Hypersensitivity (II-IV)

Question 0

Examples of Type 2 hypersensitivity

Answer 0

Blood reactions (transfusion, hemolytic disease of newborn, autoimmune dyscrasias)
Hyperacute transplant rejection
Transplant associated lung injury
Myasthenia gravis (antibodies block receptor)
Graves disease (antibodies stimulate receptor)

Question 1

Overview of Type 2 hypersensitivity

Answer 1

IgG, IgM bind to self cells

• > complement -> lysis, phagocytosis, etc
• > cytotoxic cells (NK, monocytes, macrophages, neutrophils, eosinophils)
• > phagocytosis
• > destruction via mediators (H2O2, TNF-a, perforins, etc)

Question 2

Alloantibodies

Answer 2

aka blood types, isohemagglutinins
Polymorphism, consistent across all cells
Everyone has H antigen -> modified by A and/or B enzyme -> different surface sugar residues
Antibodies (IgM) to A and/or B develop via exposure to microbes (same epitope) unless tolerant

Question 3

Transfusion reaction

Answer 3

Should not happen clinically!
Missing A and/or B surface sugar -> develop IgM antibodies (no tolerance)
Transfusion with antigen -> agglutination, complement lysis, phagocytosis (type II reaction)
Sensitization -> worse with repeat transfusions

Question 4

Hemolytic disease of the newborn

Answer 4

aka HDN, erythroblastosis fetalis, hydrops fetalis
RhD+ fetal cells -> cross to Rh- mom -> mom makes anti-RhD antibodies
Future pregnancy: anti-RhD IgG crosses placenta -> destroys fetal RhD+ RBCs

Less common if greater ABO mismatch (ABO destroys before anti-RhD happens?)
Rhogam = prophylaxis = anti-RhD antibodies (unclear mechanism)
Other Rh mismatches can have problems too (C, E)

Question 5

Blood dyscrasias

Answer 5

form of Type II hypersensitivity
Antibodies -> destruction of blood cells (RBCs, WBCs, PLT, etc)

Drug-induced: hapten (ex penicillin) binds to membrane protein -> antibodies bind -> complement, ADCC
- test for antibody binding via direct Coombs
Autoimmune: body makes antibodies to own cells
- may need to remove spleen (cells opsonized but don’t encounter macrophages)

Question 6

Hyperacute graft rejection

Answer 6

Rapid = preexisting antibodies attack graft antigen

Revascularization -> antibodies bind -> rapid neutrophil -> capillary damage, clots -> necrosis

Question 7

TRALI

Answer 7

Transfusion-related acute lung injury
Type II hypersensitivity

Donated plasma contains antibodies -> bind to host lung cells -> super bad…

Question 8

Treatment for Type 2 reactions

Answer 8

Stop drug/trigger
Exchange or transfuse plasma (temporary)
Glucocorticoids (blocks everything…)
Target cells (azathioprine -> cytotoxic, rituximab -> anti-B antibody)
Splenectomy (reduce macrophage encounters)
IV-IG
Increase RBC or platelet production to compensate

Question 9

Overview of Type 3 hypersensitivity

Answer 9

Circulating antigen + antibody -> complexes

• small -> phagocytosis
• large -> deposits in tissue -> complement -> neutrophil reaction -> local tissue damage -> fever, hives, inflammation of nodes, kidneys, heart, nerves

Question 10

Examples of Type 3 hypersensitivity

Answer 10

Serum sickness (horse serum for antivenom, diptheria, etc contains antigenic immunoglobulins)
- Arthus reaction (injected Ag + excess Ab -> local edema, erythema)
Viral antigens - Hep B vasculitis
Autoimmune antibodies - 
 - necrotising vasculitis
 - periarteritis nodosa
 - lymphadenitis
 - arthritis
 - SLE/systemic lupus erythematosus

Question 11

Steps of Type 3 reactions

Answer 11

IgG, IgM + antigen -> complexes (3 Ag:2 Ab) -> deposit based on size

• > complement -> C3a, C5a -> mast, eosinophil, neutrophil
• > IgG -> FcG neutrophil release -> leukotriene B4, IL-8, SRS-A (C4, D4, E4), TNF, lysosomal enzymes and oxygen radicals
• > permeability -> greater complex deposition, recruitment
• > thrombi, fibrin, necrosis

Question 12

Clearance of immune complexes

Answer 12

Monocytes/macrophages via Fc, C3b (esp in liver, spleen)
- neutrophils also have Fc and C3b action
- other Fc, C3b receptors - PLT, endothelium, mast cells, lymphocytes
- ex PLT Fc -> aggregation -> phagocytosis (reason for thrombocytopenia with first flu)
C3b -> CR1 receptors on RBCs -> sequester in center of vessel -> shuttle to liver for macrophage action
Complement - alternate pathway clears complexes (vs damage from antibody pathway)

Question 13

Detection of immune complexes

Answer 13

No perfect assay - depends on type of antigen, isotype of antibody, Ab:Ag ratio, size of complex, concentration, complement involvement

C1q binds IgG of complexes -> detect via anti-IgG
Serum hemolytic complement (CH50) - levels will decrease if activated
Immunohistology - detect complexes localized to tissue

Question 14

Treatment of immune complex disease

Answer 14

Withdrawal of drug, serum, etc
Symptomatic - antihistamines, NSAIDs, pain meds
Glucocorticoids if severe

Question 15

Overview of Type IV hypersensitivity

Answer 15

Delayed (15h - 5d)
T-cell mediated (necessary and sufficient)
-> cytokine -> macrophage response -> local tissue damage

Requires prior sensitization (memory T cells)
Does not require/involve antibodies

Question 16

Examples of Type IV hypersensitivity

Answer 16

Mantoux (PPD) test - reaction from memory T cells to mycobacteria (TB or other or BCG vaccine)
Contact - urushiol, nickle, neomycin = haptens - bind to skin proteins -> DC’s activated -> CD4 response
Granulomatous hypersensitivity - antigen persists in macrophages -> chronic T cell response (ex TB, leprosy)
Stevens-Johnson syndrome - drug induced skin reaction