Download Immune Disorders

4/21/2017
Immune Disorders
Mahmoud Alkawareek, PhD
Introduction
• Immune disorder is a condition that results from
inappropriate (i.e. overactive) or inadequate (i.e.
underactive) immune response
• In general, immune disorders are classified as
hypersensitivity , autoimmune and immunodeficiency
disorders
• Hypersensitivity:
– In hypersensitivity, the immune system responds in exaggerated
or inappropriate way to a foreign substance and causes harm to
the body
– Hypersensitivity is divided to:
 Immediate (type I) hypersensitivity
 Cytotoxic (Type II) hypersensitivity
 Immune complex (Type III) hypersensitivity
 Cell mediated or delayed (type IV) hypersensitivity
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Immediate (Type I) Hypersensitivity
• Type I hypersensitivity (allergy) results from exposures to
an allergen (harmless foreign substance like protein or a
chemical bound to protein) that can produce exaggerated
immunological disorder.
• Allergens could be pollens, household dust (which contains
mites & their feces), dander (tiny particles of hair, feather,
skin), venoms from insect bites, certain foods (nuts, shell
fish, milk, eggs) and drugs.
• Genetic factors are thought to play a role in the
development of allergy.
• Exposure could be by inhalation, injection or ingestion
• First exposure to allergen usually produces no symptoms.
Mahmoud Alkawareek, PhD
Immediate (Type I) Hypersensitivity
• The 2nd exposure to the allergen is the one producing
the allergic signs & symptoms, even if allergen was in
very minute amounts.
• Non allergic factors can trigger the release of
mediators from mast cells without the involvement of
IgE, e.g. emotional stress & temp extremes like cold
air which injures the cell membrane of mast cells lining
the airway thus releasing mediators causing asthma.
• Breast fed infants are less prone to food allergies than
bottle fed infants because mother’s milk seals the
immature intestinal lining of the newborn against
entry of allergens, besides cow’s milk has potential
allergens.
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Immediate (Type I) Hypersensitivity
• Mechanism of type I hypersensitivity:
– In the initial exposure to an allergen, B cells are
activated & differentiate to plasma cells which
produce IgE against the allergen.
– Fc tails of the IgE bind to mast cells in respiratory
tract & GIT and to basophils in blood, leaving the
Ag binding site free to react with same allergen in
the future. This is called sensitization of mast
cells/basophils .
Mahmoud Alkawareek, PhD
Immediate (Type I) Hypersensitivity
• Mechanism of type I hypersensitivity: (cont’d)
– In a 2nd exposure to same allergen, it attaches to sensitized
mast cells or basophils by cross linking the IgE, this causes
degranulation which results in a rapid release of preformed
mediators from mast cells & basophils
– Histamine is the main preformed mediator. It dilates capillaries
& increase their permeability, causes bronchial constriction,
increase mucus secretion, stimulates nerve endings causing
itching & pain.
– Reaction mediators release from mast cells & basophils occurs
after degranulation. These mediators include prostaglandin D2
& leukotrienes. They also dilate & increase permeability of
capillaries, causes bronchial constriction, increase thick mucus
secretion and cause pain & itching. 3 leukotriene mediators
called SRS-A (Slow Reaction Substances of Anaphylaxis) is 1001000x more potent than histamine & Pg D2, it causes slow &
prolonged bronchial constriction.
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Mahmoud Alkawareek, PhD
Immediate (Type I) Hypersensitivity
• Anaphylaxis: is the harmful effects of IgE antibodies made
in response to a certain allergen. It could be localized or
generalized.
• Localized anaphylaxis:
– Atopy (localized allergic reactions): they occur at the site of
allergen entry, if through skin causes itching, redness and
swelling (wheal and flare reaction); if inhaled causes inflamed
mucus membranes of respiratory tract, runny nose & watery
eyes; if ingested, GIT inflamed with abdominal pain & diarrhea
& may cause skin rash.
– Hay fever or seasonal allergic rhinitis: (allergen is pollen grains);
symptoms are runny nose, watery eyes, sneezing, nasal
congestion & sometimes shortness of breath. Distinguished
from common cold by elevated eosinophils in nasal secretions.
High eosinophils in blood indicates allergy or infection with
helminths.
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Immediate (Type I) Hypersensitivity
• Generalized anaphylaxis:
– Begins with sudden reddening of skin, intense itching,
hives (urticaria: dark red bumps) & then develops to
respiratory anaphylaxis or anaphylactic shock
– Respiratory anaphylaxis: constricted airways filled with
thick mucus, allergic patient may die of suffocation
– Anaphylactic shock: blood vessels dilate suddenly & more
permeable causing abrupt drop in pressure leading to
death
– Generalized anaphylaxis requires immediate treatment.
Epinephrine (adrenaline) injection is given to relax smooth
muscles of respiratory airways & constricting blood vessels
Mahmoud Alkawareek, PhD
Immediate (Type I) Hypersensitivity
• Treatment of allergy:
– Desensitization (hyposensitization):
The only cure for allergy.
It involves injecting denatured allergen subcutaneously
(allergy shots) which can induce tolerance i.e. preventing B
cells from maturing into plasma cells to make IgE.
Also allergy shots may induce B cells to produce IgG
(blocking Ab) that binds to the allergen before it reaches the
IgE molecule bound to mast cells; i.e. IgG blocks the step
that results in mast cell degranulation
Desensitization may cause anaphylactic shock, so the patient
remains in the clinic for some time after the procedure
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Mahmoud Alkawareek, PhD
Immediate (Type I) Hypersensitivity
• Treatment of allergy: (cont’d)
– Antihistamines: do not cure but they alleviate the
symptoms, they are not effective against SRS-A of
asthmatic conditions.
– Corticosteroids:
reaction.
suppress
the
inflammatory
– Mast cell stabilizer: cromolyn
– Leukotriene inhibitors: either inhibit synthesis of
leukotrienes (e.g. Zileuton), or are leukotriene
receptors antagonist (e.g. Montelukast)
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Cytotoxic (Type II) Hypersensitivity
• Specific Ab react with cell surface Ags interpreted
as foreign substance, leading to destruction of
these cells by phagocytosis, killer cell activity or
complement-mediated lysis.
• The cells to which Ab are attached & the
surrounding tissue are damaged from the
inflammatory response.
• Examples are mismatched blood transfusion &
hemolytic disease of the newborn (motherinfant-Rh incompatibility)
Mahmoud Alkawareek, PhD
Cytotoxic (Type II) Hypersensitivity
• Blood transfusion reaction:
– Human RBC has genetically determined antigens; A or
B or AB or neither (O) (ABO blood gp system) & has no
IgM against his blood Ag.
– If a sensitized patient receives blood with different
RBC Ag’s, then IgM will react with these Ag’s (on the
RBC)
and
causes
agglutination
(clumping),
complement is activated & hemolysis occurs in blood
vessels.
– This results in fever, nausea, vomiting, chest & back
pain & may lead to renal failure due to release of
hemoglobin from ruptured RBC.
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Mahmoud Alkawareek, PhD
Cytotoxic (Type II) Hypersensitivity
• Hemolytic disease of the newborn (erythroblastosis
fetalis):
– Human RBCs also have Rh antigens; RBC with Rh Ag is
designated Rh+ve, RBC lacking it are Rh-ve.
– Normally Rh antibodies are not present in serum but when Rhve woman carries Rh+ve fetus, Rh+ve antigen leaks across
placenta during delivery, miscarriage or abortion. Then immune
system of the mother becomes sensitized.
– When the mother carries another Rh+ve fetus, anti-Rh
antibodies cross the placenta & cause type II hypersensitivity
rxn in the fetus, where fetal RBCs agglutinate, complement
system activated & RBCs are destroyed.
– 12% of the cases results in stillbirths. If the baby is born, he’ll
have enlarged liver & spleen due to efforts of these organs to
remove damaged cells, high bilirubin which causes yellowcolored skin and eyes (jaundice).
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Immune Complex (Type III) Hypersensitivity
• Results from the formation of Ag-Ab complexes that are
persistent or continuously formed
• Normally, large immune complexes (resulting from Ag-Ab
rxn) are removed by phagocytosis in spleen & liver.
However, small immune complexes (Ag-Ab) escape
elimination from blood & deposit in organs, tissues or
joints.
• These complexes activate complement system and cause
basophils & mast cells to release histamine & other
allergic/inflammatory mediators.
• Phagocytes are attracted to these sites & release hydrolytic
enzymes that damage the tissues & if the Ag remains for
long time it becomes chronic. e.g. glomerulonephritis from
some streptococcal infection
Mahmoud Alkawareek, PhD
Immune Complex (Type III) Hypersensitivity
• Post-infectious glomerulonephritis:
– In this disease, some strains of Streptococcus
pyogenes has cell wall Ag which when processed by
immune system resembles tissue components in the
glomeruli.
– Ab produced can not distinguish between cell wall &
human glomerular tissue & Ag-Ab complex formed.
– These complexes are deposited in kidneys,
complement is activated, inflammatory response
starts & phagocytes release hydrolytic enzymes which
results in damage to glomeruli and leakage of blood &
protein in urine.
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Cell Mediated (Type IV) Hypersensitivity
• It is also called delayed hypersensitivity as the response
takes more than 12hrs to develop
• On first exposure, Ag bind to APC (e.g. macrophages) that
presents it to TD cells.
• When another exposure occurs & APC presents the Ag, the
sensitized TD cells release various cytokines which cause
inflammatory rxn that attract macrophages to the site.
• APCs release mediators that add to the inflammatory
process.
• This results in occurrence of reddened inflamed skin,
swelling and itching (i.e. eczema).
• This hypersensitivity rxn begins within 4-8 hrs of next
exposure & eczema starts within 48 hrs.
Mahmoud Alkawareek, PhD
Cell Mediated (Type IV) Hypersensitivity
• Examples:
– Contact dermatitis: occurs due to exposure to certain
allergens such as poison ivy, rubber, dyes, soaps,
cosmetics, topical medication, nickel and chromium
(jewels & watches).
– Granulomatous hypersensitivity: the most serious, it
occurs when macrophages engulf pathogens but failed to
kill them. The protected pathogen survive & may divide. T
cells sensitized to the Ag elicits hypersensitivity rxn
attracting several cell types to the site (skin or lungs). A
granuloma in skin (leproma) or in lungs (tubercle)
develops. This kind of hypersensitivity is the most delayed,
it appears after more than 4wks from exposure to antigen.
• Tuberculin skin test (PPD test): tuberculin (purified protein
derivative (PPD)) is injected subcutaneously. If a person has been
exposed to the bacterium before, an induration (raised, and hard
region) will form within 48 hours
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Mahmoud Alkawareek, PhD
Autoimmune Disorders
• Occurs when individuals become hypersensitive to specific
Ag on cells or tissues of their own body, i.e. a self Ag elicits
immune response that produces auto-antibodies against
his own tissues. Also it can be T cell mediated.
• These disorders may affect single organ/tissue or can affect
multiple body organs
• Examples:
– Myasthenia gravis: it involves loss (or reduced number) of
acetylcholine (ACh) receptors from neuromuscular junction due
to their attack by IgG autoantibodies.
 This results in muscle fatigue, weakness, eyelid drooping & double
vision.
 Treatment: steroids, Ach agonists (neostigmine and pyridostigmine),
removal of thymus gland (malignant & benign tumors)
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Autoimmune Disorders
• Examples: (cont’d)
– Rheumatoid arthritis (RA):
It affects the joints of hands & feet of opposite sides equally.
More prevalent in women.
Involves interaction of T cells with Ag (either self Ag in joints
or microbe Ag mimicking self Ag of joints) leading to release
of cytokines that initiate local inflammation in the joint,
attracting macrophages & release of degrading enzymes all
of which can damage the cartilage. This may lead to
deformities in fingers.
Treatment: steroids, NSAID’s, physical therapy, joint removal.
Recently, producing Ab against the cytokine (TNF = tumor necrosis
factor alpha) which triggers immune response, prevents TNF action
Mahmoud Alkawareek, PhD
Autoimmune Disorders
• Examples: (cont’d)
– Systemic lupus erythematosus (SLE):
Systemic autoimmune disease, characterized by reddened
skin rash, occurs more in women than men
Autoantibodies (IgG, IgM, IgA) produced against proteins in
the nucleus of host cells
Immune complexes are deposited between the dermis &
epidermis, in blood vessels, joints (arthritis), glomeruli &
CNS causing inflammation at these sites; patients usually die
from kidney failure
SLE has no cure, treatment includes antipyretics (fever),
coricosteroids (inflammation) and immunosuppressants (to
reduces immune rxns).
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Graft Rejection (Transplantation)
• The transfer of tissue (graft tissue) from one site to
another, if on the same individual (autograft), between
genetically identical individuals like identical twins
(isograft), if between 2 non-identical individuals
(allograft).
• All human cells (including heart, kidneys, etc..) have a
set of self Ags called histocompatibility antigens coded
from certain genes. These Ags are identical in identical
twins only, while other family members have mixture
of similar & different Ags.
• If donor & recipient Ags are different, recipient T cells
recognize these cells as foreign & destroy them by
stimulating cytotoxic cells & stimulating B cells to
produce Ab resulting in graft (transplant) rejection
Mahmoud Alkawareek, PhD
Graft Rejection (Transplantation)
• Immunosuppressant therapy is used to
minimize graft rejection, such as:
– Radiation: X-ray to lymphoid tissues suppresses
the immune system.
– Methotrexate: an antimetabolite that affects B
cells & T cells.
– Cyclosporine A: a fungus derived peptide that
suppresses (but doesn’t kill) T cells & does not
affect B cells. It is used to prevent graft rejection.
But it increases the risk of developing cancer.
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Immunodeficiency Diseases
• Disorders that result from absence of active
lymphocytes, NK cells, or phagocytes,
presence of defective lymphocytes or
phagocytes or destruction of lymphocytes.
• They are divided to:
– Primary immunodeficiency diseases
– Secondary (acquired) immunodeficiency diseases
Mahmoud Alkawareek, PhD
Immunodeficiency Diseases
• Primary immunodeficiency diseases:
– Caused by genetic defects like failure of thymus gland
to develop or absence of B cells and/or T cells.
– Agammaglobulinemia: a disease in which B cells &
therefore antibodies are absent. Treated with high
doses of gamma globulins (immune serum) &
antibiotics.
– Severe combined immunodeficiency (SCID)(bubble
boy disease): absence of B cells & T cells. Treatment:
Bone marrow transplant, gene therapy (to replace
defective gene with functional one) is a new
promising approach.
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Immunodeficiency Diseases
• Secondary (acquired) immunodeficiency diseases:
– Caused by infectious agents (e.g. HIV) certain malignancies
like (e.g. Hodgkin’s disease) and immunosuppressant
drugs.
– In this case, B cells and/or T cells are destroyed after being
developed normally
– AIDS (Acquired ImmunoDeficiency Syndrome):
 Caused by ‘human immunodeficiency virus’ (HIV)
 HIV targets & damages TH cells, dendritic cells & macrophages.
 Without activated TH cells & macrophages the immune system can
not attack the virus & without TH cells, B cells can not be
stimulated to form plasma cells to produce Ab.
 AIDS patients are exposed to several infectious (viral, fungal &
bacterial) diseases and malignancies
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