New insights into immunological responses to infection in bronchiectasis

Infection and inflammation drive the pathogenesis of lung injury in bronchiectasis. The “vicious cycle” hypothesis suggests that infection leads to inflammation, which in turn disrupts normal bronchial structure and mucociliary clearance. This stimulates excessive mucus production which fosters bronchial infection causing further airway and parenchymal injury and further amplifying the intensity of inflammation.

Chronic infection with Pseudomonas aeruginosa (PA) occurs in 20–30% of people with bronchiectasis [1] and 50% of adults with cystic fibrosis (CF). A key feature in both CF and bronchiectasis is that, unlike airway infections in individuals without bronchial pathology, infection with P. aeruginosa frequently does not resolve, but persists in a state of chronic infection. Chronic P. aeruginosa infection is associated with increased severity of disease, more frequent exacerbations and increased mortality in both diseases [2]. Some of the mechanisms that allow P. aeruginosa to evade the host immune response and persist in the airways involve alteration of the host immune function. Functional antibodies to P. aeruginosa develop in CF and bronchiectasis in response to P. aeruginosa infection, but rather than clearing the pathogen, they are associated with future P. aeruginosa infection in previously uninfected people with CF, and with persistence of infection in both CF [3] and bronchiectasis [4, 5]. While a defined immune deficiency is an established aetiology of bronchiectasis, it is only identified in a minority of patients (7–8%) using standard agreed immune function tests [6].

Innate immunity has an important role in protection from bacterial pathogens. Bacterial permeability increasing protein (BPI), expressed in neutrophils and secreted in response to bacteria [7], binds to Gram-negative bacteria and disrupts their outer membrane, neutralises endotoxin, and through the C-terminal region opsonises bacteria [8]. BPI is expressed in intestinal epithelial cells, and its expression is enhanced in the gut following disruption of the intestinal mucosa [9]. BPI expression in the gut promotes the intestinal innate immune system, which is constantly exposed to multiple bacteria, to generate an antibacterial inflammatory response only when intestinal damage occurs. Interestingly, a genetic polymorphism of BPI is associated with an increased risk of inflammatory bowel disease (IBD) [10], suggesting that BPI modulates intestinal inflammation.

In CF and bronchiectasis, a neutrophilic-dominated inflammation occurs in the airways, with markers of inflammation associated with increased severity [11]. For example, people with bronchiectasis and rheumatoid arthritis (RA) have elevated autoantibodies compared to people with RA without bronchiectasis [12], and increased severity of both RA and IBD is associated with worse lung function in individuals with associated bronchiectasis [13].

In the CF airways, anti-neutrophil cytoplasmic antibodies against BPI have been demonstrated to develop in individuals colonised with P. aeruginosa [14, 15]. These antibodies are directed against the C-terminus of BPI, and inhibit the opsonisation and phagocytosis of E. coli [16]. Presence of anti-BPI antibodies are associated with persistence of P. aeruginosa and worse lung function in children with cystic fibrosis [14].

In this issue of the European Respiratory Journal, Skopelja-Gardner et al. [17] report their findings evaluating the relationship between anti-BPI autoimmunity and chronic P. aeruginosa infection. The authors show a strong association between anti-BPI antibodies and the presence of anti-P. aeruginosa antibodies (as a marker of current or previous P. aeruginosa infection) in two heterogeneous bronchiectasis cohorts. This relationship is further examined through a retrospective longitudinal study in a single bronchiectasis cohort showing a similar temporal relationship between BPI autoimmunity and a P. aeruginosa humoral response. Although a causal relationship is not proven, given the close, synchronised relationship, the authors hypothesise that the breaking of tolerance to BPI is mediated through an association with chronic P. aeruginosa infection.

A further study by the same group shows that in contrast to the anti-citrullinated protein autoantibodies generated in bronchiectasis patients with RA, the development of anti-BPI autoantibodies may relate to novel cryptic epitope formation [18]. Their research elegantly shows that BPI co-localises to neutrophil extracellular traps in CF patients with anti-neutrophil BPI auto-reactivity mapping to the C-terminal region of BPI without requiring post-translational modification (e.g. citrullination). They have further shown that BPI cleavage is P. aeruginosa elastase dependent, thus presenting a model of P. aeruginosa dependent BPI cleavage resulting in neo-epitope formation, activation of the adaptive immune system and triggering of autoimmunity.

The role of neutrophil extracellular traps in autoimmunity is of increasing interest, with inefficient clearance of micro-organisms contributing to the development of autoantibodies and driving the pathogenesis of systemic lupus erythematosus (SLE) [19]. In CF neutrophils have a pro-survival phenotype with reduced apoptosis and increased neutrophil extracellular trap formation [20]. Neutrophil elastase has likewise been shown to correlate with exacerbations and lung function decline in bronchiectasis [11]. Thus, the inefficient neutrophil predominant immune response seen in bronchiectasis may impair immune tolerance and generate an autoimmune response. This in turn may impair clearance of bacteria, perpetuating the infection–inflammation cycle (figure 1). Further studies, including B-cell cloning, epitope mapping and in vivo modelling, are required to confirm a mechanistic understanding of antibody formation in anti-BPI autoimmunity, but the emerging importance of autoimmunity in chronic lung infection presents potential future novel therapeutic strategies.

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FIGURE 1

Inflammatory pathways promoting persistence of infection. NETs: neutrophil extracellular traps; BPI: bacterial permeability-increasing protein.

There are however some unanswered questions. First, it is unclear to what extent autoimmunity to BPI is driving pathogenesis in bronchiectasis. Secondly, are there further antigens resulting in autoimmunity in bronchiectasis and chronic lung infection that are driving disease progression and susceptibility to infection? Autoimmunity to interferon signaling pathways and cytokines have been well described but their relevance in chronic lung infection is undetermined [21, 22]. Finally, could autoimmunity reversal with B-cell targeted therapy either through pharmacological, immunotherapy or cell-based therapy halt disease progression in bronchiectasis, or would such treatments be deleterious if the function of neutrophils that partially control infection is disturbed? The development of in vivo models would enable testing of these questions. A simpler and targeted approach, however, already in trial would be to target neutrophil elastase directly to reduce neo-epitope formation and autoimmunity triggering. Analysis of autoimmunity therefore may be an important secondary outcome measure in neutrophil-targeted clinical trials.

The primary insult in bronchiectasis, which initiates the “vicious cycle” is, in most cases, unknown. Current research findings suggest that autoimmunity to neutrophil components disturb neutrophil function, allowing persistence of infection. These autoimmune phenomena may develop in response to infection, and result in an inability to overcome infection. There is hence increasing importance of immune phenomena in the aetiology and persistence of infection in bronchiectasis, whilst the complex mechanisms remain to be elucidated.

• Received December 17, 2018.
• Accepted December 17, 2018.

• Copyright ©ERS 2019