I7 Hypersensitivity and Autoimmunity Flashcards Preview

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Flashcards in I7 Hypersensitivity and Autoimmunity Deck (27):

Learning Outcomes (for general perusal)


Be able to:

• Compare/contrast organ specific vs. systemic autoimmunity

• Explain the mechanisms underlying Type I, II, III, and IV hypersensitivity reactions

• List examples of diseases in each category

• Explain the immunopathology, clinical presentation and treatment involved in each type 


What is Hypersensitivity?

What does it result in?

Exaggerated or inappropriate immune responses

Tissue damage, serious disease, death


How can different hypersensitivity reactions be distinguished from each other?

Outline the reactions


Which of these are Humoral Immunity and which are T-cell mediated?


By the type of immune response and differences in the the effector molecules generated in the course of the reaction

  • Type I - IgE mediated reactions
  • Type II - Cytolytic or cytotoxic reactions
  • Type III - Immune Toxic Reactions
  • Type IV - Cell mediated Immunity Reactions

Humoral Immunity = TI, TII, TIII

T-Cell Mediated= TIV


Outline Hypersensitivity Classification (I-IV) with examples of each


TI - IgE-Mediated Hypersensitivity

Systematic anaphylaxis and localised anaphylaxis (hay fever, asthma, hives, food allergies and eczema)

TII - IgG or IgM-Mediated

blood transfusion reactions, erythroblastosis fetalis, autoimmune haemolytic anaemia

TIII - Immune Complex-Mediated Hypersensitivity 

Localised Arthus Reaction, serum sickness, necrotizing vasculitis, glomerulonephritis, rheumatoid arthritis and systematic lupus erythematosus

TIV - Cell-Mediated Hypersensitivity

Contact dermatitis, tubercular lesions, and graft rejection


Type 1 Hypersensitivity

  1. What are the three phases?
  2. Summarise it 
  3. What are the cells involved in the 
    1. Sensitization phase
    2. Activation Phase
    3. Effector Phase

  1. Sensitization Phase, Activation Phase, Effector Phase
  2. Ag induces cross linking of IgE bound to mast cells and basophils with release of vasoactive mediators
    1. B Cell, TH2 Cell, Memory cells, Plasma Cells, Allergen-specific IgE
    2. Sensitized mast cell (with allergen-specific IgE in Fc receptor) + allergen
    3. Mast cell degranulation => HISTAMINE to histamine Rs (H1-H4)
      1. Effectors = smooth muscle cell, small blood vessel, mucous gland, blood platelets, sensory nerve endings, eosinophil


Type 1 Hypersensitivity

  1. ​Where are mast cells found?
  2. What is on their surface?
  3. What is the action of the histamine released?

  1. Throughout connective tissue, especially near blood and lymphatic vessels, skin and mucous membranes (eg. respiratory and GI tract)
  2. Fc receptor for IgE
  3. bind H1-4 receptors, induces contraction of smooth muscle, increased permeability of venules, vasodilation and increased mucous production


Type 1 Hypersensitivity

Systemic Anaphylaxis 

  1. What is it intiated by?
  2. What processes occur?
  3. What are the common human allergens
  4. What is the treatment?

  1. Initiated by an allergen introduced into blood, or absorbed by gut or skin 

  2. Smooth muscle contraction (gut, bladder, bronchiole). Systemic vasodilation (drop in blood pressure). Shock-like, often fatal 

  3. bee/wasp venom, penicillin; seafood, nut 

  4. Epinephrine  


Type 1 Hypersensitivity

Localised Hypersensitivity Reactions (Atopy)

  1. Describe this type of reaction
  2. Give examples
  3. What is the treatment?

  1. Hypersensitivity reaction localised to specific target tissue or organ 

  2. Allergic rhinitis (hay fever), Asthma, Atopic dermatitis 

  3. anti-histimines and anti-leucotrienes 


Type II Hypersensitivity

Antibody-Mediated Cytotoxic Hypersensitivity

  1. What does it involve?
  2. Describe the pathophysiology
  3. What is this reaction mediated by?

  1. Involves antibody-mediated destruction or modulation of host cells 

2. Antibody binds to cell surface antigen and can:

  • activate the complement system to target cell for destruction
  • mediate cell destruction by antibody-dependent cell
  • mediated cytotoxicity (ADCC)
  • alter cell function (promote or inhibit) 

3. IgM and IgG


Type II Hypersensitivity 

​What are the outcomes of 

  1. Complement C1-9 (give examples)


  • Lysis of cell (Cold autoimmune haemolytic anaemia, myasthenia gravis)
  • Complement Activation (warm autoimmune haemolytic anaemia, ITP)
    • C3b attachment
    • Opsonisation
    • Phagocytosis
  • Complement Activation (Goodpasture's Syndrome)
    • Activation of neutrophils
    • Tissue Damage


Type II Hypersensitivity 

​What are the outcomes of 

Functional activities being altered? (give examples)

  • Metabolic stimulation (Grave's disease)
    • Activation/cell secretion
  • Growth stimulation (euthyroid goitre)
  • Blocking of receptor (pernicious anaemia or Addison's disease)
    • or mobility (Infertility)
    • or growth (Myxoedema)


Type III Hypersensitivity (Immune Complex-Mediated Hypersensitivity)

  1. Outline this reaction
  2. What does the magnitude of the reaction depend upon?
  3. Where are the common sites for this reaction?

  1. Ag-Ab complexes deposited in various tissues induce complement activation. An inflammatory response mediated by  massive infiltration of  neutrophils follows and subsequent degranulation. Lytic enzymes from granules cause tissue damage(Classical Complement Pathway)
  2. The amount of immune complexes
  3. blood vessel walls, synovial membrane of joints, glomerular basement membrane


Type IV Hypersensitivity/ Delayed-Type Hypersensitivity (DTH) (Cell-Mediated Hypersensitivity)

  1. What is the Inflammatory response mediated by?
  2. What is it characterised by?
  3. What are the common agents?

  1. TH - T helper cells
  2.  large influx of inflammatory cells esp. macrophages. Delayed: 24-72 hours. Often helpful and plays important role in combating intracellular pathogens and contact antigens. Can cause damage and be pathological.

  3. poison oak, poison ivy, nickel, chromate, rubber 


Autoimmune Disorders

  1. ​What are these?
  2. Give examples of Organ-Specific Autoimmune Disorders
  3. Give examples of Systemic Autoimmune diseases

  1. Complex range of disorders. Inappropriate activation of immune response. Development of auto-antibodies and specific cells against self-protein/DNA/RNA. Spectrum from organ specific to systemic disease – can have devastating consequences.

  2. T1DM, Goodpasture's Syndrome, Multiple Sclerosis, Graves' Disease, Hashimoto's Thyroiditis, Autoimmune Pernicious Anaemia, Autoimmune Addison's Disease, Vitiligo, Myasthenia Gravis

  3. Rheumatoid Arthritis, Scleroderma, Systemic Lupus Erythematosus, Primary Sjogren's Syndrome, Polymyositis


Outline Immune Tolerance

The body establishes tolerance mechanisms to distinguish between self and non-self antigens

•However, self-reactive B and T cells can persist in normal subjects having failed to be eliminated in the bone marrow and thymus respectively at the immature stage (central tolerance).

• Mechanisms of peripheral tolerance to control these cells may also be impaired resulting in autoimmune disease 


Autoimmune Disease Pathogenesis

  1. What is it driven by?
  2. Outline the pathogenesis
  3. What causes activation?

  1. Antigen-driven
  2. Autoreactive lymphocytes are stimulated to proliferate by interaction with autoantigens

  3. Auto-Ag may not have been encountered before

    Auto-Ag may be present in novel form

    Auto-Ag may be at higher concentration

    Auto-Ag may be in an environment that supports

    lymphocyte activation (bystander activation)

    Molecular mimicry 


Grave's Disease

  1. Outline the pathophysiology
  2. What are the symptoms?
  3. What type of HS reaction is this?

  1. – antibodies against hormone receptor
    – activate the receptor causing overproduction of thyroid hormone leading to hyperthyroidism

  2. Weight/appetite/GI changes, deregulated temperature, blood pressure, mood, exophthalmus 

  3. Type II - IgG or IgM-Mediated Hypersensitivity

    1. Anti-TSH receptor = IgG


Myasthenia Gravis

  1. Outline the pathophysiology
  2. What are the symptoms?
  3. What is the genetic component?
  4. What type of HS reaction is this?

  1. Ab acts as an antagonist to Acetylcholine receptor – Blocks binding of ACh to receptor

  2. Severe muscle weakness. Difficulties chewing, swallowing, breathing

  3. genetic component =  HLA-DR3 alleles 

  4. TII - IgG or IgM-Mediated HS. 

    1. Organ-specific


Systemic Lupus Erythematosus

  1. Who does it predominantly effect?
  2. What are the symtoms?
  3. Describe the pathophysiology
  4. What type of HS is this?
  5. What could the triggers be?

  1. Women
  2. Fever, weakness, arthritis, skin rashes, pleurisy, kidney dysfunction, etc. 

  3. •Autoantibodies to DNA, histones, RBCs, platelets, leukocytes and clotting factors form immune complexes

    •Depositions of immune complexes accumulate along walls of small blood vessels leading to type III hypersensitivity reactions

    •Reaction activates complement system, neutrophil recruitment - leads to tissue damage. Inflammation causes local tissue damage which causes cell lysis and release of more antigens e.g. Self DNA, RNA  

  4. TIII HS - Immune Complex Mediated HS

    1. Systemic, Chronic

  5. Environmental (viral), Genetic, Role of innate immune defences (TLRs) 


Multiple Sclerosis (MS)

  1. Describe the pathophysiology
  2. Which cells have a central role?
  3. What are the targets?
  4. Which cells cause damage?
  5. What might the priming stage involve?
  6. How is MS diagnosed?

  1. Cell mediated immune attack in CNS. Destruction of myelin and axons resulting in range of neurological symptoms

  2. Central role proposed for CD4+ helper T cells

    Self antigen = peptides of myelin?

  3. myelin, oligodendrocytes, axons

  4. Numerous cells cause actual damage; prominent role for macrophages, cytotoxic T cells

  5. (viral etiology? Vit D?) 

  6. Dissemination in space and time: White matter lesions visible on MRI, then another MRI 9months later, increased lesion size and number is a positive finding


 Give an effect and an example for each mechanism below

  1. Disruption of cell or tissue barrier
  2. Binding of pathogen to self protein
  3. Molecular Mimicry
  4. Superantigen

  1. Release of sequestered self-antigen; activation of nontolerized cells (Sympathetic Ophthalmia)
  2. Pathogen acts as a carrier to allow anti-self response (Interstitial nephritis, SLE)
  3. Production of cross-reactive antibodies or T-cells (Rheumatic Fever, Diabetes, MS)
  4. Polyclonal activation of autoreactive T cells (Rheumatoid Arthiritis)


Genetic Factors

  1. What are immune genes?
  2. What have studies shown?

  1. Certain genes which in many cases predispose individuals to developing autoimmune disease i.e. raises chance of developing disease 

  2. • Recent genome wide studies in MS showed

    polymorphisms at loci for IL-2R and IL-7R

    IL-23R gene polymorphism associated with Crohn’s disease

    HLA genes have long been associated with autoimmunity... 


Patients with multiple autoimmune diseases 

Where does overlap tend to occur?

Overlaps often occur at each end of the spectrum e.g.:

Organ specific: thyroid autoimmunity/pernicious anaemia

Systemic: Features of rheumatoid arthritis often associate with SLE 


Treatment Strategies for Autoimmune Disease

Outline the main stategies

  • Immunosuppression (inhibit/block)
  • Immunomodulation (alter)
  • Plasmapheresis (clean)
  • IVIg (bind)
  • Protection of target (protect)
  • Autologous stem cell transplantation (replace)
  • In trial: Tolerance induction/T cell vaccination (train/educate) 


Treatment Strategies for Autoimmune Disease

How might it be possible to treat organ-specific symptoms?

  1. Thyrotoxicosis
  2. Pernicious Anaemia
  3. Myasthenia Gravis
  4. Insulin-dependant Diabetes

By metabolic control

  1. Antithyroid Drugs
  2. Injection of vitamin B 12
  3. Cholinesterase Inhibitors
  4. Insulin Administration


What will future treatment of Autoimmune diseases call for?

Need new, safer, more effective strategies – appropriate combination therapy!

REMERGE: Regenerative Medicine Research Groups at QUB 


Explain CNS autoimmune inflammation

  1. Myelin Specific T Helper cells in periphery
  2. Migration of T cells into CNS (Th1, Th17)
  3. Re-activation by APCs
  4. Production of chemokines and other inflammatory mediators
  5. recruitment and activation of other inflammatory cell types (monocytes, macrophages, granulocytes, T and B cells, dendritic cells etc)
  6. Immune mediated destruction of myeline and axons in the CNS