Type 3, 4

1. Hypersensitivity

2. • Hypersensitivity- injurious consequences in
the sensitized host, following subsequent
contact with specific antigens.
• Immune system- ability of host cell to
counteract with foreign substances or
microorganism.

3. Types of Hypersensitivity
 Type I hypersensitivity reactions are mediated by IgE antibodies that
bind to mast cells or basophils and induce mediator release; these reactions
include the most common responses to respiratory allergens, such as pollen
and dust mites, and to food allergens, such as peanuts and shellfish.
 Type II hypersensitivity reactions result from the binding of IgG or IgM
to the surface of host cells, which are then destroyed by complement- or
cell-mediated mechanisms. For example, this is the fate for transfused red
blood cells in transfusions between people differing in ABO blood types.
 In type III hypersensitivity reactions, antigen-antibody complexes (such
as those generated by the injection of foreign serum proteins) deposited on
host cells or tissues activate complement or the release of mediators from
granulocytes, often causing inflammatory responses.
 Type IV hypersensitivity reactions result from excessive and sometimes
inappropriate T-cell activation. Common examples are the skin reactions
caused by poison oak or poison ivy.

6. Effects of mast cell activation
 Activated mast cells immediately release preformed, granule-
associated inflammatory mediators (including
 histamine, proteases, and heparin) and
 are induced to generate lipid mediators (such as leukotrienes and
prostaglandins), chemokines, cytokines, and
 growth factors (some of which can also be packaged in granules).
 These mediators act on different cell types, and have both acute
and chronic effects. When produced over long periods of time,
mast cell mediators have a significant influence on tissue structure
by
 enhancing proliferation of fibroblasts and epithelial cells,
 increasing production and deposition of collagen and other
connective tissue proteins,
 stimulating the generation of blood vessels, and more.

12. Immune Complex–Mediated (Type III)
Hypersensitivity
 as a result of excess formation of immune complexes
(Ag-Ab complexes) which initiate an inflammatory
response through activation of complement system
leading to tissue injury
 The reaction of antibody with antigen generates immune
complexes. In general, these antigen-antibody complexes
facilitate the clearance of antigen by phagocytic cells and
red blood cells.
 In some cases, however, the presence of large numbers
and networks of immune complexes can lead to tissue-
damaging type III hypersensitivity reactions.

13.  The magnitude of the reaction depends on the levels
and size of immune complexes, their distribution within
the body, and the ability of the phagocyte system to
clear the complexes and thus minimize the tissue
damage.
 Failure to clear immune complexes may also result
from peculiarities of the antigen itself, or disorders in
phagocytic machinery.
 The deposition of immune complexes in the blood
vessels or tissues initiates reactions that result in the
recruitment of complement components and neutrophils
to the site, with resultant tissue injury.

14. Immune Complex–Mediated (Type III)
Hypersensitivity
The formation of antigen-antibody complexes
occurs as a normal part of an adaptive immune
response.
It is usually followed by Fc receptor–mediated
recognition of the complexes by phagocytes,
which engulf and destroy them; by binding to
red blood cells for clearance in the spleen or
kidney; and/or by complement activation that
results in the lysis of the cells on which the
immune complexes are found.

15. Type III Hypersensitivity
 However, under certain conditions, immune
complexes are inefficiently cleared and may be
deposited in the blood vessels or tissues, setting the
stage for a type III hypersensitivity response.
 These conditions include
1. the presence of antigens capable of generating particularly
extensive antigen-antibody lattices,
2. a high intrinsic affinity of antigens for particular tissues,
3. the presence of highly charged antigens (which can affect
immune complex engulfment), and
4. a compromised phagocytic system.
All have been associated with the initiation of type III responses

20. Mechanism of Tissue Injury
• Classical Complement Activation
Ab-immune complexes stimulate the classical pathway
of complement system, leading tissue damage
• Platelet Activation
Immune complexes bind to the Fc receptors on
platelets leading to their activation.
Platelet aggregation (leads to microthrombi
formation) and vasoactive amines released from
activated platelets, both together cause tissue
ischemia leading to further tissue damage
• Activation of Hageman Factor
leads to activation of kinin, which in turn causes
causes vasodilatalion and edema

21. Classical Complement Activation
• Products of Complement Activation- mediate the
tissue injury in type Ill reaction.
• Anaphylatoxin:
Complement by-products C3a and C5a being anaphylactic;
induce localized mast cell degranulation with consequence
increase in vascular permeability.
• Chemoatractant:
C3a and C5a also act as chemoattractants, causing
recruitment of neutrophils to the site of immune complex
deposition.
• Role of neutrophils:
Neutrophils attempt to phagocytose the large immune
complexes, but fail in doing so. Instead, they release large
number of lytic enzymes from the secretory granules
(through frustrated phagocytosis) which causes extensive
tissue damage

22. Generalized or Systemic Type III Reactions
• The pathogenesis of systemic immune complex disease
can be divided into two phases:
1. Formation of small sized soluble Ag-Ab complexes in
the circulation, which occurs following the entry of a
large dose of antigen into the body.
2. Induces inflamatory reaction:
 Deposition of the immune complexes in various tissues,
thus initiating an inflammatory reaction in various sites
throughout the body such as; blood vessels ( vasculitis ),
glomerular basement membrane (glomerulonephritis)
and synovial membrane (arthritis). This has been linked
the pathogenesis of various diseases

23. Arthus Reactions Are Localized Type III
Hypersensitivity Reactions
One example of a localized type III
hypersensitivity reaction has been used
extensively as an experimental tool.
If an animal or human subject is injected
intradermally with an antigen
large amounts of circulating antibodies exist (or
have been recently introduced by intravenous
injections), antigen will diffuse into the walls of
local blood vessels and large immune complexes
will precipitate close to the injection site.

24. This initiates an inflammatory reaction that peaks
approximately 4 to 10 hours postinjection and is
known as an Arthus reaction.
Inflammation at the site of an Arthus reaction is
characterized by swelling and localized bleeding,
followed by fibrin deposition.
Though not commonly used now, this was used
as an in vivo assay to detect the presence of
antigens and/or antibodies, especially in
situations in which the antibodies or antigen
had not been purified.

25. Delayed-Type (Type IV) Hypersensitivity
 Type IV hypersensitivity, commonly referred to as
delayed-type hypersensitivity (DTH), is the only
hypersensitivity category that is purely cell mediated
rather than antibody mediated.
 In 1890, Robert Koch observed that individuals
infected with Mycobacterium tuberculosis developed
localized inflammatory response when injected
intradermally (i.e., via the skin) with a filtrate derived
from a mycobacterial culture.
 He therefore named this localized skin reaction a
tuberculin reaction.

26.  Later, as it became apparent that a variety of other
antigens could induce this cellular response, its name
was changed to delayed-type, or type IV,
hypersensitivity.
 The hallmarks of a type IV reaction are its initiation by
T cells (as distinct from antibodies),
 the delay required for the reaction to develop (usually 1
to 2 days), and
 recruitment of macrophages (as opposed to neutrophils
or eosinophils) as the primary cellular component of the
infiltrate that surrounds the site of inflammation.

27. The Initiation of a Type IV DTH Response Involves
Sensitization by Antigen
• Type of IV hypersensitivity reactions occur through
two phases- sensitization and effector phases
 A DTH response begins with an initial sensitization
by antigen, followed by a period of at least 1 to 2
weeks during which antigen-specific T cells are
activated, clonally expanded, and mature into effector
T cells.
 Various antigen-presenting cells (APCs) are
involved in the induction of a DTH response,
including macrophages, dendritic cells, and
Langerhans cells (dendritic cells found in the
epidermis) if it is a skin reaction.

28. These cells pick up antigen and transport it to
regional lymph nodes, where T cells are activated.
In some species, including humans, the vascular
endothelial cells express MHC class II molecules
and can also function as APCs in the development
of the DTH response.
In general, the T cells activated during the
sensitization phase of a traditional DTH response
are CD4 , primarily of the T 1 subtypes.
However, recent studies indicate that T 17 and
CD8 cells can also play a role.