Mucosal Immunity

The description of protective immunity in the lung has been among the harder stories of mucosal immunology to narrate. The challenge is one of how to accurately describe the distinct correlates of protection that should be promoted to ensure defence against any one of the countless pathogens faced as a consequence of a gaseous exchange that involves 2000 exchanges per day of 0·5 l or so of air. Part of the research challenge comes from the diversity of threats contained within that inhaled 1000 l: viruses, bacteria, fungal spores, particulate pollutants, smoke from cigarettes or from burning of biomass fuels.1-3 This has to be coupled to the knowledge that for an exquisitely sensitive and fragile tissue such as the lung, virtually any pathway that has been implicated in host protection, including T helper type 1 (Th1), Th2, Th9 or Th17 immunity, has equally been implicated as a mediator of pathogenic lung damage. Furthermore, there is the potential for pathogenic cytokine‐driven damage from other cell‐types including invariant natural killer T cells, γδ T cells, and type 2 and 3 innate lymphoid cells.2, 4 Uncertainty as to the nuanced calibration needed to promote lung defence versus lung immune pathogenesis necessarily imposes a note of caution in any new respiratory therapeutics or vaccination programmes. Iwanaga and Kolls have recently considered the specific example of Th17 immunity in the lung.1 They describe the evidence for a beneficial role of interleukin‐17 (IL‐17) in contexts such as infection by Mycobacterium tuberculosis, Pseudomonas aeruginosa and Aspergillus fumigatus, and hence, the potential benefits of protocols that seek to promote local immunity of this type. However, the key caveat – a major one – is, as they put it, that ‘lessons from CF [cystic fibrosis], asthma, and COPD [chronic obstructive pulmonary disease] suggest that individuals with epithelial defects due to genetic loss of ion transport or injury due to viral infection or smoking may have adverse effects from such an approach’. Another recent review has focused on the specific case of fungal infections of the lung.2 McDermott and Klein considered evidence from murine and human studies for protective and pathogenic mechanisms in response to fungi including Aspergillus fumigatus, Histoplasma capsulatum, Cryptococcus neoformans, Pneumocystis jiroveci, Blastomyces dermatitidis and Coccidioides species. Key messages that come through are, first, the diversity of different T‐cell programmes activated in these different contexts and second, the potential for immunopathology. The example of allergic bronchopulmonary aspergillosis speaks to the complexities of pulmonary protection. This is a pathology in which damage from inhalation of fungal spores is due, not to the fungal infection itself, but to an allergic pathway that has been associated with Th2, Th1 and Th17 involvement. Contemporary understanding of the pathogenic pathways driven by chemokines and cytokines such as CXCL13 and IL‐17 in chronic diseases including COPD and bronchiectasis is helping to reinterpret classic observations from histopathology, such as the concept of ‘follicular disease’ as a marker of severity.5, 6 We now see the IL‐17‐driven formation of tertiary lymphoid follicles in lung tissue as a programmatic, structural change with potential to both focus local antimicrobial protection7 yet also, enhance local inflammatory or autoimmune disease.5, 6 Some manifestations of lung inflammatory disease may be seen as examples of the autoinflammatory disease spectrum, as recently reviewed by Scambler et al.8 In this context, small molecule and biological therapies such as recombinant IL‐1 receptor antagonists, that can target inflammasome‐driven, innate pathways are likely be of benefit. Interleukin‐8 similarly offers a double‐edged sword to lung defence, both critical for a speedy neutrophilic response to pathogen presence, yet now appreciated to exhort a price of progressive lung remodelling, mucus hyper‐secretion and fibrosis with impacts on lung function and bronchial hyper‐reactivity.9 Another piece that is being slotted into this jigsaw puzzle is the competitive interplay between exogenous pathogens and the lung microbiome. For some time, functional analysis of the lung microbiome had been relatively intractable compared with the gut, due to the much lower biomass present. As more comprehensive lung microbiota analysis has become possible, both in health and in disease, the extent to which infectious and inflammatory disease processes perturb the status quo, often greatly simplifying and contracting the species diversity present, has become clear.10 While there are many unknowns, the good news is that there have never been so many therapeutic biologics on the shelf available for intelligent, hypothesis‐driven resolution of this conundrum of maintaining lung health in the face of a daily onslaught from our environment.

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