1
Course: Immunology
Lecturer: Dr. Weam Saad
Lecture: Hypersensitivity
Hypersensitivity
Allergy is inappropriate or disturbing immune response against certain antigens.
Hypersensitivities are immunological reactions; they were classified for the first
time by the scientists Gell and Coombs into four major types according to their
immunological mechanisms:
1. Type I: Immediate Hypersensitivity.
2. Type II: Cytotoxic Hypersensitivity.
3. Type III: Immune complex Hypersensitivity.
4. Type IV: Delayed type Hypersensitivity.
Type I Hypersensitivity:
Usually called immediate , anaphylactic or atopic allergy. Has 3 arms or
components; IgE/Mast cells/Allergen.
Allergen: is an antigen that stimulates Hypersensitivity, it is commonly
innocuous environmental antigen (not harmful for normal peoples).
1. Causes or Motives:
1) Genetic susceptibility, this type of Hypersensitivity is usually hereditary.
2) Re-exposure to the same allergen.
2. Target
:
Soluble Ag or allergen. Some of them are able to induce allergy directly after
exposure e.g. house dusts and grass pollens. Other allergens need to combine
with certain body proteins (act like haptens) e.g. pencillin antibiotic. While
others may be changed inside human body and turn to allergic Ag like some
foods after digestion.
2
3. Immunological
Mechanisms:
First exposure or previous exposure:
1) Allergen (Ag) processed by APCs and certain Ags will be
expressed on APCs surface.
2) B-cells response to APCs by producing specific IgE antibodies
against that allergic Ag.
3) Binding of these IgE to the Fc reseptors of mast cells (or basophils).
Second exposure or re-exposure:
When the same Ag or allergen enters the body again; it will bind to the specific
IgE on mast cells surface that stimulate the degranulation process to release the
vasoactive and inflammatory mediators after series intracellular signal. The
granules contain the mediators:
Histamine
Serotonin
Lysosomal enzymes
Heparin
Eosinophils chemotactic factor ECF
Prostaglandine
Others
These mediators will be released to the neighboring tissues and fluids after
degranulation. Then clinical signs appear depending on allergen type and
allergic response either systemic or local. e.g. in asthma the symptoms or signs
are: nausea, sneezing, hard to breath, asphyxia coughing, tearing eyes and
others. (Figure 1)
Mast cells: they are basophils with more specification found in mucosa of
airways and gut as well as in connective tissues. They have specialized surface
receptors for the Fc portion of IgE antibodies.
4.Characteristics of this type of allergy
:
Acute allergic reaction, starts immediately after exposure to allergen (within
minutes) and lasts for 4-5 hrs.
3
Cause Eosinophilia (increase Eosinophils number in blood) and IgE levels
increase.
Severity depends on the type of allergen, dose of exposure and immune system
state. Most of these allergy kinds are seasonal e.g. Hey fever.
Examples:
Hey fever
Atopic dermatitis
Asthma
Pollen Allergy
Food and drugs Allergy
Vaccines Allergy
Clinical Example:
Anaphylaxis:
A systemic sever type I hypersensitivity, life threatening condition. Occurs
when the allergy mediators are released in high amounts and mixed to form
leukotrines mixture SRS-A (slow- reacting substance of anaphylaxis). This
mixture is 1000 times powerful than histamine or prostaglandins in contracting
bronchi.
This response physiological symptom starts with sudden anaphylactic shock,
hard to breath, abdominal cramps (some time), diarrhea, vomiting and may end
with death because of respiratory and cardiac failure.
Rapid administration of adrenaline (epinephrine) can stop shock progress.
Epinephrine raises blood pressure and reverses the action of SRS-A (SRS-A
drops down blood pressure), then restore respiratory and heart function. The
important exampleis the systemic anaphylaxis that occurs after drugs like
penicillin and bees biting. Blood pressure drops due to vasodilation after
mediators’ release. Also occurs in animals after injection with prepared Ags
during immunization experiments.
4
Type II Hypersensitivity
It is usually called Antibody-Mediated or antibody-dependent cytotoxic
hypersensitivity.
1. Causes or Motives:
Combination of surface Ag of the cell with specific Abs (IgG, IgM classes),
resulting in the death of that cell by stimulating phagocytic attack or starting the
complement pathway that leads to cell lysis. These cells are usually foreign cells
e.g. RBCs during blood transfusion.
2.
Target
:
Antigens on cell surface (part of the cell membrane), not against soluble Ag.
3. Immunological
Mechanisms:
When IgG or IgM antibodies bind to cell surface antigen forming Ag-Ab
complex, this will cause cellular damage by many ways:
1) Activation of complement system (classical pathway).C3b deposition with
anaphylatoxins C3a, C4a and C5a. then membrane attack complex
formation which cause lysis of target cell.
2) Antibody-dependant cell-mediated cytotoxicity occurs when the Abs (Fab
portion) bound to the surface Ag of the target cell. Then this bound Ab
will also bind to the phagocytic cells and natural killer cells (NK) by Fc
portion. Here the antibody works as a bridge between target cells and
effector cells of the immune system. (Figure 2)
4.
Characteristics of this type of allergy
:
1) Clinical signs depend on the type of the cell that has the target
antigen which induced this type of allergy. e.g. blood group
hypersensitivity differ from graft rejection.
2) Need specific immune response and specific antibody.
3) Cause necrosis because of cells lysis.
4) Life threatening some times.
5
Examples:
Blood grouping compatibility.
Rh Incompatibility
Graft rejection
Newborn hemolytic disease
Clinical Example:
Hemolytic disease of newborn:
Rh incompatibility occurs when Rh- negative mother and Rh+ father. When the
first fetus is Rh+ and during giving birth; the mother will expose to the Rh
antigens of the fetus. During second child Rh+; the anti-Rh antibodies (IgG) that
formed after the first child will cross the placenta and attack the Rh+ cells
(RBCs) of the fetus. After birth the infant develops Jaundice or hemolytic
disease of newborn. Before birth mothers liver filters the fetus blood. The
treatment is by remove fetal Rh+ blood and replaced by Rh- blood to stop
reaction between child Rh+ and antibodies of mother in child circulating blood
that crossed placenta.
Mothers with Rh- negative avoid these cases by passive artificial immunization
with Rhogam injections (anti-Rh antibodies commertialy called Anti-D). That to
avoid memory immune response in mothers' blood.
Type III Hypersensitivity:
Called immune complex hypersensitivity. Results after some infections e.g.
bacteria and during autoimmune diseases.
1.Causes or Motives:
1) High antigen load.
2) Weak or ineffective immune response.
3) Not enough function of macrophage to remove immune complexes
from blood.
2.Target
:
The antigen-antibody complex (Ag-Ab complex) which escape or avoid clear
(engulfment) by macrophages and deposited in body tissues.
6
3. Immunological
Mechanisms:
1) This type is also mediated by Abs(IgG or IgM) after forming, they bind to
soluble Ag(resulting from bacterial infection for example).
2) Ag-Ab complex that formed will be cleared by MФ.
3) Excess complex will deposit in any tissue and accumulate there.
4) Deposited complex will induce a number of inflammatory pathways or
reactions to clear tissues like attraction of PMNLs, releasing of proteolytic
enzymes causing local necrosis, vascular damage, odema, redness and
attraction of more PMNLs because of activation of complement system
which release of C3a, C4a and C5a anaphylatoxins, all these reactions end
with tissues necrosis.
4.
Characteristics of this type of allergy
:
1) The painful inflammatory lesions will appear during this type of
hypersensitivity in any tissue or organ that Ag-Ab complex deposited.
That will lead to this organ disorder within 7-10 days after exposure to
antigen.
2) Abs in this type formed during normal immune response against either
exogenic Ag (infectious or environmental) or endogenic Ag (self Ag in
autoimmune responses).
Examples:
Rheumatoid Arthritis (Joints)
Glomerulonephritis (Kidneys)
Lymphodenitis (Lymph Nodes)
Vasculitis (Blood Vessels)
Clinical Example:
Serum Sickness:
A disease occur because of type III hypersensitivity when a person get larg
doses of foreign serum e.g. horse serum antitoxins to protect against Tetanus
and Diphtheria.
7
Type IV Hypersensitivity:
Called Delayed type or cell-mediated type. Caused by a type of T-cells(CD4+)
Lymphocytes which called T
DTH
(Delayed Type Hypersensitivity). This type is
classified according to the clinical manifestations or signs and the body site that
involved.
1.Causes or Motives:
Cell mediated immune response against certain Ags resulting from long
standing infections or poisons exposure.
2.Target
:
Ag coated cells of the body, the Ags are:
1) Natural products, mostly Haptens of low molecular weight, like poisons
(ivy and oak) or industrial agents (Nickel compounds).
2) Prolonged infections (long standing) Ags like Leprosy, Tuberculosis,
Brucellosis and fungal infections.
3.Immunological
Mechanisms
:
1) Need first exposure and second exposure to form memory T-cells.
2) Engulfment, processing and presenting allergic or foreign Ag.
3) Sensitization and activation of T
DTH
and the production of cytokines or
lymphokines that involved in CMI e.g. Macrophage-activating factor
MAF.
4) MФ response and destroy Ag coated cells causing inflammation and
necrosis.
4.Characteristics of this type of allergy
:
1) It is called delayed because it occurs after 24-48 hr after exposure to
allergic Ag.
2) Cell-mediated immune response involving MФ, T-lymphocytes (T
DTH
) and
cytokines.
3) Cause Eosinophilia.
8
Examples:
Contact Dermatitis (Eczema)
Tuberculin reaction.
Clinical Examples:
Contact Dermatitis:
When allergic compounds penetrate to skin (Hapten), they will bind to self
protein and become immunogenic Ag , then expressed on APCs surface
(langerhance). During second exposure to same Ag it will induce type 4
hypersensitivity causing itching, redness, rash and swallow of skin site of
exposure.
Tuberculosis:
Mycobacterium tuberculosis infection is long standing intracellular infection.
When the Ag persist for long time, Granuloma will be formed. It’s the most
sever type of type 4 hypersensitivity. It is a type of chronic inflammation that
involves tissues transformation or damage. Leprosy infections are the same.
Granuloma:
It is a cyst include phagocytic cells which turned to Giant cells(large
multinucleus MФ) , and intracellular pathogen with some epithelial cells. This
can occur in lungs, heart and kidneys and cause tissues damage because of high
amounts of lysosomal enzymes released to surrounding tissues.