Autoinflammatory disease in the lung

Abstract

Ascertaining the dominant cell type driving an immunological disease is essential to understanding the causal pathology and, therefore, selecting or developing an effective treatment. Classifying immunological diseases in this way has led to successful treatment regimens for many monogenic diseases; however, when the dominant cell type is unclear and there is no obvious causal genetic mutation, then identifying the correct disease classification and appropriate therapy can be challenging. In this review we focus on pulmonary immunological diseases where an innate immune signature has been identified as a predominant aspect of the immunopathology. We describe the molecular pathology of 'autoinflammatory diseases of the lung' and propose that small molecule and biological therapies, including recombinant interleukin-1 receptor antagonist, that target key innate immune pathways, are likely be beneficial in the control of pulmonary and systemic inflammation in these conditions. In addition, the successful use of macrolide antibiotics to treat lung infections in these conditions further confirms that the innate immune system is the key conductor of inflammation in these pulmonary diseases, as there is a strong body of evidence that macrolides are able to modulate the NLRP3 inflammasome and interleukin-1β and interleukin-18 secretion, both of which are central players in the innate immune response. Throughout this review we highlight the published evidence of autoinflammatory disease in chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis and rheumatoid lung disease and suggest that the fundamental pathology of these diseases places them towards the autoinflammatory pole of the immunological disease continuum.

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

“…Monocytes from patients with CF showed increased production of IL-1β and IL-18, which was associated with higher activity of caspase-1 and raised extracellular ASCs [28]; interestingly, inhibition of ENaC decreased the exacerbated secretion IL-1β and IL-18 only in monocytes with CF mutations, while this inhibitory effect was not seen in monocytes from patients with other inflammatory conditions [28]. Furthermore, the increased levels of IL-1β and IL-18 were also detected in the sera of patients with CF [28], indicating an essential role of these two cytokines in the pathogenesis of this disease, further supporting the autoinflammatory phenotype seen in patients with CF [31,175,176]. Moreover, the CFTR modulators Ivacaftor/Lumacaftor and Ivacaftor/Tezacaftor showed a powerful anti-inflammatory effect in patients with CF, reducing the levels of IL-18, and both IL-1β and IL-18, correspondingly, in monocytes and serum of patients with CF [177].…”

Immune dysregulation increases the incidence of delayed‐type drug hypersensitivity reactions

“…Similarly, when patients with cystic fibrosis were compared to the general population, antibiotic reactions were found to be up to three times more common . The cystic fibrosis lung represents an area of chronic inflammation with high neutrophil numbers alongside elevated levels of cytokines such as IL‐8, IL‐1β, IL‐6, IL‐17 and TNF‐α . Obviously, this will have a colossal impact on the outcome of T‐cell receptor triggering through altered antigen presentation as well as differential polarization of the effector T‐cell response.…”

Neoantigens in Chronic Obstructive Pulmonary Disease and Lung Cancer: A Point of View

“…The idea that cancer has pre‐stages is widely accepted (for reviews see refs. ). The same might hold for COPD and as the risk of lung cancer is eight times higher in COPD patients one may assume that in a part of the COPD patients COPD is a pre‐stage of lung cancer.…”