Abstract
SummaryBackgroundSubsets of patients with severe asthma remain symptomatic despite prolonged, high‐dose glucocorticoid therapy. We hypothesized that the clinical glucocorticoid sensitivity of these asthmatics is reflected in differences in peripheral blood dendritic cell subsets.ObjectiveTo compare peripheral blood leucocyte populations using flow cytometry at baseline and after 2 weeks of systemic glucocorticoid (steroid) treatment to identify immunological differences between steroid‐sensitive (SS) and steroid‐resistant (SR) asthmatics.MethodsAdult severe asthmatics (SS n = 12; SR n = 23) were assessed for their response to 2 weeks of therapy with oral prednisolone. Peripheral blood was obtained before and after therapy and stained for lymphocyte (CD3, CD19, CD4, CD8 and Foxp3) and dendritic cell markers (Lineage negative [CD3, CD14, CD16, CD19, CD20, CD56], HLA‐DR+, CD304, CD11c, ILT3 and CD86).ResultsA higher median frequency of myeloid DCs (mDCs) but not plasmacytoid DCs (pDCs) was observed in the blood of SR as compared to SS asthmatics (P = .03). Glucocorticoid therapy significantly increased median B cell, but not T cell numbers in both cohorts, with a trend for increased numbers of Foxp3+ Tregs in SS (P = .07), but not SR subjects. Oral prednisolone therapy significantly reduced the median numbers and frequencies of total DCs and pDCs in both SS and SR asthmatics. Interestingly, the expression of HLA‐DR and ILT3 was also reduced on pDCs in all patients. In contrast, therapy increased the median frequency of mDCs in SS, but reduced it in SR asthmatics.ConclusionsMyeloid DC frequency is elevated in SR compared with SS asthmatics, and mDC shows a differential response to oral prednisolone therapy.
Highlights
Asthma is characterized by airway hyperresponsiveness, T cellmediated inflammation, mucus hypersecretion and airway remodelling
The median frequency of CD11c+ myeloid dendritic cells (DCs) (mDCs), within the Lineage-HLA-DR+ gate, was significantly elevated in the peripheral blood of the SR as compared to the SS asthmatics, whereas there was no significant difference in the median frequencies of CD304 plasmacytoid DCs (pDCs) between the 2 patient groups (Figure 2B)
In the SS asthmatics, there was a significant increase in the median frequency (P < .05), which is most likely due to the decreased frequency of pDCs in the Lineage-HLA-DR+ gate
Summary
Asthma is characterized by airway hyperresponsiveness, T cellmediated inflammation, mucus hypersecretion and airway remodelling. Glucocorticoids (steroids) represent the cornerstone of contemporary asthma therapy, improving lung function and asthma symptoms in many patients (steroid sensitive, SS) Beyond these global features of asthma pathophysiology, evidence continues to accumulate about the heterogeneity of the disease in terms of its natural history, the nature and degree of associated airways inflammation and its responsiveness to steroid therapy.[1] it has been evident for some time that there exists a subgroup of asthmatic patients showing no demonstrable clinical benefit, at least in terms of short- to medium-term improvement in lung function, in response to physiologically appropriate systemic steroid therapy (steroid resistant, SR). Several mechanisms have been proposed to contribute to steroid non-responsiveness at the cellular level, in T cells, including overexpression of pro-inflammatory transcriptional regulators such as NFjB and AP-1, increased expression of histone deacetylases, polymorphisms of the IL-10 gene, elevated expression of the dominant negative isoform of the glucocorticoid receptor GRb, overexpression of Th2 cytokines and vitamin D insufficiency.[2,3,4,5,6,7,8,9,10] More recent evidence suggests that IL-17A overexpression can be both a marker and a risk factor for severe and SR asthma.[11,12,13,14,15,16,17]
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