Nada Nekrep, PhD
Autoimmunity v. Hypersensitivity
Autoimmunity: response to self-antigen
Hypersensitivity: response to foreign antigen
• innocuous (harmless) antigen
• allergen
Four (4) types of Hypersensitivity
Based on the type of immune molecule that causes problematic response
• antibodies for 3/4
• T-cells 1/4
Type I (Immediate-type) Hypersensitivity
IgE
Immune mediator
•
•
•
low in serum
bound to mast cells
pre-coating / priming with various IgEs (resting mast cell)
Antigen (allergen)
•
free (water soluble)
Mechanism of action
•
•
•
antigen-induced IgE-crosslinking (activated mast cell)
degranulation
release of vasoactive mediators
Clinical outcome
Anaphylaxis (very mild to very severe)
• localized (hay fever, eczema, hives, food allergy)
• systemic (anaphylactic shock)
First exposure
• sensitization phase
Subsequent exposures
• effector phase (immediate)
• immediate response
• acute (rhinitis) or chronic (asthma)
Allergen example: pollen protein
Mast cell cargo is aimed at parasitic infections
Chemical type
Chemical type
Effect
Toxic mediators
Histamine, heparin
Poison parasites
Blood vessel dilation and permeability
Smooth muscle contraction
Enzymes
Proteases (tryptase)
Tissue destruction (helminth)
Cytokines
TNF, ILs, GM-CSF
Inflammation
Amplification of immune response
Chemokines
CCL3
WBC attraction
Lipid mediators
Leukotrienes
Amplification of immune response
Smooth muscle contraction
Smooth muscle contraction
• closes airways/throat (difficulty swallowing & breathing; wheezing)
• intestinal hypermotility (cramps, vomiting, diarrhea)
Anaphylaxis
severe allergic reaction that can lead to anaphylactic shock
Predisposing factors
Environment affects
• microbial composition
• barrier health
Genetic predisposing factors
Atopy
Type 1 Hypersensitivity Antigens
Muscle constriction can lead to Asthma
Chronic inflammation
• cell infiltration via vessels
• mucus
• air displacement
Food allergies can spread from GI tract to skin
mucosal mast cells
• GI cramps/pain
• vomiting
• diarrhea
skin mast cells
• urticaria (hives)
Mast cells are concentrated in connective tissue underneath the epithelia (skin, MM)
Helminth antigen cross reactivity can lead to allergy
consensus in scientific community is not complete (parasitic infections are mostly chronic)
Type II Hypersensitivity
Immune mediator
IgM or IgG
Antigen (allergen)
•
cell surface-bound
•
antibody binds to antigen
• complement activation
• ADCC
•
cell death (especially RBC)
Mechanism of action
Clinical outcome
Examples:
• response to incompatible blood (via transfusion)
• hemolytic disease of the newborn
• penicillin-induced hemolytic anemia
• autoimmune hemolytic anemia
Blood Typing
1. ABO system
• glycoproteins on RBC surface (antigens)
• 4 blood types (A and O most common)
Blood Compatibility
incompatible blood mixing leads to hemolysis
(destruction of red bloods cells)
universal recipient
(no antibodies!)
2. Rh factor (Rhesus factor)
• present (Rh+)
• absent (Rh-)
universal donor
(no antigens!)
Hemolytic disease of the newborn
Penicillin-induced hemolytic anemia
Improper antibiotic dosage
Type III Hypersensitivity (Immune Complex Disease)
Immune mediator
IgM or IgG (in an immune complex)
Antigen (allergen)
•
secreted soluble protein
•
•
•
•
multiple antibodies and antigens bind
immune complex formation
complement activation
neutrophil infiltration (C3b), mast cell degranulation (C5a)
•
inflammation, tissue damage in various body parts
Mechanism of action
Clinical outcome
Immune complex deposition in various body parts
Blood vessel
• blockage
• inflammation (vasculitis)
• damage
Kidney tubules
• inflammation (nephritis)
• blockage/damage
Joints
• inflammation (arthritis)
Passive antibody therapy
Convalescent plasma (polyclonal)
• human
• horse (problem?)
Serum Sickness
More common after secondary exposure to the same antigen.
Immune complexes at optimal concentrations:
• antigen: horse antibody
• antibody: human antibody against horse (from the primary exposure)
Type IV (Delayed-type; T-cell mediated) Hypersensitivity (DTH)
Immune mediator
T-cells (mostly TH1; can be TH17 or TC)
Antigen (allergen)
•
intracellular pathogen or contact antigen
Mechanism of action
•
•
delayed (3-4 days)
in lymph node (APC + T-cells)
Clinical outcome
•
tissue damage (e.g., dermatitis)
First exposure
• sensitization phase
• 1-2 weeks
Subsequent exposures
• effector phase
• DTH response
• 2-3 days
• tissue damage
also called contact hypersensitivity
Type IV: TH1 cells as initiator cells & macrophages as effector cells
TNF
IL-1
Il-6
TH1 response (IFN)
Cytokines effect vascular endothelium
Macrophage activation
Inflammatory response
PPD Tuberculin Skin Test (for tuberculosis)
DTH: time is needed to recruit memory TH1 cells to the exposure site/inflammatory response
Poison Ivy Dermatitis
urushiol
CD8+ response!
self!
Celiac Disease
Allergy
or
Autoimmunity?
CD4+ response
cytokines damage
intestinal epithelium
Consensus:
Inflammatory Disease
Treatments for Inflammatory Diseases
1. Type I Hypersensitivity
Drug
Mechanism of Action
Antihistamines (Claritin, Allegra etc.)
Block histamine receptors (H1, H2)
Epinephrine (EpiPen)
Prevents mast cell degranulation via
maintaining high cAMP levels
Steroids (Hydrocortisone, Prednisone etc.)
Various anti-inflammatory effects
(including the two above)
Desensitization Therapy
•
•
•
immunotherapy
orally or “allergy shots”
induction of TREG response in place of previous TH2
2. Autoimmunity
Drug
Cyclosporine A
Mechanism of Action
calcineurin inhibitor (T-cells)
Use
•
•
transplantation
various autoimmune disorders
with overactive T-cells
(-)
•
•
non-specific (broad inhibition of all T-cells)
immune suppression
Drug
Rituximab
(Genentech)
Mechanism of Action
anti-CD20 mAb
Use
•
•
RA
B-cell non-Hodgkin lymphoma
(+)
•
more specific (only affects mature B-cells)
B
Drug
Mechanism of Action
Cytokine-based
therapies
Disable inflammatory cytokines
or their receptors
Use
•
•
•
RA
Chron’s disease
MS
TNF-
(+)
more specific
(-)
IL-6
immunosuppression is still an issue