Men and women with severe asthma (SA) have innate differences in immune cells along their airways that could impact on treatment with biologics, a study has shown.
The findings, Science Translational Medicine, highlight the impact of not taking sex into account in studies, the researchers say.
Deep phenotyping revealed sex differences in precursors to different types of innate lymphoid cells (ILCs) at mucosal surfaces, such as the mouth and airways.
“This study emphasizes the need to recognize the phenotypic heterogeneity of ILCs in a clinical setting and highlights that examination of clinical cohorts at a population level, without considering sex-dependent differences, has the potential to mask profound immunological differences,” reported Kyle Mincham, PhD, from Imperial College London, and colleagues.
ILCs are present at mucosal surfaces, where they play a critical role in immunity and maintaining barrier functions. Their dysregulation is implicated in a variety of inflammatory diseases such as asthma.
ILCs originate from a common lymphoid progenitor that give rise to ILC progenitors that exist in the bone marrow and the circulation and in tissues such as those in the lung. ILCPs differentiate into three distinct ILC subsets determined by the cytokines they release: ILC1s, ILC2s, and ILC3s.
However, these are not fixed and display substantial phenotypic and functional heterogeneity and changes in the ILC landscape are therefore important for determining their contributions to disease and adverse outcomes.
To investigate further, researchers used high-parameter, full-spectrum flow cytometry to assess core transcription factors, surface markers, and cytokine profiles coupled with unsupervised cluster analysis to study the extent of ILC heterogeneity in the blood and airways of 19 healthy volunteers and 19 patients with SA.
The team found that conventional strategies based on surface markers such as c-Kit did not fully capture the diversity of these cells.
There was a marked difference in innate lymphoid cells in the patients with asthma depending on their sex, with women having a higher abundance of ILC1s and ILC3s and men having fewer ILC2s compared with the healthy volunteers.
Most patients with severe asthma present with pronounced airway type 2 inflammation, and monoclonal antibody therapies targeting these pathways such as mepolizumab (IL-5) and benralizumab (IL-5Rα), can therefore help.
The researchers therefore examined the impact of anti–IL-5/5Rα therapy and found that it dampened inflammatory cytokine production from innate lymphoid cells in the airways without affecting their abundance.
“Deciphering how biologic therapies attenuate type 2 cytokine production by airway ILC2s will be an important step in understanding the capacity of these treatments to ameliorate eosinophilic inflammation and instigate disease control,” they concluded.
