HYPERSENSITIVITY REACTIONS

- Exaggeration in the immune response can have damaging

consequences or even lethal results.
- Hypersensitivity reactions:

- Type-I: (immediate hypersensitivity)

- Commonly named allergic reactions or allergy, also called
anaphylactic reaction.
- It is mediated by IgE. Binding of IgE to its high affinity receptor
FcRI on mast cells through its Fc portion. The reaction takes
place in the presence of the antigen if bound to IgE.

- a cascade of events leads to release of inflammatory mediators and

cytokines from mast cells and basophils.
-Type-II:
Called cytolytic or cytotoxic reaction. The reaction takes
place when IgG or IgM bind self cells and the formed
Ag/Ab complex lead to activation of complement system.
Activation of complement shall cause destruction for cells.

-Type-III:
This reaction take place as a result of Ag/Ab complex
formation and complement system activation as a result.
Production of anaplylatoxins (C5a, C4a...) should attract
leukocytes which get activated and start to release lytic
and toxic substances that affect and cause damage to local
tissue.
-Type-IV:
- The cell mediated reactions or as ever know as delayed-type
hypersensitivity (DTH).

- This reaction is mediated by T-cells (CD4+ and CD8+). TH1

clone of CD4+ is the one who has the main role.

- The activated TH1 cells release cytokines that cause

accumulation and activation of macrophages causing
local damage. (Delayed reaction: days or weeks).
 HYPERSENSITIVITY TYPE-I

Generaal characterstics of allergic reactions take place over

THREE phases:

Sensitization: IgE produced after immune response to a

particular antigen. The produced IgE binds its receptor
on mast cells and basophiles.
- Activation: Re-exposure to the antigen which cause
immediate response for mast cells and basophils by releasing
a very potent pharmacologically active substances. These
substances usually stored in special granules within these
cells.

- Effector: As a result of the released pharmacologically active

substances which they consider as strong inflammatory
mediators, complex and strong responses takes place in the
sight of the reaction. Responses may include rhinitis,
sneezing, itchiness and asthma.
 HYPERSENSITIVITY TYPE-I
Sensitization phase:
Allergic reactions are IgE mediated. IgE can be produced normally
by individuals yet the individuals have no allergic reactions.
Some antigens if given parenterally (subcutaneous, intra-
muscular or intravenous) but not alimentary.

Sensitization to a particular antigen (allergen) can occurs through

many ways (skin contact, ingestion, injection and inhalation).

Many people produce IgE against airborn antigens specially those

whom encountered with mucosal surfaces (linings of nose, lungs,
conjunctiva).

Approximately 50% of the population generates an IgE response to

airborne antigens that are encountered only on mucosal
surfaces.
- Only few individuals when re-exposed to the same allergen develop
symptoms.
- Airborn allergens cause common symptoms referred to as hay
fever (rhinitis, sneezing and watery eyes).

- Terms like atopy “out of place”/ tendency to develop allergic diseases and
atopic is frequently used.
Atopy used to describe the reaction itself
Atopic used to describe the affected person.

- IgE production believed to be controlled by MHC molecules

(genetically).
- IgE high affinity receptor (FcRI) is also believed to play a role in
becoming atopic.
- Other IgE regulatory genes are also involved, including the TH2
IL-4 gene cluster which contains genes for IL-3, IL-4, IL-5, IL-9,
and IL-13.
 TH2 Cell Dependency of IgE Antibody Production

- Cytokines of TH2 clone, mainly the cluster of genes responsible

for the production of cytokines IL-4, IL-3, IL-5, IL-9 and IL-
13.

- Scientific evidences and clinical assays suggested that IL-4 play

a major role in IgE production:

- Neutralizing IL-4 in mice inhibit production of IgE.

- IL-4 knockout mice can’t produce IgE following infection
with Nippostrongylus (nematod).
- Atopic individuals serum has higher level of IL-4 than
normal individuals (tenfold higher)
- Sensitization can be achieved passively, by injecting serum
contains IgE from atopic individual into the skin of non allergic
individual (procedure known as Prausnitz-Kustner, PK).

• - Two day later of antibody injection, and if the recipient

injected with the proper allergen he will develop (urticarial
reaction / hives) allergic reaction called passive cutaneous
anaphylaxis (PCA).

- Low levels of IgE antibody in nonallergic individuals could be

maintained by suppressor effects mediated by IFN-γ produced by TH1
cells, which downregulates IgE production.

- Distrubtion of TH2/TH1 cytokines balance (upregulate IgE

/downregulate IgE) due to infections results in overproduction of IL-4
by TH2 cells and, ultimately, increased IgE production by B cells.
- Mast cells, the main effector cells responsible for allergic reactions,
are generally found around blood vessels in the connective tissue, in
the lining of the gut, and in the lungs.

- They are large mononuclear cells that are heavily granulated, they
are derived from progenitor cells that migrate to tissues where they
differentiate into mature mast cells.

- Basophils also take part in allergic responses

- Mast cells and basophils both have high affinity receptors (FcεRI) on
their cell membranes, that once bound persists at the cell surface for
weeks.

- So, cells are sensitized as long as enough IgE antibody remains

attached; the IgE molecules will trigger the activation.
- Activation phase:
Activation phase starts when sensitised mast cell or basophile
is activated and release its granules which contains the
highly inflammatory mediators.

Activation of sensitised mast cell should involve the presence

of two bound close IgE molecules and a multivalent
allergen that capable of cross-link the two IgE molecules.
- Activation of mast cells lead to de-granulation of these cells.

- Physiological consequences and clinical symptoms is different

according to the allergen dose and route of entry.

- De-granulation of mast cells in the GIT cause increase in the

fluid secretion and peristalsis, diarrhea and vomiting is also
present.
Degranulation of mast cells in the lungs should lead to decrease
in the diameter of trachea and bronchi, increase in the mucus
secretion. Accumulation of mucous in the narrowing airways
may lead to congestion and blockage of these passages
(coughing, wheezing and phlegm).

• Degranulation of mast cells in the blood vessels cause

increase in blood flow and increase in vascular permeability
which lead to increase in the amount of fluid in tissues
(edema).

• Degranulation of mast cells can takes place by other factors

than allergen such as anti-IgE molecules, some lectins,
chemicals like ionophores which increase Ca+ influx into the
mast cell triggering signaling cascade leading to degranulation.
Drugs such as codeine and morphine. Heat and cold-induced
urticaria. Anaphylatoxins C3a and C5a, and iodinated
activation of mast cells Cross-linking of FcεRI
can also be achieved receptors may also be
using calcium accomplished in other
ionophores, which experimentally useful
induce a rapid influx of ways,
calcium ions into the cell,
triggering the signaling
cascade leading to
degranulation.
Degranulation of mast cell is a complicated multi events process
starts with change in the fluidity of the cell membrane due to
methylation of the phospholipids. Which lead to increase in the
concentration of intracellular cAMP followed by an increase in
Ca+ influx.

High concentration of cAMP should slow the degranulation

process. The enzyme adenylate cyclease play a role in slowing
the degranulation process.

- Activation of adenylate cyclase, the enzyme that converts adenosine

triphosphate (ATP) to cAMP, play role in controlling anaphylactic
events.
- An increase in intracellular concentrations of cAMP is
effective in inhibiting the histamine release from mast cells.

- Many antiallergic drugs inhibit the increase in intracellular

Ca2+ level or to increase intracellular cAMP concentrations of
mast cells.
HYPERSENSITIVITY TYPE-I
Effector phase:

- During this phase symptoms appear due to the potent

pharmacologically active substances.

- Cytokines are also secreted by activated mast cells: IL-3, IL-4, IL-
5, IL-8, IL-9, tumor necrosis factor (TNF)-α, and GM-CSF
(granulocyte macrophage–colony stimulating factor).

- They play a role in attracting and activating inflammatory cells

locally.
pharmacologically active substances or inflammatory mediators
classified into two categories:
1- Preformed mediators
2- newly synthesised mediators (de novo).

Preformed mediators:
These mediators usually stored in the granules of mast cells,
found bounded to a matrix protein.
Histamine: synthesised from the amino acid histidine.
Found bounded by electrostatic interactions to a matrix
protein heparin.
After degranulation histamine binds different types of cells
through specific receptors H1 and H2 that found on different
tissue.
- Histamine receptors distribution is varied on cells with
different effects.
- If histamine binds H1 receptor on smooth muscles it causes
muscle constriction (‫نقباض‬J‫)ا‬, but if histamine binds H1
receptor on endothelial cells it causes contraction and
increase in gaps between cells (increase permeability).

- Binding of histamines to H2 receptor increase blood vessels

permeability. In stomach: increase mucus secretion and
cause acid secretions -Gastroesophageal Reflux Disease
(GERD).
- Symptoms may persists even with use of drugs due to the
presence of other inflammatory mediators.
The effects of histamine release are responsible for some signs of
systemic anaphylaxis:

- Difficulty in breathing (asthma) due to constriction of smooth

muscle around the bronchi.

- Drop in blood pressure due to extravasation of fluid into tissue

as a consequence of increase of permeability of blood vessels.
- Antihistamine drugs target H1 and H2 receptors if given very
soon can counteract the effect of histamine.

Diphenhydramine (Benadryl) for H1 (first generation) /

compete for H1 receptor sites with histamine.

Second generation of H1 blockers developed during the 90s

and this include loratadine (Claritin) and fexofenadine
(Allegra).

Cimetidine (Tagamet), famotidine (Pepcid), nizatidine and

ranitidine (Zantac), all are H2 blockers.
Omeprazole (Prilosec), lansoprazole (Prevacid),
pantoprazole (Protonix) and esomeprazole (Nexium), these
drugs known as proton pump inhibitors (PPIs).
Other drugs also can be used to reverse the constriction of
bronchioles and other signs.
- Bronchodilators: Aminophylline , Salmeterol,
metaproterenol and epinephrine.

- Leukotriene modifier: (used to manage allergic rhinitis or

allergies, as well as prevent asthma): Zafirlukast, Ziluton.
- Corticosteroids: Hydrocortisone, methylprednisolone,
prednisone.
Other Preformed Mediators:

Serotonin: Found in some species mast cells, it action very

similar to histamine.

Chemotactic factors: produced following degranulation of

mast cells, such as eosinophilic chemotactic factor (ECF)
which attracts eosinophils, IL-8 attracts neutrophils.

Eosinophils believed to play a relieving role by secreting

histaminase and arylsulfatase.
- Later and after the use of antihistamines they were ineffective in
controlling constriction of smooth muscles, this let to the discovery
of the slow-reacting substance of anaphylaxis (SRS-A) / A group of
molecules called leukotrienes

‘De novo’ newly synthesised mediators:

Symptoms of allergic reaction can last long time even if treated

with antihistamins. Production of other inflammatory mediators
known as SRS-A (slow-reacting substance of anaphylaxis) is
responsible for the continuation of symptoms.

SRS-A is consist of a set of peptides that are coupled to a metabolite

of arachidonic acid (membrane lipid) called leukotrienes (LTs).
• Newly synthesised substances produced from membrane lipid
(arachidonic acid) these substances called leukotrienes. LTs are
named LTB4, LTC4, LTD4 and LTE4 (cause of antihistamine-
resistant asthma). They are very potent in smooth muscles
contractors and for long and extended period. They are the
primary cause of antihistamin resistant asthma.

- Thromboxanes (TXA) and prostaglandins (PG):

Both produced from arachidonic acid but from different pathway
that produced LTs. Cyclooxygenase and lipooxygenase pathways.
- Platelet activating factor (PAF): (induces platelets to release
histamine and serotonin), most potent bronchoconstriction and
Late phase reaction:
- As a result of the degranulation process and the secretion of
proinflammatory mediators, inflammatory response and
increase the number of infiltrated cells (neutrophils and
eosinophils) take place at the site of activation.
- Production of cytokines such as GM-CSF, IL-3, IL-4 and
IL-13 promote activities of eosinophils.

- Such reaction referred to as late-phase reaction, this reaction

mostly takes place after 48 hours of re-exposure to the
allergen. The combination of all factors can drive and
initiate a second but milder attack regarding smooth
muscles contraction, with continual presence of edema.
- Bronchoconstriction causes / test, ???
Methacholine is used to diagnose bronchial hyperreactivity.
- Methacholine (Provocholine) is a synthetic cholin ester that acts
as a non-selective muscarinic receptor (acetylcholine receptors)
agonist in the parasympathetic nervous system.
- Methacholine challenge test or histamine challenge test.
Both drugs provoke bronchoconstriction. Histamine causes
nasal and bronchial mucus secretion but methacholine does not.

The degree of narrowing can then be quantified by

SPIROMETRY. Atopic people have hypersensitivity will react
to lower doses of drug.

Methacholine act on non H1 receptor manner but (M3receptor)

non-selective muscarinic receptor.
- Activation of eosinophils can takes place by other aspects
involving IgG-Ag. Eosinophils express receptors for IgG Fc
fragment. IgE also can binds FcRII (CD23) a low affinity
receptor and cause eosinophils activation.

- Secretion of major basic protein (MBP) and eosinophilic cationic

protein (ECP) are very important and effective against
parasites. MBP is highly toxic to respiratory tract epithelium
and ECP is neurotoxic substance.

- Activation of neutrophils lead to their degranulation causing

release of a strong lysosomal enzymes which cause grate
damage to tissue.

- Neutrophils also have receptor for IgG Fc portion.

Clinical aspects of hypersensitivity reactions:
Mast-cell degranulation is the central mechanism in each of these
reactions.

1- Allergic rhinitis:
- Commonly termed as hay-fever.
- Caused by airborn allergen include plant pollens, dust and
animal dander etc....

- Allergen usually reacts with IgE bound to Mast cells located

in respiratory passage and conjuctiva of eyes, causing
activation and degranulation for these cells.

- Typical symptoms of allergic rhinitis include: sneezing,

coughing, nasal congestion, red eyes, itchy eyes, runny nose.
2- Food allergies: Resulted from digestion certain types of food (eggs,
peanuts) by atopic individuals.

- The ingested food acts as an allergen and cross-link IgE bound to

mast cells located in upper and lower parts of gastrointestinal
tract.
- Foods can trigger the cross-linking of allergen-specific IgE on
mast cells of the upper and lower gastrointestinal tract.

- Mast-cell degranulation leads to localized smooth muscle

contraction and vasodilation, causing vomiting and diarrhea.

- Due to increase in the permeability; the allergen may transfer to

the peripheral system where it can react with mast cells located in
the skin causing a case called wheal and flare reactions (commonly
known as hives).
‫االنتفاخ والتوهج‬
4- Atopic dermatitis:
- Mostly seen among children , appears as skin lesions
(erythematous and pus).

- The eruption of skin is due to the degranulation of mast

cells after activation caused by the allergen, cytokines
also play a role in the inflammation process.

5- Asthma:
Common localised anaphylaxis. Chronic disease to the
lower respiratory system passages. Main and most
important clinical symptoms include airflow limitation
(difficulty in breathing)
Asthma results of three pathophysiologic events:
i- Reversible obstruction.
ii- Fast and sever responsiveness to a variety of
physical and chemical stimuli.
iii- Inflammation.

- Asthma also can develop from exercise and exposure

to cold temperature (intrinsic asthma).
- Intrinsic asthma is chronic (not episodic), comes
late with age, resulted from exposure to pollutants,
inhalation of fumes, smoking.
Clinical tests for allergies:

Skin-prick test: involves the administration of the allergen intra-

dermaly . Positive test develops sings within 10-15 min. Signs include
erythema and edema. A positive response called wheal and flare.

Quantitative assays can be applied. Radio-allergosorbent test (RAST).

- Allargen usually bounded with insoluble matrix (eg. beads).
- The allergen coated matrix then mixed with patients serum.
- If patients serum has specific IgE to the allergen they will bind the
allergen.
- The allergen coated matrix with bounded IgE then removed,
radiolabel led antibodies to IgE used and the radioactivity is measured.
 Radioallergosorbent test

RAST methodology. An allergen is adsorbed covalently to a solid particle, then

serum of patient is added to react with the allergen. Next, a radiolabeled anti-IgE
antibody identifies the previous formed immune complexes. The radiation
generated is measured by a radiation detector.
THE PROTECTIVE ROLE OF IgE: Histamine produced in response to worm antigens cross-linking
IgE on the surface of mast cells (and eosinophils). Increased permeability bring serum
components (IgG antibody) that binds to the surface of the worm and attracts
the eosinophils. The eosinophils bind to the IgG-coated worm via IgG Fc, and release MBP.
 HYPERSENSITIVITY TYPE-II & III
- Called cytolytic or cytotoxic reaction.
- The reaction is mediated mostly by IgG or IgM (rarely, IgA and IgE).
- Antibodies involved this type of reaction are mostly auto-antibodies.
- They targets are self antigens or modified self antigens (by drugs).

- Cells bounded with these antibodies practically are opsonised.

- These opsonised cells become vulnerable, and can be destroyed by

different mechanisms or compromise the cell function.
- Complement system.
- Antibody-dependent cell cytotoxicity (ADCC).
- Antibody-mediated cellular dysfunction.
Damage to the target cell may be mediated by either of two mechanisms:

- Cytolysis via complement-mediated reactions: antibodies react with cell

membrane self-antigens followed by complement fixation and activation.

- Production of C3b effectively opsonize the target cell and enhance

phagocytosis and destruction of the cell by macrophages and neutrophils
expressing surface Fc receptors or receptors that bind C3b.

- Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): utilizes Fc

receptors (on NK cells, macrophages, neutrophils, eosinophils).

- Lysis involves the release of cytoplasmic granules (modified lysosomes)

containing perforin and granzymes. ADCC reactions are typically
triggered by IgG binding to IgG-specific Fc receptors (FcγIII, also known
as CD16)
Examples of hypersensitivity type-II reactions:
1- Transfusion reactions: incompatible ABO system blood
transfusion.

- Destruction of RBCs resulted from complement-mediated

cytotoxic reactions. Based on efficiency of IgM antibody in
activating complement (a single IgM molecule is sufficient
to activate many complement molecules)

- Clinical complications extended to possible kidney damage

due to the accumulation of RBCs membranes in tubules of
kidney which can cause blockage of tubules.

- Toxic effect of the heme complex.

Drug-induced reactions: Drugs can act as haptens in some individuals,
these haptens can bind cells or some blood constituents leading to
antibody production.
- The produced antibody combines with cells coated with the drug and
cause cytotoxic damage.
- Different types of cells can be affected via this process, according to
the drug binding or coating.
- Example: lysis of the platelets and causing thrombocytopenia (low
blood platelet count).

Thrombocytopenia: low counts of blood platelets, which can cause

purpura (haemorrhage into the skin and mucous membranes).
Quinidine group, heparin, Antibiotics: Cephalosporins,
Ciprofloxacin, Clarithromycin, Gentamicin, Penicillins (Ampicillin,
Apalcillin, Methicillin). Analgesics (pain-killer): Diclofenac,
Fenoprofen, Ibuprofen. Cardiac medications and diuretics: Digoxin,
Captopril, Anti-epileptic drugs-Phenytoin.
- Leukocytopenia (agranulocytosis): low blood count of
WBCs: Most anti-psychotic drugs cause leukocytopenia-
Chlorpromazine (Chlorprothixine), Cefadyl, Cefuroxime
(cephalosporins), Aquatag.

- Haemolytic anaemia: Low count of red blood cells: many

drugs showed haemolytic anaemia: Methotrexate is used
to treat choriocarcinoma, leukemia in the spinal fluid,
osteosarcoma, breast cancer, lung cancer.
Cephalosporins, Nonsteroidal anti-inflammatory drugs
(NSAIDs).

- Destruction of normal cells (platelets, WBCs, RBCs) mostly

mediated by complement system or phagocytosis after
opsonised by C3b and bounding to Fc portion of IgG.
Rh incompatibility: Fetuses of mothers with Rh- blood is most
susceptible for the consequences, if fathers were Rh+. This
include erythroblastosis fetalis (hemolytic disease of the
newborn).

- Rh incompatibility can be prevented by giving the mother an

injection contains anti-Rh antibodies (Rhogam): Rho(D)
immune globulin (RhIG) at 26–28 weeks’ of gestation and
again within 72 hours after delivery.
This causes a rapid clearance of Rh+ cells, a reaction is
mediated by phagocytosis.
- Myasthenia gravis ‫ي‬( ‫)ا لوهنا لعضل‬: An example of antibody-
mediated cellular dysfunction. /leads to varying degrees of
skeletal muscle weakness)
- Autoantibodies interact with acetylcholine receptors located in
neuro-muscular junctions causing antigonistic effect.

- Acetylcholine released from nerve ends to facilitate transmission

of nerve impulse from the nerve to the motor effector cells
(skeletal muscles).

- The formed autoantibodies impair neuromuscular transmission

causing muscle weakness.
- Symptoms: muscular weakness and fatigability related specially
which involved in talking chewing and swallowing. Eye muscles
one of the early muscles to be affected causing ptosis (dropping
of eyelid).
Graves’ disease: An autoantibodies bind receptors of thyroid-
stimulating hormone (TSH) in the thyroid gland causing
continuous and over activation for the gland, leading to the
secretion of high concentration of the thyroid hormones
(hyperthyroidism).

- Continuous synthesis and secretion of hormones leads to

enlargement of the gland (goiter).

- Symptoms may varied from one patient to another which may

appear as insomnia, hair loss, hyperactivity, weight loss,
tremor (‫ )رعاش‬and sweating. Around 50% of patients develop
Graves’ ophthalamopathy.
Four common disorders
of the thyroid which
are:

- Hashimoto’s disease,
- Graves’ disease,
- Goiter,
- Thyroid nodules.
Reactions involving other cell membrane determinents:
1- Post certain infections some individuals raise autoantibodies against
self antigens like RBCs. These antibodies cause destruction for RBCs
causing anemic diseases.
- The reaction is mediated by complement system or phagocytic cells (C3b
bound to Fc portion).

- The reaction is promoted at lower temperatures so it is termed cold

agglutinins. Regions of lower body temperature are affected (fingers and
toes), leads to effective antibody binding and destruction of the RBCs.

2- Idiopathic thrombocytopenia purpura (immune thrombocytopenia

purpura (ITP)), an autoantibodies targets the platelets causing their
destruction.
Decrease in platelet numbers may lead to bleeding (purpura).
2- Goodpastur’s disease, where autoantibodies attack the
basement membrane of lungs or kidneys causing severe
haemorrhages in lungs and glomerulonephritis in kidneys.

3- Pemphigus vulgaris (pemphix, meaning blister), autoantibodies

against desmosomes in the skin causing destruction and
loosing of the cohesion between keratinocytes in the
epidermis. The diseases cause separation of the dermis from
the epidermis.
Wegener’s granulomatosis:
- A blood vessel inflammation mainly in the nose, lungs and
gromerluli.
- Patients show autoantibodies that react with proteinase-3
(proteolytic enzyme in neutrophils).
- These autoantibodies are referred to as classic anti-
neutrophil cytoplasmic antibodies (cANCA).
- When neutrophils get activated these antibodies expressed on
the surface and they become accessible to the cytoplasmic
proteases.
- The complex should prevent neutrophils from migration and
stimulate the oxidative burst , cytokine and enzymes release
causing damage to the vessels walls.
Prevention and treatment to hypersensitivity type-II:

- For IgM mediated reactions (incompatible transfusion) careful

checking of blood groups (cross matching).

- For IgG reactions: reduction of autoantibody levels or

prevention of effector cells from causing the damage is most
effective mechanism of treatment.
- Immunosuppressive drugs can be used (note that their
effect is slow: 2-3 weeks).

- In urgent cases plasmapheresis can be applied (extracorporeal).

HYPERSENSITIVITY TYPE-III:
- This type of reaction can be systemic or local. Its mediated by the
presence of immune complexes.
- Removal of immune complexes is usually carried out by
complement system factors. (immune complexes are removed by
phagocytic cells (have IgG Fc receptor), or via RBCs that have C3b
receptors, that later phagocytosed in liver).

- Recently a serum protein identified as histidine-rich glycoprotien

(HRG) (synthesised in the liver) found to have a role in the immune
complexes removal.

- Failure in removing these complexes can lead to the deposition of

these complexes in tissues like joints, kidneys, heart and even
skin.
- Damage caused by these complexes depends upon the location of
the deposition.
- Formation of immune complexes can be initiated by exogenous
antigens or endogenous antigens.
- Exogenous Ags can be bacteria or viruses and can access the
system by different routes.
- Whereas endogenous antigens self components or Ags can be a
target for autoantibodies (DNA is the targeted Ag in Systemic
Lupus Erythematosus-SLE).

- Type III hypersensitivity reactions can be systemic reactions

(systemic immune complex disease) or localized (localized
immune complex disease).

- CIC are deposit in the kidneys, skin, joints, choroid plexus

(brain), and ciliary artery of the eye.
- IgG is the main immunoglobulin involved. IgM can also be
involved.
Three phases of systemic immune complex
disease

1- Formation of Circulating
immunocomplexes (CIC)

2- Deposition of CIC in various tissues.

3- Initiates of inflammatory reactions.

- Larger immune complex are rapidly

removed by phagocytic cells (considered
harmless).

- Small or intermediate complexes circulate

for longer periods of time and bind less
avidly to IgG Fc. Therefore, small-to-
intermediate sized immune complexes tend
to be more pathogenic.
Systemic-immune complex disease:

1- Serum sickness:
- Some cases needed to be treated with passive immunisation.
This requires administration of antiserum from
immunized different species (heterologous serum) which
could lead to produce immune response against the
administrated antiserum.

- Production of antibodies could produce Ag/Ab complexs.

The complexes deposit in various tissues causing
symptoms like fever, joints pain and blood vessels
eruption.
Example of systemic immune complex disease: toxins of
diphtheria and tetanus.
Infection-associated immune complex disease: best example:

Rheumatic fever, some individuals had bacterial infections like

group A streptococci develop antibodies (against streptococci cell
wall and membrane) which can cross react with self antigens like
heart tissue, joints/ cartilage, and kidneys. The complex (Ag/Ab)
may lead to activation of the complement system.

- Produced anaphylatoxins (C3a, C5a) attract neutrophils,

macrophages platelets which all secrete lytic substances which
cause damage to the tissue.

- In rheumatoid arthritis, there is evidence for the production of

rheumatoid factor (an IgM autoantibody) that binds to the Fc
portion of normal IgG, leading to the formation of immune
complexes.
Localised immune complex disease:

Arthus reaction: Immune complex localised in a particular

location like lungs and kidneys causing damage.

Example of localised immune complex disease is:

farmer’s lung, patient has extrinsic allergic alveolitis.

Immune complex diseases in kidney can result in two

clinically defined syndromes.
1- Nephrotic syndrom (protein leaks into urine) and there is
gradual onset renal failure.
2- Nephritis, (presence of protein and blood in the urine)
and there is a rapid onset renal failure.
Both types of diseases caused by inflammation of the glomeruli
(glumerulonephritis).

- Nephrotic syndrome involves activation of complement

system which lead to the damage of the basement
membrane.

- Nephritis involves activation of complement system and the

infiltration of other types of cells like neutrophils.
Activated neutrophils should lead to the rupture of the
membrane.
Infection-associated antibody- Serum sickness the pileup of
mediated disease shows a linear, preformed immune complexes on
ribbonlike deposit along the the basement membrane leads to
basement membrane as would be lumpy-bumpy deposits.
expected if an even carpet of
antibody were bound to surface
antigens.
Prevention and treatment to hypersensitivity type-II:

Corticosteroids can limit the damage by effector cells.

Cyclophosphamide which stops DNA synthesis (proliferation

of cells like T-cells which subsequently effect B-cell and
finally antibody level. Used in severe SLE cases.
HYPERSENSITIVITY TYPE-IV
- This is a cell mediated hypersensitivity type.

- Antigen specific T-lymphocytes is the effector cell in this

type of reactions.
- Because antigen specific T-cell is involved, the onset of this
type of hypersensitivity comes late compared with other
types of hypersensitivities.

- Because of so it is called delayed-type hypersensitivity

(DTH).

-Activation of T-cells during this type of reactions should

bring in other types of cells like macrophages and
monocytes. Cytokines and chemokines secreted by T-cells
and other cells responsible for the damage caused to the
tissue (CD8+ / NK).
The major events leading to DTH reactions:
1- Activation of antigen specific inflammatory TH1 and TH17
cells in a previously sensitized individual.
2- Elaboration of proinflammatory cytokines by the antigen-
specific TH1 cells.
3- Recruitment and activation of antigen-nonspecific
inflammatory leukocytes.

- These events typically occur over a period of several days (48–

72 hours).
General characteristics and pathophysiology of DTH:
- Depending upon the antigen and the route of exposure.
– Contact hypersensitivity.
– Tuberculin –type hypersensitivity.
– Granulomatous hypersensitivity.
– Self antigens in some autoimmune diseases.
First time exposure to the antigen is called sensitization stage
(needs 1–2 week / normal mechanisms of T-cell activation).

- During this stage; activation, differentiation and

proliferation for TH1 and TH17 takes place, this should
allow the production of antigen-specific T-cells clones.

- When body re-exposed to the same antigen eliciting stage

takes place (cells respond by producing cytokines that promotes
DHS).
- (A previous exposure to the antigen is required).
- During the elicitation phase: (requires 18–48 hours from time
of antigenic challenge), activated TH1 and TH17 secret a
ray of cytokines mainly proinflammatory cytokines that
activate antigen non-specific cells (macrophages, NK
cells, and neutrophils).
- TH17 secretes IL17,IL-22, IL-6, IL-1 and TNF-α.
- TH1 secretes INF- , TNF-β and IL-2.
- These cytokines activate other cells like NK cells, CD8
cytotoxic cells and macrophages which secrete (macrophage
inflammatory protien:MIP-1 α,β, membrane cofactor protein: MCP
and TNF-α).

- The clinical manifestations of DTH can last for several weeks or

can be chronic in case of autoimmune dieseases.
Examples of hypersensitivity IV:
1- Contact sensitivity: also called contact dermatitis.
- Poison ivy dermatitis (J‫سام‬JJ‫لبالب لا‬JJ‫) لا‬. A dermal reaction
characterised by eczema (48-72 after contact).

- Poison ivy contains oils containing catechols (dihydroxyphenols)

mixed with long hydrocarbons side chain.
- These oils will dissolve in skin and bind other skin molecules
which will act as carriers.

- Metals like nickel and chromium (jewelry and clasps ‫ )مشابك‬also

can cause DTH (interact with skin proteins).

- Langerhans cells presents the offending allergen to T cells.

Contact sensitivity:
- Histological appearance : spongiosis
(intracellular edema of the epidermal
cells) and blister formation.
- Sensitizing antigen could remains at the site of the initial
contact for about 1 week, the antigen that persists
serves as the challenging antigen. Therefore, the
elicitation phase can occur without new contact with the
sensitizing antigen.

Patch test used for testing presence of contact sensitivity.

– Applying the suspected allergen on skin, covered for
three days. Induration (thick hard) and erythema
indicates positive test.
Allergy patch testing
Patch testing is not the same as prick
testing.

Patch testing is used to detect allergic

contact dermatitis (ACD) (type IV
hypersensitivity reaction).

This includes allergy to hair dye, shoes,

active ingredients, preservative and
fragrances in sunscreens, cosmetics and
medicaments.

The results appear 2 to 4 days after

applying the allergen on the skin.

Prick testing on the other hand is used to test type I allergy causing hay fever,
asthma and contact urticaria (hives).

Prick testing involves needle pricking and is read 20 minutes after skin
pricking.
2- Granulomataus hypersensitivity:
- lesions last relatively longer than usual DTH contact
reactions with more damage to the tissue. Antigen may
persists and become chronic cause chronic immune
response (Ags include Mycobacterium leprae (causative
agent of leprosy), schistosamal eggs antigens).

- Continuous immune response includes accumulation of M

in the site of infection leading to clusters of epithelioid cells
which then fuse to form giant cell termed granulomas.

- Granulama development takes 3-4 weeks.

2- Granulomataus hypersensitivity........

- The destructive role of granuloma comes from its displacement

of normal tissue and can cause caseous necrosis (cheesy). (a
form of cell death / with a cheese-like appearance, the dead tissue
appears as a soft and white proteinaceous dead cell mass).

- Viral infections like smallpox measles can cause such

phenomenon with more damage due to the involvement of
CD8 cytotoxic cells.

- Skin rashes in diseases (smallpox, measles, and herpes), are partly

attributable to DTH responses to the virus, with additional destruction
role of cytotoxic CD8+ T cells.
3- Tuberculin-type hypersensitivity:
- This is a cutaneous inflammatory reaction.

- Appears as a firm red swelling of the skin after 48-72 hours

challenge.

- A lipoprotein complex (soluble Ag) usually produced by

Mycobacterium tuberculosis was used to test for exposure to the
micro-organism.
- The soluble Ag also referred to as tuberculin-type.
- Other soluble antigens isolated from (Mycobacterium leprae
and Leishmania tropica, and others) induce similar
tuberculin- type DTH reactions.
3- Tuberculin-type hypersensitivity.........
- In recent days a more purified lipoprotein complex isolated
from M. tuberculosis (purified protein derivative: PPD) used in
testing for exposure to the micro-organism M. tuberculosis.
- (PPD test or Mantoux test).
- The lipoprotein injected intradermally.
- Within 24-72 hours and in case of positive tuberculin type
reaction signs include: Erythema (redness) and induration
(raised thickening ) appears (hard and non-pitting).

- Some individuals may show false negative PPD:

Immunosuppressed (HIV), or patients on high dose chemotherapy.

- Individuals vaccinated with Mycobacterium bovis (BCG) show

false positive reactions.
- Two steps-test.....
4- Allograft rejection: Transplanted cells, tissues or organs
from allogenic donors with marginal incompatibilities in
the HLA Ag could lead to the rejection of the transplanted
tissue or organ.
- The rejection is T-cell mediated, non-specific Ag cells like
monocytes also involve in the process.
DTH reactions and autoimmune diseases:

1- Rheumatoid arthritis: Is a very common disabling condition.

- The synovial membrane lining both joints and tendon sheaths

is affected and get swollen (could reach 100 times) its normal
size.
- The reaction is mediated by T-cells.
- The pathogenesis of RA is complex and involves T and B
lymphocytes as well as macrophages.

IT IS NOT CLEAR OR UNDERSTOOD WHAT EXACT Ag

THAT T-CELLS REACT AGAINST IN RA.
- Some studies suggest that T-cells respond to heat shock protein
(HSP) secreted by bacteria. A similar substance to HSP found
in human cells. During infection, secreted HSP may drive the
activation of T-cells against cell HSP (molecular mimicry).

- The major damage during RA is due to the cytokines secreted

by T-cells (large number of cytokines) include the pro-
inflammatory cytokines.

- IL-4 is not found in inflamed joint suggesting that the reaction

is TH1 pattern.
- Cytokine like TNF-α which is a pleomorphic cytokine can
cause:

- Endothelium upregulates adhesion molecules, attracting

neutrophils to the synovium.

- Activated neutrophils secrete metalloproteinases

(proteases that need metals) which cause digestion of the
synovial matrix proteins.

- Osteoclasts activation which cause bone destruction at

the joint margins causing erosions.
- Cytokines of T-cells lead to the activation of B-cells which:

- Produce antibodies of class IgM and refer to it as

Rheumatoid factor (RF).

- Rheumatoid factor is NOT specific for RA.

- RF is an IgM targets the Fc portion of IgG.

- So formation of immune complex (IgM/IgG) can deposit

in the joint and cause more damage.
2- Multiple sclerosis:
- A severe disease and 50% patients become disabled within
15 years of onset.

- The disease characterised by the presence of demyelinating

plaques (destruction of the myelin sheaths) in different parts
of the central nervous system (CNS) in early stages.

- In late phases or chronically progressive disease an

extensive axonal loss occurs.

- MS onset believed to be controlled mostly by

environmental factors and to less extend genetic factors.
- Environmental factors like infections (viral) is the most
important. (Other:.....).
- Demyelination (occasionally) is noticed and documented
following infections like measles.

- Genes are not strongly linked with the disease as noted the
concordance rate of the disease among identical twins is
just about 30%.
- MS disease is T-cell mediated and involves M.

- Early inflammation to the nervous tissue cause reversible

and relapsing disability. So patient should feel good
recovery function for a while.

- Once the disease progress and more inflammatory attacks

hits, myelin loss impairs the ability of neurons to conduct
impulses, resulting in neurologic symptoms.

- As nerve cells remylinate to some extend, axon loss from

nerve cell is irreversible.
Treatment of hypersensitivity type-IV:
- Contact dermatitis and tuberculin-type reactions are
resolved after removal of the antigen (days-weesks).

- Also immunosuppressive drugs can be used (e.g.

Corticosteroids).
- In MS useful when given intravenous at high doses.
- In RA effective but toxic in long-term use.

- Recently monoclonal antibodies used to neutralize the

effect of cytokines like TNF.
- INF-β used with MS patient,
Immunodeficiency disorders and Neoplasias
- Immunodeficiency syndromes are characterized by absences or
deficiencies.

- Neoplasia reflects excesses or uncontrolled proliferations.

- Deficiency in a particular immune element mostly affects other

elements growth.

- Autoimmune diseases usually resulted from uncontrolled immune

regulation.

- Clinical consequences (are similar) of deficiencies in which the

immune system elements shows redundancy are absent. This due to
overlap functions of immune system components (as in cytokine redundancy
function).
- IMMUNODEFICIENCY SYNDROMES:

- Divided into two categories: primary and secondary

immuno- deficiencies.

- Primary immunodeficiency syndrome the disease can be

hereditary or acquired. The deficiency is the direct cause of
the disease.

- In secondary immunodeficiency; the immune deficiency is

usually a result of other disease (HIV, chemotherapy, severe
burns or malnutrition, others).
- Primary immunodeficiency disorders classified according to
malfunction of particular element of the immune system
(cellular or soluble). This deficiency may involve in:

1- T-lymphocyte deficiency (cell mediated immunity).

2- B-lymphocyte deficiency (antibody mediated immunity).
3- Combination of both T and B lymphocytes deficiency.
4- Non specific immune cells mediated by M and NK cells.
5- Complement factors activation.

- Patients with recurrent infections (bacterial, viral...) always

in suspect of having immunodeficiecy syndrome.
General examples:

1- Recurrent bacterial pneumonia infection is common in

individuals with B-lymphocytes and antibody deficiency.
2- Whereas fungal protozoan and viral infections highly seen in
individuals with T-lymphocytes and cell mediated
deficiencies.
3- Pyogenic bacterial infections and systemic infections with
bacteria known to be low virulence suggest deficiencies in
phagocytic cells.
4- Recurrent Pyogenic infections also associated with deficiency in
complement factors.
5- Opportunistic infections (e.g. Candida, Toxoplasma gondii,
cytomegalovirus CMV) associated with cell mediated.

- Timing of infections:
- deficiencies in humoral immunity begin from 6 months to 1 year
of age.
- Defects in T-cell–mediated immunity or combined defects in T-
and B-cell function often present from birth as failure to thrive.
The frequency of primary
immunodeficiency syndromes is
very low (1 in 10,000).

- 50% of all cases are antibody

Deficiencies.
- 20% are combined deficiencies
- 18% are phagocytic disorders.
- 10% are disorders of cell-
mediated immunity.
- 2% are complement deficiencies.
PRIMARY IMMUNODEFICIENCY SYNDROMES:
- Severe Combined Immunodeficiency Disease (SCID).
- Originally called Swiss-type agammaglobulinemia.

- The disease comprises a heterogeneous group of diseases by

which both cell-mediated and antibody mediated immunity
affected.
- Patient can suffer recurrent infections of bacterial, viral,
fungal and protozoal microorganisms and most commonly
CMV.
- Vaccination with attenuated live virus could prove fatal in
infants with SCID.
- The disease can be sub-classified into different subgroups
designated as T-B+, T+B-, T-B-, T+B+.
T−B+: has no T cells with normal or increased numbers of nonfunctioning B cells.
T−B−: has severe lymphopenia due to the absence of both T and B cells.
T+B+: few patients.
T+B−: rare patients.
The preferred treatment for all SCID patients is a T-cell-depleted bone marrow transplant!!!
from an HLA-matched sibling donor.
T- B+ subgroup: Patients show complete absence of T-cells
with normal or elevated number of non-functioning B-
cells, patients also lack NK cells.
Two undistinguished types of this disease:
1- X-linked SCID.
2- Autosomal recessive SCID. (small subgroup)

- 50% of patients with T-B+ subgroup are X-linked SCID

patients. The disease is due to a mutation found on X
chromosome that codes for -chain which is common to
the receptors for IL-2, IL-4,IL-7, IL-9and IL15.
- Less common than X linked, the autosomal recessive SCID,
the mutation found on autosomal chromosome responsible
for coding JAK3 tyrosine kinase (Janus kinase) (which
responsible for transmitting signals from the γ chain of the
cytokine receptors). This molecule is restricted to
haematopoietic stem cells.

- Another smaller group of patients with autosomal recessive

SCID have mutations in IL-7Rα or in a chain of CD3.
In mouse:
- γ-chain knockouts show defective development of both T
and B-cell lineages.
- Similar results related to IL-7 and IL-7R knockouts

- IL-7 is crucial for T-cell and B-cell development and absence of

IL-7 is not compensated for by other cytokines.

- In contrast, IL-2 knockouts show only some immune

dysfunction, with normal T- and B-cell development and without
a SCID phenotype.
T-B- subgroup: Three specific disorders.
1- Adenosine deaminase deficiency (ADA).
2- Purine nucleoside phosphorylase deficiency (PNP).
3- Recombinase deficiencies.

1- ADA involves absence of the enzyme which is important in

the purine salvage pathway (from intermediates formed
during degradation of RNA and DNA).
- Patients with this disease shows complete absence of both T
and B lymphocytes.
- Deficiency of the enzyme lead to accumulation of toxic wastes
in cells. Enzyme supplementation used as treatment.
- The salvage pathway is imprtant in lymphocyte development and it can be targets
for drug development (antifolates).???
T-B- subgroup: Three specific disorders.

2- PNP (Purine nucleoside phosphorylase deficiency): involves

absence of another enzyme which is important in the purine
salvage pathway formation.

- The deficiency of the enzyme also lead to the accumulation

of toxic wastes mainly in neurologic system and lymphoid
organs (thymus, lymph nodes, spleen.....).
3- Recombinase deficiencies involves mutations within the
genes RAG1 and RAG2 (recombination activating genes).
The gens responsible for synthesis of enzymes involved in
rearrangement of the Ig genes (VDJ) in pre-B-cell and
TCR of T-cell.
- Typically, NK-cell function is intact

- Mutations in genes for other proteins (such as Artemis), which

are involved in Ig and T-cell receptor (TCR) recombination
and DNA repair, will generate a similar clinical picture.
- T+B- subgroup: (Omenn’s syndrome):

- infants have severe immunodeficiency to every type of pathogen,

along with enlarged lymphoid tissues (lymphadenopathy), high
IgE levels, high eosinophil levels in the peripheral blood and severe
erythroderma (skin redness).

- Patients (infants) have partial RAG activity (leaky SCID) . Patients’

blood show normal T-cells count but no B-cells.
- Activation of T-cells through TH2 clone. Skin and gastrointestinal
tract show high infiltration of eosinophils and high level of IgE

- Transplantation is not effective due to graft rejection.

T+B+ subgroup: Bare lymphocyte syndrome (BLS):
- The disease is due to failure in the expression of HLA
molecules, causing problems in Ag presentation
- Patients show normal number of T and B lymphocytes.
According to problems in HLA the disease can be divided
into three groups:
1- HLA-I deficiency.
2- HLA-II deficiency.
3- HLA-I and II deficiency.

Individuals with HLA-II deficiency always show combined

immunedeficiencies.
T+B+ (combined immunodeficiency!!!):

- Help is not provided to B cells for antibody production or to T

cells for cytotoxic T-cell generation.

- MHC class II expression is required on thymic epithelial cells

for positive selection of CD4+ T cells, so, fewer CD4+ T cells are
produced in the thymus.

- Most patients have a decreased proportion of CD4+ to CD8+

T cells.

- GVH disease can still occur in these patients, HLA matched

bone marrow donors are required for treatment.
Autoimmune
lymphoproliferative syndrome
- For BLS affecting HLA-II molecules the problem is not in
the HLA genes but in another set of genes that code for
regulatory factors that are important in the transcription of
class II genes. CD4+ to CD8+ ratio affected.

- In HLA –I defect the problem is due to Transporter protein

(Tap).

- HLA-I also affects the generation of CD8+ cells in the thymus.

- ZAP-70 Mutation:

- Patients with a mutation in the T-cell tyrosine kinase ZAP-70,

which transduces the signal transmitted through the TCR,
also present with a SCID-like phenotype.

-The peripheral blood counts, lymph nodes, and thymus are

normal.

- CD8+ T cells are missing in patients defective in ZAP-70

expression, which indicates the need for ZAP-70 for CD8+ T-
cell differentiation in the thymus.
Other multisystem disorders: / Wiskott-Aldrich syndrome:

- Is X-linked disease, characterised by:

- bleeding diathesis (tendency to bleed) due to

thrombocytopenia (by low count of platelets and small
in size)
- recurrent bacterial infections,

- Allergic reactions (including eczema, elevated IgE levels,

and food allergies).
- Wiskott-Aldrich syndrome:
- The disease is due to a mutation in a gene responsible for
the synthesis of Wiskott-Aldrich syndrome protein
(WASP).
- WASP affects actin cytoskeleton, cell movement, signaling,
and cell division

- The protein found in all haematopoietic stem cells.

- It facilitates the interaction between different immune cells.
- In this disease both T and B cells affected, cells intend not to
respond to polysaccharide Ags.
- If not treated (antibiotics with each infection); patients life
expectancy only three years.
- T and B cell transplantation should be effective as a
treatment.
TUMOUR IMMUNOLOGY
- Because of expression of cell-surface components on malignant
cells that do not occur normally on normal cells, the immune
system response against these components and they are
recognized as antigenic molecules. These surface components
also referred to as (tumour antigens).

- Tumor antigens / have been demonstrated for many tumors in

a variety of animal species, including humans.

- Every day and in normal individuals tumour cells generated

and arise in their systems, but these cells very soon after
generate get destroyed by different mechanisms used by the
immune system.
The phenomena of monitoring the generation of tumour
cells in the body and different mechanisms used by the
body to destroy these abnormal cells without any notice
or development of pathological consequences referred to
as immunosurveillance.

The two major goals of tumor immunology are

- To elucidate the immunologic relationship between the
host and the tumor

- To utilize the immune response to tumors for the purpose

of diagnosis, prophylaxis, and therapy.
TUMOUR ANTIGENS:

The antigenic prerequisites that apply to foreign immunogens

also apply to tumor antigens.
- Foreignness!!!,
- High molecular weight,
- Chemical complexity,
- Degradability.

Immunogenic tumor antigens fulfill these criteria and thus have

the potential to induce immune responses.

Nonimmunogenic tumor antigens, on the other hand, are in

many cases self-antigens to which some degree of tolerance
exists.

This poses major barriers vaccine induced tumor immunity.

TUMOUR ANTIGENS:
- There are different mechanisms by which lead to the
appearance of tumour antigens on cells surfaces:
- Mechanisms include mutation, gene activation and clonal
amplification.

- Tumour antigens consist of structures that are unique to the

cancerous cells and are not present on their normal
counterparts.

- Other tumour antigens may represent structures that are

common to both malignant and normal cells but are masked
on the normal cells and become unmasked on malignant cells.
Other antigens on malignant cells represent structures
that are present on foetal or embryonic cells but
disappear from normal adult cells. These latter
antigens are referred to as oncofoetal antigens.

Some tumour antigens expressed on tumour cells

represent structures that are qualitatively not
different from those found on normal cells, but that
are over-expressed and therefore found at higher
levels on the cancer cell. These are usually products
of oncogenes.
Human epidermal growth factor receptor (HER) is an example
of oncogenes over-expression in certain breast and ovarian
cancers due to over-expression of the HER-2/neu-1
oncogene (clonal amplification)

- Oncogenic retroviruses (e.g., human T-cell leukaemia virus)

that can transform normal cells into cancer cells also
induce tumour cell antigens that exhibit extensive
structural similarity..

- Most genes responsible for controlling the synthesis of

tumour antigens are silent genes. But these silent genes can
be activated by different factors termed as carcinogens.
(hot spots for mutations).
It is important to know that there is little or no cross-reactivity
between carcinogen-induced tumours.
- Absence of cross-reactivity is probably due to the random
mutations induced by the carcinogens, leading to a large array
of different antigens.
- Example: chemical carcinogen that induce sarcomas will
exhibit antigens unique to each induced tumor, (no
immunologic cross-reactivity between the tumors).
CATEGORIES OF TUMOR ANTIGENS
Tumor antigens may be classified into several major categories that induce
the malignancy and the immunochemical properties of the tumor antigens.
Normal Cellular Gene Products:
Some tumour antigens are derived from normal genes that,
under normal circumstances, are programmed to be
expressed only during embryogenesis.
Example:
1- Oncofoetal antigens: melanoma-associated antigen (MAGE)
(family of proteins) is a tumour antigens that is not
expressed in any normal adult tissues except for the testes.
- MAGE proteins are used as tumour vaccine antigens
because their expression is shared by many melanomas.
2- cancer testes (CT) antigens: is an oncofoetal antigens.

- These antigens are encoded by genes that are normally

expressed only in the human germline cells but are also
expressed in various tumour types, including melanoma,
and carcinomas of the bladder, lung, and liver.
3-Carcinoembryonic antigen (CEA) and α-fetoprotein (AFP): Are
other examples of oncofoetal antigens

- CEA is found primarily in serum of patients with cancers of

the gastrointestinal tract, especially cancer of the colon,
pancreatic cancer, and some types of breast and stomach
cancer.

- Elevated levels of CEA have also been detected in the

circulation of patients with non-neoplastic diseases, such as
emphysema (damaged air sacs in the lungs /short breath,
ulcerative colitis, and pancreatitis.
AFP, which is normally present at high concentrations in fetal
and maternal serum but absent from serum of normal
individuals. (used as tumor marker)

AFP is rapidly secreted by cells of a variety of cancers

(hepatomas and testicular teratocarcinomas).

--------------------------------------------------------------------
Example on how normal cellular gene products can serve as
tumor antigens:
-Clones of malignant B or T cells that express antigen-
specific receptors

- The idiotype of the particular BCR or TCR expressed by

transformed B or T cell could effectively identifies that clone as
a unique population of malignant cells.
Lymphokine activated
killer (LAK) cells
Transplantation
Types of graft:
- Autograft :tissue grafted back on to the original donor.

- Isograft : graft between syngeneic individuals (i.e., of

identical genetic constitution) such as identical twins or
mice of the same pure inbred strain.

- Allograft :graft between allogeneic individuals (i.e., members

of the same species but different genetic constitution), for
example, human to human and one mouse strain to
another.
- Xenograft : graft between xenogeneic individuals (i.e., of
Types of rejection:
- Immunological mechanisms can contribute to rejection, which
can occur immediately (within minutes) after
transplantation or may take longer to develop.

- There are three main types of rejection based on the time

course of their development.

- Hyperacute rejection.
- Acute rejection.
- Chronic rejection:
Hyperacute rejection:
- Occurring within minutes of transplantation.
- A reaction that resulting from pre‐existing anti‐donor
antibodies: (anti-HLA due to pregnancy, previous
transplantation, blood transfusions /carbohydrates expressed
on blood vessel endothelial cells of the transplanted tissue).

- The preformed antibodies activate complement system. causing

swelling and interstitial hemorrhage in the transplanted tissue
thereby decreasing the flow of blood through the tissue.

- Cell mediated immunity is not involved at all in hyperacute

rejection.
- Hypersensitivity???
Test for possibility of hyperacute rejections:

1- Incubating donor’s RBCs with recipient serum and

complement mediated lysis molecules. If there is
preformed antibodies this cause cells lysis.

2- Incubating donor’s T cells and B cells (they have class I

and II MHC) with recipient sera, if there is possible
anti-HLA this will cause cell lysis.

____________________________________________
- Plasmapheresis , high dose of immunosuppressers
Acute rejection: (direct pathway of alloantigen recognition)

-Taking place days or weeks following transplantation and mainly

mediated by T-lymphocytes. (Donor DCs may activate host T cells).
(If CD8=Transplant lysis, if CD4= activation of Th1=inflammation)

- Two types of acute rejection for solid organs.

1- Antibody mediated or humoral acute rejection.

2- Acute cellular rejection (sometimes abbreviated as acute

rejection). More common than antibody mediated.
- Cell-mediated immunity, manifested by intense infiltration of
lymphocytes and macrophages.
Acute rejection (cont...):
- The distinction between humoral acute rejection and acute
cellular rejection is important because treatments may differ.
- If antibody mediated: treatment directed against B cells (or
plasmaphoresis).
- Corticosteroids is used for both types of acute rejections.

Test for possible acute rejection:

- Mixed lymphocyte reaction:
Mixing donor’s T, B, monocytes, and DC, with a mixture of
recipient T cells. If alloreactive T cells are present this will
cause T cell proliferation.
Chronic rejection: Indirect way of allorejection.
- Taking months or years to manifest itself and involving
mechanisms that are often somewhat poorly defined.

- Caused by both antibody and cell-mediated immunity

occurs in allograft transplantation.

- This may produced after the death of some organ

transplant cells that are taken by host APCs followed by
donor HLA (minor H) peptide antigen presentation via
class I and II MHC.
- Because the damage caused by immune injury has already
taken place, immunosuppressive therapy at this point is
useless.
Mechanisms of alloantigen recognition by host T cells:

Two mechanisms:

direct mechanism:
- is presumably due to the recognition of donor’s MHC bound to
donor-derived peptides.

- Self proteins are routinely digested by proteosomes, and peptides are delivered to
the endoplasmic, then bund with MHC class I and expressed on cell surface
(tolerance).

- The donor-derived peptides are presented to T cells by antigen

presenting cells (APCs) came in the transplanted tissue (donor
dendritic cells), so they are recognized as foreign. These activated
APCs become potent stimulators of host T cells.
Indirect mechanism:

- involves the APCs of the recipient.

- Host APCs process alloantigenic proteins and present the

resulting peptides on self-MHC molecules to T cells expressing
TCRs that bind to these foreign epitopes.

- The source of the donor-derived peptides are the minor H

antigens (peptides) encoded by genes outside the MHC (Minor
histocompatibility antigens (MiHAs).

- The response is mediated by CD8+ T cells because H antigens

are presented by class I MHC molecules.
- Direct activation of T cells by
alloantigens :
Recognition of donor-derived
MHC antigens expressed by
donor cells serving as APCs.
- Indirect activation of T cells:
Recognition of donor-derived
cellular peptides (mostly minor
H antigens) bound to MHC
antigens expressed by host
APCs