Adaptive Immunity to Fungi

Dendritic cells present fungal peptides on major histocompatibility complex class II to CD4 T cells, and cross present on class I to CD8 T cells.

Cytokines released at priming decide the subset that emerges:

• interleukin 12 produces Th1 cells
• interleukin 1 beta, interleukin 6 and interleukin 23 produce Th17 cells
• interleukin 4 produces Th2 cells
• transforming growth factor beta with interleukin 10 produces regulatory T cells

The subsets inhibit each other: interferon gamma suppresses interleukin 17 production, which is relevant to diseases caused by excess interferon signalling.

Fungal control depends on matching the response to the organism and the site. Too little response causes uncontrolled growth, and a wrongly polarised response causes allergy or immunopathology.

Interferon gamma is the central cytokine for control of intracellular and dimorphic fungi. It activates macrophages for oxidative killing, nutrient restriction and phagosome acidification. Tumour necrosis factor and GM-CSF act with interferon gamma, and tumour necrosis factor is needed for granuloma formation and maintenance.

The clinical correlates are consistent. Defects in the interleukin 12 and interferon gamma axis (IL12RB1, IL12B, IFNGR1, IFNGR2), anti interferon gamma autoantibodies, and anti tumour necrosis factor therapy lead to disseminated histoplasmosis, coccidioidomycosis, paracoccidioidomycosis and talaromycosis. Interferon gamma deficient patients fail to contain organisms that survive inside macrophages, and the lesions contain organisms in large numbers.

Gain of function mutations of STAT1 raise interferon signalling and suppress Th17 responses, so they cause chronic mucocutaneous candidiasis, dermatophytosis and disseminated endemic mycoses.

Interleukin 17A, interleukin 17F and interleukin 22 act on epithelial cells and keratinocytes to induce antimicrobial peptides and neutrophil attracting chemokines. This is the principal adaptive defence against Candida at the skin, nails and oropharyngeal mucosa. It also supports neutrophil recruitment in the lung in aspergillosis.

Loss of Th17 immunity produces mucocutaneous candidiasis, not candidaemia. This distinction has diagnostic value: bloodstream candidiasis is a neutrophil and barrier problem, whereas chronic oral, oesophageal, skin and nail candidiasis is a Th17 problem.

• Autosomal dominant hyper IgE syndrome (STAT3 loss of function): impaired Th17 differentiation, with chronic mucocutaneous candidiasis and pulmonary Aspergillus infection in pneumatoceles.
• IL17RA, IL17F and TRAF3IP2 (ACT1) deficiency: isolated chronic mucocutaneous candidiasis.
• AIRE deficiency (autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy): autoantibodies against interleukin 17A, interleukin 17F and interleukin 22.
• Anti interleukin 17 biologics (secukinumab, ixekizumab, brodalumab): mostly mild oral or oesophageal candidiasis.

Th2 responses are not protective against fungi and cause allergic disease in susceptible hosts. Interleukin 4, interleukin 5 and interleukin 13 produce IgE, eosinophilia and mucus hypersecretion.

• Allergic bronchopulmonary aspergillosis: Aspergillus grows in the airway mucus of people with asthma or cystic fibrosis, with a strong Th2 response, raised total and specific IgE, eosinophilia, central bronchiectasis and mucus plugging. Genetic risk includes HLA DR2 and DR5 and CFTR variants.
• Allergic fungal rhinosinusitis: noninvasive fungal colonisation of the sinuses with eosinophilic mucin.
• Severe asthma with fungal sensitisation: IgE sensitisation to fungi, with fungal exposure driving exacerbations.
• Hypersensitivity pneumonitis: a type III and IV response to inhaled spores in settings such as farming and mouldy buildings.

In Cryptococcus infection, a Th2 skewed response with alternatively activated macrophages worsens outcome and permits intracellular growth. Eosinophilic pneumonia with Cryptococcus gattii shows the same pattern.

CD8 T cells contribute interferon gamma and cytotoxicity and partly compensate for CD4 depletion in experimental Pneumocystis infection. Their clinical role is secondary to CD4 cells.

Antibody has a limited and organism specific role.

• Antibodies to glucuronoxylomannan opsonise Cryptococcus. Low IgM memory B cell numbers in HIV and transplantation have been associated with cryptococcosis.
• B cell depletion with rituximab, especially combined with corticosteroids or chemotherapy, is associated with Pneumocystis pneumonia, probably through loss of antigen presentation as well as antibody.
• Antibody responses are weak in immunosuppressed patients, so serological tests have low sensitivity precisely where fungal disease is commonest. This is why antigen detection and molecular testing, not serology, are used in advanced HIV and after transplantation.

A granuloma is an organised collection of activated macrophages, epithelioid cells and multinucleate giant cells with surrounding lymphocytes, held together by interferon gamma and tumour necrosis factor. It contains organisms that cannot be killed. Granuloma formation is characteristic of Histoplasma, Coccidioides, Blastomyces, Paracoccidioides, Sporothrix and Cryptococcus in immunocompetent hosts.

• Granulomas can wall off viable organisms for years, which is the basis of latency and later reactivation under immunosuppression (Histoplasma, Coccidioides, Cryptococcus).
• Caseation and calcification are common in histoplasmosis, with residual calcified nodes and spleen lesions.
• In advanced HIV, granulomas are poorly formed or absent, and macrophages are packed with organisms.
• Fibrosing mediastinitis in histoplasmosis reflects an excessive fibrotic reaction to residual antigen.

Restoration of T cell function can produce disease from a fungal antigen load that was previously tolerated. Two patterns occur:

• Paradoxical immune reconstitution inflammatory syndrome: worsening of a known, treated infection after antiretroviral therapy or reduction of immunosuppression, with negative cultures. It is well described with Cryptococcus, Histoplasma, Pneumocystis and Talaromyces.
• Unmasking: a previously subclinical infection presents with inflammatory features soon after immune recovery.

Cryptococcal meningitis is the classic setting. Starting antiretroviral therapy too early during cryptococcal meningitis increases mortality, so it is delayed for several weeks after antifungal therapy has begun, typically by 4 to 6 weeks.

Immune recovery is also part of therapy. Neutrophil recovery in neutropenic aspergillosis, withdrawal or reduction of corticosteroids in invasive mould infection, and reduction of calcineurin inhibitor dose are as important as antifungal choice. Reduction of immunosuppression for a stem cell recipient with graft versus host disease and fungal infection is balanced against the risk of graft injury.

Delayed type hypersensitivity skin tests (for example spherulin, coccidioidin or histoplasmin) show prior exposure and cellular sensitisation and are not diagnostic of active disease. A positive test means cell mediated immunity has been engaged. Skin test anergy is expected in disseminated infection and in profound T cell depletion, and so indicates a poor prognostic state and not absence of exposure. Antibody tests are most useful in immunocompetent patients with subacute or chronic disease and least reliable in immunocompromised hosts.