This document discusses immunopathology and hypersensitivity reactions. It defines hypersensitivity as an exaggerated immune response that harms the host. Hypersensitivity reactions are classified into four types based on the time between exposure and reaction, the immune mechanisms involved, and the site of action. Type I is an immediate IgE-mediated reaction. Type II involves antibodies against antigens on cell surfaces. Type III involves antibody-antigen complexes in circulation. Type IV is cell-mediated and involves T cells. Examples of each type are provided.

1. IMMUNOPATHOLOGY
Dr. Kaduyu Dennis
1, BASIC CONCEPTS OF IMMUNITY AND IMMUNE RESPONSE
2, IMMUNITY AND IMMUNISATION
3, DISEASES CAUSED BY DEFECTIVE OR INNAPROPRIATE IMMUNE
RESPONSES

2. DISEASES OF IMMUNITY
Diseases due to disorders of immune system
Deficient or impaired immunity(immunodeficiency)
Body reacting against (Autoimmunity)
Immunological disorders (hypersensitivity)

3. APPROACH TO HYPERSENSITIVITY RXNS
DEFINITION
ETIOLOGY
MECHANISMS OF HYPERSENSITIVITY RXN
EXAMPLES

4. Hypersensitivity
Definition
Hypersensitivity is a condition in
which the immune response results in
exaggerated reactions that are harmful to
the host.

5. CLASSIFICATIONS OF HYPERSENSITIVITY
Hypersensitivity reactions are classified
into 4 types basing on
•Time between exposure and reactions
•Immune mechanisms involved
•Site of action

6. OVERVIEW
TYPE I HYPERSENSITIVITY
This is mediated by IgE antibody which are bound to mast cells
TYPE II HYPERSENSITIVITY
This is mediated by antibodies directed against Antigen present on cell
surfaces
TYPE III HYPERSENSITIVITY
This involves Antibody directed against Antigen present in circulation or
deposited Antigen.
TYPE IV HYPERSENSITIY
This is cell mediated Hypersensitivity because it is meadiated by T cells
(CD4+and CD8+ Lymphocytes)

7. TYPE 1 HYPERSENSITIVITY
DEFINITION
This is a type of immune response that rapidly develops to an antigen to
which an individual is previously sensitized.
NOTE;
Reactions rely on immunoglobulin E (IgE) Antibody which is a specific type of
antibody .So because IgE is involved in with type 1 hypersensitivity reactions ,they
are also called IgE- mediated hypersensitivity. This type of reaction is sometimes
called immediate hypersensitivity because the reactions happen supper fast within
minutes.

8. ETIOLOGY
Type 1 reaction is mediated by humoral antibodies of IgE
type in response to antigen. Although definite cause for this
form of immediate reaction to allergen is not known. Following
are possible hypothesis
GENETIC BASIS
There is evidence that ability to respond antigen and
produce IgE are both linked to genetic basis because of
inheritance of particular genes(HLA and Non –HLA genes).e.g.
there is a 50% chance that a child born to both parents allergic
to an antigen may have similar allergy.
ENVIROMENTAL POLLUTANTS
Another proposed hypothesis is that environmental
pollutants increase mucosal permeability and thus may allow
increased entry of allergen into the body which in turn leads to
raised IgE level.

9. MECHANISMS INVOLVED
N.B An allergic reaction happens in 2 steps
First exposure or sensitization
second exposure (subsequent exposure ) which is when it gets a lot more serious.
During the first contact of the host to the antigen sensitization takes place .
When a person is exposed to an antigen(e.g pollen )via the nose it gets picked up
by immune cells hanging out in membranes along the airway and migrate with it to the
lympnodes which happens regardless if the person is allergic or not these cells are called
antigen presenting cells e.g. dendritic cells , macrophages since they carry the antigen to
lymphnodes and present it to the T-helper cells living there.
When the patient is allergic the antigen presenting cells will also express
costimulatory molecules which are needed to mount an effective immune response
.Before the T-helper cell sees the antigen its called a naïve T-helper since even though its
built to recognize the antigen it has not actually seen it before when the naïve T-helper
cell binds with the costimulatory molecules of antigen presenting cell its now primed it
differentiates into Type 2-helper cell (TH2) in presence of some interleukins' (IL4,IL5,IL10)

10. TH2 cells release their own IL4 which which make Bcells undergo
antibody class swithing from making IgM ( normally produced in acute
infections) to making IgE antibodies which are specific to that particular
pollen .
The formed pollen specific IgE antibodies have high affinity for Fc
receptors present in plenty on the surface of mast cells and basophil
cells.
During the same contact with the same antigen ,IgE antibodies
on the surface of mast cells and basophils are so firmly bound to Fc
receptors which signals the mast and basophile cells to degranulate and
release inflammatory mediators .one of the major mediators is
histamine others include serotonin, vasoactive intestinal peptide(VIP)
,Prostaglandins.

12. Effects of the mediators
Increased vascular permeability
Vasoconstriction followed by vasodilatation
Smooth muscle contraction
Shock especially if systemic
Increased gastric secretion
Increased nasal and lacrimal secretion
Clinical examples of anaphylaxis may be system or local
local , Bronchial Asthma -due to allergy to inhaled allergens
Seasonal allergic rhinitis –due to pollen sensitization of conjunctiva/ nose
Cutaneous anaphylaxis – due to contact with skin allergen
Systemic, Administration of drugs e.g penicillin
Administration of antisera e.g Anti-tetanus serum
Sting by bee or wasp.

13. TYPE 2 HYPERSENSITIVITY
DEFINITION
Type 2 hypersensitivity or cytotoxic
hypersensitivity reactions are reactions
mediated by antibodies directed against antigen
on the surface of tissues or cells so that the
tissue or cell is destroyed or the function of the
cell is altered.

14. ETIOLOGY
Intrinsic Antigen /Self Antigen
is an antigen the host cell normally makes i.e innately part of the
patients cell.
However when circulating antibodies(self reactive antibodies)
react with a host cell surface, tissue damage may result or incase
Example; RBCs possesses Antigen on their surfaces it is on many types
like A antigen , B antigen which decides blood group of a person.
.
Extrinsic antigen/ non self antigen
Is an antigen from an infection or even some medications like
penicillin that gets attached to the host cell. E.g. The drug binds to the
surface of the cells and serves as a target for anti drug IgG antibodies
that cause destruction of the cells.

15. MECHANISMS INVOVED IN CELL DEATH
Three different Antibody dependent mechanisms
are involved in this type of reaction.
1, Complement dependent reaction
Activation of Complement system
Membrane Attack Complex (MAC)
Opsonisation and phagocytosis
2, Antibody Dependent Cell-mediated Cytotoxicity
(ADCC)
3,Antibody –mediated cellular dysfunction

16. COMPLEMENT DEPENDENT REACTION
Complement system is a family of small proteins that work in an
enzymatic cascade to fight off infections using a variety of mechanisms
Activation of complement system(Inflammation)
The antigen on the surface of target cell attracts antibody(IgG,IgG) binds
via Fc portion of antibody
The unattached Fc fragment of antibody form a link between the antigen
and complement which activates the complement system , the C3a,C4a
and C5a act as chemotactic factors attracting neutrophils and monocytes
which degranulate releasing lysosomes killing the cell .
Membrane Attack Complex
It is formed by C5 to C9 which attacks the cell by inserting itself into
cell membrane punching a hole which allows fluid and molecules to flow
in and out because of osmotic difference fluid rushes into the cell
making it swell and it bursts

18. OPSONISATION AND PHAGOCYTOSIS
Phagocytosis is largely responsible for depletion of cells coated with antibodies
.this happens when IgG /IgM coat a cell and are bound by C3b another
complement protein fragment at this point the cell has been opsonized hence
targeted for phagocytosis hence engulfed and destroyed by phagocytes.

19. ANTIBODY –DEPENDENT CELL- MEDIATED CYTOTOXITY (ADCC)
This type of antibody mediated cell injury does not involve
fixation of complements .
cells that are coated with IgG antibody are killed by mainly by
Natural killer cells and other cells like macrophages .
In this case the bound antigen-antibody complex gets
recognized by immune cells called natural killer cells via Fc
receptor of the antibody and it releases toxic granules which
contain perforins which like MAC(membrane attack complex)
form pores also allows entry of enzymes called granzymes as
well as granulysin which work together to cause apoptic cell
death without inducing inflammation .

21. ANTIBODY-MEDIATED CELLULAR DYSFUNCTION
This is a non cytotoxic type II hypersensitivity where antibodies are directed
against cell surface receptors impairing or disrupting cell function without causing
cell injury or inflammation .
E.G
Myasthenia Gravis
Antibodies bind with acetylcholine receptors in the motor end plate
of skeletal muscles impairing neuromuscular transmission and cause muscle
weakness .
Graves disease
Where antibodies against the thyroid stimulating hormone receptor
on thyroid epithelial cells stimulate the cells to produce more thyroid hormones.

23. EXAMPLES
Most common examples of type II reaction on RBCs
1, Autoimmune haemolytic Anaemia
2, Transfusion reaction
3, Hemolytic disease of the new born
Cellular injury may be brought about by autoantibodies reacting with some components of tissue
cells in certain disease
4, Graves disease
Thyroid autoantibodies is formed which reacts with TSH receptor to cause
hyperfunction(production of thyroid hormone).
5, Myasthemia
Antibody to acetylcholine receptors of skeletal muscle is formed which blocks the
neuromuscular transmission at the motor end-plate resulting in muscle weakness.
6, Male sterility
Antisperm antibody is formed which reacts with spermatozoa after injury
7, Type 1 diabetes mellitus
Islet cell autoantibodies are formed which react against islet cell tissue.

24. TYPE III HYPERSENSITIVITY/
IMMUNE-COMPLEX HYPERSENSITIVITY
DEFINITION
This occurs when soluble Antigens combine to form
immune complexes.
The compliment system is activated and leukocytes
are recruited (neutrophils and monocytes)produce tissue
damage by release of lysosomal enzymes and generation
of toxic free radicals.

25. NOTE
Antigens are of different types some are soluble i.e
float around in blood but some are bound to cell surfaces.
Immune complexes are formed when antibodies bind
to soluble antigens.
This is the major distinction between type II
hypersensitivity reactions which involve antibodies
binding to antigens on cell surface and type III
hypersensitivity involves immune complexes with soluble
antigen.

26. ETIOLOGY
Type III hypersensitivity reaction is not tissue specific and occurs when antigen –
antibody complexes fail to get removed by the body's immune system .
EXOGENOUS ORIGIN
Exogenous antigens may be inhaled into the lungs e.g. antigens derived from molds
,plants .the inhaled antigen combines with antibody in the alveolar fluid and forms
antigen-antibody complex which is deposited in the alveolar wall
Persistence of low grade microbial infection with bacteria e.g. post streptococcal
glomerulonephritis or viruses stimulates weak antibody response. Persistence of
infection (antigen)and corresponding weak antibody response leads to chronic antigen-
antibody complex formation since these complexes fail to get eliminated from body fluids
and they are deposited in tissues e.g. in blood vessel wall ,glomeruli , joint tissue.
ENDOGENOUS ORIGIN
Another in type III reaction can be formation of autoantibodies against own tissue
(self antigen )can be circulating or tissue derived (e.g. DNA).immune complexes
containing both components from body's own system can thus be deposited in tissue.

27. PATHOGENESIS
The pathogenesis of type III hypersensitivity disease has 3 phases
Formation of immune complexes
The introduction of an antigen triggers an immune response that results in
the formation of antibodies typically about a week after exposure .these antibodies
are secreted into blood where they react with the antigen still present in the
circulation and form Antigen-Antibody complexes.
Deposition of immune complexes
In this phase the circulating Antigen-Antibody complexes are deposited in
various tissues .Organs where blood is filtered at high pressure to form other fluid
are sites where immune complexes become concentrated and lead to deposit
hence immune complex disease often affects glomeruli and joints.

28. Immune deposition depends on
1, size of immune complexes
Large complexes in great antibody excess are rapidly removed by mononuclear
phagocytic system(MPS) .
2,Functional status of mononuclear phagocytic system
MPS clears circulating immune complexes however its overload or dysfunction
increase the persistence of immune complexes in circulation and resulting in tissue
deposition .
Inflammation and injury
After immune complexes are deposited in tissues acute inflammatory reactions
ensues and the damage is similar despite the nature and location of tissues.

29. Due to this inflammatory phase 2 mechanisms operate
1,Activation of complement cascades
C3b the opsonizing and C5 fragment the chemotaxin are characterized by
neutrophilic aggregation ,phagocytosis of complexes and release of lysosomal
enzymes that result in necrosis,C3a , C5a contribute to vascular permeability and
edema .
2, Activation of neutrophil and macrophages through their Fc receptors .
Phagocytosis of immune complexes is effected with subsequent release of
chemical mediators at site of immune deposition and subsequent tissue necrosis.
CLINICAL ASPECT
The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels
,glomerulonephritis if it occurs in renal glomeruli arthritis if it occurs in joints etc.

31. EXAMPLES
Immune complex glomerulonephritis
in which the antigen may be GBS or exogenous agents (streptococcal antigen)
SLE
In which there is nuclear antigen (DNA,RNA) and there is formation of
Antinuclear autoantibodies
Rheumatoid Arthritis
In which there is nuclear antigen
Drug induced vasculitis
in which the drug acts as an antigen
ETC.

32. T-CELL-MEDIATED (TYPE IV )HYPERSENSITIVITY
DEFINITION
This is cell-mediated type of hypersensitivity initiated by specifically sensitized
T lymphocytes.
Also called Delayed hypersensitivity.
The response is delayed for at least 2-3 days after contact with the
antigen.
This type of reaction is not mediated by antibodies but result from the
reaction of antigen specific T cells .

33. TWO FORMS/TYPES OF TYPE IV HYPERSENSITIVITY
Delayed type hypersensitivity
Mediated by CD4+ T cells (also called helper T cells).
These do not damage the cells but rather activate a number of other cells like macrophages ,monocytes damage the
cells/tissue
Direct cell cytotoxicity
Mediated by CD8+cells
These cells damage the infected cells themselves.
MECHANISM OF DELAYED TYPE HYPERSENSITIVITY
• When an allergen enters the body e.g. deposited on the epidermis of the skin,Antigen-Presnting Cells(APC) called
dendritic(Langerhans) cells take it to the naïve T cells in the lympnodes.
• The antigen presenting cells secrete interleukins leading to maturation of naïve T cells into 2 types of t cells
APC if it secretes IL-12 causes Naïve T cell to mature into T helper type 1 cells
APC if it secretes IL-1,IL-6,IL-23 causes T cell to mature into T helper type 17
Some of these activated cells enter into circulation and remain in memory pool of T cells for long period of time
• These secrete cytokines which are responsible for many manifestations of delayed type hypersensivity
Example
T helper type 1 cells secrete cytokines mainly interferon –gamma which acts on macrophages and other cells like causes
increased ability of macrophages to phagocytose ,secrete pro-inflammatory cytokines( IL-1,IL-6 and tnf-alpha ) which also
stimulate macrophages to secrete lysosomal enzymes ,stimulate complement system etc. causing cell death
T helper 17 cells secrete IL-17,IL-22 which in more inflammatory cells like neutrophils and monocytes to the site of allergy
causing local cell damage ,inflammation ,oedema which manifest as Redness,itching ,vesicle eruption at site of contact.

35. PATHOGENESIS OF DIRECT CELL CYTOTOXICITY
The CD8+Tcells kill the Antigen bearing cells directly without activating the
macrophages or bringing in neutrophils .
• when a virus enters the body cells the infected cell or tumor cell express
certain type of antigen on their cell membrane signaling that the cell has been
infected which is recognized by CD8+ T cell which becomes activated producing
perforins(chemicals) which make holes in the cell membranes and also produce
granzyme which enters the viral /tumor infected cell and activates apoptosis
hence death of the cell.

37. EXAMPLES
DELAYED TYPE HYPERSENSITIVITY
Reaction against mycobacterial infection e.g tuberculin reaction
,granulomatous reaction in TB ,leprosy
Contact dermatitis
Reaction against Transplant organ transplantation e.g transplant
rejection ,graft vs host reaction
DIRECT CELL CYTOTOXICITY
Reaction against viral infected cells
Reaction against malignant(tumor) cells