Pathogenesis of asthma Part 1

• LO: 


  • Outline the key features of asthma
  • Categorise different risk factors for asthma
  • Compare hypotheses explaining changes is asthma prevalence
  • Describe different stages of allergic asthma and explain the underlying immune response characteristic of each
• Asthma


  • Chronic inflammatory disease of the lung
  • Affects 300 million people world-wide (extra 100 million by 2025?) 250,000 asthma-related deaths annually
  • Cells of the immune system act with epithelial cells to cause:

  1. B ronchial hyper-reactivity (BHR)
  2. Mucus overproduction
  3. Airway wall remodelling
  4. Airway narrowing

  • 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

  
• Asthma is a heterogeneous, complex condition


  • Traditionally, two forms of asthma described, allergic and non-allergic • Clinicians now accept that asthma has a spectrum of phenotypes and diverse pathophysiologies. These vary in terms of:

  Clinical presentation

  1. Age of onset
  2. Genetic susceptibility
  3. Response to environmental factors
  4. Degree of inflammation/BHR
  5. Degree of remodelling
  6. Response to therapy / Prognosis

  
• Prevalence of asthma diagnosis in children in the UK


  • Asthma prevalence has increased over time

  • Diagnosis of asthma is now plateauing

  • Currently, estimated that over 12% of the population in the UK has been diagnosed with asthma

  
• Asthma cause factors


  • Host risk factors - genetics (asthma heritability rate 35-95%)

  • Environmental risk factors

  Susceptibility factors

  Precipitating factors

  Complex interplay between these factors decide development and severity of asthma
• Asthma susceptibility loci

  
• 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
• 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
• Asthma: a condition of affluent societies?


  (industrialisation + urbanisation → pollution + exposure to indoor allergens)

  Large-scale international collaboration, 1998

  • 463,801 children studied
  • 56 different countries
  • UK highest prevalence

  
• 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
• Th1 versus Th2 balance

  
• Von Mutius’ Westernisation hypothesis


  • Proposed by allergist Erika von Mutius in 1994
  • Studied asthma and allergy in children in East and West Germany → impact of environmental factors on ethnically similar group of children
  • |Significantly more asthma and hay fever in children from West Germany

  
• 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

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

  • Supporting evidence from mice

  1. Germ-free mice have various defects in immune response generation
  2. 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
  • 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
  • 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

  • May be modifiable?

  
• The epithelial barrier hypothesis

  
• The immune response in allergic asthma sensitisation, acute, late and chronic immune responses in asthma
• Evidence for allergic asthma as a Th2-mediated disorder

  
• 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, e.g. from Dermatophagoides pteronissinus

  1. Derp1 and Derp9 = major house dust mite allergens, serine and cysteine protease activity
  2. Cleaves tight junction occludin proteins → increased epithelial permeability = access to immune cells including dendritic cells which induce Th2 responses
  3. Cleaves CD23 (FcεRII) 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) → release cytokines including: IL-33, IL-25 and TSLP

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

  • DC migrate to lymph nodes, present antigen to naïve CD4+ T cells, driving Th2 cell differentiation

  
• Dendritic cells drive Th2 cell responses during sensitisation and challenge (Pt. 1)


  • Mouse models show DC are 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 the production of chemokines, forming clusters in airways and blood vessels
• Dendritic cells drive Th2 cell responses during sensitisation and challenge (Pt. 2)


  • 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

  
• Sensitisation to allergens: establishing the immune response underlying asthma


  • Maintained in the airway sub-mucosa by IL-9

  • Rapidly activated by allergen cross-linking of IgE at the cell surface (bound to FcεR1)

  • Low levels of antigen can trigger degranulation = release of pre-formed inflammatory mediators

  • Histamine acts directly on blood vessels → increased blood flow and vascular permeability

  • Histamine acts directly on blood vessels → increased blood flow and vascular permeability

  
• Mast cells cause acute responses in asthma following allergen exposure

  
• Induction of the late phase reaction in asthma


  • Dependent on allergen dose
  • Continued synthesis of inflammatory mediators by mast cells perpetuates inflammation in the lung, e.g.

  1. Vascular endothelial growth factor (VEGF) causes vasodilation and vascular leakage → oedema
  2. Cytokines and chemokines secreted by mast cells (and others) activate and recruit other immune cells

  • Late phase reactions are characterised by influx of eosinophils and Th2 cell
• Eosinophil recruitment in asthma


  • Ordinarily, only very small numbers of eosinophils found in the circulation (eosinophils are dangerous!)

  • Eosinophils accumulate in asthmatic airways

  • Th2 cells produce IL-5 → eosinophil production and release from the bone marrow, to the circulation

  • IL-4 and IL-13 act on endothelial cells and fibroblasts → eotaxin secretion

  • Eotaxins recruit eosinophils from the blood to sites of inflammation: CCL11, CCL24 and CCL26 (bind to CCR3)

  • CCR3 is also expressed by Th2 cells- also attracted by eotaxins
• Recruitment of Th2 cells and eosinophils


  • Histamine and leukotrienes released by mast cells during the acute response increase expression of P-selectin and E-selectin on endothelium

  • These initiate leukocyte rolling

  • IL-13 induces ↑ ICAM1 and VCAM1 expression on airway endothelium

  • These interact with integrin receptors on leukocytes, arresting their movement

  • Diapedesis in to inflamed lung tissue

  
• Eosinophils in the pathogenesis of asthma


  • Granules contain highly toxic proteins and free radicals → significant tissue damage

  • Eosinophil cationic protein, platelet activating factor and leukotrienes → late phase bronchoconstriction

  • Eosinophil derived cytokines amplify increased eosinophil production in bone marrow, promote Th2 cell driven inflammation

  • Chemokines e.g. CXCL8 recruit more immune cells, drives further inflammation

  • Eosinophil extracellular traps contribute to airway inflammation
• Eosinophils in the pathogenesis of asthma


  • Major basic protein = the major constituent in core of eosinophil granule

  • Potent toxin for helminths, also toxic to host cells

  • Causes mast cell and basophil degranulation

  • Causes epithelial damage, opening of tight junctions, ↑ vascular permeability, oedema, ↑ mucus production

  • Major basic protein → more antigen access, perpetuating inflammatory responses to allergen

  
• Th2 derived cytokines are key in pathology of allergic asthma

  
• Epithelial cytokines also play important role

  
• Summary


  • Asthma is a chronic inflammatory disease of the lung
  • Heterogeneous and complex condition- genes and environment contribute to development
  • Asthma is prevalent in developed/westernised countries
  • Several hypotheses proposed to explain this
  • Allergic asthma = type 2 immunity, involving Th2 cells, IgE-secreting B cells and eosinophils (amongst others)
  • The immune response in asthma:

  Sensitisation

  Acute/immediate response

  Late phase response
• Immediate and late phase reactions in asthma