Unravelling fungal immunity through primary immune deficiencies

Unravelling Fungal Immunity through Primary Immune

Deficiencies

Suda Sibunruang, M.D.

Picture from www.kids.nationalgeographic.com

Lilic D. Current Opinion in Microbiology 2012,15:420–6

Outline

• Introduction

• Immunity to fungi

- Innate immune response

- Adaptive immune response

• Primary immunodeficiencies with susceptibility to fungal infections

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%

Pfaller MA, Diekema DJ. Critical Reviews in Microbiology 2010;36:1–53

Vinh DC. Lancet Infect Dis 2011;11:780-92

Medical mycology and fungal immunology

• 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;11:780-92Lilic D. Current Opinion in Microbiology 2012,15:420–6

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


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 oligomerizationdomain (NOD) proteins, sense intracellularbacteria and viruses

Hardison SE, Brown GD. Nat Immunol 2012;13:817-22Engelhardt KR et al. J Allergy Clin Immunol 2012;129:294–305

Structure of the fungal cell wall

Different components of cell wall are recognizedby different receptors

TLR 4

MINCLE

Romani L. Nat Rev Immunol 2004;4:1-23

These forms express different antigens

β glucan is exposed exclusively at bud and birth scars ofblastoconidia and beingrecognized by dectin 1

α mannans in both yeast andhyphal forms are recognized by dectin-2

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 lymphoidtissue lymphoma translocation protein 1)

(NLR family,pyrindomain containing 3 Inflammasome)

Vautier S. et al. Cytokine 2012;58:89–99

Plato A. et al. Semin Immunopathol 2015;37:97–106


Production of proinflammatorycytokines and chemokines


TH17-priming cytokines signal through STAT3->Transcription factor retinoic acid–relatedorphan receptor γt

Upregulation of chemokine receptors

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

Miossec P. et al. N Engl J Med 2009;361:888-98

Local cytokine milieufrom innate immune cells

Miossec P. et al. N Engl J Med 2009;361:888-98

Vautier S. et al. Cytokine 2012;58:89–99

Huppler et al. Arthritis Research & Therapy 2012;14:217

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 ofDNA and histones and contain granule-derived proteins withantimicrobial activity


Primary immune deficiencies with

susceptibility to fungal infections

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


Parvaneh N. et al. J Allergy Clin Immunol 2013;131:314-23Ochs 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

Sillevis Smitta JH, Kuijpers TW. Curr Opin Pediatr 2013;25:492–7

Plantinga TS. et al. Medical Mycology 2012;50:785–94


Netea M. et al. N Engl J Med 2011;364:60-70

McDonald DR. J Allergy Clin Immunol 2012;129:1429-35

Kisand K. and Peterson P. Curr Opin Pediatr 2013;25:715–21

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 bindβ-glucan or C. albicans

Ferwerda B. et al. N Engl J Med 2009;361:1760-7

Both monocytes and macrophagesshowed poor in vitro production of IL-6,IL-17, and TNF-α on stimulation with β-glucan

Phagocytosis and killingof C.albicans were normal


Glocker EO. et al. N Engl J Med 2009;361:1727-35

A Homozygous CARD9 Mutation in a Familywith Susceptibility to Fungal Infections

4 patients from a large consanguineous family from Iran3 died from invasive candida infections of brain in early childhood

• Recurrent oral candidiasis • Vaginal candidiasis• Angular cheilitis• Tinea corporis• Dermatophytosis


Q295X mutation and lack of CARD9 expression


Low numbers of IL-17–producing T cells


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

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

Conti HR. et al. Mucosal Immunol 2011;4:448-55


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 STAT1IFN- production has been reported as both normal and decreased. Interestingly, they are not particularly susceptible to intracellular microorganisms that provoke aTh1 protective immune response

accumulation of phosphorylated STAT1 in nucleus

STAT1 gain-of-function mutations,leading to an IPEX-like presentation


Varying symptoms, sometimes reminiscent of HIES, but frequently have associated hypothyroidism and

oral/oesophageal squamous cell cancer

van de Veerdonk FL. et al. N Engl J Med 2011;365:54-61

STAT1 Mutations in Autosomal DominantChronic 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

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


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 patientshad associated CMC

de Beaucoudrey L. et. al. J Exp Med 2008;205:1543-50

IL-12R1 deficiency impairs developmentof IL-17 producing T cells

Interestingly, other known mutations that disrupt IFN- mediatedimmunity resulting in MSMD are not associated with increased incidence of CMC


Zepp J et. al. Trends in Immunology 2011;32:1-8

Eyerich K. et al. J Invest Dermatol 2008;128:2640-5

Patients with Chronic Mucocutaneous CandidiasisExhibit Reduced Production of Th17-Associated

Cytokines IL-17 and IL-22

In 2008, Eyerich et al. studied a group of patients withisolated CMC in whom no other infectious or autoimmune

manifestations occurred and showed a smaller proportion ofIL-17–producing T cells and low levels of IL-17

Eyerich K. et al. J Invest Dermatol 2008;128:2640-5

Puel A. et al. Science 2011;332:65-8

Chronic mucocutaneous candidiasis in humans with inbornerrors of interleukin-17 immunity

2 genetic defects leading to CMC• AD deficiency of IL-17F• AR deficiency of the IL-17RA

Puel A. et al. Science 2011;332:65-8


Browne SK. Annu. Rev. Immunol. 2014;32:635–57

Plantinga TS. et al. Medical Mycology 2012;50:785–94Ochs 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

Kisand K. et. al. Eur J Immunol 2011;41:1517-27

Ng WF et. al. J Allergy Clin Immunol 2010;126:1006-15


Normal or even increasedIL-17 production


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 autoimmunepolyendocrine syndrome type I

Plasma of 33 patients with APECED,29/33 had CMC, and found neutralizing IgGautoantibodies 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 least1 of these cytokines. This also included patients without CMC

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

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



Take home messages

Thank you for your attention

Health & Medicine

Unravelling fungal immunity through primary immune deficiencies