Fungal Immunity

Question 1

What are fungi opsonised by?

Answer 1

• Pentraxin-3

&

• Mannose-binding lectin (MBL)

Question 2

What cells are involved in cellular immunity to fungal infection?

Answer 2

Phagocytes
• critical 1st-line defence

NK Cells
• provide early INF-gamma

Dendritic cells
• influence T-cell differentiation

Th1 & Th17 cells

Question 3

Explain the virulence of fungal spores

Answer 3

1. Candida
   • dimorphism allows tissue invasion
2. Cryptococcus
   • capsule evades phagocytosis
3. Aspergillus
   • inhaled as conidia
   • invade as hyphae

Question 4

What is required for fungal immunity in flies?

Answer 4

Toll

It is an innate PRR (Pattern Recognition Receptor)

Question 5

3 human deficiencies that can lead to fungal infections?

Answer 5

(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

Question 6

Explain how Dectin 1 deficiency leads to fungal infection

Answer 6

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

Question 7

Explain how CARD-9 deficiency leads to fungal infection

Answer 7

Leads to CHRONIC MUCOCUTANEOUS CANDIDIASIS

CARD-9 is required for:
• TNFa production in response to Beta-glucan stimulation
• T-cell Th17 differentiation

Question 8

Explain how TLR4 polymorphisms leads to fungal infections

Answer 8

Increases risk of INVASIVE ASPERGILLOSIS (IA)

• in transplantations (i.e. haematopoietic SC. transpl.)

Question 9

What has been found in relation to SNPs to fungal infections?

Answer 9

Many major SNPs associated with increased susceptibility to invasive fungal infections & disease
• e.g. IL1-2, TLR-2/4/6/9

Question 10

What effect does plasminogen have on fungal infections?

Answer 10

Plasminogen DIRECTLY BINDS to Aspergillus

• so mutations increases susceptibility to aspergillus in S.C transpl.

Question 11

What is Conclusion 1?

Answer 11

1. Wide range of PRR are implicated in fungal immunity

2. Mutations in Dectin-1, TLR4 & plasminogen confer increased susceptibility to fungal disease

Question 12

What cellular defences are in place against fungal infection?

Answer 12

(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

Question 13

What innate defences are in place against fungal infections?

Answer 13

Mucosal immunity

• governs fungal TOLERANCE & RESISTANCE

Question 14

What treatments are in place against fungal infections?

Answer 14

(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

Question 15

Conclusion 2?

Answer 15

1. BOTH macrophages & neutrophils contribute to fungal immunity
   • HOWEVER, for Aspergillus, neutrophils are of 1o importance
2. Dendritic cells modulative adaptive I.R
3. Adaptive T-cell INF-gamma responses augment host immunity to fungi
4. New treatments
   • INF-gamma OR adoptive T-cell therapy
   • Gene therapy for 1o immunodeficiences

Question 16

What conclusions can be made about fungal allergies?

Answer 16

1. Many fungal SPORES are INHALED daily
2. The host response may be NORMAL, INEFFECTIVE or EXAGGERATED (allergic response)
   • leads to either an allergic OR invasive fungal disease
3. Aspergillus is a 1o driver (other fungi may contribute)
   • Aspergilli - Aspergillus niger, Aspergillus fumigatus
   • Other supporting fungi inc. Pencillium, Cladosporium etc.
4. 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

Question 17

ABPA?

Answer 17

Allergic Bronchopulmonary Apergillosis

Question 18

What is the criteria for diagnosis of ABPA?

Answer 18

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

Question 19

What are radiologic abnormalities of ABPA?

Answer 19

• Dilated bronchi w. thick walls
• Ring or linear opacities
• Upper OR central region predeliction
• Proximal bronchiectasis
• Lobar collapse due to mucous impaction
• Fibrotic scarring

Question 20

What is the management of ABPA?

Answer 20

(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

Question 21

Conclusion 4?

Answer 21

1. Variety of pulmonary allergies to fungi exist
   • ABPA is the best recognised
2. Severe asthma w. fungal sensitisation is controversial
3. There is evidence for fungal sensitisation in hypersensitivity pneumonitis
4. Diagnosis of these is driven by:
   • skin tests
   • IgE & IgM in clinically relevant populations