Immunobiology of Steroid-Unresponsive Severe Asthma

Abstract

Asthma is a heterogeneous respiratory disease characterized by airflow obstruction, bronchial hyperresponsiveness and airway inflammation. Approximately 10% of asthma patients suffer from uncontrolled severe asthma (SA). A major difference between patients with SA from those with mild-to-moderate asthma is the resistance to common glucocorticoid treatments. Thus, steroid-unresponsive uncontrolled asthma is a hallmark of SA. An impediment in the development of new therapies for SA is a limited understanding of the range of immune responses and molecular networks that can contribute to the disease process. Typically SA is thought to be characterized by a Th2-low and Th17-high immunophenotype, accompanied by neutrophilic airway inflammation. However, Th2-mediated eosinophilic inflammation, as well as mixed Th1/Th17-mediated inflammation, is also described in SA. Thus, existing studies indicate that the immunophenotype of SA is diverse. This review attempts to summarize the interplay of different immune mediators and related mechanisms that are associated with airway inflammation and the immunobiology of SA.

Tight Junctions, the Epithelial Barrier, and Toll-like Receptor-4 During Lung Injury

“…Several mechanisms may exist for steroid resistance, and these may differ in patients who are non-responsive to corticosteroid treatment [151]. Increased expression of the non-responsive beta isoform of glucocorticoid receptor, activation of p38 MAPK leading to phosphorylation of glucocorticoid receptors and reduced corticosteroid binding affinity within nucleus, excessive activation of the JNK pathway, reduced suppression or no effect of corticosteroid on cytokine release, impaired nuclear localization of glucocorticoid receptors, and defective histone acetylation are some of the plausible reasons for steroid-resistance [163][164][165][166]. One report has also identified that the circadian clock gene disruption corroborates with the loss of efficacy of synthetic dexamethasone [114].…”

Recent insights in the role of biomarkers in severe asthma management

“…Therefore, targeted treatment options, as well as clinically applicable biomarkers, are still largely under exploration ( 92 ). In this context, the clinically relevant issue of whether “true” non-T2 asthma really exists has been raised, as high-dose ICS and oral corticosteroids (OCS) may potentially minimize blood eosinophils and FeNO levels, therefore masking preexisting T2 inflammation ( 93 ).…”

Immune Repertoire and Advancements in Nanotherapeutics for the Impediment of Severe Steroid Resistant Asthma (SSR)

“…Most patients require combinatorial therapy due to the presence of different immune phenotypes. 7 For instance, a study conducted on asthmatic patients by dividing them into different groups like mixed asthmatics (eosinophilic/neutrophilic), paucigranulocytic, neutrophilic with usual FEV1, and neutrophilic with less FEV1 (asthmatics with smoking are included). Macrophage counts were estimated and observed a specific incline in the interferon regulatory factor 5 (IRF5+) levels and decline in the interferon regulatory factor 10 (IRF 10) levels.…”

“…The degree of unresponsiveness towards corticosteroid therapy in asthmatic patients is up to 10%. 7 Corticosteroids can modulate the gene expression of certain genes to minimize the pathophysiology underlying asthma; in certain cases, the prolonged usage of corticosteroids can induce variable gene expression as a result, the asthma patients attain steroid resistance. Side effects arising from corticosteroid therapy worsen the quality of life in asthma patients and cause a higher socio-economic burden for the patients receiving regular therapeutic interventions.…”