Fungal Immunity Flashcards
What are fungi opsonised by?
• Pentraxin-3
&
• Mannose-binding lectin (MBL)
What cells are involved in cellular immunity to fungal infection?
Phagocytes
• critical 1st-line defence
NK Cells
• provide early INF-gamma
Dendritic cells
• influence T-cell differentiation
Th1 & Th17 cells
Explain the virulence of fungal spores
- Candida
• dimorphism allows tissue invasion - Cryptococcus
• capsule evades phagocytosis - Aspergillus
• inhaled as conidia
• invade as hyphae
What is required for fungal immunity in flies?
Toll
It is an innate PRR (Pattern Recognition Receptor)
3 human deficiencies that can lead to fungal infections?
(1) Dectin 1
(2) CARD-9
(3) TLR4 polymorphisms (Toll-Like Receptor)
All of these are part of signalling pathways in INNATE recognition of fungi
Explain how Dectin 1 deficiency leads to fungal infection
Leads to MUCOCUTANEOUS FUNGAL infections
• e.g. vulvovaginitis & onychomycosis
Leads to impaired
• macrophage IL-6 production & binding
in response to fungal infections
Can also lead to increased susceptibility to
• invasive aspergillosis in stem cell transplants
Explain how CARD-9 deficiency leads to fungal infection
Leads to CHRONIC MUCOCUTANEOUS CANDIDIASIS
CARD-9 is required for:
• TNFa production in response to Beta-glucan stimulation
• T-cell Th17 differentiation
Explain how TLR4 polymorphisms leads to fungal infections
Increases risk of INVASIVE ASPERGILLOSIS (IA)
• in transplantations (i.e. haematopoietic SC. transpl.)
What has been found in relation to SNPs to fungal infections?
Many major SNPs associated with increased susceptibility to invasive fungal infections & disease
• e.g. IL1-2, TLR-2/4/6/9
What effect does plasminogen have on fungal infections?
Plasminogen DIRECTLY BINDS to Aspergillus
• so mutations increases susceptibility to aspergillus in S.C transpl.
What is Conclusion 1?
- Wide range of PRR are implicated in fungal immunity
2. Mutations in Dectin-1, TLR4 & plasminogen confer increased susceptibility to fungal disease
What cellular defences are in place against fungal infection?
(1) Neutrophils - Neutrophils NETS
• neutrophils throw out CHROMATIN “nets” to capture pathogens
• these chromatin molecules outside the nucleus act as “danger signals” & recruit EFFECTOR CELLS to the area as well
(2) Fungal morphogenesis
• fungi can transition betw. yeast, candida & hyphae forms
• this can drive a modulation of DENDRITIC CELL response
• can be BAD for the I.R as it gets confused
What innate defences are in place against fungal infections?
Mucosal immunity
• governs fungal TOLERANCE & RESISTANCE
What treatments are in place against fungal infections?
(1) Adoptive Immunotherapy
• generate lots of ANTIFUNGAL T-CELLS in a sample
• give these to patient to fight infection
(2) Gene therapy
• e.g. restore gp91 function (make reactive oxidative species to FIGHT fungal spores)
• e.g. treat Chronic Granulomatous Disorder - restoration of neutrophil NET formation
Conclusion 2?
- BOTH macrophages & neutrophils contribute to fungal immunity
• HOWEVER, for Aspergillus, neutrophils are of 1o importance - Dendritic cells modulative adaptive I.R
- Adaptive T-cell INF-gamma responses augment host immunity to fungi
- New treatments
• INF-gamma OR adoptive T-cell therapy
• Gene therapy for 1o immunodeficiences
What conclusions can be made about fungal allergies?
- Many fungal SPORES are INHALED daily
- The host response may be NORMAL, INEFFECTIVE or EXAGGERATED (allergic response)
• leads to either an allergic OR invasive fungal disease - Aspergillus is a 1o driver (other fungi may contribute)
• Aspergilli - Aspergillus niger, Aspergillus fumigatus
• Other supporting fungi inc. Pencillium, Cladosporium etc. - Important fungal reactions include type 1,3 & 4 hypersensitivity reactions
o T1 – IgE-driven, involves histamine and leukotrienes, in minutes
o T2 – IgG-, IgM-driven, involves complement, in 1-24 hours
o T3 – IgG-, IgM-driven, involves complement, in 1-24 hours
o T4 – T-cell-driven, involves lymphokines, in 2-3 days
ABPA?
Allergic Bronchopulmonary Apergillosis
What is the criteria for diagnosis of ABPA?
Predisposing Condition
• asthma OR CF
Obligatory criteria - either:
• high baseline serum IgE
• +VE T1 hypersensitivity (immediate response) skin test
• Aspergillus-sepcific IgE
Supportive criteria (more than two)
• eosinophillia
• IgG Abs to Aspergillus fumigatus
• consistent radiologic abnormalities
What are radiologic abnormalities of ABPA?
- Dilated bronchi w. thick walls
- Ring or linear opacities
- Upper OR central region predeliction
- Proximal bronchiectasis
- Lobar collapse due to mucous impaction
- Fibrotic scarring
What is the management of ABPA?
(1) Corticosteroids
(2) Itraconzaole (steroid-sparing agent)
• benefit past-16 weeks is UNCLEAR
• Indicated if NOT responding to steroids or if steroid-dependency
(4) Reduction in circulating IgE, steroid dependecy & improved PFT (pulmonary function test)
(3) Omalizumab
• recombinant IgE monoclonal Abs may be useful
Conclusion 4?
- Variety of pulmonary allergies to fungi exist
• ABPA is the best recognised - Severe asthma w. fungal sensitisation is controversial
- There is evidence for fungal sensitisation in hypersensitivity pneumonitis
- Diagnosis of these is driven by:
• skin tests
• IgE & IgM in clinically relevant populations
