Pathology Review

Inflammation
 Inflammation is a beneficial host response to foreign invaders and necrotic tissue but may cause damage as well
 Main components are a vascular reaction and a cellular reaction, both activated by mediators derived from plasma proteins or
various cells

 Steps of inflammation (5 Rs):  Typified by 5 cardinal signs:

o Recognition of injurious agent o Heat (Calor) – caused by increased blood flow through dilated
o Recruitment of leukocytes capillaries
o Removal of the agent o Redness (Rubor) – erythema caused by increased blood flow
o Regulation (control) of the response through dilated capillaries
o Resolution (repair) o Swelling (Tumor) – caused by extracellular exudate
o Pain (Dolor) – caused by release prostaglandins etc.
o Loss of Function (Functio Laseo) – numerous combined causes
ACUTE CHRONIC
Definition Rapid onset, short in duration Longer duration (days to years)
Hallmark Signs Vascular Changes Infiltration of mononuclear cells
Edema Tissue Destruction
Neutrophilic Infiltrate Repair – Angiogenesis (new vessels) and
Fibrosis (scarring)
Initiatied by Resident Cells – macrophages (histiocytes),
dendritic cells, mastocytes
Primary Neutrophilic leukocyte accumulation Lymphocytes (B cells- humoral, T-Cells –
Responders (polymorph nuclear cellular), Macrophages, Plasma Cells,
leukocytes/granulocytes) Fibroblasts
After 24-48 hrs: replaced by monocytes
Stimuli Infection Persistent acute inflammation due to non-
Trauma degradable pathogens
Tissue Necrosis Persistent foreign bodies
Foreign Bodies Impairment of body's defenses, cellular or
Immune Reactions (Hypersensitivity) humeral immunity, autoimmune reactions
Any cause of delayed healing like
malnutrition, poor blood supply, DM etc.
Events VASCULAR EVENTS 3 PHASES
CHANGES in VASCULAR CALIBER and FLOW ACUTE INFLAMMATION: comprising of initial
Transient Vasoconstriction vascular and exudative phenomenon
Arteriolar Vasodilatation DEMOLITION: is a phase of macrophage
Increased Blood Viscosity (As RBCs become activity in which dead cells and inflammatory
more concentrated) debris are removed by phagocytosis by
Stasis macrophages
INCREASED VASCULAR PERMEABILITY HEALING: by which dead cells and lost tissue
Release of Transudate are replaced by the process of repair and
(Just fluid release due to increased regeneration.
hydrostatic
pressure) TYPES
Endothelial Cell Contracture (reversible; Granulomatous inflammation: Characterized
elicited by by the formation of granulomas, they are the
histamine, bradykinin, leukotrienes etc.; result of a limited but diverse number of
slower diseases, which include among others
more prolonged contracture may be tuberculosis, leprosy, sarcoidosis, and
induced by syphilis.
cytokines, TNF, IL-1: Induce E-Selectin)
Release of Exudate (fluid plus plasma Fibrinous inflammation: Inflammation
proteins, due resulting in a large increase in vascular
to endothelial contracture. This permeability allows fibrin to pass through the
accumulates: blood vessels. If an appropriate
edema) procoagulative stimulus is present, such as
 Exudate moves into extravascular tissues
Angiogenesis
Secondary inflammation of Lymphatics
CELLULAR EVENTS
LEUKOCYTE RECRUITMENT
Margination of leukocytes (neutrophills
mainly)
Rolling – mediated by Selectins (P, E & L)
Adhesion - Integrins
Transmigration/Diapedesis – Integrins
(occurs mainly in venules)
Chemotaxis – leukocytes move to infection
LEUKOCYTE ACTIVATION
Phagocytosis
Recognition – leukocytes bind to
organisms based
on their receptors or if they are coated
with
opsonins: IgG binds to C3, collectins bind
plasma
carbohydrates: Phagosome
Engulfment – IgG binds to FC; lysosome
binds with
phagosome: Phagolysosome
Killing and Degradation of Microbes
Production of Mediators
Possible Resolution – termination of infl. response
Outcomes Chronic Inflammation
Fibrosis – Scarring
Abscesses – leads to scarring; from
extensive Neutrophillic infiltrates
cancer cells,[4] a fibrinous exudate is
deposited. This is commonly seen in serous
cavities, where the conversion of fibrinous
exudate into a scar can occur between serous
membranes, limiting their function.
Purulent inflammation: Inflammation
resulting in large amount of pus, which
consists of neutrophils, dead cells, and fluid.
Infection by pyogenic bacteria such as
staphylococci is characteristic of this kind of
inflammation. Large, localized collections of
pus enclosed by surrounding tissues are
called abscesses.
Serous inflammation: Characterized by the
copious effusion of non-viscous serous fluid,
commonly produced by mesothelial cells of
serous membranes, but may be derived from
blood plasma. Skin blisters exemplify this
pattern of inflammation.
Ulcerative inflammation: Inflammation
occurring near an epithelium can result in the
necrotic loss of tissue from the surface,
exposing lower layers. The subsequent
excavation in the epithelium is known as an
ulcer.
Fibrosis
Hyperplasia of monocyte-phagocytic system
involving L.N., Spleen, bone marrow etc.
Blood Changes:
- Increased immunoglobulins in serum
- Anemia
- Leucocytosis
- Raised ESR
Constitutional symptoms: headache,
malaise, tiredness, anorexia, Wt. loss and
pyrexia

Cell-Derived Mediators in Inflammation

Name Type Source Description
IL-8 Chemokine Primarily Activation and chemoattraction of neutrophils,
macrophages with a weak effect on monocytes and eosinophils.
IFN-γ Cytokine T-cells, NK cells Antiviral, immunoregulatory, and anti-tumour
properties. This interferon was originally called
macrophage-activating factor, and is especially
important in the maintenance of chronic
inflammation.
 TNF-α and IL-1 Cytokines Primarily Both affect a wide variety of cells to induce many
macrophages similar inflammatory reactions: fever, production
of cytokines, endothelial gene regulation,
chemotaxis, leukocyte adherence, activation of
fibroblasts. Responsible for the systemic effects
of inflammation, such as loss of appetite and
increased heart rate.
Leukotriene Eicosanoid Leukocytes Able to mediate leukocyte adhesion and
B4 activation, allowing them to bind to the
endothelium and migrate across it. In neutrophils,
it is also a potent chemoattractant, and is able to
induce the formation of reactive oxygen species
(ROS) and the release of lysosome enzymes by
these cells.
Prostaglandins Eicosanoid Mast cells A group of lipids which can cause vasodilation,
fever, and pain.
Nitric oxide Soluble gas Macrophages, Potent vasodilator, relaxes smooth muscle,
endothelial cells, reduces platelet aggregation, aids in leukocyte
some neurons recruitment, direct antimicrobial activity in high
concentrations.
Histamine Vasoactive Mast cells, Stored in preformed granules, histamine is
amine basophils, released in response to a number of stimuli. It
platelets causes arteriole dilation and increased venous
permeability.

Plasma-Derived Mediators in Inflammation

Name Produced by Description
Bradykinin Kinin system A vasoactive protein which is able to induce vasodilatation, increase
vascular permeability, cause smooth muscle contraction, and induce
pain.
C3 Complement Cleaves to produce C3a and C3b. C3a stimulates histamine release by
system mast cells, thereby producing vasodilatation. C3b is able to bind to
bacterial cell walls and act as an opsonin, which marks the invader as a
target for phagocytosis.
C5a Complement Stimulates histamine release by mast cells, thereby producing
system vasodilatation. It is also able to act as a chemoattractant to direct cells
via chemotaxis to the site of inflammation.
Membrane Complement A complex of the complement proteins C5b, C6, C7, C8, and multiple
attack complex system units of C9. The combination and activation of this range of
complement proteins forms the membrane attack complex, which is
able to insert into bacterial cell walls and causes cell lysis with ensuing
death.
Plasmin Fibrinolysis Able to break down fibrin clots, cleave complement protein C3, and
system activate Factor XII.
Thrombin Coagulation Cleaves the soluble plasma protein fibrinogen to produce insoluble
system fibrin, which aggregates to form a blood clot. Thrombin can also bind
to cells via the PAR1 receptor to trigger several other inflammatory
responses, such as production of chemokines and nitric oxide.
Cellular Injury
 Reversible
o Reduced oxidative Phosphorylation
o Reduced ATP production
o Cellular swelling
o Fatty Change
o Influx of Ca2+
 Irreversible
o Membrane damage
o Lysosomal digestions
o Severe mitochondrial damage
o Necrosis – Cell Death (leakage of contents)
 Karyolysis – basophilia of chromatin fades
 Pyknosis – nuclear shrinkage and increased basophilia
 Karryohexis – pyknotic nucleus undergoes fragmentation
o Apoptosis – Programmed cell death (formation of apoptotic bodies which are
phagocytosed)
Adaptive Cell Change
 Metaplasia: reversible replacement of one differentiated cell type with another mature
differentiated cell type
 Hyperplasia: general term referring to the proliferation of cells within an organ or tissue beyond
that which is ordinarily seen
 Neoplasia: (new growth in Greek) is the abnormal proliferation of cells. The growth of the cells
exceeds, and is uncoordinated with that of the normal tissues around it
 Anaplasia: a reversion of differentiation in cells and is characteristic of malignant neoplasms
(tumors)
 Aplasia: is defined in general as “defective” development or congenital absence of an organ or
tissue
 Hypertrophy: increase in the volume of an organ or tissue due to the enlargement of its
component cells
 Atrophy: partial or complete wasting away of a part of the body. Causes of atrophy include
mutations (which can destroy the gene to build up the organ), poor nourishment, poor
circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of
exercise or disease intrinsic to the tissue itself
Wound Healing - STEPS
 Initial gap is filled by blood that upon clotting (formation of fibrin polymers) provides the initial
stability of the wound.
 Plasma fibronectin cross-links with ECM components and fibrin  strengthen wound
 Chemoattractants – fibronectin, cell debris, bacterial products
 Leukocytes and macrophages secrete collagenases and other proteases  removal of debris
 Macrophages also phagocytose cell remnants and damaged ECM
 Following inflammatory cells, fibroblasts begin to move into injured area
 Activated new ECM - fibronectin, proteoglycans, collagen types I and III
 (Thought that macrophages secrete growth factors)
 Angiogenesis begins- 48 to 72 hours after injury
o endothelial cells from nearby capillaries divide and form solid sprouts then form
intracytoplasmic vacuoles
 o Fusion produces lumen and capillary bed formed
o Granulation tissue - has more capillaries per unit volume than any other tissue
 Initial response to a wound and consists of a richly vascular connective tissue,
which contains new capillaries, abundant fibroblasts and inflammatory cells
o Sprouting capillaries tend to protrude from surface of wound as minute red granules
o Eventually, portions differentiate into arterioles and venules
 Many are reabsorbed
 Inadequate vascularization is associated with poor fibroblast proliferation
 The concentric migration of epidermal cells fills wound gap and is sustained by mitotic activity of
trailing cells
 This displaces remnants of original clot toward surface
 Contact with other epidermal cells stop migration
 Concerted activity of fibroblasts, myofibroblasts, macrophages, endothelial cells fills the dermal
gap
o Most capillaries reabsorbed
 Dermal gap filled by dense, almost avascular EM  type III collagen
 Healing by Primary Intention
o Occurs in a wound with closely apposed edges and minimal tissue loss
o requires only minimal cell proliferation and neovascularisation
o results in a small scar
o this is the desired result in all surgical wounds
 Healing by Secondary Intention
o Occurs in a gouged wound : edges far apart, substantial tissue loss
o requires extensive cell proliferation, granulation tissue to heal
o results in a large scar
 Factors affecting Healing
o Vascular supply: poorly perfused, poor healing e.g. legs of diabetics
o Infection: delays or prevents healing
o Movement: persistent trauma retards healing
o Ionizingradiation: blocks cell proliferation, retards formation of granulation tissue
o UV light: accelerates healing
o Circulatory status: determines blood
 supply to area e.g. in old people
o Metabolic status: uncontrolled diabetics
o Malnutrition: delays healing. For example, Vitamin C is needed for collagen synthesis
and secretion.
o Hormones: Corticosteroids impair wound healing - anti-inflammatory. Thyroid
hormones, androgens, estrogens and GH - general metabolic status
 Down Edwards Patou .

Genetic
Abnormality Genetic Name Type Cause Manifestation
Down’s Trisomy 21 Aneuploidy 1) Chromosome Upslanting palebral fissues
Syndrome 47,XX,+21 or 47,XY,+21 Trisomy 21 non- Small overfolded ears
46,XX/47,XX,+21 disjunction (80- Short neck
46,XY/47,XY,+21 Critical 90% in maternal Flattend occiput
Region: meiosis) Brachydactyly
21q22 2) Robertsonian Simian crease
translocations Sandal gap
(5%) Hypotonia
3) Mosaicism (1- Mental retardation
3%) Congenital heart defects
Duodenal, oesophageal or anal atresia
Increasing Leukemia
maternal age Hearing loss
Sterility in males
Edward’s Trisomy 18 Aneuploidy Non-disjunction Intrauterine growth deficiency
Syndrome 47,XX,+18 or 47,XY,+18 Trisomy at chromosome Mental deficiency
46,XX/47,XX,+18 18 Prominent occiput
46,XY/47,XY,+18 Small malformed ears
Increasing Small mouth
maternal age Hypertonia
Clenched fists
Short sternum
Short first toes
Congenital heart defects
Patau Trisomy 13 Aneuploidy 95% lost in pregnancy
Syndrome 47,XX,+13 or 47,XY,+13 Trisomy 95% of live births die in first year
46,XX/47,XX,+13 Cleft Palate/Lip
46,XY/47,XY,+13 Polydactyly
Sloping forehead
Cyclopia - holoprosencephaly
Turner Monosomy X Aneuploidy Non-disjunction Short stature
Syndrome Monosomy in paternal Triangle shaped face
meiosis Posteriorly rotated ears
Broad webbed neck
Broad chest
Normal intelligence
Bicuspid aortic valve (50%)
Coarction of Aorta (15-30%)
Streak Gonads – streaks of CT in place of ova
May go unrecognized (lymphedema of hand
and feet)
Adolescence – no period
Adulthood – infertility
Trisomy X 47, XXX Aneuploidy Non-disjunction No physical abnormalities
Trisomy in maternal Normal fertility
meiosis I May have mild mental deficiency
Increased
maternal age
Kleinfelter’s 47, XXY Non-disjunction Taller than average
Syndrome 47, XXY/46,XY in maternal Disproportionately long arms and legs
meiosis Small testes
Increased Gynecomastia
maternal age Sparse body hair
Hypotonia
Infertility (may not happen due to mosaicism
Slighter lower IQ
47, XYY 47, XYY Aneuploidy Non-disjunction Taller than average
47, XYY/46,XY in paternal Slighter lower IQ
meiosis Usually no other physical problems
May be mosaicism
Polyploidy

NON-ANEUPLOIDIC DISORDERS OF SEX CHROMOSOMES

Swyer XY pure gonadal De novo mutation of SRY Genital tract feminized
Syndrome dysgenesis Deletion of SRY (due to Dysgenic streak gonad (Tumors may develop
46, XY (female) aberrant recombination in Lack of female sex hormones
paternal meiosis) Amenorrhea and failed pubertal developme
Intact SRY but mutation of
another gene in testis-
determining pathway
Complete Testicular feminization Mutation in androgen receptor Functional Testis
Androgen syndrome gene (Xq11 – Xq12) Genital tract resistant to testicular hormone
Insensitivity 46, XY (female) Short vagina
Syndrome X-Linked recessive Rudimentary uterus and FT
(CIS) Amenorrhea and absent pubic hair
46, XX 46, XX (male) SRY present on one X
chromosome (due to aberrant
recombination in paternal
meiosis)
SRY absent – activating
mutation of genes normally
activated by SRY
SRY+ commoner than SRY-
Normal height
Unimpaired intelligence
Normal male external genitalia
Testicular atrophy with azoospermia
SRY- : variable phenotype

True Herma- 46, XX (usually SRY-) Ambiguous external genitalia

phroditism 46,XX/46,XY) – loss of X Both ovarian and testicular tissue present
and Y in separate cells One ovary and one testis
from original XXY One ovary or testis and one ovotestis
Two ovotestis
Predominant steroid hormone produces
phenotype
Cri-du-chat 46,XY,del(5p) Deletion Deletion of distal Mental retardation
46,XX,del(5p) portion of 5p Microcephaly (small head)
Survival to adulthood uncommon
Prader WIlli Micro- 15q11-13 of Mental retardation
deletion paternal Short stature
chromosome 15 Obesity
Narrow head
Small hands and feet
Undescended testes
Angelman Micro- 15q11-13 of Severe mental retardation
deletion maternal Episodes of inappropriate laughter
chromosome 15 Absent Speech (<6 words)
Brachycephaly
Large mouth
Ataxia and jerky arm movements (puppet ga
DiGeorge 22q11 deletion Absent thymus
Congenital heart disease
Growth retardation
Mental retardation
Hypoparathyroidism
Hypocalcemia
Seizures
Velo-Cardio- 22q11 deletion Learning disabilities
Facial Short stature
syndrome Cleft palate
Prominent nose
Microcephaly
Slender limbs
Cardiac defects

Name Source [1] Target receptors Target cells[1] Function[1]

IL-1 T helper cells co-stimulation [3]
 macrophages, B CD121a/IL1R1, B cells maturation & proliferation [3]
cells, monocytes CD121b/IL1R2 NK cells activation[3]
[3]
, dendritic macrophages, inflammation[3], small amounts induce acute phase
cells [3] endothelium, other reaction, large amounts induce fever
IL-2 Th1-cells CD25/IL2RA, activated[3] T cells and B stimulates growth and differentiation of T cell respon
CD122/IL2RB, cells, NK cells, Can be used in immunotherapy to treat cancer or
CD132/IL2RG macrophages, suppressed for transplant patients. Has also been use
oligodendrocytes clinical trials (ESPIRIT. Stalwart) to raise CD4 counts in
positive patients.
IL-3 activated T CD123/IL3RA, hematopoietic stem differentiation and proliferation of myeloid progenito
helper cells[3], CD131/IL3RB cells [3]
to e.g. erythrocytes, granulocytes
mast cells, NK mast cells growth and histamine release[3]
cells,
endothelium,
eosinophils
IL-4 Th2 cells, just CD124/IL4R, activated B cells proliferation and differentiation, IgG1 and IgE synthe
activated naive CD132/IL2RG Important role in allergic response (IgE)
CD4+ cell, T cells proliferation[3]
memory CD4+ endothelium
cells, mast cells,
macrophages
IL-5 Th2 cells, mast CD125/IL5RA, eosinophils production
cells, CD131/IL3RB B cells differentiation, IgA production
eosinophils
IL-6 macrophages, CD126/IL6RA, activated B cells differentiation into plasma cells
Th2 cells, B CD130/IR6RB plasma cells antibody secretion
cells, astrocytes, hematopoietic stem differentiation
endothelium cells
T cells, others induces acute phase reaction, hematopoiesis,
differentiation, inflammation
IL-7 bone marrow CD127/IL7RA, pre/pro-B cell, pre/pro- differentiation and proliferation of lymphoid progeni
stromal cells CD132/IL2RG T cell, NK cells cells, involved in B, T, and NK cell survival, developme
and thymus and homeostasis, ↑proinflammatory cytokines
stromal cells
IL-8 macrophages, CXCR1/IL8RA, neutrophils, basophils, Neutrophil chemotaxis
lymphocytes, CXCR2/IL8RB/CD128 lymphocytes
epithelial cells,
endothelial cells
IL-9 Th2 cells, CD129/IL9R T cells, B cells Potentiates IgM, IgG, IgE, stimulates mast cells
specifically by
CD4+ helper
cells
IL-10 monocytes, Th2 CD210/IL10RA, macrophages cytokine production[3]
cells, CD8+ T CDW210B/IL10RB B cells activation [3]
cells, mast cells, mast cells
macrophages, B Th1 cells inhibits Th1 cytokine production (IFN-γ, TNF-β, IL-2)
cell subset Th2 cells Stimulation

IMMUNE SYSTEM
 Cellular Immunity
 o This type of immunity is mediated through a subset of lymphocytes called T
lymphocytes. These lymphocytes are developed during embryogenesis in the thymus
gland and have specific immune functions.
 Humoral Immunity (B humorous with that bony aunty body! LOL)
o This type of immune response is mediated through antibodies produced by another
subset of lymphocytes called B lymphocytes. During embryogenesis, B lymphocytes
develop in the bone marrow.
 These responses involving T & B lymphocytes are effected through the LYMPHOID SYSTEM
which has two main anatomical divisions:
o The primary lymphoid organs
 The primary lymphoid organs come into play during embryological development
and are the sites at which antigen independent differentiation of precursor cells
occur leading to the development of immunocompetent lymphocytes, i.e.
lymphocytes capable of mediating immune responses
 The Thymus Gland in which there is differentiation of precursor stem
cells, originating in the bone marrow, to form immunocompetent T
lymphocytes capable of mediating cellular immune responses
 The other primary lymphoid organ is the Bone Marrow in which there is
differentiation of precursor stem cells to form B lymphocytes capable of
producing antibody and mediating humoral responses.
o The secondary lymphoid organs
 The secondary lymphoid organs are active throughout life and represent sites of
interaction of specific antigen with specific immunocompetent lymphocytes
resulting in specific immune responses directed against the specific antigen that
initiated the response
 These immunocompetent lymphocytes, once developed in the primary
lymphoid organs, migrate from their sites of development, to specific
anatomical sites in the Secondary Lymphoid Organs
 LYMPH NODES
o Lymph nodes are small organs found in groups or chains in
anatomical locations draining specific regions of the body e.g.
cervical, axilla and groin. They represent the sites of generation
of specific immune responses to specific antigens.
o Within the lymph node, lymphocytes T and B occupy specific
anatomical locations:
 The outermost part of the lymph node (Cortex) is
occupied predominantly by B lymphocytes, disposed as
spherical structures called germinal centers or follicles.
 T cells are found interspersed between these follicles.
The area subjacent to the cortex (Paracortex) is
occupied predominantly by T lymphocytes.
 The innermost part of the lymph node (Medulla) is
occupied by a mixture of T lymphocytes, B lymphocytes
and plasma cells.
o The lymph node is a kidney shaped structure which is
surrounded by a connective tissue capsule subjacent to which is
a space called the Subcapsular Marginal Sinus.
o The capsule is perforated by afferent lymphatics which empty
 into the sinus. Lymph from the sinus percolates through the
substance of the node in between the Medullary Cords (MC)
and collecting in the Medullary Sinuses (MS) eventually
draining into the efferent lymphatic channel exiting the node at
the hilum.
o The lymph node is supplied by an artery and drained by a vein,
both located at the hilum.
o The outermost portion of the lymph node is the Cortex (pale
blue area on diagram. This is the area in which B cells are
predominantly found.
o B lymphocytes are disposed in tightly packed spherical
structures (Bright blue structures) called Primary Lymphoid
Follicles in the un-stimulated node.
o On exposure to antigen, the primary follicles become enlarged
and less dense resulting in the formation of secondary follicles
or germinal centers.
o T lymphocytes are predominantly found in the area subjacent to
the cortex, called the Paracortex.
o T lymphocytes are also found in the areas in between the
follicles in the cortex.
 THE SPLEEN
o The spleen is an encapsulated organ located just below the left
costal margin. It is composed of the red pulp and the white
pulp. The white pulp represents the lymphoid area of the spleen
and encircles the splenic arterioles in the form of a
periarteriolar sheath. Within the sheath, T lymphocytes are
found in the innermost portion (Blue area) and B lymphocytes
peripherally in the outermost portion of the sheath (Light blue
area). In this area, in the stimulated node, B lymphocytes form
follicles with germinal centers. The red pulp is composed of
intercommunicating splenic cords forming venous sinuses.
 MUCOSA ASSOCIATED LYMPHOID TISSUE (MALT)
o The mucosa associated lymphoid tissue is less organized than
the lymph node and the spleen and is distributed along mucosal
surfaces such as the gastrointestinal tract where it is found
beneath the epithelium within the connective tissue of the
lamina propria.
o B lymphocytes are found within follicles and T lymphocytes are
interspersed in between the follicles.
 T LYMPHOCYTES:
o T lymphocytes arise from progenitor precursor stem cells in the bone marrow, which
early in development, migrate to the thymus gland where they undergo differentiation
to form immunocompetent T lymphocytes capable of effecting cell mediated immune
responses.
o They subsequently home to the peripheral lymphoid organs where they occupy specific
anatomical sites as discussed earlier.
o They bear on their cell surface, a specific receptor for antigen – the T cell receptor,
composed of polypeptide chains.
 o T lymphocytes are identical to B lymphocytes morphologically. They can however be
differentiated by utilizing immunohistiochemical techniques. The latter involves the use
of specific (monoclonal) antibodies that are restricted to surface antigens present on
certain cell types. The most common monoclonal antibodies used to identify T cells are
UCHL1 & MT1.
o T lymphocytes account for 60-70% of lymphocytes present in the peripheral blood.
o T lymphocytes are sub-divided into various subsets which express specific surface
markers and also have specific effector functions
 T helper/inducer – bearing the so called cluster differentiation antigen – CD4
 The T helper lymphocytes are important in initiating immune responses.
 This response is controlled through the T suppressor subset which is
important in terminating the response
 T suppressor/cytotoxic- bearing the cluster differentiation antigen – CD8
 Cytotoxic T lymphocytes are important in destroying other cells, in
particular, tumour cells and virally infected cells.
 The normal ratio of CD4:CD8 = 2:1.
 B LYMPHOCYTES:
o Like T lymphocytes, B lymphocytes arise from progenitor stem cells in the bone marrow
and migrate to the peripheral lymphoid organs where they occupy specific anatomical
sites as discussed earlier
o (BMW) B lymphocytes carry IgM on the cell surface and this immunoglobulin bears an
antigen specific binding site.
o B lymphocytes carry surface immunoglobulin as well as a receptor for the Fc portion of
immunoglobulin G. (IgG)
o Like T lymphocytes, B lymphocytes can be identified by immunohistochemical tests
using a variety of monoclonal antibodies, in particular, 4KB5 and L26.
o Activation of B lymphocytes following exposure to specific antigen results in
morphological transformation to a larger cell (lymphoblast) which ultimately transform
to plasma cell which in turn actively secretes antibody directed against the antigen that
initiated the response.
o Interestingly, during this process, there is production of so called memory lymphocytes.
These lymphocytes are capable of recalling exposure to the original antigen and react
promptly and effectively upon subsequent exposure to the same antigen.
o Antibody production will therefore vary depending on the type of exposure to antigen
and this is the basis of vaccination.
o Antibody production is characterized by two types of responses – primary and
secondary:
 The primary response follows the initial or first exposure to antigen and is
different qualitatively and quantitatively to the secondary response. The
primary response is characterized by a long period of time (latent period) before
antibody can be detected. The antibody formed is of the IgM type, the titer low
and the level falls off rapidly.
 The secondary response follows re-exposure to the original antigen. Here the
antibody is formed after a relatively short latent period. The antibody is of the
IgG type, the titer high and remains elevated indefinitely. A small amount of IgM
is also formed.
 NATURAL KILLER (NK) CELLS/ NULL CELLS
o These cells are devoid of the characteristics that define T cells or B cells as described
 above.
o They, however, have on their surface, a receptor for the Fc portion of IgG, which is
important for effector function of these cells
o These cells are responsible for mediating Antibody-Dependent-Cell-Mediated
Cytotoxicity (ADCC) reactions.
 These interactions require that target cells be coated with IgG antibody.
 Natural Killer cells will bind to these coated cells through the receptor for the Fc
portion of IgG that is present on its cell surface.
 This cell-cell interaction results in destruction of the target cell coated with
antibody.

THE MONONUCLEAR PHAGOCYTIC SYSTEM

 This system plays an important role in eliciting effective immune responses
 Macrophages are derived from hematopoietic precursor stem cells in bone marrow
 They circulate in the blood as monocytes and are distributed in various tissues where they are
called macrophages
 These cells augment the immune response through a number of mechanisms
 They process and present antigen to T cells during the induction phase of the immune response
(APCs)
 They produce soluble factors e.g. Interleukin 1, that promote the differentiation of T & B cells
thereby amplifying the immune response
 They are capable of destroying tumor cells and are therefore are important in tumor
immunology
 They engulf and destroy particulate matter and are therefore important in removing debris
formed during inflammation
POLYMORPHS
 These cells are important in destroying bacteria. In order to facilitate this, these cells are armed
with receptors, such as the receptor for C3b, that interact with bacteria after which follows the
process of phagocytosis and ultimately destruction of the bacteria.
CYTOKINES
 Another important participant in the immune response is a family of biologically active
substances secreted by a variety of cell types collectively called cytokines. These can be
 regarded as messenger molecules of the immune response which function together to amplify
the immune response. They are secreted by a number of cells including lymphocytes,
monocytes and endothelial cells. A large number of cytokines have been described over the
years which have a wide spectrum of overlapping properties which can be categorized as
follows:
o Cytokines that mediate natural immunity:
 Interleukin 2, Tumor Necrosis Factor a, Interferon and Interleukin 6. Interferon
is important in the protection against viral infection.
o Cytokines that regulate lymphocyte growth, activation and differentiation:
 Interleukin 2, 4, 5, 13, 15 and transforming growth factor b.
o Cytokines that activate inflammatory cells:
 Interferon g & TNF a
o Cytokines that affect leukocyte movement:
 These are therefore important for chemotaxis during inflammation.
o Cytokines that stimulate haematopoeisis:
 These induce haematopoetic stem cells in the bone marrow to differentiate into
mature cells e.g. Colony Stimulating Factor.
 Cytokines have a rapid protective effect:
o Enhance microbicidal effect of phagocytes
o Cause further release of cytokines by other cell types, e.g. natural killer cells
o Increase vascular permeability and transudation of cells into sites of inflammation
 T cell-dependent cell-mediated responses
o TH (CD4) cells:
o Determine which antigens and which epitopes are recognized
o Select the effector mechanism to be used against target antigens
o Aid proliferation of the appropriate effector cell types
o Enhance the functions of phagocytes and other effector cells
 Antigen/epitope recognition by T helper cells is:
o brought about through their interaction with antigen presenting cells bearing antigenic
peptides associated with the MHC Class II

Questions:
1. Which of the following is a function of T lymphocytes?
a. Induction of the immune response
b. Secretion of antibodies and cytokines
c. Processing of antigen
d. Antibody dependent cytotoxicity

2. Which of the following is NOT involved in Innate (Natural Immunity)?

a. Lysozyme present in saliva
b. Commensal organisms in the gut
c. Cilia lining the respiratory tract
d. Memory B lymphocytes

Answers & Explanations:

1. The answer is a). T lymphocytes, particularly the T helper subset, are important in inducing or
initiating immune response. They also secrete a variety of cytokines but they do not secrete antibody.
Antibodies are secreted by plasma cells which are differentiated from B lymphocytes. Macrophages
process and present antigens to T and B cells during the immune response.
Natural killer cells mediate antibody dependent cytotoxicity by virtue of the presence of a receptor for
IgG on its cell surface. The interaction requires that the target cell be coated with IgG antibody.
2. The answer is d). Memory B lymphocytes are generated during acquired immune responses. They
form a pool of lymphocytes that are capable of ‘remembering’ prior exposure to antigen. On re-
exposure to that antigen there is a more rapid and effective immune response. This is the basis of
vaccination. Lysozyme present in saliva and tears is capable of non-specifically splitting bacterial cell
wall. Commensal organisms compete with pathogenic bacteria for nutrients and are therefore
important in the prevention of disease. Cilia and mucus at epithelial surfaces aid in the removal of
invading microorganism.

AUTOIMMUNE RESPONSE
 Autoimmunity implies (by definition) that immune responses have been generated against self
antigens, within an individual, and has resulted in tissue damage and the development of disease.
 Central to this concept, is the loss of normal immunoregulation or loss of what is referred to as self
tolerance.

Self tolereance/ Immunological Tolerance:

 Under normal conditions there is non-reactivity to self antigens (the body does not mount
immune responses to self antigens). We accept that normally antigens are present on cells as
exemplified by transplant rejection in non-identical individuals. This phenomenon is known as
self tolerance. Tolerance to self antigens is fundamental to normal immune function – if this
fails, the body basically rejects and destroys its own tissues.

Mechanisms postulated for Self Tolerance:

 Mechanisms postulated to account for self tolerance in the normal individual include:
o Clonal Deletion
 The theory of clonal deletion postulates that during embryological development
of an individual, all potentially self reactive clones or populations of
lymphocytes were removed or eliminated from the body… thus an individual is
incapable of mounting immune responses against self antigens. It was
subsequently, however, documented that even in normal individuals, there
were in fact self reactive clones of lymphocytes.
o Clonal Anergy
 The theory was therefore modified to the theory of clonal anergy.
 This theory postulates that contact or exposure to self antigens during early
development results in some form of functional paralysis of the immune
system whereby immune responses are not generated against self antigens.
o Suppression by T suppressor
 In addition, suppression of immune responses directed against self antigens, is
mediated by the T suppressor subset of lymphocytes.

Breakdown of self tolerance and the development of Autoimmune Diseases:

 Abnormal antigenic stimulation:
o This is seen in situations where extrinsic or exogenous antigens bear similarities to self
antigens resulting in cross reacting immune responses. When the body reacts to the
extrinsic antigen, the antibody formed cross reacts with the antigenically similar self-
 antigen. The best example of this is seen in the development of Rheumatic Heart
Disease. Rheumatic Fever is preceded by the development of a streptococcal sore
throat. Cardiac tissue shares antigenic similarities to streptococcal antigen. The
antibody formed against the streptococcal antigen cross reacts with antigens present on
cardiac tissue resulting in tissue damage and cardiac disease.
 Modified self antigens:
o If for any reason, self antigens are modified or changed … the immune system no longer
recognizes that antigen as self and therefore mounts an immune response directed
against that antigen. This is seen in some patients as a result of drugs binding to cell
surfaces. An example of this is seen in some hypertensive patients on treatment with
the anti-hypertensive drug -  methyl dopamine. This drug binds to the surface of red
blood cells thus altering the red blood cells. The altered red blood cells are no longer
seen as self and an immune response develops against the red cells resulting in
destruction and the development of autoimmune hemolytic anemia. It is also believed
that cells altered by malignant transformation may express new antigens on their cell
surfaces which might not be recognized as self.
 Sequestered/ Hidden antigens:
o It is well established that early contact of the immune system with antigen during
embryological development is crucial to the development of self tolerance. There are
many self antigens, however, that are anatomically sequestered under normal
conditions. If these antigens are subsequently (later in life) exposed to the immune
system, they would be viewed as foreign and not self antigens. For example,
spermatozoa occupy an immunologically privileged site in the testes. Following
vasectomy, spermatozoa may be released and subsequently antibodies formed.
Similarly, traumatic damage to the eye might result in formation of antibodies directed
against lens protein.
 Abnormal Host Response:
o Mutations involving populations of lymphocytes into clones forming auto-antibodies to
self antigens can lead to autoimmune disease. In addition, abnormality of the T
suppressor subset of lymphocytes can lead to loss of regulatory control of immune
responses and the development of autoimmune disease.
 Genetic Factors:
o It is well established that genetic factors are important in the pathogenesis of
autoimmune diseases and many show familial clustering. There is a striking
predominance of autoimmune diseases in females. We think that female hormones
may play a role. Many autoimmune diseases also have HLA associations.

THE SPECTRUM OF AUTOIMMUNE DISEASES

 Autoimmune diseases fall within a spectrum ranging from:
o Organ Specific to
o Multisystem in which many organ systems are affected.

ORGAN SPECIFIC
Hashimoto’s Thyroiditis
 Form of autoimmune disease characterized by the formation of auto-antibodies directed
against thyroid gland constituents associated with infiltration of the gland by lymphocytes
resulting in destruction of the gland which is reflected in loss of function of the gland.
  The disease is far more common in females with a M:F ratio of 10:1. It is more common in
whites than in blacks and commonest in middle age with an age range of 45 – 65yrs.
 As with most autoimmune diseases there is a distinct tendency to aggregate in families. There is
also a strong association with HLA –DR5.
 These patients present with a swelling in the neck which may be asymptomatic in the early
stages. In some instances the gland may be so enlarged that it compresses the oesophagus
resulting in difficulty in swallowing (dysphagia).
 Rarely, there may also be compression of the trachea resulting in shortness of
breath (dyspnoea) or compression of the larynx resulting in hoarseness. As the
disease progresses, there is continued destruction of the gland with gradual loss of
function and the development of hypothyroidism.
 At this stage there is fatigue and weight gain in spite of lack of appetite. This is
associated with intolerance to cold. Other symptoms include dryness of the skin and
hair as well as muscle cramps.
 The autoantibodies found are directed predominantly against thyroglobulin as well
as the Thyroid Stimulating Hormone (TSH) receptor.
 The gland is enlarged with an irregular surface and the consistency is firm in
comparison to the soft meaty consistency of the normal thyroid gland.
 On histological examination, there is extensive infiltration of the gland by
lymphocytes, associated with destruction of thyroid follicles and depletion of colloid.
This is usually associated with cytological atypia of the epithelial cells lining the
follicles. The inflammatory process leads to progressive fibrosis resulting in loss of
thyroid function.
 Grossly enlarged symptomatic glands are surgically removed. Symptoms of
hypothyroidism are treated with exogenous thyroid hormone.

MULTISYSTEM AUTOIMMUNE DISEASE

Systemic Lupus Erythematosus (SLE)

 The classic prototype of multisystem autoimmune disease is Systemic Lupus Erythematosus

(SLE).
 This disease is characterized by a wide array of auto-antibodies in particular, auto-antibodies
directed against nuclear antigens.
 The exact cause of SLE is not known. The following factors have been implicated:
o Genetic Factors: This is evidenced by an increase in the incidence among family
members and association with specific HLA types. There is a high concordance rate
among identical twins.
o Hormonal Factors: The disease is more common in women in their reproductive years
and is exacerbated during menstruation and pregnancy.
o Drugs: The disease may be precipitated by drugs e.g. Hydralazine used in the treatment
of hypertension and Dilantin used in the treatment of epilepsy.
o Environmental Factors: The disease is exacerbated by exposure to ultraviolet light.
 The pathology of SLE revolves around the formation of immune complexes composed of nuclear
antigens and their corresponding autoantibodies in blood, and the deposition of these
complexes within vessel wall and the subsequent destruction of the
vessel wall leading to an acute necrotizing vasculitis.
o Phase 1:
 Antigen (green circles) binds to specific antigen receptor
on the surface of B cell which undergoes transformation to
form plasma cell which actively secretes antibody (dark
blue Y shaped) directed against antigen. Antigen binds to
antibody to form Ag:Ab complex.
o Phase II:
 Cytokines released from inflammatory cells encourage the
deposition of complexes within the vessel wall.
o Phase III:
 Deposition of complexes in vessel wall activates the
complement system leading to the release of chemotactic
factors resulting in the accumulation of neutrophils. These
cells phagocytose the immune complexes and during this
process release lysosomal enzymes including elastase,
protease and collagenase which destroy the vessel wall.
This then becomes the site of platelet aggregation
(thrombus formation). The process results in an acute
necrotizing vasculitis with damage to the tissues supplied
by the relevant vessel.
 Immunological Features
o Positive LE cell: An LE cell represented phagocytic cell that has
engulfed immune complexes. These cells can be demonstrated in
the peripheral blood using special techniques.
o High titre of anti-nuclear antibody
o Anti-native DNA and anti-double strand DNA
o ↓ serum complement: This occurs as a result of continual activation of complement as
a result of immune complex deposition within vessel walls
o Deposition of Ig & complement in various sites: This can be demonstrated using special
techniques such as immunofluorescence. Common sites include the glomerular
basement membrane and the dermal:epidermal junction in the skin.
o OTHER ANTIBODIES FOUND:
 Vs Red blood Cells  Haemolytic anaemic
 Vs WBC  Leukopenia. These patients are prone to developing serious
infections
 Vs Platelets  Thrombocytopenia resulting in bleeding tendencies
 Antiphospholipid antibody (Lupus Anticoagulant) : This is present in 40-50% of
patients with SLE. Antibodies are formed against plasma protein complexed to
phospholipid including prothrombin, protein S and protein C. Some of these
antibodies interfere with in vitro clotting tests such as PPT and are therefore
referred to as lupus anticoagulant. Despite having a circulating antibody that
delays clotting in vitro – these patients have a tendency for in vivo thrombosis.
 Clinical Features
o Constitutional symptoms: Malaise, anorexia, fever, weight loss
o Kidneys: There is renal damage (lupus nephritis) of varying severity in
patients with SLE.
o Skin: The skin shows the characteristic ‘butterfly’ rash in patients with lupus
nephritis. This occurs as a result of the underlying vasculitis and manifests
as an erythematous rash, most marked on the face over the malar region.
o Joints: Many joints are affected
o Lungs: Interstitial pneumonia
o Serositis: Involving pleura, peritoneum, pericardium (inflammation of the
serous tissues of the body)
o CNS: Focal neurological deficits
 Treatment
o The main stay of treatment of SLE is with non-steroidal anti-inflammatory drugs and
corticosteroids. Infections are treated accordingly. Some patients with renal failure
undergo renal transplantation.
 Allogeneic homograft (allograft) – graft between genetically non-identical
individuals within the same species
 Autograft – graft from an individual to himself/herself
 Syngeneic homograft – graft between genetically identical individuals (identical
twins)
 Xenograft – graft between different species
 The majority of transplants are allografts. Among those that have been
transplanted are:
 Heart
 Heart and lung
 Kidney
 Liver
 Cornea
 Face
 Pancreas
 Bone marrow
 The major factor involved in the transplantation of organs is rejection. Different
organs vary in their capacity to generate an immune response when
transplanted. Bone marrow and skin elicit the greatest response while liver
elicits the least response.
 Rejection of transplants involves the recognition of foreign donor antigens by
the recipient and the mounting of an immune response.
 The major donor antigens are those of the HLA system present on all nucleated
cells and blood group antigens present on the surface of red cells. The rejection
immune response is largely cell mediated but humoral mechanisms also
contribute.
 Renal transplantation for the treatment of end-stage kidney disease has been in
practice for decades and the rejection phenomena associated with this
transplant have been well documented:
 Hyperacute rejection (within minutes of the transplant) due to an
immune reaction to preformed circulating antibodies.
  Acute rejection (7 – 21 days) due to cell mediated immunity to antigens
in the donor kidney
 Chronic rejection (> 3 months) due to a combination of cell mediated
immunity and humoral immunity resulting from disturbances in
graft/host tolerance.
 The rejection phenomenon can be controlled by immunosuppressive
drugs (steroids; cyclosporine; azathioprone) but these have side effects
particularly the development of (post transplantation) renal cancers in
the donor kidney.
Questions
1. Hyperacute rejection of renal transplants is due to?
(a) Humoral immunity
(b) Cell-mediated immunity
(c) Infection in the donor kidney
(d) Ischemia of the donor kidney

2. A graft from between genetically identical individuals is?

(a) Isograft
(b) Autograft
(c) Syngeneic homograft
(d) Xenograft

Cancer Immunity
 The immune surveillance theory of cancer suggests that the immune system constantly removes
neoplastic cells/clones from the body when they are recognized as “non-self” or foreign. If the
immune system is compromised for any reason this culling function becomes ineffective, allowing
neoplastic cells/clones to proliferate.
 In support of the theory of immune surveillance are the following:
o Tumors are common at the extremes of age: In the young whose immune system is not
fully developed; in the old whose immune system is undergoing involution.
o Tumors are common in those with immune deficiency either congenital or acquired
through infection or drugs.
o Tumor cells may express antigens that are recognized by the immune system e.g. HLA,
tissue specific, retrogenetic, blood group, virus encoded and differentiation antigens.
While these antigens may generate an immune response this may not be sufficient to
eliminate the tumor.
o Tumor cells often escape the immune surveillance system. Cells may shed their surface
antigen, may invert antigens into the cytoplasm or produce blocking antibodies with
regard to humoral immunity.
o Tumor cells may also escape immune surveillance by promoting tolerance in the presence
of antigen excess.
o Cell-mediated immunity (cytotoxic T-lymphocytes) is thought to be the major mechanism
at work against the proliferation of tumor cells but humoral immunity may also play a
role.
o A third mechanism involves natural killer cells binding to tumor antigens. In the diGeorge
syndrome where individuals are born without a thymus and therefore do not generate T-
cells for an effective cell-mediated immune response, there is an increased risk for tumor
 development. Similarly, in individuals with acquired immune deficiency (HIV/AIDS or
drug-induced) there is an increased risk for tumor development.

IMMUNOTHERAPY
Principles
 Attempts may be made to eliminate tumors with the use of immune methods. These include:
o Active immunization - Utilization of a vaccine using tumor cells whose immunogenicity
has been eliminated by prior irradiation.
o Passive immunization - Injecting serum containing antibodies to tumor cells in order to
induce humoral immunity.
o Non-specific enhancement of immunity - The activation of NK cells, T-cells and
macrophages e.g. BCG vaccination, interferon and IL 2
o Monoclonal “magic bullet” - In this method a magic-bullet is created by linking a
toxin/poison to monoclonal antibody which when injected will target specific antigen on
tumor cells resulting in their death e.g. anti tac (antibody) with yttrium (toxin) in the
treatment of Adult T-cell leukemia where the neoplastic lymphocytes express the tac
antigen.
o Note that methods 1, 2 and 3 have been tried and proven unsuccessful in humans but
method 4 (monoclonal “magic bullet”) appears to have potential as a successful treatment
protocol.

Questions
1. BCG therapy for tumors utilizes the principle of?
(a) Active immunization
(b) Passive immunization
(c) Non-specific enhancement of immunity
(d) Direct toxicity by BCG on tumor cells

2. Which of the following is NOT associated with an increased risk of tumor development?
(a) Di George syndrome
(b) Congenital hypoimmunoglobulinaemia
(c) HIV/AIDS
(d) Chemotherapeutic drugs

Hypersensitivity
Hypersensitivity
 Definition: An overreaction of the immune system resulting in undesirable effects (damaging,
discomfort-producing and sometimes fatal)
 Hypersensitivity reactions require a pre-sensitized state of the host
 Classification:
o Type 1: immediate/anaphylactic
o Type 2: cytotoxic
o Type 3: immune complex
o Type 4: cell-mediated/ delayed-type
Type I Hypersensitivity
 Called immediate reactions because manifestations can begin seconds or minutes after contact
with the antigen.
 The mediators that induce these events are
o already present in the cells and
o need only to be released to begin immediate activity
o Examples:
 Hay fever, Betalactam (penicillin) allergy, asthma
o Response time: seconds-minutes
 Pathogenesis
o Antigen (allergen) exposure induces IgE specific antibody
o IgE antibody binds to basophil and mast cells
o Antigen cross link cell-bound IgE molecules
o Mediators are released from basophil and mast cells

 Diagnosis
o In vivo
 Skin tests: skin prick, patch tests, skin biopsy
 Challenge/provocation tests
o In vitro
 serum allergen specific IgE (RAST, ELISA)
 Serum β-tryptase
 Allergens
o Antigens that induce specific IgE responses in genetically susceptible individuals
o These antigens ordinarily have little or no intrinsic toxicity
o Allergens are classified by
 route of exposure and
 Source
 Classification of allergens
o Aeroallergens: pollens, mold spores, animal dander, insect droppings
o Food allergens: milk, eggs, peanuts, soy, wheat, gluten, fish, chocolate
o Insect venom allergens: wasp, ant, bee
o Pharmaceuticals: Antibiotics: penicillin, cephalosporin, sulphonamides
o Latex: latex rubber
 IgE – EEMEDIATE
o IgE is the main antibody involved in immediate hypersensitivity
o IgE is homocytotropic i.e. it has high affinity for mast cells and basophils which have
receptors for IgE
o IgE is produced by plasma cells
 Mediators
o Primary (preformed)
 Histamine
 Tryptase,
 Eosinophil chemotactic factor of anaphylaxis (ECF-A)
 Chondroitin sulfate
o Secondary (newly formed)
 Leukotrienes
  Prostaglandins
 Thromboxanes
 Platelet activating factor (PAF)
 Cytokines
 Histamine
o Histamine is stored in preformed granules within cells (basophils and mast cells)
o Histamine has 2 main receptors: H1 and H2 receptors
o Binding of histamine to H1 receptors on:
 Smooth muscle cells cause constriction endothelial cells
 Endothelial cells  vascular permeability
o Binding to H2 receptors results in
  Mucous secretion,  vascular permeability
 Allergies
o Predisposing factors:
 Environmental, genetic
o Hygiene hypothesis:
 Exposure to microbes in early life  risk of allergy
 Children with asthma live in cleaner houses
 Farm exposure  risk of asthma
o Atopy trait
 Familial predisposition to allergies
o The “allergic march”

 Anaphylaxis
o Anaphylaxis
 Is an IgE mediated potentially life threatening clinical syndrome characterized by
the sudden onset of generalized symptoms affecting multiple organ systems in
the body.
o Anaphylactoid reaction
 a systemic reaction clinically similar to anaphylaxis but is not caused by IgE
mediated immune response
 Direct trigger to mast cells
 Anaphylaxis/anaphylactoid reactions
o Anaphylaxis
 Drugs
 Food
 Insect bites and stings
o Anaphylactoid
 Direct release of mediators from mast cells and basophils
 Drugs (opiates and radiocontrast media)
 Physical causes (cold, heat, sunlight, exercise)
 Idiopathic
Anaphylaxis
 Risk factors
o History of atopy
 o Route of administration of agent
 Parenteral > oral
o Patient’s age: adults > children
o Patients gender: F>M food, M>F in stings
 Etiology
o Food 33%
o Insect allergy 14%
o Medications 13%
o Exercise 7%
o Unknown 19%
 Clinical features
o Pruritus, urticaria, angioedema >90
o Dyspnea and wheezing 47-60
o Dizziness, near syncope, syncope, hypotension 30-33
o Flushing of Skin >28
o Nausea, vomiting and abdominal cramps 25-30
o Laryngeal edema, tongue swelling, choking, dysphonia 24
o Note: pruritus (itch reflex), urticaria (hives), angioedema (rapid swelling of dermis and
submucosa), dysphonia (inability to produce vocal sounds)
 Management
o General: Airway, Breathing, Circulation
o Epinephrine
 Immediate response (sec to mins)
 Stimulates -,β-, adrenergic receptors
o Antihistamines
 Response time 5-30 mins, last 2-4hrs
o Corticosteroids
 Response time 4-8hrs, last 24hrs
 Long term care
o Epi-pen, DPH, medic alert bracelet

Type II Hypersensitivity
 Type II hypersensitivity reactions are a consequence of IgG/IgM antibodies binding to cell
surface antigens
 Reaction time: minutes to hours
 Examples:
o Transfusion reactions, haemolytic disease of the newborn, rheumatic fever
o Drug induced haemolysis (sulphonamides)
 Pathogenesis
o exposure to cell-bound antigen leads to IgG/IgM
o Antibody binds to cell-bound antigen
o Antigen-antibody complex formed 
o Activation of complement membrane attack complex lysis; opsonization
 o Antibody binds to NK cell  lysis (Antibody dependent cellular cytotoxicity-ADCC)

Haemolytic disease of the new born (Erythroblastosis foetalis)

 Mechanism: Rh incompatible blood groups
 Rh (-) mothers and Rh (+) foetus
 First pregnancy:
o mother becomes sensitized to Rh (+) antigens and develop anti-Rh antibody (IgG)
 Second or subsequent pregnancies:
o anti-Rh antibody (IgG) crosses the placenta and binds to Rh antigens on foetal RBCs
destruction of foetal RBC
Blood transfusion reaction

Type III hypersensitivity

 Type III hypersensitivity occurs when antibody binds with antigen and the antigen–antibody
complex is deposited in tissue
 Response time: hours
 Examples:
o Localized:
 Arthus reaction, Farmer’s lung
o Systemic:
 Serum sickness (penicillin, cephalexin, cefaclor)
 Systemic Lupus Erythematosus (SLE), Rheumatoid arthritis (RA), vasculitis,
glomerulonephritis
 Pathogenesis
o Exposure to antigen induces antibody
o Antibody binds antigen and form an immune complex
o Immune complex becomes deposited into tissue
o Activation of complement, macrophages, neutrophils
 Arthus reaction
o Mechanism: localized immune complex reaction
o Definition: localized dermal reaction consisting of erythema, edema, and necrosis
occurring at the site of injection of antigen
Type IV Hypersensitivity
 In Type IV hypersensitivity damage to tissue results solely from cellular events
 Immune reactions do not involve antibody and complement
 Examples:
o tuberculin reaction, contact dermatitis (neomycin), poison ivy, rheumatoid arthritis
 Response time: 48-72h (tuberculin reaction, contact dermatitis)
 Pathogenesis
o Antigens are taken up by antigen presenting cells (APC)
o Antigens are presented to T cells in association with MHC molecules
o T cells become sensitized (activated) and release mediators
o T helper cells release cytokines- recruit and activate macrophages to kill (phagocytosis)
o Cytotoxic T cells release perforins and granzymes lysis of target cells
 Tuberculin reaction/ Mantoux
o Cutaneous inflammatory reaction characterised by an area of firm red swelling of the
skin that appears slowly after 12-24 h and become maximal at 48-72 h after challenge.
 o A purified lipoprotein extract isolated from M. tuberculosis
called purified protein derivative (PPD) is injected intradermally
o Initially erythema:
 neutrophil infiltration
o Later induration:
 monocytes and lymphocytes infiltration
 Adverse Drug Reaction (ADR)
o any noxious, unintended and undesired effect of a drug that
occurs at doses used in human for prevention, diagnosis, or
treatment
o Drug hypersensitivity: a specific immune mediated
hypersensitivity
o Drug allergy: IgE mediated or immediate type hypersensitivity

 Penicillin allergy
o Only 15% of patients claiming penicillin allergy have evidence of allergy on skin prick
o A history of penicillin allergy increases the risk of reaction to other antibiotics
 Cephalosporins by 2-4.4%
 Carbapenems by 11%