26. INFLAMMATION - LAMBERT

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BASICS OF INFLAMMATION AND HYPERSENSITIVITY REACTIONS
BY
Dr. Bhuvan Nagpal
B.D.S. (Hons.), M.D.S. (Oral Pathology)
(Gold Medalist)
Consulting Oral & Maxillofacial Pathologist
Ex. Post Graduate Resident,
Dept. of Oral Pathology & Microbiology,
JSS Dental College & Hospital,
JSS University,
Mysuru, Karnataka, India
Dr. Anuradha Nagpal
M.B.B.S. (Hons.)
House Surgeon
Teerthanker Mahaveer Medical College & Research Centre,
Teerthanker Mahaveer University,
Moradabad, Uttar Pradesh, India
Dr. Anupam Nagpal
B.D.S. (Hons.)
(Gold Medalist)
House Surgeon
Teerthanker Mahaveer Dental College & Research Centre,
Teerthanker Mahaveer University,
Moradabad, Uttar Pradesh, India

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S. No CONTENTS Page No.
1. INTRODUCTION 3
2. TYPES OF INFLAMMATION 4
3. ACUTE INFLAMMATION 5
4. CHEMICAL MEDIATORS OF INFLAMMATION 11
5. INFLAMMATORY CELLS 16
6. MORPHOLOGY OF ACUTE INFLAMMATION 18
7. APPLIED ASPECTS OF INFLAMMATION IN DENTISTRY 19
CHRONIC INFLAMMATION 20
GRANULOMATOUS INFLAMMATION 26
SYSTEMIC EFFECTS OF INFLAMMATION 29
11. INTRODUCTION TO HYPERSENSITIVITY 34
12. CLASSIFICATION 34
13. MECHANISM 35
14. OVERVIEW OF TYPES OF HYPERSENSITIVITY 35
15. TYPE I ANAPHYLAXIS 36
16. TYPE II CYTOTOXIC TYPE 41
17. TYPE III IMMUNE COMPLEX MEDIATED TYPE 44
18. TYPE IV DELAYED TYPE HYPERSENSITIVITY 45
19. TYPE V STIMULATORY HYPERSENSITIVITY 57
20. SUMMARY OF HYPERSENSITIVITY 58
21. REFERENCES 59

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INTRODUCTION
Inflammation is defined as a local response of living mammalian tissue to
injury due to any agent. It is a body defense mechanism in order to eliminate the
spread of injurious agent as well as to remove the consequent necrosed cells and
tissues.
The agents causing inflammation may be as under :
Physical agents like heat, cold, radiation, mechanical trauma.
Chemical agents like organic and inorganic poisons
Infective agents like bacteria, viruses and their toxins.
Immunological agents like cell mediated and antigen antibody reactions.
Signs of inflammation
Rubour (redness)
Tumor (swelling)
Calor (heat)
Dolor (pain)
Functio laesa (loss of function)

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Functions of inflammation
1. Destroy and remove pathogens
2. If destruction is not possible, to limit effects by confining the pathogen and its
products.
3. Repair and replace tissue damaged by pathogen and its products.
Types of inflammation
Depending upon the defense capacity of the host and duration of response,
inflammation can be classified as acute and chronic.
1. Acute inflammation
It is of short duration and represents the early body reaction and is usually
followed by repair.
The main features of acute inflammation are :
1. Accumulation of fluid and plasma at the affected site.
2. Intravascular activation of platelets.
3. Polymorphonuclear neutrophils as inflammatory cells.
2. Chronic inflammation
It is of longer duration and occurs either after the causative agent of acute
inflammation persists for a long time, or the stimulus is such that it induces chronic
inflammation from the beginning.
The characteristic of chronic inflammation is presence of chronic inflammatory
cells such as lymphocytes, plasma cells and macrophages.

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ACUTE INFLAMMATION
The changes in acute inflammation can be described under the following 2
headings
1. Vascular events
2. Cellular events
I. Vascular events
Alteration in the microvasculature (arterioles, capillaries and venules) is the
earliest response to tissue injury. These alterations include hemodynamic changes and
changes in vascular permeability.
Hemodynamic Changes
1. Transient vasoconstriction : Irrespective of the type of injury, immediate
vascular response is of transient vasoconstriction of arterioles. With mild form
of injury, the blood flow may be reestablished in 3 5 seconds while with more
severe injury the vasoconstriction may last for about 5 minutes.
2. Persistent progressive vasodilatation : It involves mainly the arterioles, but to a
lesser extent, affects other components of the microcirculation like venules and
capillaries. This change is obvious within half an hour of injury.
3. Increase in local hydrostatic pressure : Progressive vasodilatation, in turn, may
elevate the local hydrostatic pressure resulting in transudation of fluid into the
extracellular space.
4. Slowing or Stasis : It occurs next. It is attributed to increased permeability of
micro vasculature that results in increased concentration of red cells, and thus
raised blood viscosity.
5. Leucocyte margination : It is the peripheral orientation of leucocytes (mainly
neutrophils) along the vascular endothelium. The leucocytes stick to the

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vascular endothelium briefly, and then move and migrate through the gaps
between the endothelial cells into the extravascular space.
Pathogenesis of increased vascular permeability
There is a loss of fluid balance which is normally maintained by two opposing
sets of forces i.e.
1. Forces that cause outward movement of fluid
Intravascular hydrostatic pressure
Interstitial osmotic pressure
2. Forces that cause inward movement of fluid
Intravascular osmotic pressure
Interstitial hydrostatic pressure
Mechanisms of increased vascular permeability
In acute inflammation, normally permeable endothelial layer of
microvasculature becomes leaky. This is explained by one or more of the following
mechanisms.
1. Contraction of endothelial cells
This is the most common mechanism of increased leakiness that affects venules
exclusively while capillaries and arterioles remain unaffected. The endothelial cells
develop temporary gaps between them due to their contraction resulting in vascular
leakiness. It is mediated by the release of histamine, bradykinin and other chemical
mediators. It is reversible and of short duration (15 30 mins).

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2. Retraction of endothelial cells
Here, there is structural re-organization of the cytoskeleton of endothelial cells
that causes reversible retraction at the intercellular junctions. This change too affects
venules and is mediated by cytokines such as IL1 and TNF. The onset of response
takes 4 6 hours after injury and lasts for 24 hours or more.
3. Direct injury to endothelial cells
It causes cell necrosis and appearance of physical gaps at the site of detached
endothelial cells. This change affects all levels of microvasculature. The increased
permeability may either appear immediately after injury and lasts for several hours or
days, or may occur after a delay of 2 12
4. Endothelial injury mediated by leucocytes
Adherence of leucocytes to the endothelium at the site of inflammation may
result in activation of leucocytes. The activated leucocytes release proteolytic
enzymes and toxic oxygen species which may cause endothelial injury and increased
vascular leakiness. This form of increased vascular leakiness is al late response.
5. Other Mechanisms
Also the newly formed capillaries during the process of repair are excessively
leaky. Vesicles and vacuoles within the cytoplasm of endothelial cells of blood vessels
in tymours may account for leakage of fluid across the cytoplasm.
II. Cellular events
The cellular phase of inflammation consists of two phases
1. Exudation of leukocytes
2. Phagocytes

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Exudation of leukocytes
The escape of leucocytes from the lumen of microvasculature to the interstitial
tissue is the most important feature of inflammatory response.
The changes leading to migration of leucocytes are as follows:
1. Changes in the formed elements of blood
The normal axial flow of blood consists of central stream of cells comprised by
cell free layer of plasma close to vessel wall.
Due to slowing and stasis, the central stream of cells widens and peripheral plasma
zone becomes narrower because of loss of plasma by exudation. This phenomenon is
known as margination. Now the neutrophils of the central column come close to the
vessel wall and this phenomenon is known as pavementing.
2. Adhesion and rolling
Peripherally marginated and pavemented neutrophils stick briefly to the
endothelial cells lining the vessel wall or roll over it. Injury leads to nertralisation of
the normal negative charge on leucocytes and endothelial cells so as to cause
adhesion. This mechanism is brought about by 4 types of adhesion molecules. They
are :
a. Selectins mainly P selectin, E selectin, and L selectin.
b. Addressins
c. Integrins and
d. Immunoglobulin superfamily adhesion molecule (ICAM 1,2)
3. Emigration
After sticking of neutrophils to endothelium, the former move along the
endothelial surface till a suitable site between the endothelial cells is found where the

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neutrophils throw out cytoplasimc pseudopods. Subsequently, the neutrophils lodged
between the endothelial cells and basement membrane cross the basement membrane
by damaging it locally with secreted collagenases and escape out into the
extravascular space. This is known as emigration. Simultaneous to emigration of
leucocytes, escape of red cells through gaps between the endothelial cells, diapedesis
takes place. It is a passive phenomenon
hydrostatic pressure or may escape through the endothelial defects left after
emigration of leucocytes.
4. Chemotaxis
The chemotactic factor mediated transmigration of leucocytes after crossing
several barriers (endothelium, basement membrane, perivascular myofibroblasts and
matrix) to reach the interstitial tissues is called chemotaxis.
The agents acting as potent chemotactic substances for different leucocytes
called chemokines are as follows:
i. Leukotriene B4 (LTB4)
ii. Platelet factor 4 (PF4)
iii. Components of complement system (C5a in particular)
iv. Cytokines (particularly IL8)
v. Soluble bacterial products (such as formylated peptides)
vi. Monocyte chemoattractant protein (MCP 1)
vii. Chem9otactic factor for CD4 + T cells
viii. Eotaxin chemotactic for eosinophils
There are specific receptors for each of the chemoattractants listed above. In
addition, chemotactic agents also induce leucocyte activation that includes: the
production of arachidonic acid metabolites, degranulation and secretion of lysosomal
enzymes, generation of oxygen metabolites, increased intracellular calcium, and
increase in the leucocyte surface adhesion molecules.

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5. Phagocytosis
It is defined as the process of engulfment of solid particulate material by the
cells (cell eating). The cells performing this function are called phagocytes. There
are two main types of phagocytic cells. Viz Microphages (Neutrophils) and
Macrophages.
The process of phagocytosis involves the following 4 steps:
1. Attachment stage (Opsonisation)
2. Engulfment
3. Secretion (Degranulation)
4. Killing or degradation
1. Attachment stage
The phagocytic cells as well as micro organisms to be injested have usually
negatively charged surface and, thus, they repel each other. In order to establish a
bond between bacteria and the cell membrane of phagocytic cell, the micro
organism get coated with opsonins which are naturally occurring factors in the serum.
The two main opsonins present in the serum and their corresponding receptors on the
surface of phagocytic cells are as under:
a. IgG Opsonin and its corresponding receptor on the surface of polymorphs is
Fc fragment of immunoglobulin.
b. C3b Opsonin fragment of complement and corresponding receptor for C3b on
the surface of phagocytic cells

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2. Engulfment stage
Here pseudopods are formed around the particle, enveloping it in a phagocytic
vacuole. Eventually, the plasma membrane enclosing the phagovytic vacuole breaks
from the cell surface so that the membrane lined phagocytic vacuole lies free in the
cell cytoplasm. The lysosome of the cell fuse with the phagocytic vacuole and form
phagolysosome or phagosome.
3. Secretion stage
During this process, the preformed granule
discharged or secreted into the phagosome and the extracellular environment.
4. Killing or Degradation stage
Here, killing and digestion of micro organisms takes place. After being killed
by antibacterial substances, the micro organisms are degraded by hydrolytic enzymes.
Chemical mediators of inflammation
They are of two types:
I. Cell derived mediators
1. Vasoactive amines (Histamine, 5 hydroxyl tryptamine)
2. Arachidonic acid metabolites
a. Via cyclo oxygenase pathway
b. Via lipo oxygenase pathway
3. Lysosomal components
4. Platelet activating factor
5. Cytokines
6. Nitric oxide and oxygen metabolites

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II. Plasma derived mediators
These are the products of
1. The Kinin system
2. The Clotting system
3. The Fibrinolytic system
4. The Complement system
I. Cell derived mediators
1. Vasoactive amines
i. Histamine : It is stored in the granules of mast cells, basophils and
platelets. The main actions of histamine are : Vasodilation, increased
vascular permeability, itching and pain.
ii. 5 Hydroxytryptamine (serotonin): It is present in tissues like chromaffin
cells of GIT, spleen, nervous tissue, mast cells and platelets. The actions
are similar to histamine but it is a less potent mediator of increased
permeability and vasodilatation than histamine.

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2. Arachidonic Acid Metabolities
i. Via cyclo oxygenase pathway
Activated arachidonic acid
Cyclooxygenase
PGG2 PGH2 + Free oxygen radical
PGD2, PGE2 PGF2 TXA2 PGI2
Vasodialator Vasodialator Vasoconstrictor Vasodialator
Bronchodialator Bronchoconstrictor Bronchoconstrictor
Bronchodialator
Permeability Platelet aggregation Anti aggr agent

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ii. Via lipooxygenase pathway
Activated Arachidonic acid
Lipo oxygenase
5 HPETE 5 - HETE
Chemotactic
LTA4
LTB4 LTC4 LTD4 LTE4
Chemotactic Smooth muscle constrictor
Cell adherence Vasoconstrictor
Bronchoconstrictor
3. Lysosomal Components
i. Granules of neutrophils: They are of two types: specific granules and
azurophil granules. The specific granules contain lactoferrin, lysozyme,
alkaline phosphatase and collagenase while the large azurophil granules
have myeloperoxidase, acid hydrolases and neutral proteases such as
elastase, collagenase and proteinase.
ii. Granules of monocytes and tissue macrophages : These cells on
degranulation also release mediators of inflammation lke acid proteases,
collagenase, elastase and plasminogen activator.

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4. Platelet Activating Factor (PAF)
It is released from IgE sensitized basophils or mast cells, other leucocytes,
endothelium and platelets. Its fuctions are Platelet aggregation, increased vascular
permeability, vasodilatation in low concentration and vasoconstriction,
bronchoconstriction, adhesion of leucocytes to endothelium and chemotaxis.
5. Cytokines
They are polypeptide substances produced by activated lymphocytes and
monocytes. The actions of various cytokines are as under
i. IL1 and TNF - - induce endothelial effects in the form of
increased leucocyte adherence, thrombogenicity, elaboration of other
cytokines, fibroblastic proliferation and acute phase reactions
ii. IF
with synthesis of nitric acid synthase.
iii. Chemokines are a family of chemoattractants for inflammatory cells and
include IL8, PF4, MCP1 and eotaxin.
6. Nitric Oxide and Oxygen Metabolites
NO plays the following role in inflammation:
i. Vasodilatation
ii. Anti Platelet activating agent
iii. Possibly microbicidal action.

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II. Plasma derived mediators
These include the various products derived from activation and interaction of 4
interlinked systems.
1. The Kinin System : Bradykinin is the end product of this system. Its effects
include smooth muscle contraction, vasodilatation, increased permeability and
pain.
2. The Clotting System : The action of fibrinopeptides in inflammation are
increased permeability, chemotaxis for leukocyte and anticoagulant activity.
3. The Fibrinolytic System : The action of plasmin in inflammation are activation
of factor XII to form prekallikrein activator, split off complement C3 to C3a
and degrades fibrin to form fibrin split products.
4. The Complement System : It can occur by Classical or Alternate pathway. It
yields anaphylatoxins. Its action in inflammation are to release histamine from
mast cells and basophils, increase permeability, C3b augments phagocytosis and
C5a is chemotactic for leukocytes.
The inflammatory cells
The cells participating in acute and chronic inflammation are circulating
leucocytes, plasma cells and tissue macrophages. They are described as follows :
1. Polymorphonuclear Neutrophils (PMN )
The functions of neutrophils in inflammation are initial phagocytosis of micro
organisms, engulfment of antigen antibody complexes and non microbial
material.

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2. Eosinophils
Eosinophils share many structural and functional similarities with
neutrophils like their production in the bone marrow, locomotion, phagocytosis,
lobed nucleus and presence of granules in the cytoplasm containing a variety of
enzymes, of which major basic protein and eosinophil cationic protein are the
most important which have bactericidal and toxic action against helminthic
parasites.
3. Basophils
They comprise about 1% of circulating leukocytes and are
morphologically and pharmacologically similar to mast cells of tissue. The role
of these cells in acute inflammation is in immediate and delayed type of
hypersensitivity reactions and release of histamine by IgE sensitized basophils.
4. Lymphocytes
Besides their role in antibody formation and in cell mediated immunity,
these cells participate in chronic inflammation as these are the dominant cells in
the tissues and also their number is increased in chronic infections like
tuberculosis.
5. Plasma Cells
Their number is increased in prolonged infection with immunological
responses e.g. syphilis, RA, tuberculosis, hypersensitivity states and in multiple
myeloma.
6. Mononuclear Phagocyte System
This cell system includes cells derived form 2 sources namely Blood monocytes
and Tissue macrophages. Their functions in inflammation are Phagocytosis and

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elaboration of a variety of biologically active substances like proteases,
plasminogen activator, products of complement, some coagulation factors,
chemotactic agents, metabolites of arachidonic acid, growth promoting factors for
fibroblasts, blood vessels and granulocytes, cytoines and oxygen derived free
radicals.
Morphology of Acute Inflammation
1. Pseudomembranous Inflammation : It is an inflammatory response of mucous
surface to toxins of diphtheria or irritant gases. As a result of denudation of
epithelium, plasma exudes on the surface where it coagulates, and together
with necrosed epithelium, forms false membrane that gives this type of
inflammation its name.
2. Ulcer : Ulcers are local defects on the surface of an organ produced by
inflammation. Common sites for ulcerations are the stomach, duodenum,
intestinal ulcers in typhoid fever, intestinal tuberculosis, bacillary and amoebic
dysentery, ulcers of legs due to varicose veins etc.
3. Suppuration : When acute bacterial infection is accompanied by intense
neutrophilic infiltrate in the inflamed tissue, it results in tissue necrosis. A
cavity is formed which is called an abscess and contains purulent exudates or
pus and the process of abscess formation is known as suppuration.
4. Cellulitis : It is a diffuse inflammation of the soft tissues resulting from
spreading effects of substances like hyaluronidase released by some bacteria.
5. Bacterial infection of the blood : This includes the following 3 conditions.
a. Bacterimia : It is defined as the presence of small number of bacteria in
the blood which do not multiply significantly.
b. Septicemia : means presence of rapidly multiplying pathologic bacteria
in blood.
c. Pyaemia : It is the dissemination of small septic thrombi in blood which
cause their effect at the site where it is lodged.

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APPLIED ASPECTS IN DENTISTRY
DRY SOCKET It is called as alveolitis sicca dolorasa. This is most common and
painful complication in the healing of human extraction wounds. Basically this is a
focal osteomyelitis in which the blood clot has disintegrated or been lost, with the
production of a foul odor and severe pain of the throbbing type, but no suppuration.
More common in women and tobacco users and most frequently related with difficult
or traumatic extraction.
Destruction of clot is caused by the action of proteolytic enzymes produced by
bacteria or fibrinolytic activity.
Safe and skilled procedure of extraction is the prevention from this condition.
Treatment includes sulfanilamide, aureomycin, trypsin and iodoform gauze packing.
OSTEOMYELITIS This is defined as inflammation of bone and its marrow
contents. Changes in the calcified tissue are secondary to inflammation of the soft
tissue component of the bone. Dental infection through periapical infection is the most
frequent cause of inflammation of jaw. Clinical features include pain, swelling,
paresthesia, leukocytosis,elevated temperature. Types of osteomyelitis are acute and
chronic osteomyelitis. Difference between these two is the duration of the
inflammation and severity of the condition. Antibiotics are effective to reduce the
effects of the disease. In advanced stages of osteomyelitis sequestromy is the
treatment of choice.
Gingivitis, periodontitis, pulpitis are the other main inflammatory conditions of the
oral cavity.

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CONCLUSION
Inflammation is basically a protective response intended to eliminate initial cause of
cell injury as well as necrotic cells and tissues resulting from original insult.
Inflammation is also intimately interwoven with repair process whereby damaged
tissue is replaced by regeneration of parenchymal cells or by filling of any residual
defect with fibrous scar tissue.
CHRONIC INFLAMMATION
This is considered to be inflammation of prolonged duration (weeks or
months) in which active inflammation, tissue destruction and attempts at
repair are proceeding simultaneously.
It may follow either an acute inflammation or even may begin insidiously as
a low grade smouldering , often asymptomatic response. This latter type
causes tissue damage in some of the most common and disabling human
diseases like rheumatoid arthritis, TB etc.
CAUSES OF CHRONIC INFLAMMATION:
It usually arises in the following settings :
Persistent Infection which is usually of low toxicity and thus evokes an
immune reaction called the Delayed Type of Hypersensitivity. This form of
inflammation sometimes takes on a specific pattern called
GRANULOMATOUS REACTION. The organisms involved are like
Tubercle bacilli, Treponema Pallidum and other viruses, fungi or parasites.
Prolonged Exposure to potentially toxic agents (exogenous / endogenous).
Exogenous agents like SILICA when inhaled over prolonged exposure
causes an inflammatory lung disease called SILICOSIS.

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ATHEROSCLEROSIS is said to be a chronic inflammatory process of the
arterial wall induced in part by endogenous toxic plasma lipid components.
Autoimmunity: Sometimes in certain conditions immune reactions develop
perpetuating immune reaction resulting in chronic tissue damage and
inflammation. Eg : SLE, rheumatoid arthritis etc.
MORPHOLOGIC FEATURES
Infilteration with mononuclear cells which include macrophages, lymphocytes
and plasma cells.
Tissue destruction induced by the persistent offending agent or by the
inflammatory cells.
Healing attempts by replacement of the damaged tissue with connective tissue
done by angiogenesis and fibrosis.
MONONUCLEAR CELL INFILTERATION:
The mononuclear phagocyte system (RE system) consists of closely related
cells of bone marrow origin, incl blood monocytes and tissue macrophages. Of
this the most dominant cellular component is the macrophage which is diffusely
scattered in the connective tissue or located in the organs like liver (kupffer
cells), spleen and lymph nodes (sinus histiocytes) and lungs( alveolar
macrophages).
Mononuclear phagocytes arise from a common precursor in the bone marrow
which initially gives rise to blood monocytes which further migrate into various
tissues and differentiates into macrophages. The half life of a blood monocyte is
1 day but that of the macrophages is several months to years.
In acute inflammation, the monocytes begin to emigrate quite early and within
the first 48 hrs they constitute the predominant cell type. Once they reach the
site of inflammation they transform into a bigger cell type called the

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macrophage. These are then activated by various factors like cytokines,
bacterial endotoxins and other chemical mediators. Activation results in
increased cell size, increased levels of lysosomal enzymes leading to more
active metabolism thus greater ability to phagocytose and kill ingested
microbes. To do this they secrete a wide variety of biologically active products
which if left in a longer situation also causes tissue injury and fibrosis
characteristics of chronic inflammation.
In short lived inflammation the macrophages eventually disappear but in
chronic inflammation, macrophage accumulation persists and is mediated by
different mechanisms :
Recruitment of monocytes from the circulation results from the expression of
adhesion molecules and chemotactic factors.
Local proliferation of macrophages after their emigration from the bloodstream
and this is found to be very prominent in chronic inflammatory lesions like
atheromatous plaques.
Immobilization of macrophages is done within the site of inflammation. This
maybe caused by certain cytokines and oxidized lipids.
The products of activated macrophages serve to eliminate injurious agents such
as microbes and to initiate the process of repair and are also responsible for
much of the tissue destruction occurring in chronic inflammation. Thus the
macrophages are powerful allies in the body defense against unwanted invaders,
but at the same time the same weaponry can also induce considerable tissue
destruction when the macrophages are inappropriately inactivated and thus
making TISSUE DESTRUCTION as one of the hallmarks of chronic
inflammation.
Other substances also are capable of tissue damage like---
Necrotic tissue itself can perpetuate an inflammatory cascade.
In cellular immune reactions, T lymphocytes may directly kill cells.Thus as we
see sometimes the features of both acute and chronic inflammation may co-exist
in certain circumstances.

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OTHER CELL TYPES IN CHRONIC INFLAMMATION
LYMPHOCYTES
Mobilized in both Ab mediated and cell mediated immune reactions and even in
non-immune inflammation.
Ag stimulated lymphocytes (T & B) use various adhesion molecule pairs
(integrins and ligands) and chemokines to migrate into inflammatory sites.
Lymphocytes and macrophages interact in a bidirectional way, which helps in
chronic inflammation.
Macrophages display Ag to T cells stimulate the T cells.
Activated T lymphocyte--- produces cytokines of which one particular one is a
macrophage activator.
Activated B lymphocytes form plasma cells.
Plasma cells produce Ab directed either against a persistent Ag in the
inflammatory site or against altered tissue components.
Sometimes in strong chronic inflammatory reactions like long standing
rheumatoid arthritis the accumulation of lymphocytes, Ag presenting cells and

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plasma cells may end up assuming the morphologic features of lymphoid
organs called lymphoid organogenesis.
EOSINOPHILS
They are abundant in immune reactions mediated by IgE and in parasitic
infections.
The important chemokine for their extravasation is eotaxin.
They possess granules that contain major basic protein, a highly cationic is
toxic to parasites but also causes lysis of mammalian epithelial cells.

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So they are good for control of parasitic infection but in long standing immune
reactions it also has a tendency to cause tissue damage.
MAST CELLS widely distributed in connective tissue and participate in both acute
and chronic inflammation. They express on their surface the receptor that binds the Fc
portion of IgE Ab . basically found in acute inflammation but in chronic inflammation
they may produce cytokines which contribute to fibrosis.

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NEUTROPHILS they are predominantly the cells found in acute inflammation but
in long standing chronic inflammation, lasting for months, continue to show large
numbers of neutrophils induced either by persistent microbes or by mediators
produced by macrophages and T lymphocytes. In chronic bacterial infection of bone
(osteomyelitis) a neutrophilic exudate can persist for months. They are also found in
the chronic damage induced in lungs by smoking and irritant stimuli.
GRANULOMATOUS INFLAMMATION
This is a distinctive pattern of chronic inflammatory reactions characterized by
focal accumulations of activated macrophages, which often develop an
epithelial - like (epithelioid) appearance.
It is encountered in a limited number of immunologically mediated, infectious
and noninfectious conditions.
- scratch disease,
lymphogranuloma inguinale, leprosy, brucellosis, syphilis, some mycotic
infections, berylliosis and reactions of irritant lipids are also included.
A granuloma is a focus of chronic inflammation consisting of a microscopic
aggregation of macrophages that are transformed into epithelium-like cells

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The prototype here is the bacillus of TB. Here the granuloma is referred to as a
tubercle and is classically characterized by the presence of central caseous
necrosis. This type of necrosis is rare in other granulomatous diseases
thoughtheir morphologic pattern maybe sufficiently different to allow a
reasonably accurate diagnosis.

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LYMPHATICS IN INFLAMMATION
The system of lymph nodes and lymphatics filter and polices the extravascular
fluid and along with the mononuclear phagocytic system it forms the 2nd
line of
defense that is called into play whenever a local inflammatory reaction fails to
contain and neutralize an external agent like a microbe.
Lymphatics are delicate channels that are not readily visualized in normal tissue
sections as they collapse. They are lined by continuous, thin endothelium with
loose , overlapping cell junctions, scant basement membrane and no muscular
support except in the larger ducts.
In inflammation there is an increase in the lymph flow and it helps to drain the
edema fluid from the extravascular space. As they have loose overlapping
junctions, the lymphatic fluid eventually equilibrates with extravascular fluid.
Valves are present in the collecting lymphatics, allowing the lymph content to
flow only in one direction proximally. The vessel patency is maintained by
delicate fibrils which are attatched at right angles to the walls of the vessels.
In severe injuries the lymph may transport the offending organism or toxin
which may lead to secondary inflammation of the lymphatics (lymphangitis) or
of the draining nodes (lymphadenitis). Enlargements of the lymph nodes is
caused by the hyperplasia of the lymphoid follicles as well as by hyperplasia of
the phagocytic cells lining the sinuses of the lymph nodes. This constellation of
nodal histologic changes is called reactive, or inflammatory lymphadenitis.
Basically the lymph functions to contain the spread of the infection though in
severe infections it becomes difficult to contain thus leading to bacteremia.
SYSTEMIC EFFECTS OF INFLAMMATION
The systemic changes associated with inflammation, especially in patients who have
infections are called the Acute phase response or the systemic inflammatory response
syndrome SIRS. These changes are reactions to cytokines whose productions is
stimulated by bacterial products and other inflammatory stimuli.

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This acute phase response consists of several clinical and pathological changes
FEVER
usually characterized by the elevation of body temperature by 1 4 C
especially when inflammation is associated with infection. Fever is produced in
response to substances called Pyrogens act by stimulating prostaglandin
synthesis in the vascular and perivascular cells of the hypothalamus.
In amphibians the raise of temperature is meant to ward off any microbial attack
which even though the mechanism is unknown it is thought to be a reaction to
the same as the fever may induce shock proteins that enhance lymphocyte
responses to microbial agents.
ACUTE-PHASE PROTEINS
These are plasma proteins, mostly synthesized in the liver, whose plasma
concentrations may increase several hundred fold as part of the response to
inflammatory stimuli. The best known examples being C- reactive protein
(CRP), fibrinogen and serum Amyloid A (SAA) protein.
CRP and SAA bind to the microbial cell walls and may act as opsonins and fix
complement. They also bind the chromatin, possibly aiding in the clearing of
necrotic cell nuclei.
SAA protein replaces apolipoprotein A which is a high density lipoprotein
particle and this changes the target of the high density protein from the liver
cells to the macrophages, which further can utilize these particles as a source of
energy producing lipids.
The rise in fibrinogen causes the erythrocytes to form stacks or go into rouleaux
formation which causes them to sediment thus making the ESR test important
for information of inflammation.
These proteins do have a beneficial effect on inflammation but prolonged
production of these proteins causes secondary amyloidosis in cases of chronic

31
inflammation. Thus, the CRP elevated levels in a patient with coronary artery
disease, are used as a marker for risk to MI.
LEUKOCYTOSIS
This is a common feature of inflammatory reactions especially ones associated
with bacterial infection. The count may usually be raised to 15,000 20,000
of 40,000
they are similar to the WBC count obtained in leukemia. This leukocytosis
occurs mainly due to initially an accelerated release of cells from the bone
marrow postmitotic pool and is therefore, associated with a rise of more
immature cells mainly neutrophils.
Prolonged infection also induces proliferation of precursors in the bone marrow,
caused by increased production of colony stimulating factors (CSFs). Thus, the
bone marrow output of leukocytes is increased to compensate for the loss of
these cells in the inflammatory reaction.
Bacterial infections Neutrophilia
Viral infections Lymphocytosis
Parasitic infection and allergic reactions Eosinophilia
Certain infection ( typhoid fever and infections caused by viruses, rickettsiae,
and certain protozoa) Leukopenia
Debilitating infection due to disseminated cancer or rampant TB.
Other manifestation of the acute phase responses:
Increased pulse and blood pressure
Decreased sweating
Rigors, chills, anorexia, somnolence and malaise
Because of redirection of blood flow from cutaneous to deep vascular beds and
to minimize heat loss through the skin.

32
SEPSIS
Due to severe bacterial infections there is the presence of a large no. of
organisms which stimulate to produce cytokines ( TNF and IL-1). High levels
of TNF cause DIC.
Thrombosis is due to two main simultaneous reactions
LPS and TNF induce tissue factor on the endothelial cells initiates
coagulation and these same agents will inhibit the natural anticoagulation
mechanisms by decreasing the expression of tissue factor pathway inhibitor
(TFPI) and endothelial cell thrombo- modulin.
Cytokines cause liver injury and thus impaired liver function which results in
the failure to maintain normal blood glucose levels due to lack of
gluconeogenesis from stored glycogen.
Overproduction of NO by the cytokine activated cardiac myocytes and vascular
smooth muscle cells leads to heart failure and loss of perfusion pressure
consequently resulting in hemodynamic shock.
Septic shock = DIC + Hypoglycemia +Cardiovascular Failure (Triad)
Multiple organs show inflammation and intravascular thrombosis resulting in
multi organ failure.
Tissue injury in response to LPS can also result from the activation of
neutrophils before they are extravasated thus causing damage to the endothelial
cells and resulting in reduced blood flow.
Lungs and liver are more susceptible to injury by the neutrophils. This lung
damage in the systemic inflammatory response , commonly called ARDS and
results from neutrophil mediated endothelial injury which allows the fluid to
escape from the blood into the airspace. The kidney and the bowel are also
injured largely due to reduced perfusion. This condition is fatal.

33
DEFECTIVE / EXCESSIVE INFLAMMATION
Defective Inflammation ---
This results in increased susceptibility to infections and delayed healing of the
wounds and tissue damage. Thus the innate immunity of the person is
compromised.
Delayed repair is because the inflammatory response is essential for clearing
damaged tissue debris and provides the necessary stimulus to get the repair
process started.
Excessive Inflammation ---
It is the basis of many categories of human disease. Allergies in individuals
have a tendency to mount unregulated immune responses against commonly
encountered environmental antigens; in cases of autoimmune diseases the
immune responses develop against normally tolerated self antigens and here the
fundamental cause of tissue damage is inflammation.
Also, prolonged inflammation and the fibrosis that accompanies it are
responsible for much of the pathology in many chronic infectious, metabolic
and other diseases. As these are the major scourges of mankind this normally
protective inflammatory response is being called the SILENT KILLER.

34
HYPERSENSITIVITY
Definition
manner resulting in tissue damage.
It does not manifest on first contact, which is sensitizing / premising dose
and appears on subsequent contact, known as shocking dose.
Allergy altered state, coined by von Pirquest.
Allergen any foreign substance capable of inducing allergy is an allergen.
Types I Natural
Synthetic
II Specific
Nonspecific
Routes of entry
1) Inhalation
2) Ingestion
3) Injection
4) Skin contact
Classification of Hypersensitivity
By Philip Gell and Robin Coombs in 1963
1) Type I: Anaphylactic /Ig E dependent Hypersensitivity
2) Type II: Cytotoxic/ cell stimulating Hypersensitivity
3) Type III: Immune complex Hypersensitivity
4) Type IV: Delayed/ cell mediated Hypersensitivity
5) Type V: Stimulatory Hypersensitivity

35
Type I, II, III and V are immediate hypersensitivity and are Ag-Ab reactions.
Type IV is delayed hypersensitivity and involves T- lymphocyte response to antigen
via inflammation mediation and lymphokines.
Mechanisms of Hypersensitivity
1) Ig E/mast cell mediator pathway.
2) IgG/IgM immune complex/ complement/ neutrophil pathway.
3) T- lymphocyte/ Lymphokine pathway.
Overview of types of Hypersensitivity
1) Type I Mast cell + IgE/ Ag Fc
Mast cell + mediators
Inflammation
2)Type II hypersensitivity
a) K cell + IgG/Ag (cell surface)
LYSIS OF TARGET CELL
b) IgG/IgH+ target cell (Antigen) complement
LYSIS OF TARGET CELL
Complement PMN
3)Type III Ag+ Ig immune complex deposition
Tissue damage by FRUSTRATED PHAGOCYTOSIS
Lymphokines
4) Type IV: Ag+ T cells macrophage
inflammation+ mediators

36
Type I Hypersensitivity
It is characterized by immediate reactions following the contact with
Ag/allergen in sensitized host. It takes few minutes.
It depends on presence of IgE Ab to the antigen.
IgE+ mast cell /Basophil
Via Fc gragement of IgE and FcER1 on the cell.
FcER1 for mast cell or Basophils Allergies
FcER1 for eosinophils or platelets parasitic infections
Anaphylaxis classical immediate type I hypersensitivity reaction.
Anaphylaxis Ana without, phylaxis- Protection
Coined by Richet (1902)
Tissues/organs involved in anaphylactic reaction
organs.
Species variation to Anaphylaxis.
1) Highly susceptible Guinea pigs
2) Inter mediate Rabbit, Dog and Human beings.
3) Very resistant Rats.
Clinical effects
a) Vascular permeability
b) Edema, coagulation of blood.
c) B.P or temperature.
d) Smooth muscle contraction.
e) Thrombocytopenia.
f) Fusing of skin.
g) Difficulty in breathing due to bronchospasm.
h) Nausea, vomiting, abdominal pain.
i) Acute hypotension, unconsciousness and death in severe cases.

37
Uriticaria, eczema, allergic Rhinitis (Hay fever)
Allergens for Anaphylaxis
1) Foods pear, peanuts, fish, egg white, crab, cotton seeds, mustard seed,
berries, milk and milk products, wheat etc.
2) Drugs Penicillin, St.mycin, cephalosporin, tetracyclin, insulin, Barbiturates,
diazepams phenytoin, salicylic acid, parathormone, dextran, thiamine, folic
acid, etc.
3) Insect Honey bee, wasp, fire ants, deer flies, bed bug, snake venome rarely.
4) Others Latex, pollen, animal dandruff, house dust mites etc.,
Mechanism of Anaphylaxis
very complex gp
D2 Vasodilatation or vascular permeability
E1 and E2 smooth muscle relaxation or vasodilatation
I2 and F2x promote mast cell mediator release
Regulation of mast cell degranulation
Regulated by cyclic nucleotides. c AMP/ c GMP inhibit mast cell
degranulation finally on c AMP- c GMP ratio.
2 Types of receptor on mast cell and for adreno receptors.
Stimulation of receptor c AMP c GMP mast cell degranulation
Stimulation of adreno receptor vice versa
-adreno receptor stimulators Nor adrenaline, phenylephrine
- Adrenoreceptor stimulators adrenoline, salbutamol
In Atopy impairment in adrenoreceptor by B. pertusis, H. influenza, auto
antibodies.

38
Role of mediators in Anaphylaxis
I Preformed mediators: (Primary mediators)
1) Histamine smooth muscle contraction, vascular permeability sections.
2) Serotonin vasospasm, smooth muscle contraction.
3) ECF-A Eosinophil chemotaxis
4) PAF platelet aggregation and secretion..
5) NCF-A Neutrophil chemotaxis.
II Newly generated mediators: (Sec mediators)
1) Prostaglandins influence vascular and smooth muscle tone, platelet
aggregation, and immune reactivity.
2) Leukotrienes smooth muscle contraction, V. Permeability, neutrophils
and eosinophil chemotaxis.
3) Bradykinin Smooth muscle contraction or vasospasm.
4) Serotonin
Histamine: Preformed in granules of mast cells, basophils & platelets.
In skin: stimulates sensory nerves burning and itching sensation, vasodilation,
cap permeability (wheal effect)
Smooth muscle: smooth: Smooth muscle contraction in B.V. intestine, branchioles,
uterus, uri. Bladder.
Mucosal surfaces: secretions bronchus, stomach, and lacrimal gland, mouth
Chemotoxis: eosinophils or basophils for C5a
Serotonin (5-HT)
Derivative of tryptophan.
From mast cells and platelets, preformed.
Heart: Causes vasoconstriction, wheal or flare effect B.P.
Leukotrienes
4 types, synthesized by mast cells after stimulation by Ag.
LTB4 Neutrophil or eosinophil chemotaxis

40
Clinical tests for Anaphylaxis
1) PK list: It is a skin test. Serum from allergic individuals is injected Idly, into a
normal individual, after 24-48 hours the Ag is injected again. In the reaction,
wheal and flare reaction is seen at the same site with in 2-3 minutes.
2) PLA list: Several separate injections of different dilutions of serum are used.
They are administered Intravenously. If +ve, at each site an immediate
inflammation response is seen.
3) Schultz- Dale technique: In vitro experiment. A strip of smooth muscle is
removed from is sensitized animal, kept in saline. The tissue is cyposed to Ag,
degranulation of mast cell will louse contraction of muscle. Modification:
Incubate muscle from normal person in serum from sensitized individual.
Muscle contracts when exposed to Ag.
4) RAST: (Radio allegren Sorbent test) done for IgE detection for specific Ag.
Atopy
Means- out of place / strangeness.
By Coca and Cooke in 1923.
Refers to naturally occurring familial hypersensitivity of human beings typed
by hay fever asthma.
Ag involved are pollen, house dust, egg, milk.
5-10% have this type.
Difficult to induce artificially.
Strong hereditary association.
50% chance in children
If one parent is allergic 30% chance
Not allergic to specific Ag, but tendency to produce IgE Ab in large quantities.

41
Anaphylactoid reactions
Reaction clinically and pathologically identical anaphylaxis but without IgE
antibody and corresponding allergen.
Same chemical mediators and is a non-specific mechanism involving activation
of complement and anaphylatoxins.
Types
a) Exercise- induced during exercise, familial tendency.
b) Cholinergic during emotions, allergies, body temp.
c) Aggregate in globulin prophylaxis for immunodeficiency diseases.
d) Non IgE IgE anti IgA anaphylaxis in plasma transfusions.
e) From ionic compounds
f) Others Dextrans, gum, resins, tooth pastes, mouth washes.
g) Idiopathic
Anaphylatoxins: Peptides with mediate inflammation by release of histamine. Seen
in complement during cleavage of C4, C3 and C5.
Type II Hypersensitivity (Antibody dependant cytotoxicity)
Involve combination of IgG/IgM Ab against cell surface molecules/ tissue
components with complement and other variety of effector cell, causing damage
to target cells.
A) Ab (IgG/ IgM) link target cells to effector cell by Fc receptor on effector
cells.
B) Ab+ complement cell lysis.
C5b
1) Ab+ target cell lysis.
C3b
2) Ab + target cell lysis.

42
Normally, neutrophils + target cell+ complement phagocytosis by fusion of
lysosomes (phagolysome).
In this, target cell self or large, Type II neutrophil + IgG + complement +
target cell
contents outside the cell.
Lysosomal content + free oxygen radicals, arachidonic acid
Examples of Type II Hypersensitivity
1) Transfusion reaction.
2) Rh incompatibility.
3) Organ transplantation.
4) Autoimmune reactions Autoimmune Hemolytic Anemia
SLE.
Type I DM
Myasthenia gravis.
5) Pemphigus vulgaris.
6) Drugs penicillin, chlorpromazine, sulfonamides guanidine.

44
Triggered by deposition of circulating immune complexes in tissues causing
inflammation.
vaccines self-antigens. Complement is activated with results in inflammation.
Type III is similar to Type II, both by IgG/ IgM. The distinction is in
Type II Type III
1) Ag Specific Widely distributed
2) Ag site Specific target cells In serum
3) Nature of Ag Membranes bound Soluble
4) Damage Only target cell/tissue Involved organ
5) Quantity Ag Ab Small Large
The area of vascular permeability (blood flow) and turbulence B.P (Hemo-
dynamics) are the predilection for this complex deposition.
The bifurcation of heart value and renal glomeruli frequently involved organ
sites.
Types localized
Generalized serum sickness glomerulonephritis.
These immune complexes damage tissue, occlude b.v damage joints and
produce necrosis by blood supply.
I Microbial agents:
1) Leprosy (LL)
2) Bacterial endocarditic
3) Malaria.
4) Hepatitis-B
II Autoimmune
1) Rheumatoid arthritic.
2) SLE

45
3) Polyarteritis.
4) Fibrosing alveolitis.
Examples
1) SLE.
2)
3) Steven- Johnson syndrome.
4)
5)
Type IV Hypersensitivity (DTH)
FEATURES
1. Appears slowly & lasts longer.
2. Induced by infection, injection of antigen intradermally or by skin contact with
chemicals or with Freund`s adjuvant.
3. Circulating antibodies may be absent, not responsible for reaction. It is
CMI reaction.
4. Transfer - Serum - not possible.
- Lymphocytes or transfer factor- possible.
5. Desensitization - Difficult, long lasting.
6. Sensitization- Sensitising or priming dose required.
Elicitation- Shocking or second dose required
7. Tissue induration & Monocyte accumulation seen.
INDUCING AGENTS OF DHS :
BACTERIAL : Tuberculosis, Leprosy, Salmonella infection etc.
FUNGAL:Candidiasis,Dermatomycosis, Histoplasmosis, Coccidioidomycosis,
Blastomycosis.

46
PARASITIC : Leishmaniasis, Schistosomiasis.
VIRAL : Herpes simplex, Measles.
CHEMICAL : Contact dermatitis. Metals - Nickel, Chromium etc. Chemicals - dye
stuffs, potassium dichromate, poison ivy, paraphenylene diamine(from hair dyes).
Topical drugs - sulfonamides, neomycin, cosmetics & soaps.
SENSITIZATION & ELICITATION :
Sensitization of an individual refers to the exposure of the antigen to an
individual for the first time. It is liable to occur when the antigen contacts an area of
inflamed skin (contact type) or due to intrdermal injection of the antigen (tuberculin).
For the contact type the antigen should be applied in an oily base. Antigenicity is
acquired on combining with skin proteins. Sensitization requires percutaneous
absorption. Since most of the antigens are fat soluble, the passage is thought to be via
the sebaceous glands.
Factor for sensitization :The antigen dose / unit area, than the total dose or total
area is important in determining the sensitization potential.
The T- cell has specific recognition for the hapten-carrier complex & not for
hapten or carrier individually.
Elicitation occurs when the individual is exposed to the same or similar antigen
for the second time.
LIST OF LYMPHOKINES & MONOKINES
I . FACTORS THAT AFFECT MACROPHAGE FUNCTION :
1. Gamma interferon - Migratory inhibitory factor(MIF)
- Macrophage activating factor(MAF)
- Macrophage aggregating factor
- Factor that causes disappearence of
macrophages from the peritoneal cavity

47
2. Macrophage chemotactic factor(MCF)
3. Factors that alter surface tension
4. Antigen dependent MIF
II . FACTORS THAT AFFECT NEUTROPHIL FUNCTION :
1. Chemotactic factor
2. Leucocyte inhibitory factor(LIF)
III . FACTORS THAT AFFECT LYMPHOCYTE FUNCTION :
1. IL-1 (lymphocyte activating factor)
2. IL-2 (T-Cell growth factor)
3. IL-3
4. B-Cell growth factor
5. Chemotactic factor
6. Antigen dependent helper factor
7. Antigen dependent suppresor factor
8. Antigen independent helper factor
9. Antigen independent suppresor factor
10. E-Rosette augmenting factor (E-RAF)
11. Transfer factor
NOTE : Through these lymphokines, lymphocytes cause accumulation of
inflammatory cells & injury to tissues.
IMPORTANT CYTOKINE MEDIATED EFFECTS IN DTH :
1. IL-2 : Proliferation of activated T-Cells.
Increased concentration of IL-2 stimulates bystander T-Cells not specific for antigen
& augments synthesis of cytokines by CD4 + T-Cells, specially IFN-gamma, TNF. T-
Cells have receptors for IL-2, so IL-2 causes T-Cell proliferation

48
2. INF-gamma : Acts on antigen presenting cells & increases class II MHC molecule
expression, thus the efficiency of the antigen presentation to CD4 + T-Cells at local
site is increased. It also acts on Keratinocytes & Endothelial cells of dermal
capillaries to express ICAM-1 within 24 hours & HLA-DR around 48 hours, which
are the intercellular adhesion molecules.
ICAM-1 on the keratinocyte binds with Integrin LFA-1 present on the cells of
lymphoid & myeloid lineage. Expression of ICAM-1 is important in localization of
lymphocytes & macrohages to skin.
Activated keratinocytes release IL-1, IL-6 & GM-CSF, which promote activation &
proliferation of T-Cells. GM-CSF also stimulates langerhan`s cells. It also releases
PGE which inhibit lymphocyte.
IFN-gamma activates monocytes to macrophages, hence important in DTH.
3. TNF : It acts on venular endothelial cells to augment their capacities to bind &
activate WBCs leading to inflammation. IFN-gamma & IL-4 have similar functions &
thus specific mononuclear cells are recruited.
4. PGE : From keratinocytes & macrophages. It has inhibitory effect on IL-1 & IL-2
production. Thus PGE prodution & it`s binding to activated T-Cells, to keratinocytes
& the enzymatic & cellular degradation of hapten-carrier complex, all act in down
regulation of the DTH reaction.
ROLE OF VENULAR ENDOTHELIAL CELLS :
1. They act as APCs during elicitation phase.
2. They regulate infiltration of WBCs into the inflammatory reaction & contribute to
inflammation.

49
a) The production of prostacyclin & nitric oxide(vasodialators) causes increase in
the blood flow & delivery of WBCs at the site of inflammation.
b) TNF causes increased expression of enzymes in endothelial cells that synthesise
prostacyclin & along with IFN-gamma increases production of nitric oxide.
c) The expression of the adhesion molecule(E-Selectin, VCAM-1, ICAM-1) on
endothelial cells. This binds the WBCs, first the neutrophils & then the
lymphocytes & monocytes.
d) TNF causes synthesis & expression of chemokines, IL-8, MCP-1 etc. These
activate WBCs, increase their integrin affinity & cell motility. (MCP-
Monocyte chemotactic protein)
e) TNF & IFN-gamma causes the change in shape of the endothelial cells &
basement membrane remodelling. This favours the leakage of macromolecules
& extravasation of cells.
The leakage of fibrinogen is the basis of induration. Deposition of fibrinogen, fibrin &
plasma fibronectin in tissue sccafold facilitates WBC migration & extravasation &
retention in extravascular tissues. Leakage of plasma reduces the shear forces of
flowing blood which favours WBC attachment to endothelium.
MACROPHAGE DIFFERENTIATION :
MACROPHAGE ACTIVATION - causes an increase in the gene transcription for
certain enzymes. Eg : The cytochrome enzymes help in generating the reactive oxygen
species such as the superoxide, which has a microbicidal action by increasing the
oxidative burst. The increase in this enzyme is an example of macrophage activation.
The factors which help in macrophage activation are - Cytokines ( INF-gamma, IL - 2,
etc.) .
- Lipopolysaccharides
- Extracellular matrix molecules.

50
THE ROLE OF ACTIVATED MACROPHAGES IN DTH
1. ACTIVATED MACROPHAGES KILL MICRO-ORGANISMS :
IFN-gamma induces transcription of gene encoding the enzyme that generates
active oxygen.Thus macrophage are activated and the mi crorganisms are killed.
2. ACTIVATED MACROPHAGES STIMULATE ACUTE INFLAMMATI-
ON THROUGH SECRETION OF SHORT LIVED INFLAMMATORY
MEDIATORS :
MACROPHAGES ----------- Tissue factor (Protein). IFN-gamma increases
it`s synthesis.
Prostaglandins Leukotrienes - Initiates extrinsic cascade
- Thrombin & Blood protease
activation causes
- PMN & Endothelial cells
to secrete PAF.
Infectious organism is destroyed & the injured tissue is rid off.
3. ACTIVATED MACROPHAGES BECOME MORE EFFECTIVE ANTI-
GEN PRESENTING CELLS :
GM-CSF & IFN-gamma causes increase in Class II MHC genes.Activated
macrophages increase expression of ICAM-1 & LFA-3.
4. ACTIVATED MACROPHAGE PRODUCTS - CYTOKINES & GROW-
TH FACTORS MODIFY LOCAL TISSUE ENVIRONMENT :
Initially there is tissue destruction & later there is replacement by connective
tissue.

52
CHARACTERISTICS OF THE TYPES OF DTH :
DTH TYPE REACTIO
N TIME
CLINICAL
APPEARANC
E
CHARECTERSTI
C
HISTOLOGICAL
APPEARANCE
ANTIGEN
CONTACT
(DERMATITI
S
or
STOMATITIS
)
48-72 hrs
Eczema,
erythema,
itching,
vesication, skin
necrosis.
Infiltration of
lympho-
cytes & later
macrop-ges,
intracellular ede-
ma of epidermis.
Few basophils may
be seen.
Epidermal :
Chemicals -
nickel,
chromium.
Plant product
-poison ivy,
poison oak.
Topical drugs
-
Neomycin,
sulpo
namides.
Cosmetics &
soaps.
TUBERC-
ULIN
48-72 hrs
Local
hardening &
swelling with
fever(+ or -),
necrosis(+ or -).
Infiltration of
lympho-
cytes, monocytes &
macrophages.
Subepidermal
edema(?).
Intradermal
injection of
tuberculin,
mycobacteria
&leishmanial
antigens.
GRANUL-
OMATOUS
4 wks
Hardening.
Eg:in skin or
lung.
Granuloma
containing
epitheloid cells,
giant cells &
macrophages.
Fibrosis, + or -
necrosis.
Persistent
antigen or
antigen-
antibody
complexes in
macrophages
or
non-
immunologica
l. Eg : Cotton,
gauze etc.

53
FEW IMPORTANT DISEASES MANIFESTING DTH :
1. TUBERCULOSIS :
Granulomatous kind of DTH.
Tuberculin test done in order to
- diagnose active infection in infants & young children.
- measure the prevalence of infection in a community.
- select suceptibles for BCG vaccination or as an indication of
successful vaccination.
2. LEPROSY :
FEATURES TUBERCULOID BORDERLINE LEPROMATOUS
DHS(Granulomatous)
+++
+++
Either due to
drug treatment or
naturally.
+
or
-
LEPROMIN SKIN
TEST(MITSUDA
REACTION).Indicate-
the prognosis.
+++ ++ _
MICRO-ORGANISM - + +++
ANTIGEN-
ANTIBODY
COMPLEX
- +
+
or
-
3. SARCOIDOSIS :
Unknown etiology. Kveim test is done to confirm this diagnosis. It is a positive
granulomatous reaction. In this test unknown splenic antigens derived from other
Sarcoid patients is used as the antigen.

54
4. SCHISTOSOMIASIS :
Typical granulomatous type of DTH seen in the parasitized tissue. The antigens
are known as the schistosomes.
ORAL ASPECTS OF DELAYED HYPERSENSITIVITY :
Contact Stomatitis, also known as Stomatitis Venenata is the DTH reaction seen
to occur in the oral cavity. The causative agents are
I) DENTAL or COSMETIC PREPARATIONS :
- Dentifrices
- Mouth washes
- Denture powders
- Lipstick, Candy, Cough drops & Chewing gum.
II) DENTAL MATERIALS :
- Vulcanite
- Acrylic
- Metal alloy bases
III) DENTAL THERAPEUTIC AGENTS :
- Alcohol
- Antibiotics
- Chloroform
- Iodides
- Phenol
- Procaine
- Volatile oils

55
However the contact stomatitis is less compared to the cotact dermatitis because - the
saliva dilutes the allergens.
the saliva washes the allergens from the surface of the mucosa.
the saliva digests the allergens with it`s enzymes.
the keratin layer which has a rich source of the proteins (haptens) is absent
or limited in the oral mucosa.
JONES - MOTE HYPERSENSITIVITY :
It is also known as CUTANEOUS BASOPHIL HYPERSENSITIVITY.
A transient DTH develops on immunisation with protein antigens, in absence of the
adjuvants, antibody response develops.
DIFFERENCE FROM CLASSICAL DTH :
- Rapid appearance (12-24 hrs)
- Transitory in nature
- Basophils & mononuclear cells present in the infiltrate
- Transfer by serum antibodies, T or B cells.
- In humans it is seen in Renal allograft rejection & allergic contact
dermatitis.
TESTS TO DETERMINE DTH REACTIONS :
I) PATCH TEST TO DETERMINE CONTACT DERMATITIS :
The suspected allergen is placed on normal non-hairy skin, (upper portion of the
back being the most suited place) with the help of an adhesive plaster & is allowed to
remain in contact with the skin for 48hrs. A control of plain adhesive plaster is also
placed to rule out allergy to it. Once the patch is removed the development of
erythema within 2-4hrs indicates a positive test.

56
II) PATCH TEST TO DETERMINE CONTACT STOMATITIS :
The test is similar to contact dermatitis, but the suspected allergen is placed
directly in contact with the oral mucosa. This is done by incorporating the test
substance in Orabase & it is held in place by use of a prosthetic appliance or rubber
cup attached to the teeth.
III) TUBERCULIN TEST TO DETERMINE TUBERCULIN TYPE OF DTH
The test substance to be used is either the dead tubercle bacilli or sterile
infiltrate of the broth in which they have been grown ( old tuberculin OT ) or purified
protein derivative (PPD) extracted from the bacilli. 0.1ml of 1 in 1000 dilution of the
allergen is injected intradermally. After 24-48hrs of the injection of the allergen a red
zone of at least 5mm in diameter develops. The skin in this area is firm, swollen &
indurated. The red zone fades in a day or so, but the induration remains palpable for a
few days.
Similar tests can be done for Histoplasmosis (using Histoplasmin antigen) & for
Coccidioidmycosis (using Coccidioidin antigen).
TREATMENT OF DTH :
- Removal of the offending agent.
- Application of topical steriods.
DESENSITIZATION :
It was established by administering an antigen to a sensitized individual. Partial
desensitization is possible when an individual with DTH is tested simultaneously at
many skin sites with the same antigen reaction at each site. It is less intense than when
a single test is applied because the number of antigen specific sensitized T cells is
limited. Similarly in overwhelming infections like Miliary Tuberculosis, Disseminated
fungal & protozoan infections the DTH skin reactions are not usually elicited, because
large number of disseminated antigen bearing cells saturates the sensitized T cells.

57
Comparable events sometimes develop in the industrial workers who exhibit
loss of skin sensitivity during prolonged & intense exposure to the sensitizer.
The deliberate desensitization of CMI responses is difficult to acheive.
LATEST ADVANCES :
The experimental animal studies have shown that the DTH can be induced &
used in the treatment of tumours. When certain skin tumours were painted with a
simple chemical antigen & thus a DTH reaction being induced, healing with the
disappearance of the tumour was noted. This has been implied to be due to the
lymphokines-lymphotoxins released during DTH, which destroys the tumour cells.
It has also been noted that the injection of BCG vaccine a week before the
injection of the tumour cells (to induce the tumour experimentally) the tumour is
destroyed more readily. Hence it is thought that the tumour mass has to be reduced by
drug or X-ray therapy before treatment with BCG. An additional finding with the
BCG vaccine is that, when injected directly into the tumours they suppress the tumour
growth.
However further studies need to be done to arrive at any conclusions.
Type V stimulatory Hypersensitivity
Cells receive instructions by hormones activate interior cell signaled.
Ab + surface component (hormone receptor) Activate the messenger in an
organ for functioning.
EX: 1) TSH from pituitary Thyroid cell receptor Activation of cAMP second
messanger stimulates thyroid cell

58
Summary of Hypersensitivity Reactions
Hypersensitivi
ty
Effector
cells
Immuno-
globulin
Compleme
nt
activation
Duratio
n
Example
Type I
Anaphylactic
Basophils
mast cells
Eosinophils
platelets
IgE
(Hemocytotraphi
n)
No <30min Atopic
allergy insect
bite
Type II
cytotoxicosis
- IgG/IgM Yes - Rh incomp-
atibility
pemphigus
vulgaris
Type III
immune
complex
- IgG/IgM Yes 3-8hrs SLE,
Rheumatoid
arthritis
Type IV cell
mediated
T-cells
macrophag
es
- No 24-48
hrs and
3-4
weeks
Tuberculosis
, syphilis
diseases
Type V
stimulatory
- IgM/IgG No - Thyrotoxicos
is
Histology of types of Hypersensitivity
1) Type I Wheal and flare reaction degranulation of mast cells, vasodilation
edema, and eosinophilic infiltration.
2) Type III
3) Type IV Granuloma formation Erythema, induration, and perivascular
inflammation mononuclear cells predominance.

59
References
1. Immunology ---- D. M. Weir, 5th eds.
2. Fundamentals of Immunology & Allergy ---- Lockey & Bukantz.
3. Text Book of Microbiology ---- Ananthanarayan R and Jayaram Panicker C.
K., 4th eds.
4. Essentials of Medical Microbiology ---- Rajesh Bhatia and Rattan Lal
Ichhpujani.
5. Fundamentals of Microbiology ---- Frobisher, Hinsdill, Crabtree and
Goodheart, 9th eds.
6. Microbiology ---- Bernard D Davis, Renato Dulbecco et al, 4th eds.
7. Principles of Bacteriology, Virology & Immunity, Vol 1(General
Microbiology & Immunity) ---- Alan H Linton and Heather M Dick, 8th eds.
8. Immunology ---- Roitt, Brostoff and Male, 3rd eds.
9. Cellular and Molecular Immunology ---- Abdul K Abbas, Andrew H
Lichtman and Jordan S Poeds.

26. INFLAMMATION - LAMBERT

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