Hypersensitivity and Systemic Lupus Erythematosus

Question 1

Define Type I, II, III and IV hypersensitivity

Answer 1

1. Type I: Immediate hypersensitivity / anaphylaxis
   
   • IgE dependent
2. Type II: Cytotoxic reaction
   
   • IgG, IgM dependent
3. Type III: Immune Complex Reaction
   
   • IgG- or IgM-complex dependent
4. Type IV: Cell mediated (Delayed)
   
   • T lymphocyte dependent

Question 2

Define the processes involed in a type I hypersensitivity (anaphylaxis) reaction

Answer 2

• Antigen reacts with IgE expressed on sensitized mast cells
• Antigen binding to cell surface causes cross-linkage of two IgE molecules - triggers mast cell activation
• Interaction causes release of histamine and other inflammatory mediators (mast cell granules)
  
  • heparin
  • serum proteases - tryptase
  • serotonin - promotes platelet activation
  • cytokines - TNFa, chemokines,
  • reactive oxygen species
  • eicosanoids - thromboxane, PAF, leukotrienes, prostaglandin D2 - secondary mediators due to stimulation of the arachadonic acid pathway
• Prior exposure to antigen or hapten necessary for activation of the mast cells
• Granule exocytosis - seconds to minutes
• arachadonic acid pathway - minutes
• Cytokine synthesis and secretion - 2-24 hours

Question 3

List the pathophysiological consequences of a type I hypersensitivity reaction

Answer 3

1. Histamine and leukotriene release
   
   • Vasodilatation and hypovolaemia
   • Increased vascular permeability
2. Vascular leak - leakage of fluid and protein into interstitial space
3. H1 receptors
   
   • bronchospasm and pruritis
   • Endothelial cell production of nitric oxide - further vasodilatation of the vascular smooth muscle
   • Coronary artery vasoconstriction and cardiac depression
4. H2 receptors:
   
   • Systemic and coronary artery vasodilation
   • Myocardial contractility increased
   • Increase gastric acid secretion
5. H3 Receptors:
   
   • Located on pre-synaptic membrane of sympathetic nerves that innervate the heart and vasculature
   • Inhibit the release of endogenous norepinephrine
   • decrease the normal compensatory sympathetic response

Question 4

Describe the pathophysiology of Type II hypersensitivity reactions

Answer 4

• IgG or IgM bind to receptors on cell surface
• Binding causes three potential processes
  
  • Complement activation
  • Cell lysis or phagocytosis
    
    • Opsinisation for phagocytosis
    • Complement mediated lysis
  • Inhibition or activation of downstream signaling pathways
  • Antibody dependent, cell-mediated cytotoxicity
• Examples - myasthenia gravis, transfusion reaction, IMHA

Question 5

Describe the pathophysiological mechanism of a Type III hypersensitivity reaction

Answer 5

• IgG antibodies bind to circulating antibodies
• IgG immune complexes are formed
• Immune complexes lodge in tissues causing inflammation and complement activation
• Neutrophilic lysis or phagocytosis of damaged cells
• Type III reactions tend to be systemic as immune complexes are widely distributed within the body
• Examples: Glomerulonephritis, vasculitis, polyarthritis, systemic lupus

Question 6

Describe the pathogenesis of a Type IV hypersensitivity reaction

Answer 6

• Type IV is a delayed or (T) cell-mediated reaction

1. Sensitisation - contact - skin penetration - uptake by Langerhan’s cell - migrate to lymph node - formation of sensitized T cells
2. Eruption: repeated contact - T cell mediated release of lymphokines and cytokines (eg. TNFa, INFg) -> macrophage activation and inflamation
   
   • Antigen presenting cells (expressing MHC class II) - stimulate CD4+ T cells - release inflammatory cytokines
   • Antigens on somatic cells - CD8+ cells triggered - cell-mediated cytotoxic response

• Examples: Contact allergy / atopy, Guillain-Barre syndrome / idiopathic polyradiculoneuritis, transplant rejection

Question 7

Describe the effectors of SLE

Answer 7

1. Pathogenic antibodies
   
   • broad range of antibodies against cell surface, nuclear and cytoplasmic molecules
2. Immune complexes
   
   • Elevated levels due to increased production or reduced / defective clearance
   • Lodge in blood vessels where there is physiological outflow of fluid (glomerulus, synovia, choroid plexus)
   • Immune complexes trigger complement activation
3. Aute-reactive T cells
   
   • Cytotoxic T-cell mediated damage

Question 8

List potential clinical signs in dogs with SLE

Answer 8

1. Non-erosive polyarthritis
2. Fever - intermittent or persistent
3. Glomerular lesions with proteinuria
   
   • endothelial/mesangial hypertrophy
   • proliferative or membranous glomerulonephritis
4. Dermatological lesions
   
   • erythema, scaling, depigmentation, crusting, alopecia
   • may be worse in sites with poor hair covering (UV triggered)
5. Anaemia / thrombocytopenia
   
   • Most often mild anaemia of chronic disease
   • Severe IMHA and ITP are uncommon (< 15%)
6. Myositis - rare
7. CNS signs - rare or rarely identified alone

Question 9

Define the diagnostic criteria proposed for SLE

Answer 9

• Defined by the presence of two separate manifestations of auto-immunity together with a positive ANA titre
• Three (or more) auto-immune diseases without positive ANA
• Polyarthritis, together with dermatological disease and glomerular disease is most common +/- IMHA, IMT.

Question 10

List and discuss specific tests used to diagnose SLE

Answer 10

• Lupus Erythematosus Cell Test
  
  • Phagocytosed nuclear material within neutrophils
  • Highly specific / suggestive of a diagnosis
  • Poor sensitivity, especially on cytological smears
• Antinuclear Antibodies
  
  • Antibodies directed against various nuclear antigens
  • Cornerstone of SLE diagnosis
  • Many limitations
  • Poor specificity
    
    • ~10% normal animals test positive
    • Chronic inflammatory disease
    • Neoplasia
    • Infectious diseases
  • No universally accepted veterinaryt laboratory protocol
• Auto-antibodies (generally not-available in vet medicine)
  
  • Antibodies to DNA (double-stranded)
  • Extractable nuclear antigens
  • Anti-histone antibodies
  • Anti-phospholipid antibodies (lupus anti-coagulant)