Pathology

• Hypersensitivity


  An exaggerated or uncontrolled immune response that is harmful to the host

  
• Allergy


  A disorder caused by an immediate hypersensitivity reaction
• Atopy


  A genetic tendency to develop allergic diseases especially due to immediate hypersensitivity reactions

  
• Allergen


  An antigen that triggers an allergic reaction
• Gell & Coombs classification of hypersensitivity

  • Type I (Immediate)
  • Type II
  • Type III
  • Type IV (delayed)
• Type I (Immediate) hypersensitivity

  • Important examples: Hay fever, asthma, food allergies, eczema, anaphylaxis (e.g. due to penicillin)
  • Mediator: IgE
  • Main mechanism(s): Granulocytes release vasoactive mediators
  • Onset (post-exposure): Minutes (< 1 hr)

  
• Type II hypersensitivity


  • Important examples: Blood transfusion reaction
  • Mediator: IgG or IgM
  • Main mechanism(s): Complement or ADCC cytotoxicity (e.g. red blood cells)
  • Onset (post-exposure): May be immediate i.e. few (3-6) hrs (acute conditions)
• Type III hypersensitivity


  • Important examples: Rheumatoid arthritis, systemic lupus erythematosus
  • Mediator: Immune complexes
  • Main mechanism(s): Deposition of complexes inflammatory response
  • Onset (post-exposure): > 12 hrs ( 1 to 3 days)

  
• Type IV (delayed) hypersensitivity


  • Important examples: Contact dermatitis, graft reaction
  • Mediator: T cells
  • Main mechanism(s): Cytokines macrophages or Tc cytotoxicity
  • Onset (post-exposure): > 12 hrs ( 1 to 3 days)

  
• The Gell and Coombs classification is simplistic, which makes it useful, but also imperfect
• The pathogenesis of some conditions may include features that overlap more than one type of hypersensitivity e.g. Asthma (Types I and IV), Rheumatoid Arthritis (Type III and IV)
• Mechanism of Type I Hypersensitivity reaction

  1. Mast cell mediators - release

  2. Mast cell mediators – pre-formed vs. de novo

  3. Mast cell mediators - Effects
• Preformed mediators e.g. histamine are stored in granules and released by degranulation
• Some mediators, including many cytokines, are synthesized de novo following transcriptional activation
• Preformed mediators


  • Histamine – increases vascular permeability, vascular dilation, (bronchial and intestinal) smooth muscle contractility, increased nasal mucus production
  • Proteases: Tissue damage

  
• Newly formed mediators


  • Prostaglandins, leukotrienes: vascular dilation, prolonged smooth muscle contraction
  • Cytokines and chemokines: inflammation (recruitment of leukocytes, esp. neutrophils and eosinophils), neutrophils and eosinophils release proteases that cause further tissue damage
• Patterns of allergy


  • Atopic march: Atopic eczema infant, Food allergy toddler, Allergic rhinitis and asthma school
  • Allergies may occur in isolation (e.g. penicillin but not other allergies)
  • Allergies may improve over time
  • Route of entry of allergen determines type of allergic reaction: Bloodstream anaphylaxis, ingestion food allergy, Skin atopic eczema, respiratory allergic rhinitis

  
• Hay Fever


  1. Inhalation of allergens (proteins found in pollen, cat dander, house dust mite) leads to production of allergen-specific IgE antibodies

  2. IgE antibodies bind to mast cells in nasal mucosa

  3. Repeated exposure to allergen cross-link IgE and activate mast cells

  4. Activated Mast cells release histamine etc acute symptoms (e.g. nasal congestion, rhinorrhea, sneezing etc)

  5. Cytokines and other mediators late-phase reactions that may lead to more prolonged (chronic) inflammation

  
• Asthma (acute phase)


  1. Inhaled allergens (undefined) activate bronchial mast cells in the lower airways

  2. Mediators e.g. leukotrienes are rapidly released by the activated mast cells which cause transient bronchial smooth muscle constriction and secretion of fluid into the airways

  3. This leads to airway obstruction, trapping of air in the lungs and wheezing

  4. In severe cases, this is life-threatening and requires emergency treatment
• Asthma (chronic phase)


  1. Repeated exposures to the allergen(s) results in the accumulation of eosinophils and other lymphocytes in the airways, leading to chronic inflammation and excessive mucus secretion

  2. Eventually the airways become hyperreactive and remodelled: Hyperplasia + hypertrophy of bronchial smooth muscles + fibrosis leading to thickened airway walls = permanent narrowing of the airways

  3. The airways become hyper-reactive (even to non-immunological stimuli) e.g. viruses and cigarette smoke
• Food allergies


  May be IgE-mediated e.g. peanut allergy (common), Symptoms: swelling of lips, cramping, nausea, vomiting, If they reach the bloodstream, can cause urticaria, asthma and anaphylaxis, Anaphylaxis is most likely with peanuts, shell-fish, Issue in schools and food outlets, Must be differentiated from intolerance (e.g. to lactose)
• Peanut allergy


  • The allergen found in peanuts is a protein ara h2 which is stable and is not destroyed by cooking and gastric acid, One of the most common causes of severe allergy and death, Even minute quantities can cause anaphylaxis
• Non IgE-mediated food allergies

  E.g. Coeliac disease, Due to immune response to gluten, Gluten is a complex of proteins found in wheat, oat and barley, Leads to chronic inflammation (cellular infiltration) of intestines, Villous atrophy malabsorption and diarrhoea, Has autoimmune component, Auto-antibodies to transglutaminase
• Eczema (atopic dermatitis)


  Complex condition with an (alleged) allergic component, Association with other atopic conditions (e.g. asthma and hay fever) – atopic march, May be exacerbated by certain foods in some cases, Multiplicity of mechanisms: epidermal barrier dysfunction, genetic factors, Th2 cell-skewed immune dysregulation, altered skin microbiome, environmental triggers of inflammation

  
• Epidermal barrier dysfunction in eczema

  Skin barrier dysfunction skin inflammation ("outside-in" hypothesis), Immune dysregulation skin inflammation skin barrier dysfunction ("inside-out" hypothesis)

  
• Atopic dermatitis: pathogenesis


  1. Antigen-presenting cells in the skin express pattern recognition receptors (PRR)

  2. PRR are stimulated by tissue damage or microorganisms

  3. This leads to the release of a wide range of danger signals (alarmins)

  4. Alarmins stimulate an inflammatory response including Th2 cells

  5. Th2 cells release cytokines that promote inflammation and IgE release

  6. Symptoms: dry skin and severe pruritis

  
• Penicillin allergy


  Penicillin is a small molecule and a hapten, A hapten and host protein (carrier) are not immunogenic individually, but a conjugate of both (hapten + carrier) is immunogenic, The beta-lactam ring in penicillin (hapten) binds with host proteins (carrier), The penicillin-modified host proteins are then recognised as foreign
• Penicillin allergy (cont)


  1. In some individuals, the penicillin-modified host proteins induces production of IgE antibodies

  2. Penicillin-modified proteins can then cross-link IgE on mast cells leading to degranulation

  3. If the degranulation is widespread, it can lead to a severe reaction, including anaphylaxis

  
• Anaphylaxis


  Most severe form of immediate hypersensitivity = medical emergency, Most common causes: peanuts, shellfish, penicillin, bee stings, The reaction is systemic (due to widespread mast cell degranulation), Main features: Myocardial effects incl. arrhythmias & ventricular function, Massive fluid shift, due to increased vascular permeability, Tissue (including pulmonary) edema, Laryngeal edema may cause asphyxiation, Hypotension, Severe bronchospasm and mucus plugging
• Penicillin-modified host proteins


  Recognized as foreign
• Penicillin allergy


  1. Penicillin-modified host proteins induce production of IgE antibodies

  2. Penicillin-modified proteins cross-link IgE on mast cells

  3. Widespread degranulation leads to severe reaction, including anaphylaxis
• Anaphylaxis


  • Most severe form of immediate hypersensitivity
  • Medical emergency
  • Most common causes: peanuts, shellfish, penicillin, bee stings
  • Systemic reaction due to widespread mast cell degranulation
  • Myocardial effects, massive fluid shift, tissue edema, laryngeal edema, hypotension, severe bronchospasm

  
• Anaphylaxis - emergency treatment


  1. Remove cause

  2. Administer epinephrine

  3. Provide oxygen

  4. Secure airway

  5. Give IV fluids

  6. Place in supine position with legs elevated
• Diagnostic tests for allergies

  1. Take careful history

  2. In vitro tests (blood test for allergen-specific IgE)

  3. Skin tests

  
• Skin tests for allergies

  • Introduce small amount of suspected allergen into skin
  • Positive test indicates mast cell sensitization and potential reaction upon exposure

  
• Wheal and flare reaction

  Visible and transient skin reaction indicating positive skin test

  
• Drugs to treat allergies

  • Anti-histamines
  • Anticholinergic drugs
  • Inhaled bronchodilators
  • Steroids
  • Monoclonal anti-IgE antibodies
• These drugs dampen inflammation and/or reduce symptoms, but are not curative. Lifelong or long term therapy is often needed
• Allergen Immunotherapy (desensitization)


  1. Allergen administered gradually in small, increasing doses

  2. Must be done in facility ready to treat anaphylaxis

  3. Repeated dosing induces Treg cells to secrete regulatory cytokines

  4. Cytokines skew antibody response from IgE to IgG

  5. If successful, restores ability to tolerate the allergen and permanently eliminates the allergic response

  
• Type II Hypersensitivity


  • Cells coated with antibodies can be destroyed by complement, opsonisation, or cytotoxic cells