Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Innate lymphoid cells and their emerging role in asthma pathogenesis

  Asthma affects roughly one in nine Australians, placing the country among the higher-prevalence regions worldwide. In major centres such as Sydney, Melbourne, and Brisbane, clinicians manage a steady stream of patients whose symptoms are shaped by a complex mix of environmental exposures, allergen sensitivities, and underlying immune patterns. Over the past decade, research into innate immunity has brought a particular family of cells into sharper focus: innate lymphoid cells, or ILCs. These tissue-resident sentinels are now recognised as pivotal early responders that shape the inflammatory landscape of the airways long before adaptive immunity fully engages.

  While T helper 2 (Th2) cells have long dominated discussions of allergic airway disease, ILCs provide the upstream signal that often sets the stage. Their rapid cytokine output, strategic positioning at barrier surfaces, and responsiveness to epithelial alarmins make them attractive candidates for explaining both the onset and the persistence of asthma. Understanding how these cells operate is becoming essential for clinicians and researchers who want to interpret the heterogeneity of asthma phenotypes seen in everyday practice.

  The biology of innate lymphoid cells in airway tissue

  Innate lymphoid cells arise from common lymphoid progenitors but lack the antigen-specific receptors that define T and B cells. They are classified into three principal groups based on transcription factor expression and cytokine profiles. Group 1 ILCs (ILC1s) mirror Th1 cells and produce interferon-gamma, while group 3 ILCs (ILC3s) secrete IL-17 and IL-22 and are more prominent in mucosal barrier defence. Group 2 ILCs (ILC2s) are the subset most closely tied to asthma, expressing GATA3 and releasing IL-4, IL-5, IL-9, and IL-13 in response to alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin.

  In the lung, ILC2s concentrate near the airway epithelium and within peribronchial regions, where they sit in direct contact with the cellular layer that first encounters inhaled substances. Their activation requires no prior sensitisation, which means they can drive inflammation during a first encounter with an allergen or after exposure to irritants that damage the epithelial barrier. This property is especially relevant in Australia, where seasonal thunderstorm asthma events in Melbourne and the grassy surrounds of inland New South Wales can provoke sudden, severe flares in people who have never previously wheezed.

  ILC2-driven type 2 inflammation and airway remodelling

  Once activated, ILC2s amplify the classic type 2 cytokine cascade. IL-5 recruits and sustains eosinophils, which contribute to airway narrowing and tissue injury, while IL-13 drives goblet cell hyperplasia, mucus hypersecretion, and airway smooth muscle hypersensitivity. The downstream effects of these cytokines overlap closely with the histological hallmarks of eosinophilic asthma, a phenotype commonly identified in Australian adults presenting to specialist clinics in Adelaide, Perth, and other metropolitan referral centres.

  Research suggests that ILC2s also influence airway remodelling through their production of amphiregulin and other growth factors. Repeated activation can promote subepithelial fibrosis, smooth muscle thickening, and angiogenesis, all of which are features seen in chronic disease. For patients with severe or treatment-resistant asthma who attend tertiary services such as Sydney's Woolcock Institute or the John Hunter Hospital respiratory unit, these cellular processes may explain why symptoms persist despite high-dose inhaled corticosteroid use.

  Environmental triggers shaping innate responses in Australian settings

  Australian environments present a distinctive catalogue of stimuli that activate innate immune pathways. Rye grass pollen, dominant across the southern states during late spring and early summer, is one of the most potent triggers of seasonal allergic asthma. The 2016 thunderstorm asthma event in Melbourne, which overwhelmed emergency departments and resulted in multiple fatalities, highlighted how massive allergen loads combined with weather changes can rapidly activate airway epithelial cells and, by extension, ILC2s.

  Bushfire smoke presents another challenge, particularly during the intense fire seasons of 2019 to 2020 that blanketed Sydney, Canberra, and surrounding regions in hazardous particulate matter. Fine particulates and combustion-derived compounds disrupt epithelial integrity and increase alarmin release, creating conditions favourable to ILC2 activation. Indoor air quality concerns in newer, well-sealed homes also add complexity, as reduced ventilation can concentrate airborne triggers that continually stimulate innate pathways in susceptible individuals.

  Biomarkers, phenotypes, and clinical relevance

  Distinguishing asthma phenotypes that involve ILC2-driven inflammation from those dominated by other pathways remains a clinical priority. Blood eosinophil counts and fractional exhaled nitric oxide (FeNO) measurements provide indirect indicators of type 2 activity, but emerging biomarker research is exploring ILC2-specific signatures, including circulating ILC2 frequencies and epithelial alarmins in sputum or serum. These tools are gradually being incorporated into research protocols at institutions such as the Hunter Medical Research Institute and the University of Melbourne's allergy research groups.

  Such stratification matters because therapies that dampen ILC2 responses, including monoclonal antibodies targeting IL-5, IL-4 receptor alpha, and thymic stromal lymphopoietin, depend on accurate identification of patients whose disease is driven by these pathways. Australians enrolled in severe asthma registries have helped clarify responder profiles, and ongoing translational work continues to refine which combinations of biomarkers best predict treatment success.

  Therapeutic targeting of the innate lymphoid axis

  The therapeutic landscape for asthma has expanded considerably with agents that interrupt type 2 cytokine signalling, several of which are listed on the Pharmaceutical Benefits Scheme for appropriate patient groups. Anti-IL-5 biologics such as mepolizumab and benralizumab reduce eosinophil burden and indirectly limit ILC2-sustaining signals, while dupilumab blocks IL-4 and IL-13 signalling downstream of both ILC2s and Th2 cells. Newer candidates targeting the alarmin receptors, including anti-IL-33 and anti-TSLP antibodies, are being evaluated in Australian clinical trial sites and may directly suppress ILC2 activation at its source.

  Future strategies may also focus on restoring epithelial resilience, since alarmins are a major input to ILC2 activity. Interventions that support barrier integrity, reduce oxidative stress, or modulate the airway microbiome hold promise as adjunct approaches. As the field matures, the goal is to move beyond symptom suppression toward interventions that modify the upstream drivers of disease.

  In practice, clinicians attending to patients with difficult-to-control asthma can begin by mapping each case against the dominant inflammatory pattern, paying close attention to environmental triggers, eosinophil trends, and biomarker trajectories that suggest innate lymphoid cell involvement. Recognising when innate immunity sits at the centre of disease activity allows earlier escalation to targeted biologic therapy and supports more individualised long-term management.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)