Download Chapter 13 Hypersensitivity Reactions

Chapter 13 Hypersensitivity Reactions
General Features
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Type I  immediate hypersensitivity
Type II  antibody-mediated hypersensitivity
Type III  immune-complex mediated hypersensitivity
Type IV  cell-mediated hypersensitivity (delayed hypersensitivity)
Type I: Immediate Hypersensitivity Reactions
Sensitization phase
- IgE is produced in response to an allergen and it then binds to the FcR of mast
cells/basophils
- CD4 T cells differentiate to Th2 and secrete IL-4, IL-10. REMEMBER IL-4
required for isotype switching to IgE
Effector phase
- when the person is re-exposed to the antigen it binds to the IgE bound to mast
cells/basophils
- mast cells degranulate releasing histamine, prostaglandins, leukotrienes and
platelet activating factors, all of which increase inflammation
- these induce increased vascular permeability, smooth muscle contraction (e.g.
asthma, bronchial muscle is smooth muscle), and vasodilation
- primary exposure to the antigen does not produce a response because antibodies
are required and they are not made until a person has encountered the antigen
- can do skin testing  erythema and edema due to increased vascular permeability
Clinical manifestations
- Local  asthma, allergic rhinitis
- Systemic  anaphylaxis
Allergic rhinitis
- inflammation of the nasal mucus membranes
- sneezing, nasal congestion, runny eyes
Asthma
- bronchoconstriction  wheezing
- can also be caused by external stimuli (e.g. infection, exercise, cold air)
Anaphylaxis
- potentially fatal reaction that affects the cardiovascular and respiratory system
- leads to cardiac arrhythmia and hypotension
Therapy
- minimizing exposure to antigen that produces the reaction
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pharmacological intervention
desensitization
1.
2.
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Pharmacological
antihistamines (H1 receptor inhibitors) or sodium cromoglycate
epinephrine for treatment of anaphylaxis (not prophylactic!!!)
steroids
Desensitization
aka allergy shots
bias the T cell response to a Th1 response and producing IgG instead of IgE in
response to the antigen
IgG binds to the antigen before it can bind to mast cell
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Type II: Antibody-Mediated Hypersensitivity Reactions
Sensitization phase
- IgG and IgM are made against cell surface antigens
- Antigens are either cell components or exogenous (e.g. drugs)
Effector phase
- destruction of cells expressing Ag-Ab complexes by complement (via MAC or
opsonin-mediated phagocytosis (C3b, IgG)
- cell destruction can also occur by ADCC (NK cells)
- more exposure to antigen more exaggerated response (memory)
Clinical manifestations
- transfusion reactions
- hemolytic disease of the newborn (erythroblastosis fetalis)
- hyperacute rejection of transplanted tissue
Transfusion reactions
- IgM (isohemagglutinins) bind to RBCs and activate complement leading to either
cell lysis or opsonin-mediated phagocytosis (C3b)
- Blood groups: A has anti-B, B has anti-A and O has anti-A and anti-B
- O is universal donor and AB universal recipient
Hemolytic disease of the newborn
- Rh- mother and Rh+ fetus
- Mother develops anti-Rh IgG which cross the placenta and bind to the fetal RBCs
causing their lysis by previously discussed mechanisms
- Prevention: passive anti-Rh Ig (RhoGam)
Autologous cell destruction
- Goodpasture’s syndrome  Abs to antigens in the glomerular and pulmonary
basement membranes
- Type 1 diabetes  Abs to pancreas
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Neutrophils are activated they release reactive oxygen intermediates and the
proteolytic enzymes, elastase and collagenase which cause local tissue damage
Type III: Immune-Complex Mediated Hypersensitivity
Sensitization phase
- IgM and IgG bind to soluble antigens forming immune complexes
Effector phase
- excess immune complexes are deposited in the capillary walls which activate
complement generating anaphylotoxins and C3b
- C5a attracts neutrophils
- C5a also binds to mast cells and causes release of inflammatory mediators that
increase vascular permeability
- Neutrophils phagocytose (C3b, IgG)
- Enzymes secreted by neutrophils damage the endothelium
- Exposed subendothelium activates intrinsic coagulation pathway
- Bradykinin  vasodilator
- Histamine + bradykinin  increase vascular permeability
Clinical manifestations
Localization of immune complexes (autoimmune diseases)
- SLE  kidney glomeruli: glomerulonephritis
- Rheumatoid arthritis  joint
- Farmer’s lung  lung
Systemic lupus erythematosus (SLE)
- autoimmune disease
- antibodies to DNA, histones
- immune complexes in the kidneys as well as other organs (localized or systemic)
Serum sickness (systemic)
- passive immunization with horse serum led to a reaction consisting of fever,
edematous rashes, enlarged lymph nodes, and swollen joints
- patients produced antibodies to soluble horse serum antigens
- second injection could lead to anaphylaxis and death
- e.g. anti-snake venom
Arthus reaction (localized)
- cutaneous vasculitis and necrosis
- IgG
Type IV: Cell-Mediated Hypersensitivity
Sensitization phase
- naïve CD4+ T cells differentiate to Th1/Th2 secreting cytokines  memory cells
1. chronic type IV hypersensitivity (granulomatous inflammation)
2. acute type IV hypersensitivity (Mantoux reaction)
3. contact hypersensitivity (poison ivy dermatitis)
4. cellular cytotoxicity (CD8+ mediated destruction of virally infected cells)
Effector phase
- re-exposure to antigen and activation of memory Th1 cells
1. memory Th1 cells activated by antigen  IFN  activates macs
2. activated macs secrete IL-1, TNF and chemokines that increase expression of
adhesion molecules on endothelium and lymphocytes, cytokines induce secretion
of cytokines that activate neutrophils (IL-8) and monocytes (MCP-1)
3. inflammatory mediators increase vascular permeability and cause tissue damage.
Tissue damage activates Hageman factor (Factor XII) so kallikrein is made.
Kallikrein produces bradykinin (vasodilator) and cleaves C5 producing C5a,
chemotactic for neutrophils. C5a also binds to receptor on mast cells releasing
histamine. Histamine + bradykinin  increase vascular permeability  edema
4. leukocytes adhere to the endothelium. Activated neutrophils secrete enzymes that
degrade the basement membrane. Diapedesis.
5. Neutrophils secrete inflammatory mediators that cause tissue damage when
phagocytozing
6. IFN a) monocytes  macrophages b) activate macrophages to kill. Activated
macrophages secrete IL-1, TNF stimulate processes producing inflammatory
mediators that cause tissue injury
Regulation of the response
- Th 2 suppresses Th1 response
- Th1 response  tuberculoid leprosy
- Th2 activation  leprotamous leprosy (failure of Th1 activation prevents
activation of bacterium)
Clinical manifestations
Chronic granulomatous inflammation
- microorganisms within the macrophage
- e.g. Mycobacterium leprae and Mycobacterium tuberculosis
- chronically infected macrophages fuse to from multinucleated giant cells
surrounded by lymphocytes and macs = granuloma
- granulomas in lung in TB; sarcoidosis – granulomas in LNs, bone, skin, and lungs
- Crohn’s colitis (GI tract)
Mantoux reaction (acute)
- tuberculin test, PPD
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antigen present to Th1 cells in sensitized individuals
activated Th1 cells secrete cytokines (IFN, TNF) that activate macs
erythema and induration at 24-48 hours
delayed type hypersensitivity reaction (DTH)
Contact hypersensitivity
- poison ivy dermatitis
- activation of memory Th1 cells
- erythema and swelling cytokine-mediated
- APCs are Langerhans cells (macs of the skin) and keratinocytes release cytokines
Cutaneous basophil hypersensitivity
- aka Jones Mote Reaction
- intradermal injections of soluble antigen mixed with adjuvant
- adjuvants increase an immune response
Cellular cytotoxicity
- activated memory Th1 cells secrete IL-2 required to go from pCTL to CTL
- kills virally infected cells expressing antigen in the context of MHCI