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Unravelling fungal immunity through primary immune deficiencies

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Unravelling fungal immunity through primary immune deficiencies

Presented by Suda Sibunruang, MD.

March 13, 2015

Published in: Health & Medicine
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Unravelling fungal immunity through primary immune deficiencies

  1. 1. Unravelling Fungal Immunity through Primary Immune Deficiencies Suda Sibunruang, M.D.
  2. 2. Picture from www.kids.nationalgeographic.com
  3. 3. Lilic D. Current Opinion in Microbiology 2012,15:420–6
  4. 4. Outline • Introduction • Immunity to fungi - Innate immune response - Adaptive immune response • Primary immunodeficiencies with susceptibility to fungal infections
  5. 5. Pfaller MA, Diekema DJ. Critical Reviews in Microbiology 2010;36:1–53 Emerging importance of fungal infections Increase >200% in number of sepsis cases caused by fungal organisms with mortality rate in invasive fungal infections of 30–70%
  6. 6. Pfaller MA, Diekema DJ. Critical Reviews in Microbiology 2010;36:1–53
  7. 7. Vinh DC. Lancet Infect Dis 2011;11:780-92 Medical mycology and fungal immunology
  8. 8. • Epidermis and epithelium act as a physical barrier reinforced by antimicrobial peptides (defensins, cathelicidins, S100 proteins) • If this barrier is breached, fungi are recognized and processed by both innate and adaptive immune system Vinh DC. Lancet Infect Dis 2011;11:780-92 Lilic D. Current Opinion in Microbiology 2012,15:420–6
  9. 9. Innate immunity • Recognize ‘pathogen associated molecular patterns’ (PAMPs), initiating a rapid, conserved response that activates inflammatory cells • Triggering signaling pathways, which result in targeted cytokine production, recruitment and polarization of relevant T, B and natural killer (NK) lymphocyte Lilic D. Current Opinion in Microbiology 2012,15:420–6
  10. 10. Abbas AK et al. Cellular and Molecular immunology. 2014 Eighth Edition • Transmembrane PRRs, Toll-like receptors (TLRs) and C-type lectin receptors are both involved in antifungal immunity • Cytosolic receptors, such as retinoic acid–inducible gene I and nucleotide-binding oligomerization domain (NOD) proteins, sense intracellular bacteria and viruses
  11. 11. Hardison SE, Brown GD. Nat Immunol 2012;13:817-22 Engelhardt KR et al. J Allergy Clin Immunol 2012;129:294–305 Structure of the fungal cell wall Different components of cell wall are recognized by different receptors TLR 4 MINCLE
  12. 12. Romani L. Nat Rev Immunol 2004;4:1-23 These forms express different antigens β glucan is exposed exclusively at bud and birth scars of blastoconidia and being recognized by dectin 1 α mannans in both yeast and hyphal forms are recognized by dectin-2
  13. 13. Engelhardt KR et al. J Allergy Clin Immunol 2012;129:294–305 (spleen tyrosine Kinase) (caspase recruitment domain–containing protein 9) (B-cell lymphoma/ leukemia 10) (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) (NLR family,pyrin domain containing 3 Inflammasome)
  14. 14. Vautier S. et al. Cytokine 2012;58:89–99
  15. 15. Plato A. et al. Semin Immunopathol 2015;37:97–106
  16. 16. Engelhardt KR et al. J Allergy Clin Immunol 2012;129:294–305 Production of proinflammatory cytokines and chemokines
  17. 17. Engelhardt KR et al. J Allergy Clin Immunol 2012;129:294–305 TH17-priming cytokines signal through STAT3-> Transcription factor retinoic acid–related orphan receptor γt Upregulation of chemokine receptors
  18. 18. Puel A. et al. Curr Opin Allergy Clin Immunol 2012;12:616–22 Gain-of-function STAT1 mutations shift cellular response toward TH17 cell–inhibiting cytokines
  19. 19. Miossec P. et al. N Engl J Med 2009;361:888-98 Local cytokine milieu from innate immune cells
  20. 20. Miossec P. et al. N Engl J Med 2009;361:888-98
  21. 21. Vautier S. et al. Cytokine 2012;58:89–99
  22. 22. Huppler et al. Arthritis Research & Therapy 2012;14:217
  23. 23. Hickey MJ, Kubes P. Nat Rev Immunol 2009;9:364-75 Neutrophils: the final killers 3 main mechanisms to kill microbes • Phagocytosis • Degranulation and activation of oxidative burst • Neutrophil extracellular traps Thus, neutropenia (<1,500) is more severe and predisposes to systemic fungal infection Traps consist of a web of DNA and histones and contain granule-derived proteins with antimicrobial activity
  24. 24. Romani L. Nat Rev Immunol 2011;11:275-88
  25. 25. Primary immune deficiencies with susceptibility to fungal infections
  26. 26. Primary immune deficiencies (PIDs) • Conventional PIDs were defined by an overt immunological phenotype resulting in a broad susceptibility to a range of microorganisms • Non-conventional PIDs include selective susceptibilities to weakly pathogenic and/or opportunistic microorganisms (atypical mycobacteria, herpes simplex, pneumococci) as well as opportunistic fungi Lilic D. Current Opinion in Microbiology 2012,15:420–6
  27. 27. Parvaneh N. et al. J Allergy Clin Immunol 2013;131:314-23 Ochs HD et al. Ann Allergy Asthma Immunol 2014;112:489-95 New genes associated with PIDs are discovered at increasing velocity 19 novel single-gene defects were described within 1 year of the last IUIS report published in 2011
  28. 28. Sillevis Smitta JH, Kuijpers TW. Curr Opin Pediatr 2013;25:492–7
  29. 29. Plantinga TS. et al. Medical Mycology 2012;50:785–94
  30. 30. Plantinga TS. et al. Medical Mycology 2012;50:785–94
  31. 31. Netea M. et al. N Engl J Med 2011;364:60-70
  32. 32. McDonald DR. J Allergy Clin Immunol 2012;129:1429-35
  33. 33. Kisand K. and Peterson P. Curr Opin Pediatr 2013;25:715–21
  34. 34. Ferwerda B. et al. N Engl J Med 2009;361:1760-7 Human Dectin-1 Deficiency and Mucocutaneous Fungal Infections Dutch Homozygous nonsense mutation (Y238X) in DECTIN1 resulted in lost of capability to bind β-glucan or C. albicans
  35. 35. Ferwerda B. et al. N Engl J Med 2009;361:1760-7 Both monocytes and macrophages showed poor in vitro production of IL-6, IL-17, and TNF-α on stimulation with β-glucan Phagocytosis and killing of C.albicans were normal
  36. 36. Kisand K. and Peterson P. Curr Opin Pediatr 2013;25:715–21
  37. 37. Glocker EO. et al. N Engl J Med 2009;361:1727-35 A Homozygous CARD9 Mutation in a Family with Susceptibility to Fungal Infections 4 patients from a large consanguineous family from Iran 3 died from invasive candida infections of brain in early childhood • Recurrent oral candidiasis • Vaginal candidiasis • Angular cheilitis • Tinea corporis • Dermatophytosis
  38. 38. Glocker EO. et al. N Engl J Med 2009;361:1727-35 Q295X mutation and lack of CARD9 expression
  39. 39. Glocker EO. et al. N Engl J Med 2009;361:1727-35 Low numbers of IL-17–producing T cells
  40. 40. Kisand K. and Peterson P. Curr Opin Pediatr 2013;25:715–21
  41. 41. Marodi L. et al. J Allergy Clin Immunol 2012;130:1019-27 Submental staphylococcal abscess in a 7-month-old girl and nail candidiasis in her mother from a family with AD-HIES and R382W mutation in STAT3
  42. 42. Conti HR. et al. Mucosal Immunol 2011;4:448-55 Oral candidiasis is encouraged by reduced antifungal activity in saliva of STAT3- deficient patients with reduced expression of antimicrobial effectors, such as β-defensin 2 and histatins
  43. 43. Conti HR. et al. Mucosal Immunol 2011;4:448-55
  44. 44. Kisand K. and Peterson P. Curr Opin Pediatr 2013;25:715–21
  45. 45. Puel A. et al. Curr Opin Allergy Clin Immunol 2012;12:616–22 Gain-of-function STAT1 acts in 2 ways with regard to impaired generation of TH17 cells: • cytokines that antagonize development of TH17 cells, such as IL-27, IFN- are increased • cytokines that normally promote TH17 differentiation through activation of STAT3 are shifted toward STAT1 IFN- production has been reported as both normal and decreased. Interestingly, they are not particularly susceptible to intracellular microorganisms that provoke a Th1 protective immune response accumulation of phosphorylated STAT1 in nucleus STAT1 gain-of-function mutations, leading to an IPEX-like presentation
  46. 46. Plantinga TS. et al. Medical Mycology 2012;50:785–94 Varying symptoms, sometimes reminiscent of HIES, but frequently have associated hypothyroidism and oral/oesophageal squamous cell cancer
  47. 47. van de Veerdonk FL. et al. N Engl J Med 2011;365:54-61 STAT1 Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis 14 patients from 5 families of Dutch and British decent Patients’ PBMCs showed poor production of TH17 cytokines (IL-17/IL-22, respectively) in response to C.albicans
  48. 48. van de Veerdonk FL. et al. N Engl J Med 2011;365:54-61 CMC, severe oropharyngeal chronic candidiasis, and severe dermatophytosis, together with autoimmune phenomena, such as hypothyroidism and autoimmune hepatitis. One patient also had squamous cell carcinoma
  49. 49. Kisand K. and Peterson P. Curr Opin Pediatr 2013;25:715–21
  50. 50. de Beaucoudrey L. et. al. Medicine (Baltimore) 2010; 89: 381–402 Revisiting Human IL-12Rβ1 Deficiency: A Survey of 141 Patients From 30 Countries 23% of patients had associated CMC
  51. 51. de Beaucoudrey L. et. al. J Exp Med 2008;205:1543-50 IL-12R1 deficiency impairs development of IL-17 producing T cells Interestingly, other known mutations that disrupt IFN- mediated immunity resulting in MSMD are not associated with increased incidence of CMC
  52. 52. Kisand K. and Peterson P. Curr Opin Pediatr 2013;25:715–21
  53. 53. Zepp J et. al. Trends in Immunology 2011;32:1-8
  54. 54. Eyerich K. et al. J Invest Dermatol 2008;128:2640-5 Patients with Chronic Mucocutaneous Candidiasis Exhibit Reduced Production of Th17-Associated Cytokines IL-17 and IL-22 In 2008, Eyerich et al. studied a group of patients with isolated CMC in whom no other infectious or autoimmune manifestations occurred and showed a smaller proportion of IL-17–producing T cells and low levels of IL-17
  55. 55. Eyerich K. et al. J Invest Dermatol 2008;128:2640-5
  56. 56. Puel A. et al. Science 2011;332:65-8 Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity 2 genetic defects leading to CMC • AD deficiency of IL-17F • AR deficiency of the IL-17RA
  57. 57. Puel A. et al. Science 2011;332:65-8
  58. 58. Kisand K. and Peterson P. Curr Opin Pediatr 2013;25:715–21
  59. 59. Browne SK. Annu. Rev. Immunol. 2014;32:635–57
  60. 60. Plantinga TS. et al. Medical Mycology 2012;50:785–94 Ochs HD et al. Ann Allergy Asthma Immunol 2014;112: 489-95 autoimmune regulator Phenocopies of PIDDs is a new category that was first presented in IUIS 2014 update. This category includes conditions that resemble PIDDs and are not due to germline mutations. A typical example would be autoantibodies against IL-17 or IL-22 in APECED, which is similar to IL-17 pathway defects and leads to CMC
  61. 61. Kisand K. et. al. Eur J Immunol 2011;41:1517-27
  62. 62. Ng WF et. al. J Allergy Clin Immunol 2010;126:1006-15
  63. 63. Ng WF et. al. J Allergy Clin Immunol 2010;126:1006-15 Normal or even increased IL-17 production
  64. 64. Ng WF et. al. J Allergy Clin Immunol 2010;126:1006-15
  65. 65. Puel A. J Exp Med 2010;207:291-7 Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I Plasma of 33 patients with APECED, 29/33 had CMC, and found neutralizing IgG autoantibodies against IL-17A (67%), IL-17F (94%), and IL-22 (91%) but not against other cytokines, such as IL-1b, IL-6, IL-23, and IL-26. All patients had autoantibodies against at least 1 of these cytokines. This also included patients without CMC
  66. 66. Autoantibodies to IL 17A, 17F, and 22 • Sometimes demonstrably preceding mycosis, suggesting a causative role in, rather than a result of, infection • Moreover, autoantibodies to other cytokines were not recorded, except for interferons α and ω • Antibodies against IL 17 and 22 are not known in other autoimmune disorders, suggesting that association between these neutralizing autoantibodies and CMC in APECED is specific Vinh DC. Lancet Infect Dis 2011;11:780-92
  67. 67. Translating basic research into clinical practices • New antifungal drugs • Immune therapies; PRR agonism or antagonism • Vaccines • Functional genomics; risk assessment of patients at highest risk of developing a life- threatening infection Romani L. Nat Rev Immunol 2011;11:275-88
  68. 68. Lilic D. Current Opinion in Microbiology 2012,15:420–6 Take home messages
  69. 69. Thank you for your attention

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