L6 - pathogenesis asthma 1

• what is asthma?

  it is a chronic inflammatory disease of the lung

  affects 300 million people world wide

  250,000 asthma-related deaths
• cells of the immune system act with epithelial cells to cause:

  bronchial hyper-reactivity (BHR)

  mucus overproduction

  airway wall remodelling

  airway narrowing
• asthma is very common and increasing and causes

  repeated episodes of wheezing, shortness of breath and chest tightness
• histologic changes in the asthmatic airway

  Hyperplasia of epithelium (Ep)

  Hypersecretion of mucus (blue)

  Thickening of the basement membrane (BM)

  Increased Smooth muscle (SM) volume - when contracts, significant narrowing of the lumen
• asthma is heterogeneous
• two forms of asthma described

  allergic and non-allergic
• allergic asthma

  most common - 50% adults and most children

  need allergen reactive to IgE to be diagnosed

  skin prick tests for allergen
• non-allergic asthma

  no allergic specific IgE

  more in adults than children
• asthma has a spectrum of phenotypes and diverse pathophysiologies

  • clinical presentation
  • age of onset
  • genetic susceptibility
  • response to environmental factors
  • degree of inflammation/BHR
  • degree of remodelling
  • response to therapy/prognosis
• prevalence of asthma diagnosis in children in UK

  increased a lot over time, currently plateauing due to being better at diagnosing asthma more accurately

  currently estimated over 12% of the population in the UK has been diagnosed with asthma
• what causes asthma?

  host risk factors - genetics

  environmental risk factors - susceptibility and precipitating factors

  the complex interplay between these factors decide development and severity of asthma
• asthma susceptibility loci

  No mutation in one single gene is the cause

  Polygenic disorder

  genes expressed in airway epithelial cells

  genes regulating CD4 T-cell and ILC2 differentiation and function

  genes with other functions
• genes regulating CD4 T-cell and ILC2 differentiation and function

  Transcription factors, cytokines and cytokine receptors important in type 2 responses

  MHC class II (→CD4+ T cells)
• concordance for asthma in monozygotic twins = ~75%

  environmental risk factors are also important
• environmental risk factors - susceptibility

  • indoor allergens
  • outdoor allergens
  • occupational sensitisers
  • tobacco smoke (passive/active)
  • air pollutants
  • respiratory infections
  • parasitic infections
  • socioeconomic status
  • family size
  • diet and drugs
  • obesity
• occupation can be a risk factor
• environmental risk factors - precipitating

  • Air pollutants
  • Tobacco smoke (passive/active)
  • Exercise & hyperventilation
  • Respiratory infections
  • Weather changes
  • Sulphur dioxide
  • Extreme emotional expression
  • Indoor allergens
  • Outdoor allergens
• precipitating environmental risk factors drive the asthma attack
• asthma - a condition of affluent societies?

  industrialisation and urbanisation leads to pollution and exposure to indoor allergen

  The more polluted and western countries, the more likely to develop asthma

  Some don’t fit like costa rica - middle-low income country

  • Humidity, exposure to different environmental allergens

  Difficult disease - multifactorial disorder that will lead to asthma
• the hygiene hypothesis


  Originally proposed in 1989 by David Strachan

  Studied hay fever prevalence in 17,414 British children

  Striking association observed between hay fever and household size

  Hay fever prevalence inversely related to number of children in the household

  the more children, the less likely to have asthma
• Th1 vs Th2 balance

  Th1 - bacterial and viral infections drive Th1 responses

  Th2 - Th2-mediated responses drive IgE and allergy

  Th1 responses inhibit Th2 and Th2 responses inhibit Th1

  more Th1 = no allergy

  more Th2 = allergy develops

  have mutually antagonistic relationship - more TH1, shut down Th2 - lots of infections have more Th1
• Von Mutius’ Westernisation hypothesis

  Significantly more asthma and hay fever in children from West Germany

  Sensitisation to aeroallergens derived from mites, cats and pollen significantly higher in children living westernised lifestyles

  east = poorer, less developed, more pollution, more bronchitis
• Platts-Mills’ Obesity hypothesis

  The indoor lifestyle includes at least three elements relevant to asthma: increased time exposed to indoor allergens, overeating and decreased physical activity

  • Children sit around more
  • More exposure to dust mites in warm, carpeted houses
  • Less physical activity → less deep breathing → increased non-specific bronchial reactivity
• The microflora hypothesis


  Westernised lifestyle → dramatic changes in gut microflora

  • Positive correlation between antibiotic use and risk for asthma/allergy
  • Correlation between altered faecal microbiota composition and atopy
  • Successful suppression of allergy by alterations in diet/probiotics

  Supporting evidence from mice

  • Germ-free mice have various defects in immune response generation
  • Antibiotic treatment can promote Th2 responses
  • Probiotics can reduce airway airway allergic responses
• how does gut flora influence lung immunology?

  Mucosal surfaces are home to 10-100 trillion microbes

  Most inhaled micro-particles stick to mucus in the nasopharynx and upper airways → swallowed → exposed to immune cells in the gut mucosa

  Several mechanisms contribute to maintenance of mucosal tolerance- prevent damaging immune responses
• how does gut flora influence lung immunology cont.

  Microbiota influences mucosal tolerance

  Changes in gut flora → perturbation of normal mucosal tolerance mechanisms → immune hyperreactivity to harmless antigens

  ✓ A ‘balanced’ microbiota helps to maintain mucosal tolerance to allergens, preventing allergy/asthma
• growing up on a farm reduces asthma susceptibility


  Study compared cohorts in Finland and Germany, characterising home dust microbiota (farm/urban)

  Rural farms have a rich home dust microbiota (indoor), shapes lung immunity

  Asthma risk for non-farm home children decreases the more similar their home bacterial microbiota composition is to a farm home

  Alterations in select bacterial species likely responsible for protective effect
• the epithelial barrier hypothesis - circle

  exposure to barrier-damaging agents

  inflammation in epithelium and barrier damage

  colonisation of opportunistic pathogens

  microbial dysbiosis and decreased biodiversity

  translocation of microbiota to subepithelial areas

  immune response to commensals and opportunistic pathogens

  defective barrier healing capacity of epithelium
• evidence for allergic asthma as a Th2-mediated disorder

  • increased numbers CD4+ T-cells producing IL-4 and IL-5
  • eosinophils in respiratory tract fluids and bronchial biopsies
  • serum IgE (IL-4-driven class switching)
  • unsupervised clustering algorithms reveal Th2hi and Th2lo sub-types
• Evidence for asthma as a Th2-mediated disorder: the OVA model of airway inflammation


  sensitisation -> challenge -> asthma-like airway inflammation
• sensitisation

  OVA+alum in mouse
• challenge

  intranasal-aerosolised OVA
• asthma-like airway inflammation

  Eosinophilic inflammation, Th2 cytokines, airway hyperresponsiveness
• Evidence for asthma as a Th2-mediated disorder: the OVA model of airway inflammation

  ✓ Deplete CD4+ T cells → abolishes key features of asthma

  ✓ Adoptive transfer of OVA-specific Th2 cells → asthma

  ✓ Adoptive transfer of Th1 cells or IL-12 administration→ suppresses asthma

  ✓ IL-4, IL-5 or IL-13 deficient mice have substantially fewer features of asthma in the OVA model

  ✓ Epigenetic changes in CD4+ T cells which inhibit Th1 cytokine production, but not Th2 cytokines
• Sensitisation to allergens: establishing the immune response underlying asthma


  many clinically relevant allergens are enzymes - directly interfere with physiological systems eg. from Dermatophagoides pteronissinus
• Derp1 and Derp9

  major house dust mite allergens, serine and cysteine protease activity

  cleaves tight junction occludin proteins -> increased epithelial permeability = access to immune cells including dendritic cells - which induce Th2 responses

  cleaves CD23 on B cells -> up-regulation of IgE synthesis
• dendritic cells drive Th2 cell responses

  Dc sample antigens in the airway lumen or leaked through

  DC activated by endogenous and exogenous danger signals

  epithelial cells also activated (allergens, pollutants, irritants) and release cytokines including IL-33, IL-25 and TSLP (thymic stromal lymphopoietin)

  epithelial-derived cytokines drive DC maturation and condition DC to induce type 2 responses

  DC migrate to lymph nodes, present antigen to naive CD4+ T-cells, driving Th2 cell differentiation
• Dendritic cells drive Th2 cell responses during sensitisation and challenge


  mouse models used

  • DC necessary for induction of Th2 responses upon the first encounter to inhaled allergen (sensitisation)
  • Depletion of DC in sensitised mice during allergen-challenge also suppresses many features of asthma
  • DC recruit effector T cells to the site of inflammation in the lung by production of chemokines, forming clusters in airways and blood vessels
• Dendritic cells drive Th2 cell responses during sensitisation and challenge cont.

  • Numbers of activated DC increase in the airways of asthmatics

  • Polymorphisms at HLA-DRB1 and HLA-DQA1 locus associate with asthma

  • Produce chemokines and cytokines that activate other immune cells, e.g. Th2 cells, perpetuating inflammation
• Sensitisation to allergens: establishing the immune response underlying asthma

  1. enzyme Derp1 cleaves occludin in tight junctions and enters mucosa - Derp1 taken up by DC for antigen presentation and Th2 priming
  2. DC primes T-cell in lymph node - Th2 cell induces B-cell switch to IgE production - Th2 cytokines drive class switching to IgE
  3. plasma cell travels back to mucosa and produced Derp1-specific IgE antibodies - IgE binds to FceRI receptor on mast cell
  4. Derp1-specific IgE binds to mast cell; Derp1 triggers mast-cell degranulation - mast-cell granule contents cause allergic symtpoms