Hypersensitivity Reactions

Question 1

4 Types

Answer 1

• Type I- Immediate Hypersensitivity - release of mediators from mast cells; depends on production of IgE antibodies against environmental antigens and then these IgE binding mast cells in various tissues (in pre-senzitized people)
• Type II- Antibody-Mediated Other Than IgE - when antibodies other than IgE (mainly IgG and IgM) bind cell or tissue antigen and then damage this cell or tissue or impair their function; may induce ADCC
• Type III- Immune Complex Diseases - antibodies against soluble antigen form antigen-antibody complex that despots in blood of tissues —> injury to that tissue
• Type IV- T-Cell Mediated - direct damage from reaction of T lymphocytes against self antigens in tissues OR exaggerated/persistent reactions to environmental antigens

Question 2

5 Steps of Immediate Hypersensitivity Reaction

Answer 2

• 1- Exposure to allergen
• 2- Antigen activation of Thf and Th2 cells AND stimulation of IgE class switching in B cells
  
  • Only some people elicit the Th2 response to environmental antigens
  • Th2 and Thf release IL-4 and IL-13 to induce isotype switching
• 3- Plasma cells make IgE —> blood
• 4- IgE binds Fc-epsilon-RI on mast cells
  
  • Mast cell now coated in IgE for specific allergen (sensitization)
  • Fc-epsilon-RI has high affinity for IgE
• 5- Upon repeat exposure, allergen activates mast cell (need 2 or more allergens to bind antibodies)—> release mediators via cross linking of bound antibodies and signal paths

Question 3

What happens when mast cells are activated in immediate hypersensitivity reactions?

Answer 3

• Rapid degranulation of vasoactive amines (esp histamine) and proteases —> dilation of blood vessels, inc permeability of vessels and transient smooth muscle contraction + tissue damage
• Enzymatic modification of arachidonic acids —> lipid mediators (prostaglandins for dilation and leukotrienes for prolonged smooth muscle contraction)
• Transcriptional activation of cytokine genes; cytokines later secreted —> inflammation and recruitment of leukocytes (late phase)

Question 4

Time course of immediate hypersensitivity reaction

Answer 4

• Immediate Rxn (w/in minutes)- Vasodilation, congestion, edema, swelling and redness
• Late Phase Rxn (6-24 hours)- Inflammatory infiltrate rich in eosinophils, neutrophils and T cells
  • Mast cells release TNF and IL-4 & chemokine —> recruitment of eosinophils & neutrophils which then liberate proteases —> tissue damage
  • Th2 cells can exacerbate by releasing more cytokines

Question 5

Hay Fever

Answer 5

• inhaled allergens (like protein of ragweed pollen) —> mast cells in nasal mucosa produce histamine and Th2 cells produce IL-13 —> inc mucous production (allergic rhinitis and sinusitis - inflammation of upper airway and sinuses)
• Treatment: antihistamines

Question 6

Bronchial Asthma

Answer 6

• usually respiratory allergen —> bronchial mast cells release leukotrienes —> bronchial constriction and airway obstruction
• If chronic asthma…eosinophils accumulate in bronchial mucosa —> excess mucous secretion here AND bronchial smooth muscle hypertrophy and hyperactive to certain stimuli
• Treatment: cortical steroid to reduce inflammation; leukotriene antagonists to relax bronchial smooth muscle; phosphodiesterase inhibitors to relax bronchial smooth muscle

Question 7

Anaphylaxis

Answer 7

• systemic reaction; edema in numerous tissues (including larynx), fall in BP, broncho-constriction and swelling of epiglottis
• Common inducers = bee stings, ingested penicillin or other abx, nuts or shellfish
• Caused by systemic mast cell degranulation in response to widespread distribution of antigen
• Can be life-threatening
• Treatment: epi; vasoconstriction, inc cardiac output and inhibits bronchial smooth muscle constriction

Question 8

Food Allergies

Answer 8

• ingested allergens —> degranulation and histamine release in intestine —> inc peristalsis —> vomiting and diarrhea
• Treatment de-sensitization (repeated administration of low doses of allergen to alter response away from Th2 or IgE dominance; T cell tolerance)

Question 9

How does antibody deposition lead to tissue damage? (4 ways)

Answer 9

• Inflammation - Fc-mediated recruitment/activation of neutrophils and macrophages AND complement system activation —> ROS and lysosomal enzymes released that damage tissue cells
• Opsonization/phagocytosis - RBCs and platelets can be opsonized and ingested by macrophages —> destroyed
• Abnormal Cellular Response - like preventing hormone form binding receptor (MG- antibody against Ach receptor) OR the antibody itself binds the receptor (Graves- stimulate thyroid secretion)
• ADCC- direct killing of cells coated in antibody

Question 10

Where do type II and type III reactions take place?

Answer 10

II- Antibody-mediated reactions normally deposit in specific tissue; antibody binds specific antigen of the cell or ECM component

III- Immune complex reactions normally deposit in blood vessels of areas w/ high pressure (ex- renal glomeruli and joint synovium); complexes bind Fc receptors of leukocytes in area —> inflammation
- SO… presents as widespread vasculitis, nephritis or arthritis

Question 11

Treatment for type II and type III reactions (5)

Answer 11

• Limit inflammation w/ corticosteroids
• Plasmaphoresis to dec levels of circulating antibodies or immune complexes
• IVIG
• Antibody specific for CD20 protein on B cells - depletes B cells
• Antibodies that block CD40 or CD40L to inhabit T cell-mediated activation of B cells

Question 12

Type IV

Answer 12

• T Cell Mediated Reactions
• Usually NOT systemic b/c directed against antigen that is limited to few organs
• ALSO takes longer than other reactions (24-48 hr)
• Superantigens - create excessive T cell activation by binding invariant parts of TCRs regardless of antigen specificity —> activate multiple clones of T cells
• Mechanisms of Tissue Injury…
  
  • Cytokine-mediated inflammation -CD4+ cells release cytokines that induce local inflammation and activate macrophages
    
    • Th1 cells release IFN-gamma which activate macrophages
    • Th17 cells mainly recruit neutrophils
    • Delayed-Type Hypersensitivity (DTH) -this reaction takes place 24-48 hrs after infection —> edema, fibrin, permeability, inflammatory damage all due to cytokines; used for PPD sin test
• CD8+ T cells directly kill host cells

Question 13

Treatment of Type IV Reactions (5)

Answer 13

• Potent anti-inflammatory steroid (SIDE EFECTS)
• TNF antagonists
• Drugs that block co-stimulators like B7
• Antagonists against cytokines
• Immunosupression (methotrexate)

Question 14

Type II Examples

Answer 14

Autoimmune thrombocytopenia purpura

MG

Graves

Autoimmune hemolytic anemia

Goodpasture syndrome

Pemphigus Vulgaris

Pernicious Anemia

Rheumatic Fever

Erythroblastosis Fetalis

Question 15

Type III Examples

Answer 15

Systemic lupus erythematosus

Serum Sickness

Polyarteritis Nodosa

Post-streptococcal Glomerulonephritis

Arthus Reaction - local/subcutaneous

Question 16

Type IV Examples

Answer 16

MS

Rheumatoid Arthritis

Type I Diabetes

Chron’s

Contact Sensitivity (like poison ivy)

Chronic Inflammation (like Tb)

Viral Hepatitis (HBV HCV)

Superantigen Mediated Disease (like TSS)