Download 11th B Hypersensitivity reactions

Hypersensitivity reactions
An adaptive immune response to innocuous molecules that
causes inflammation and tissue damage
Hypersensitivity reactions are grouped into four types according to
the effector mechanisms producing the reaction:
I.
II.
III.
IV.
Immediate, IgE/mast cell-mediated
Antibody-mediated
Immune complex-mediated
T cell-mediated
Immediate hypersensitivity
(Type I)
 Production of IgE antibodies in response to an antigen  binding of
IgE to Fc receptors of mast cells  cross-linking of bound IgE by the
antigen  release of mast cell mediators
 Mast cell mediators- vasoactive amines, lipid mediators and cytokines result in:
• Rapid increase of vascular permeability (histamine, PGs)
• Smooth muscle contraction that occurs within minutes (histamine, LTs)
• Recruitment of neutrophils and eosinophils- late phase reaction (cytokines
TNF and IL-4). Th2 cells recruit eosinophils (IL-5) and increase mucus
secretions (IL-13)
• Local tissue damage by neutrophils and eosinophils (proteases)
 IgE production is a result of a dominant Th2 response against the allergen for
an unknown reason (genetic basis).
Immediate hypersensitivity
(Type I)
Immediate hypersensitivity reactions are called allergy or atopy. An individual
developing this reaction is said to be atopic.
Antigens causing a state of immediate hypersensitivity/allergy are called allergens.
In developed countries 10-40% of the population are allergic to one or more
environmental allergens!
• Mast cells are always coated by IgE through FcεRI high affinity to ε chain of
IgE.
• Mast cell coating with IgE is called “sensitization” – Mast cells become
sensitive to activation by the encounter with that antigen.
The evolutionary purpose of mast cells is in the defense against helminthes,
unfortunately, they are also responsible for these allergic reactions
Clinical syndrome
Allergic rhinitis,
sinusitis
(hey fever)
Pathologic
manifestations
Inflammation of
upper airways
Increased mucus
production
Therapy
Antihistamines
Anti-IgE
“Desensitization”
Cromolyn
Food allergies
Increased peristalsis
Avoidance
Bronchial asthma
Bronchial
hyperesponsiveness,
contraction,
inflammation and
tissue injury
PDE inhibitors
Vascular dilation- BP
drop (shock)
Laryngeal edema
(obstruction)
Epinephrine
Anaphylaxis
Corticosteroids
Mechanism of action
Blocks histamine
Neutralizes IgE
Inhibit IgE production
and tolerance
Inhibits mast cell
Degranulation
Relax bronchial
smooth muscle
Reduce inflammation
Vascular contraction,
increase CO
Inhibits mast cell
degranulation
Antibody-mediated hypersensitivity
(Type II)
 Antibodies directed against cell or tissue antigens, damage or impair
their function
 Often IgG or IgM autoantibodies are involved (failure of self tolerance)
 Some cases involve antibodies produced against a foreign antigen.
For example: poststreptococcal glomerulonephritis and Rheumatic
fever.
 IgG1 and IgG3 subclasses bind Fc receptors on macrophages and
neutrophils  leukocyte activation  inflammation.
 IgM, IgG1 and IgG3 activate the classical pathway of complement
 leukocyte recruitment  inflammation.
 ROS, lysosomal enzymes bring about the tissue damage.
Antibodymediated disease
Target antigen
Autoimmune
hemolytic anemia
Erythrocyte protein
(Rh blood group)
Idiopathic
thrombocytopenia Platelet membrane
purpura
protein
Goodpasture’s
syndrome
Glomeruli and alveoli
basement membrane
protein
Mechanism of
disease
Opsonization and
phagocytosis of
erythrocytes
Opsonization and
phagocytosis of
platelet
Clinical
manifestations
Hemolysis,
anemia
Bleeding
Complement and Fc
Nephritis, lung
mediated inflammation hemorrhages
Myesthenia gravis AchR
R inhibition
Muscle
weakness,
paralysis
Grave’s disease
TSHR
R stimulation
Hyperthyroidism
Acute rheumatic
fever
Ab cross-reaction of
Streptococcal Ag to
myocardial Ag
Inflammation,
Myocarditis,
macrophage activation arthritis
Pemphigus
vulgaris
Epidermal cell
intracellular protein
Proteases disrupting
intracellular adhesion
Skin vesicles
(bullae)
Immune complex mediatedhypersensitivity (Type III)
 Antibodies form complexes with the antigens and deposit in blood
vessels causing inflammation and injury
 Deposition in sites of turbulence and high pressure;
- Vessel branches (vasculitis)
- Kidney glomeruli (nephritis)
- Synovium (arthritis)
 Therapy intends to limit inflammation- corticosteroids
and reduce circulating antibodies and immune complexes plasmapheresis.
Clinical syndrome
Antibody specificity
Clinicopathologic
manifestations
Systemic lupus
erythematosus
(SLE)
DNA, nucleoproteins
Nephritis
Arthritis
Vasculitis
Polyarthritis nodosa
HBV surface Ag
Vasculitis
Poststreptococcal
glomerulonephritis
Streptococcal cell wall Ag
Nephritis
Serum sickness
Different protein Ag
Systemic vasculitis,
nephritis, arthritis
Arthus reaction
Different protein Ag
Cutaneous vasculitis
(Experimental)
T cell-mediated hypersensitivity
(Type IV)
 Delayed type hypersensitivity reactions are mediated by CD4+ or CD8+ CTLs
 A result of autoimmunity or a response to environmental antigens
 Usually restricted to a tissue, not systemic. However, chronic and progressive
 Contact sensitivity to chemicals
 T cell response against Mycobacterium tuberculosis  chronic (not able to be
eradicated)  granulomatous inflammation  tissue injury
 CTL response to HBV infected hepatocytes  liver injury
 Superantigens  polyclonal T cell stimulation  systemic shock
 The mechanism of injury to the tissue is the same as what T cells use to
eliminate cell-associated pathogens. CTL- direct killing. Th1- Macrophage
activation through IFN-γ.
 Therapy is designed to reduce inflammation- corticosteroids, cytokine antagonists
(MAB targeting TNF in RA and IBD, IL-2), immunosuppressive agents acting on T
Disease
Type I diabetes mellitus
Pathogenic T cell
specificity
Pancreatic islet antigens
Clinicopathologic
manifestations
Impaired glucose metabolism
Rheumatoid arthritis (RA) Unknown joint Ag
Synovial inflammation,
cartilage and bone erosion
Multiple sclerosis (MS)
Myellin protein
Neural demyelination in CNS,
sensory and motor
dysfunction
Inflammatory bowel
disease (IBD)
Unknown
Bowel inflammation; pain,
diarrhea, hemorrhage
Contact sensitivity
(ex: poison ivy)
Modified skin proteins
Rash
Chronic infections
(ex: MTB)
Microbial proteins
Chronic granulomatous
inflammation
Viral hepatitis (HBV, HCV) Virally-encoded proteins
CTL-mediated hypatocyte
death
Superantigen-mediated
disease
Fever, systemic inflammation,
cytokine release - shock
Polyclonal activation
T-cell mediated hypersensitivity reaction (type IV)
Contact sensitivity to poison ivy