergy Clin N Am 28(2008) 227-291
  13. 13. Recurrent pyogenic pneumonia Organisms : S aureus, Streptococcus pneumoniae and Haemophilus influenzae Complication : pneumatoceles, bronchiectasis Structural abnormalities --> gram negative bacterial infection ex. Pseudomonas and fungal infection Immunol Allergy Clin N Am 28(2008) 227-291
  14. 14. Not much Do not have Th2 predominance Most IgE is not allergen-specific Impaired IL-10 induced generation of tolerogenic dendritric cells --> reduced generation of induced regulatory T cell SO patient may manifest anaphylaxis and have more allergy compared to healthy Cur Opin Hematol 2015, 22:12-22
  15. 15. Immunol Allergy Clin N Am 28(2008) 227-291
  16. 16. Facial asymmetry Broad nose Deep-set eye Prominent forehead Immunol Allergy Clin N Am 28(2008) 227-291 India Journal of Dermatology2015
  17. 17. Scoliosis : vary in severity Osteopenia Minimal trauma fractures Hyperextensibility : large and small joint Degenerative joint disease Immunol Allergy Clin N Am 28(2008) 227-291
  18. 18. Craniosynostosis Chiari 1 malformation Unspecific white matter lesion Immunol Allergy Clin N Am 28(2008) 227-291 Journal of Clinical Immunology 2013
  19. 19. Failure of the primary dental teeth to exforiate Immunol Allergy Clin N Am 28(2008) 227-291 Oral disease 2008
  20. 20. Peripheral and brain artery abnormalities Coronary artery abnormalities : ectasias and aneurysm In mouse model, inhibited STAT3 signaling and IL-17A blockage resulted in increased aneurysm severity and fatal ruptures Cur Opin Hematol 2015, 22:12-22
  21. 21. Hodgkin's lymphoma Non-Hodgkin's lymphoma : B cell Leukemia Solid tumors : liver, lung Immunol Allergy Clin N Am 28(2008) 227-291
  22. 22. Artritis research and therapy 2012 14:228
  23. 23. Gold standard : molecular diagnosis with sequencing of STAT3 Often leucocytosis, rare neutopenia Normal IgG Immunol Allergy Clin N Am 35 (2015) 767-778
  24. 24. DOCK8-deficient autosomal recessive hyper-IgE syndrome
  25. 25. Firstly described in 2004 by Renner et al. Consanguineous families Feature of HIES but lack of connective tissue disease and skeletal affect Increased in viral infections More neurologic symptoms, autoimmunity, food allergy and higher rate of malignancies Cur Opin Hematol 2015, 22:12-22
  26. 26. DOCK8 : guanine nucleotide exchange factor Interacts with Rho GTPases Regulatory function in cell migration, morphology, adhesion and growth Cur Opin Hematol 2015, 22:12-22
  27. 27. Mutation in DOCK8 : 9p24.3 Premature termination Frameshift Splice site disruption Single exon deletions Microdeletion Cur Opin Hematol 2015, 22:12-22
  28. 28. Mutation in DOCK8 : 9p24.3 Premature termination Frameshift Splice site disruption Single exon deletions Microdeletion Cur Opin Hematol 2015, 22:12-22 Loss of function
  29. 29. Severe reduction of memory B cells Some impaired antibody responses to immunization and long term memory T cell number below average and some diminishes proliferation Cur Opin Hematol 2015, 22:12-22
  30. 30. Impaired NK cell function Decreased plasmacytoid dendritic cell numbers Decreased expression of TNF-alpha, IFN- gamma and IL-2 Cur Opin Hematol 2015, 22:12-22
  31. 31. Elevated serum IgE level with CD3+, CD4+, naive CD8+ T cell Lymphopenia Normal total B lymphocyte percentage but low memory B lymphocyte value
  32. 32. Immunol Allergy Clin N Am 28(2008) 227-291
  33. 33. Immunol Allergy Clin N Am 28(2008) 227-291
  34. 34. Immunol Allergy Clin N Am 28(2008) 227-291 • Molluscum contagiosum • Herpes simplex • Varicella zoster
  35. 35. Herpetic dermatitis and mucositis at eyelid Oral ulcer of herpetic gingivostomatitis The Journal of Pediatrics 2016
  36. 36. Immunol Allergy Clin N Am 28(2008) 227-291 Ranging from facial palsy to hemiplegia Some had severe vasculits
  37. 37. Food allergy esp. Cow milk Increased ratio of IL-4 compared to other cytokine --> Th2 predominance Cur Opin Hematol 2015, 22:12-22
  38. 38. DOCK 8 Tumor surveillance Tumor suppressor function 20% of patients develop at least one cancer 10% of patients dying from cancer
  39. 39. Most common : squamous cell carcinomas Second common : lymphoma Others : microcystic adenoma, leiomyoma
  40. 40. Autoimmune hemolytic anemia CNS vasculitis
  41. 41. Gold standard : molecular sequencing of DOCK8 gene Usually low T cell in number, low IgM level and failure to sustain protective titer against vaccination Immunol Allergy Clin N Am 35 (2015) 767-778
  42. 42. Other hyper-IgE syndrome
  43. 43. First reported in 2006 Multiple episodes of staphylococcus disease, severe eczema and elevated IgE level Additionally, suffered from susceptibility to BCG and Salmonella : IFN-gamma/IL-12 defect Cur Opin Hematol 2015, 22:12-22
  44. 44. Cur Opin Hematol 2015, 22:12-22
  45. 45. Compilation of most commonly reported immunological abnormalities Cur Opin Hematol 2015, 22:12-22
  46. 46. Cur Opin Hematol 2015, 22:12-22
  47. 47. Cur Opin Hematol 2015, 22:12-22
  48. 48. Overall survival propability(%) Age-related event- free survival(%) 10 years of age 20 years of age 30 years of age J Clin Immunol 2015, 35:189-98
  49. 49. Multidisciplinary approach Prevention and management of infection Bone marrow transplantation may be curative Immunol Allergy Clin N Am 35 (2015) 767-778 Ann N.Y. Acad. Sci. 1246(2011) 26-33
  50. 50. Coverage organism Staphylococcus aureus Haemophilus influenzae Streptococcus pneumoniae Pseudomonas aeruginosa Other gram negative bacteria Fungi ex. Aspergillus fumigatus Ann N.Y. Acad. Sci. 1246(2011) 26-33
  51. 51. Coverage organism Staphylococcus aureus Haemophilus influenzae Streptococcus pneumoniae Pseudomonas aeruginosa Other gram negative bacteria Fungi ex. Aspergillus fumigatus Abnormal structural lung Pneumatocele Bronchiectasis Ann N.Y. Acad. Sci. 1246(2011) 26-33
  52. 52. Thank you

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