Immunity to Fungal Infections

Question 1

What opsonises fungi?

Answer 1

pentaxin-3 and mannos-binding lectin (MBL)

Question 2

What cells are involved in cellular immunity to fungal infections?

Answer 2

• Phagocytes – are the first line of defence
• NK cells – provide early INF-gamma
• Dendritic cells – influence T-cell differentiation
• Th1 and Th17 cells

Question 3

Which fungi produce spores?

Answer 3

• Candida – dimorphism allows tissue invasion
• Cryptococcus – capsule evades phagocytosis
• Aspergillus – inhaled as conidia, invade as hyphae

Question 4

What is toll?

Answer 4

innate PRR (Pattern Recognition Receptor) required for fungal immunity

Question 5

How does dectin 1 lead to fungal infections?

Answer 5

fungal PRR
- deficiency leads to mucocutaneous fungal infections – e.g. vulvovaginitis & onychomycosis -> impaired macrophage IL-6 production and binding in response to fungal infections

Also leads to increased susceptibility to invasive aspergillosis in stem cell transplants

Question 6

How does CARD-9 deficiency lead to fungal infection?

Answer 6

leads to chronic mucocutaneous candidiasis

CARD-9 is required for:

• TNFa production in response to b-glucan stimulation
• T-cell Th17 differentiation

Question 7

What are the consequences of TLR4 polymorphisms?

Answer 7

lead to an increased risk of Invasive Aspergillosis (IA) in transplantation (i.e. haematopoietic stem cell transplants)

Question 8

What are the cellular defences against fungal infections?

Answer 8

Neutrophil are very important in fungal defence:
- Neutrophil NETS – neutrophils throw out chromatin “nets” to capture pathogens
> These chromatin molecules outside the nucleus act as “danger signals” and recruit’s effector cells to the area as well

Fungal morphogenesis – fungi can transition between yeast, candida and hyphae forms (multicellular) and this can drive a modulation of Dendritic cell response and can be bad for the immune response (as it gets confused)

Question 9

What is the innate defence against fungal infections?

Answer 9

Mucosal immunity governs fungal tolerance and resistance

Question 10

What treatment is there for fungal infections?

Answer 10

Adoptive immunotherapy – generate lots of antifungal T-cells in a sample and then give these to the patients that need to fight a fungal infection

Gene therapy – e.g. restore gp91 function (make reactive oxidative species to fight fungal spores) to treat chronic granulomatous disorder. E.g. restore neutrophil NET formation

Question 11

What are the types of hypersensitivity reactions?

Answer 11

T1 – IgE-driven, involves histamine and leukotrienes, in minutes

T2 – IgG-, IgM-driven, involves complement, in 1-24 hours

T3 – IgG-, IgM-driven, involves complement, in 1-24 hours

T4 – T-cell-driven, involves lymphokines, in 2-3 days

Question 12

What are the criteria for diagnosis of allergic bronchopulmonary aspergillosis (APBA)?

Answer 12

• Predisposing condition – asthma or cystic fibrosis
• Obligatory criteria – high baseline serum IgE, +ve T1 hypersensitivity (immediate response) skin test OR Aspergillus-specific IgE
• Supportive criteria (more than 2) – eosinophilia, IgG AB to Aspergillus fumigatus, consistent radiologic abnormalities
• Radiologic abnormalities – also have hyper-dense mucus:
• Dilated bronchi, thick walls - Upper/central predilection - Lobar collapse
• Ring or linear opacities - Proximal bronchiectasis - Fibrotic scarring

Question 13

How is ABPA managed?

Answer 13

• Corticosteroids
• Itraconazole (steroid-sparing agent) – benefit past 16 weeks is unclear however- Indicated if not responding to steroids or if steroid-dependency
• Omalizumab – recombinant IgE monoclonal ABs may be usceful