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.

Keywords: COPD; autoimmunity; bronchiectasis; cystic fibrosis; inflammation; panbronchiolitis.

Figure 1

Non‐resolving cycle of autoinflammation in the lung and its related diseases. Chronic inflammation of the lungs results from the accumulation of a number of different factors, ranging from environmental insults (cigarette smoke, viral, bacterial, air pollution etc) to genetic predisposition; these cycles feed into each other resulting in innate immune driven autoinflammation, and ultimately results in chronic inflammation of the lungs, without resolution. A number of innate immune cells, such as neutrophils, monocytes and epithelial cells of the bronchi, play pivotal roles in the excessive response to stimuli and combine to secrete a range of inflammatory cytokines. DPB, diffuse panbronchiolitis; COPD, chronic obstructive pulmonary disorder; CF, cystic fibrosis; RA, rheumatoid arthritis.

Figure 2

Innate immune frontier. The lung is one of the main organs where the environment comes into direct contact with the innate immune system, termed here as the innate immune frontier. The autoinflammatory lung diseases CF, COPD, panbronchiolitis, bronchiectasis and RA lung disease all have a similar innate immune frontier response, which results in a chronic inflammatory state, with cytokines, such as IL‐18 and TNF, and fever inducing IL‐1β being released in excessive amounts into the lung parenchyma and stroma. Anti‐IL‐1 treatments are effective in reducing this exaggerated response.