Download Hypersensitivity Ch. 18-19

Hypersensitivity I & II
Ch. 18-19
March 6th, 2006
Ricky Chang
Objectives
• Know the mechanism of Type I
hypersensitivity
• Know the mediators of Type I
hypersensitivity
• Know the diseases associated with
Type II hypersensitivity
Hypersensitivity
• Adaptive immunity is important against
microbial infections, but it is also capable of
causing tissue injury and disease
(autoimmune diseases)
• Occurs when immune responses are directed
against self-ag and also from uncontrolled or
excessive responses to against foreign ag,
such as microbes and allergens
Hypersensitivity
• Common cause is failure of self-tolerance,
which ensures that individuals do not respond
to their own antigens
• Leads to tissue injury that occurs in
autoimmune diseases due to the same
effector mechanisms used to protect against
microbes
Hypersensitivity
• Type I: IgE antibodies bind to Fc receptors on
mast cells. IgE induces mast cell
degranulation and release inflammatory
mediators
• Type II: Ab mediated immune response
against self antigen or foreign antigen (ie ag
on transfused RBC)
• Type III: Immune complexes are deposited in
tissue
• Type IV: T-cell mediated response where Ag
sensitized T-cells release lymphokines
Hypersensitivity
Hypersensitivity
Roles of Mast Cells
• Part of connective tissue (contains granules
of histamine and heparin)
• Allergic diseases (asthma,eczema,itch)
• Anaphylaxis (systemic shock to allergens
such as bee sting,nuts,drugs)
• Autoimmune disorders/Acute or chronic
inflammation (MS, Rheumatoid arthritis)
• Wound healing
• Innate response for clearing bacteria and
viruses
Mast Cell
Basophil
Type I (Immediate)
1)
2)
3)
4)
5)
Ag/allergen stimulate
CD4+Th2
Th2 releases IL-4, which
promote B-cells specific for
that Ag to differentiate into
IgE producing cells
Circulating IgE binds to Fc
receptors on mast cells
and basophils
Elicits a transduction event
to release mediators stored
in granules (Degranulation)
Immediate hypersensitivity
response (5-10 minutes)
Mediator Release from Mast Cells
Type I Mediators and Effects
Figure19.3
Type I Mediators and Effects
IgE-Mediated Allergic Reactions
Type I: Mast Cells
• Type I reaction is dependent upon the
specific triggering of IgE-sensitized mast-cells
by allergen (Ag)
• Ag enter via mucosal surfaces and are taken
up by APC
• Th2 cells release IL-4 to facilitate the B-cell
proliferation and differentiation, producing IgE
specific for the allergen
• REMEMBER: THIS IS A TH2 RESPONSE!
Activation of Mast Cells
• IgE from B-cells binds to FcRI on
mast-cells
- is the heavy chain responsible for IgE
isotype switching
• FcRI on mast-cells cross-links with Agbounded IgE and induces degranulation
of mediators
Cross-linking of FcRI to
IgE bounded to Ag
Degranulation of Mediators
Activation of Mast-cells
Cross-linking
Mast-Cell Mediators
• Inflammatory Mediators released
-Histamine
-Proteases (tryptase or chymase), acid
hydrolases
-Proteoglycans (heparin, chondroitin sulfate)
Mast Cells: Lipid Mediators
• Prostaglandins D2
• Leukotrienes C4, D4, E4
• Platelet-activating factor
Mast-Cells: Cytokines
• IL-3: Promote mast cell proliferation
• IL-4, IL-5: Promote Th2 differentiation
and IgE AB production
• TNF-, MIP-1 : Enhance inflammatory
reaction
Allergen Induced
Hypersensitivity
• Allergen: are antigens that induce production
of specific IgE AB
• Examples: plant pollens, dust, animal hair,
animal anti-serum, insect venom, chemicals,
and foods
• Once the allergen reaches the sensitized
mast cells, the allergen crosslinks the
surface-bound IgE intracelluar Ca+2 and
triggers degranulation of mediators
Atopy
• Atopy: Describes individuals that produce IgE
AB in response to various environmental Ag
and develop immediate hypersensitivity (Type
I) responses.(Asthma, eczema, hay fever,
and urticaria)
• These individuals normally have a strong
family history (autosomal transmission of
atopy)
Atopy
• HLA vs. Allergen Responsiveness
-Some allergens response have a
relationship to HLA
-HLA-DR2 and HLA-A2: high responder
to low dos of ragweed
-HLA-B8: high responder to ragweed
and also associated to other forms of
hyperimmunity (autoimmunity)
IgE
• IgE blood concentrations are often
increased in allergic disease and are
grossly elevated in parasitic infections
• IL-4: promote B-cells to differentiate into
IgE-producing specific cells
Eosinophil
• Th2 produce IL-5: Promotes the
synthesis and secretion of IgA from Bcells and also important in stimulating
eosinophil development and activation
• IL-4 and IL-5 production by Th2 cells
may account for the eosinophilia seen in
type I hypersensitivity and parasitemia
Two Types of Mast Cells
1) Connective tissue mast cells (CTMCs)
2) Mucosal mast cells (MMC)
Connective Tissue Mass Cells
• CTMCs are found most in blood vessels
but vary in size and number of granules
at different regions of the body
• Diseases such as Crohn’s disease,
ulcerative colitis, and RA all present with
increase in CTMCs
Types of Fc Receptors for IgE
• There are two types of receptors for IgE
1) FcRI (high affinity): Expressed on
mast cells and basophils
2) FcRII (low affinity): Expressed by
lymphocytes
Mast Cells Activation
• Cross-linking can be artificially induced
with lectins such as PHA
(Polyhydroxyaldehyde) and ConA
• These carbohydrates cross-link with IgE
and cause degranulation
• This explains urticaria in individuals
allergic to fruits (ie strawberries-contain
large amt of lectin
Degranulation
• C’ products of C3a and C5a are very
active in degranulating mast cells
• Compounds that affect Ca+2 influx into
mast cells can induce degranulation
• Drugs such as morphine, codeine,
synthetic ACTH can create clinical
manifestations related to mast cells
Modulation of Mast Cells
Therapy for Allergy
1) Agents that increase intracellular cAMP
(-agonist)-inhibits contraction
-Theophyllines: Prevents cAMP degradation
2) Blocking mediator release, such as
sodium cromolyn: mechanism not clear,
but seem to antagonize IgE-induced
mediator release.
Therapeutics
• Direct Inhibitors
-Theophyllines, Xanthines
-Sodium cromolyn
-Epinephrine
-PGE1, PGE2
• Indirect Inhibitor
-Glucocorticoids
Histamine Receptors
• H1
- Bronchial
constriction
- Musous secretion
- Intestinal smooth
muscle contraction
- Itching and pain at
sensory nerve
endings
• H1 and H2
- Reduces BP
- Increase
permeability in skin
• H2
- Gastric secretion in
stomach
Antihistamines
• Nausea,vertigo,motion
sickness
-Cyclizine
-Dimenhydrinate
-Diphenhydramine
(Benadryl, Tylenol
PM)
-Meclizine
• H1 Antagonists
-Promethazine
(Phenergan)
-Cetirizine (Zyrtec)
-Desloratadine
(Clarinex)
-Fexofenadine
(Allegra)
-Loratadine (Claritin)
Type II Hypersensitivity
Type II
• Antibodies are directed against ag on
particular cells/tissue or extracellular matrix,
causing damage (ie RBC transfusion)
• These cell- or tissue-specific Ab cause
diseases
-Myasthenia Gravis: Ab blocks Ach-binding
and cause muscle weakness and paralysis
-Graves’ Disease: Ab stimulate TSH and
casue hyperthyroidism)
Type II
Type II
• Type II causes disease by 3 mechanism
1) Opsonization and phagocytosis of
cells
2) Complement and Fc receptormediated inflammation and tissue injury
3) Interference of normal cellular
function by binding to important
molecules or receptors
Reaction Against RBCs and
Platelets
• Transfusion Reactions: There are 200
genetic variant of the RBC, but the ABO
is the main designation
• The Rh system is also important
because its cause of hemolytic disease
in the newborn
Reaction Against RBCs and
Platelets
Reaction Against RBCs and
Platelets
• Hemolytic disease of the newborn (2nd born)
-RhoGam: It’s an Anti-Rh+ Antibody given to
mother after the first born to prevent future
complications in later newborns
• Autoimmune Hemolytic Anemia
-When provoked by allergic reactions to
certain drugs, including Penicillin, quinine,
and sulphonamides
Idiopathic Thrombocytpenic
Purpura (ITP)
• Autoantibody to platelets from the rapid
removal of platelets from circulation
• Most often develop in women after
bacterial or viral infections
• Associated with autoimmune disease
Systemic Lupus Erythematosus (SLE)
Type II Mediated
Autoimmune Diseases
•
•
•
•
•
Myasthenia Gravis
Graves’ Disease
Insulin-resistance Diabetes
Hemolytic Anemia
Rheumatoid Arthritis
Advise of the Day
TYPE III & Type IV..To Be Continued…