Pathogenesis of asthma (Pt. 2)

• LO:


  • Explain the long term consequences of asthma (immunopathology)
  • Describe the contribution of innate and adaptive immune cells to the spectrum of asthma endotypes, driving type 2 and non-type 2 responses
  • Explain how our understanding of the immune processes underlying asthma immunopathology has informed the development of new therapies for the treatment of asthma
• Chronic asthma: long-term exposure to allergen


  • Long term natural exposure to allergen drives repeated inflammatory episodes → chronic inflammation, serious long term illness.
  • Airways of asthmatics show characteristics of chronic wounding, with evidence of ongoing epithelial injury and repair

  
• Tissue remodelling in the asthmatic airway

  • Hyperplasia of epithelium (Ep)
  • Hypersecretion of mucus (blue) due to goblet cell metaplasia
  • Thickening of the basement membrane (BM) mediated by myofibroblasts
  • Increased Smooth muscle (SM) volume
  • Increased angiogenesis and lymphangiogenesis

  
• Type 2 cytokines in the pathogenesis of asthma


  • Act on innate and adaptive immune cells

  • Act on non-immune cells, driving many salient features of asthma

  • Involved in tissue remodelling

  
• Cycle of inflammation in chronic asthma

  
• Asthma increases susceptibility to respiratory virus infection


  • Allergic sensitisation and Th2-driven eosinophilic inflammation may suppress anti-viral immunity

  • Epithelium has ↑ICAM-1 expression → human rhinovirus binds, more viral entry to epithelium

  • Epithelial cells from asthmatic patients produce less type I and type II IFN in response to HRV

  • Normal anti-viral function of DC hampered by IgE, less type I IFN production

  • Th2 and Th17 cells drive eosinophilic/neutrophilic inflammation

  
• Which cells cause non-allergic asthma?

  • Patients with atopic or non-atopic asthma can have high eosinophil counts

  • Blockade of IL-4 and IL-5 receptors in these groups → improved clinical outcome

  • Rag-deficient mice challenged with aeroallergen → airway eosinophilia

  Implies there are ways of generating Th2-type cytokines and eosinophilia without the adaptive immune system
• Innate Lymphoid Cells (ILC)


  • ILC initially defined as non-T, non-B effector cells- lymphoid lineage

  • No TCR → no antigens-pecific responses

  • ILC and corresponding Th subsets coordinate the three major types of immune response

  
• Type 2 Innate lymphoid cells (ILC2)


  • Initially described in gut of mice infected with helminths, contribute to tissue eosinophila and mucus production → worm expulsion

  • Develop from common lymphoid precursors in response to IL-7 and IL-33

  • Resemble Th2 cells in many ways (despite lack of TCR), produce type 2 cytokines

  • Dependent on the transcription factor GATA-3

  
• ILC2 in non-allergic asthma


  • Activated and expand in response epithelialderived cytokines produced in response to injury

  • Produce IL-5 → promotes release of eosinophils from bone marrow

  • Produce IL-13 → drives bronchial hyperreactivity, goblet cell metaplasia • Precise signals recruiting ILC2 to lung unknown

  • Some overlap with Th2 cells suggested (use of CCR4 and CCR8)

  
• ILC2 can also contribute to allergic asthma

  • Allergens stimulate epithelial cells → IL-33

  • IL-33 activates ILC2 → IL-5 and IL-13 → eosinophila and bronchial hyperreactivity

  • ILC2 can be activated very quickly in response to allergen exposure, independent of T cells

  
• ILC2 in allergic asthma (Pt. 1)


  • Relative contribution of Th2 cells versus ILC2 unclear, but ILC2 accumulate in sputum following Ag challenge

  • ILC2 provide an early source of IL-13 which aids Th2 polarisation. Help DC to re-stimulate Th2 cells. Potentially act as APC
• ILC2 in allergic asthma (Pt. 2)

  • ILC2 express low levels of MHC II and costimulatory molecules → may act as APC activating CD4+ T cells during sensitisation/effector phases of asthma
  • Many studies investigating ILC2 in asthma rely on RAG-deficient mouse models
  • In RAG-sufficient mice OVA or house dust mite-induced asthma models, ~50% of cells producing Th2 cytokines are ILC2
• A putative role for ILC2 in airway remodelling


  • Results: reduced airway eosinophila, without much effect on airway remodelling

  
• Role of the ILC2 population in asthma

  • ILC2 may be particularly important in a subgroup of patients

  Severe non-allergic asthma, ↑ eosinophil counts in the blood/lungs

  Th2hi signature, despite lack of allergic respons

  These patients are often steroid refractory

  ILC2 production of IL-5 and IL-13 is not suppressed by steroids

  • In these patients, chronic epithelial activation (→ IL-33, TSLP, IL-25) in response to pollutants, irritants etc. may drive ILC2 responses
• Non-type 2 responses: Th17 cells in allergic asthma


  • Some patients show neutrophil-dominated disease

  • Usually late-onset, severe asthma

  • Mixed Th1- and Th17-type cytokine signatures present, not Th2

  • Th17-type cytokine production resistant to steroid inhibition, drives neutrophilic infiltration of the airways

  
• How do Th17-type cytokines contribute to the pathogenesis of asthma?


  ✓IL-17 sometimes protects mice, sometimes exacerbates asthma

  ✓IL-17A or IL-22 can have a protective role upon experimental allergen challenge in both mice and humans

  X Asthma exacerbation in children after exposure to diesel exhaust particles is concomitant with increased IL-17A in the serum

  X IL-17A contributes to tissue remodelling in some experimental models X In mice and humans IL-17 can induce bronchial smooth muscle contraction
• Th1 cells can contribute to the pathogenesis of asthma


  • Airways of asthmatics ↑ IFN-g secreting CD4+ T cells

  • IFN-g levels rise in the serum during severe asthma attacks

  • IFN-g acts with IL-13 → smooth muscle contraction and innate cell activation

  • IFN-g promotes homing of Th2 cells to the lung

  
• Th9 cells in asthma 


  • Th9 numbers in draining lymph nodes/ airways correlate with asthmatic disease

  • IL-9 exacerbates asthma through actions on immune and non-immune system cells

  • IL-9 neutralisation reduces asthma symptoms in OVA-model, reducing airway remodelling in a chronic asthma model

  • ILC2 can also make IL-9, relative contribution unknown

  
• The role of T regulatory cells in asthma (Treg)


  • Treg cells play an important role in maintaining peripheral tolerance

  • CD4+ Treg cells expressing the transcription factor Foxp3 may be important in asthma

  • Foxp3 CNS-1-deficient mice develop strong Th2 responses at mucosal sites due to lack of peripheral Treg differentiation (TGF-b)
• Evidence suggesting a role for Treg in asthma


  Treg numbers

  • Reduced Treg numbers in sputum and blood of severe asthmatics

  • Treg cell numbers in lungs of adults controversial (numbers ↑ or ↓)

  • Treg detected in the airway fluids of paediatric asthmatics

  Treg function

  • Suppressive capacity of Treg in severe asthmatics impaired

  • Treg in asthmatics may be able to regulate Th1 and Th17 but not Th2 type responses
• Frontline treatment strategies for asthma


  Inhaled corticosteroids

  • Suppress Th2 responses

  • Not effective during viral-induced exacerbation, smokers, nor for Th17dominated asthma endotypes

  Inhaled b2-adrenoceptor agonists

  • Short-acting e.g. salbutamol, for disease management

  • bronchodilator, induces smoothmuscle relaxation

  • Long-acting e.g. formoterol, bronchodilation for ~12 hours, used for asthma endotypes not controlled well by corticosteroids

  • May improve responsiveness to corticosteroids ‘combination inhaler’
• IgE as a therapeutic target in allergic asthma 


  • Omalizumab, humanised anti-IgE monoclonal antibody

  • Licenced for treatment of moderate to severe allergic asthma

  • Prolonged treatment → reduced Th2 cytokines in lung tissue

  
• Targeting Th2-type cytokines: anti-IL-4Ra


  • Dupilumab, human anti-IL-4Ra antibody

  • Blocks downstream signalling via receptors for IL-4 and IL-13

  • Improves lung function

  • Reduces frequency of exacerbation in patients with moderate/severe asthma with high blood eosinophil levels

  • Licenced for severe asthma with type 2 inflammation

  
• IL-5 inhibition: blocking eosinophils in asthma


  • Mepolizumab, humanised monoclonal anti-IL-5

  • Licenced for severe eosinophilic asthma

  ✓ Reduces eosinophils numbers in blood

  ✓ Reduces frequency of exacerbations

  ✓ Reduction of ECM components

  ✓ Reduce the use of systemic steroids

  • Benralizumab, an anti-IL-5R antibody, depletes eosinophils for months after a single injection by ADCC. Licenced for severe eosinophilc asthma
• Blocking IL-13 in asthma


  • IL-13 involved in several aspects of asthma e.g. mucous secretion, airway remodelling

  • Lebrikizumab, humanised anti-IL-13 antibody

  • 2 identical Phase III trials for severe asthma in 2016

  • In successful trial, asthmatics with high blood eosinophil levels or high periostin levels (biomarker for IL-13-mediated airway inflammation) experienced:

  ✓ Significant reduction of asthma exacerbation

  ✓ Significant improvement in lung function

  • BUT may not be sufficient to provide clinically meaningful improvements in reducing asthma exacerbations
• Blocking IL-17 signalling in asthma


  • Brodalumab, human monoclonal anti-IL-17RA antibody

  • Blocks the activity of IL-17A, IL-17F and IL-25

  • Didn’t control mild/moderate asthma in phase II trial

  • Sub-groups of patients (high neutrophil counts) might respond more favourably
• Targeting epithelial cell derived cytokines: thymic stromal lymphopoietin (TSLP)


  • Epithelial cells produce cytokines like TSLP which help to promote Th2 responses, acting via DC

  • TSLP also contributes to airway remodelling

  • Tezepelumab = human anti-TSLP antibody ✓Blocks late asthmatic response and bronchochonstriction ✓Reduces eosinophil counts

  • Trials underway investigating targeting IL-33

  
• Asthma is a spectrum of conditions


  • Asthma is a complex condition

  • There may be significant overlap in cells/cytokine profiles involved in asthma endotypes

  • No single drug likely to be effective for all

  • Understanding the underlying immunology → targeted therapy
• Precision medicine and phenotypes, endotypes, genotypes, regiotypes, and theratypes of allergic diseases

  
• Summary


  • Chronic asthma: consequence of long-term inflammation

  • Leads to tissue remodelling, permanent narrowing of the airways

  • Immune cells and epithelial cells secrete cytokines/growth factors which drive tissue remodelling

  • Chronic asthma: consequence of long-term inflammation

  • Leads to tissue remodelling, permanent narrowing of the airways

  • Immune cells and epithelial cells secrete cytokines/growth factors which drive tissue remodelling