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PAPER OF PATHOLOGY

THE ROLE OF MACROPHAGES IN PHATOLOGICAL EVENTS

Created by:
1. Dhea Fany R.
(061411131171)
2. Aditya Wahyu V.
(061411131172)
3. Kevin
(061411131173)
4. Fladyan Armandito
(061411131174)
5. Alycius Noveno

7. Bryan Ahmad A.L.


(061411131178)
8. Shendy Canadya
(061411131185)
9. Alya Miranti
(061411131190)
10. Kevin Eddoardo
(061411131196)
11. Christopher Mulia

(061411131175)

(061411131197)

6. Rizka Mulia A.

12. Nina Sagitha P.

(061411131176)

(061411133001)

13. Ryandika Wahyu


(061411133002)

15. Kentari Hasna L.


(061411133004)

14. Nuril Ihtiarna


(061411133003)
16.
17. FACULTY OF VETERINARY MEDICINE
18. AIRLANGGA UNIVERSITY

19.2016
20.
21. CHAPTER I
22. PREFACE
23.
24. 1.1 Background
25.

The world in which we live can be a messy place. Since everything in

nature tends toward chaos, our lives tend to do the same. Houses become cluttered.
Litter gathers along the side of the road. It's a constant job just to keep things picked
up and tidy.Interestingly enough, a similar situation is happening inside our bodies all
the time. Cells are dying, bacteria are wandering in, and viruses are attempting mass
takeovers. Our immune system is constantly hard at work destroying these intruders
and cleaning up the mess. One cell in particular, the macrophage, is an integral part of
this cleanup process. In this lesson, we'll take a closer look at the work of a
macrophage and learn about its importance within the body.

26.

A macrophage is a large white blood cell that is an important part of our

immune system. The word 'macrophage' literally means 'big eater.' It is an amoebalike organism and its job is to clean our body of microscopic debris and invaders. A
macrophage has the ability to locate and 'eat' particles such as bacteria, viruses, fungi,
and parasites.
27.

Macrophages are born from white blood cells called monocytes, which

are produced by stem cells in our bone marrow. Monocytes move through the
bloodstream and when they leave the blood, they mature into macrophages. They live
for months, patrolling our cells and organs and keeping them clean.
28.
29. 1.2 Aims
1. To know about the definition of macrophages
2. To know how macrophages work inside the bodies
30.
31.
32.
33.
34.
35. CHAPTER II
36. DISCUSSION
37.
38. 2.1 Macrophages Definition
39.

A macrophage is a large white blood cell that is an important part of our

immune system. The word 'macrophage' literally means 'big eater.' It is an amoeba3

like organism and its job is to clean our body of microscopic debris and invaders. A
macrophage has the ability to locate and 'eat' particles such as bacteria, viruses, fungi,
and parasites.
40.
41. 2.2 Types of Macrophages
42.

Macrophages are specialised cells involved in the detection,

phagocytosis and destruction of bacteria and other harmful organisms. In addition,


they can also present antigens to T cells and initiate inflammation by releasing
molecules (known as cytokines) that activate other cells.
43.

Macrophages originate from blood monocytes that leave the circulation

to differentiate in different tissues. There is a substantial heterogeneity among each


macrophage population, which most probably reflects the required level of
specialisation within the environment of any given tissue. This heterogeneity is
reflected in their morphology, the type of pathogens they can recognise, as well as the
levels of inflammatory cytokines they produce (i.e. IL-1, IL-6, tumour necrosis factor
alpha). In addition, macrophages produce reactive oxygen species, such as nitric
oxide, that can kill phagocytosed bacteria. The heterogeneous nature of these cells
may not solely be the result of their differentiation process, but it is likely to be
inherited from their monocyte precursors.
44.

Macrophages have two active forms that M1 macrophages that have

function to kill pathogens by stimulating lymphokine produced by T cells and M2


macrophages play a role in wound healing and damaged tissue repair by accelerating
the process of angiogenesis. IFN- and LPS will activate the M1 and secretion of the
cytokine IL-12. In contrast, macrophages M2 will produce cytokines IL-10, TGF-
and increased IL-4 which has the function as anti-inflammatory agent.
45.

Macrophages migrate to and circulate within almost every tissue,

patrolling for pathogens or eliminating dead cells. The table below describes the
location and function of a few different macrophage populations.

47. Anatomic
46. Cell Name

48. Function

al
Location
51. Protects

49. Adipose

tissue

macrophages

50. Adipose
tissue

against

microbes and help the


adipose cells to keep
the body's
52. sensitivity to insulin

54. Bone
53. Monocytes

marrow/bl

55. Influence the process


of adaptive immunity

ood
58. Initiate
56. Kupffer cells

57. Liver

immune

responses and hepatic


tissue remodeling
61. Contains endogenous
pigment
(hemosiderin,

59. Sinus histiocytes

60. Lymph
nodes

lipofuscin)

or

exogenous

pigments

reflecting
uptake

antigen
from

the

digestive tract
64. Phagocytosis of small
63. Pulmonar
62. Alveolar
macrophages (dust cells)

particles, dead cells or

bacteria. Initiation and

alveoli of

control of immunity

lungs

to

respiratory

pathogens
65. Tissue
macrophages (histiocytes

66. Connectiv

67. Kills microbes

e tissue

) leading to giant cells


70. Serve the function of
69. Skin and

68. Langerhans cells

mucosa

the immune system


and

helps

in

the

development of skin
cells

71. Microglia
74. Hofbauer cells

73. Cleans up the debris

nervous

of CNS and protects

system

nerves system

75. Placenta

77. Intraglomerular

78. Kidney

mesangial cells
80. Osteoclasts
83. Epithelioid cells
86. Splenic

72. Central

Metallophilic

82.

84. Granulom

85.

as
zone,

and

79.

81. Bone

macrophages

(marginal

76.

red

pulp macrophages)

89.
88. Red pulp
of spleen

87.
90. Peritoneal macrophages

91. Peritoneal

92.

cavity

93.
94.

Macrophages are able to detect products of bacteria and other

microorganisms using a system of recognition receptors such as Toll-like receptors


(TLRs). These receptors can bind specifically to different pathogen components like
sugars (LPS), RNA, DNA or extracellular proteins (for example, flagellin from
bacterial flagella).
95.
96.

2.3 Life Cycle of Macrophages


6

97.

In bone marrow

of invertebrate, a hematopoietic
stem cell origins from a yolk sac.
Which process as a primitive
hematopoiesis

to

be

granulocyte / macrophages colonyform and move to fetal liverand


finally

to

the

bone

marrow.

Macrophages move from yolk


sack to various organs and tissue via vitteline veins
98.

In the yolk sac, mature macrophages as a fetal macrophages and

immature macrophages as primitive macrophages. The primitive macrophages are


differentiated from hematopoietic stem cells, bypassing the developmental stage of
monocytic cells and mature into fetal macrophages.

99.
100. Macrophages will not released from bone marrow if not differentiate

into monocytes via monoblast and promonocytes. During differentiation, monocytes


obtain a small number of immature macrophage progenitor cels, as the premonocytic cell lineage stage of differentiation, are released from the bone marrow
into peripheral blood, migrate into tissues and differentiate into tissue macrophages.
101. Monocytes-derivaded macrophages are short-lived in peripheral tissue
and die within 2 weeks. But for tissue macrophage able to survive for long period.
102.
103.

2.4 Location of Macrophages

104. A majority of macrophages are stationed at strategic points where


microbial invasion or accumulation of foreign particles is likely to occur. These cells
together as a group are known as the mononuclear phagocyte system and were
previously known as the reticuloendothelial system. Each type of macrophage,
determined by its location, has a specific name:
a. Adipose tissue
105.

On adipose tissue , macrophages named Adipose tissue

macrophages , the function is Involved in control of insulin sensitivityand


adaptive thermogenesis
b. Blood
106.

On blood , macrophages named monocyte the function is

Function analogously as 'intravascular housekeepers', clearing endothelial


cell debris
c. Bone
107.

On Bone , Macrophages named Osteoclasts, the function is

Multinucleated cells formed by fusion that resorb bone by disruption of


the mineralized matrix
d. Central nervous system

108.

On

Central

nervous

system,

Macrophages

named

Microglia , the function is Promote neuronal survival and are involved in


frontline immune surveillance, removal of dead neurons and synaptic,
remodelling derived from yolk sac and maintained in adult and during
inflammation independently of the bone marrow
e. Gastrointestinal tract
109.

On Gastro intestinal track, Macrophages named Intestinal

macrophages , the function is Maintenance of intestinal homeostasis and


regulation of immune responses to commensals, monocyte-derive
f. Liver
110.

On Liver, Macrophages named Kupffer cells (sessile), the

function is Clearance of microorganisms and cell debris from the blood,


and clearance of aged erythrocytes, prenatal origins, maintained in the
adult independently of the bone marrow.
g. Lung
111.

On Lung, Macrophages named Alveolar macrophages , the

function is
112.

Immune surveillance of the lung for inhaled pathogens and

homeostatic regulation of tissue function, for example, clearance of


surfactant; prenatal origins, maintained in adult and during inflammation
independently of the bone marrow.
h. Serosal tissues
113.

On Serosal Tissues , Macrophages named Peritoneal

macrophages that has function as imune surveillance and regulation of


homeostatic

environment,

apoptotic

cell

clearance,

prenatal

origins,maintained in adult and during inflammation independently of the


bone marrow, and Pleural macrophages that has function as Immune

surveillance, maintained in adult and can expand during TH2 cell


inflammation independently of the bone marrow.
i. Skin
114.

On Skin , Macrophages named Dermal macrophages for

Immune surveillance and Langerhans cells for Interaction with T


lymphocytes, derived from yolk sac and/or fetal liver and maintained
independently of the bone marrow.
j. Spleen
115.

On Spleen, Macrophages named Red pulp macrophages

for Erythrocyte clearance and iron metabolism, prenatal origins,


maintained in adult independently of the bone marrow. and White pulp
(tingible body) macrophages for Clearance of apoptotic cells resulting
during the germinal center reaction.
116.
117.
118.

2.5 Macrophages General Function

10

119.

Macrophages arise from monocytes that migrate into the tissues. Some
macrophages
macrophages),

are

freely

whereas

mobile
others

(free
(fixed

macrophages) remain restricted to a certain


area, such as the hepatic sinus (Kupffer cells),
the pulmonary alveoli, the intestinal serosa,
the splenic sinus, the lymph nodes, the skin
(Langerhanscells),thesynovia (synovial A cells), the brain (microglia), or the
endothelium (e.g., in the renal glomeruli). The mononuclear phagocytic
system (MPS) is the collective term for the circulating monocytes in the blood
and macrophages in the tissues. Macrophages recognize relatively unspecific
carbohydrate components on the surface of bacteria and ingest them by
phagocytosis. The macrophages have to be activated if the pathogen survive
within the phagosomes.
120. The cells whose primary function it is to recognize and respond to
invading microbes are called sentinel cells. The major sentinel cell types, namely
macrophages, dendritic cells, and mast cells, are scattered throughout the body but are
found in highest numbers just below body surfaces at sites where invading
microorganisms are most likely to be encountered. All these cells are equipped with
multiple, diverse PRRs, so they can detect and then respond rapidly to both PAMPs
and DAMPs. Other cell types scattered throughout the body, such as epithelial cells,
endothelial cells, and fibroblasts, can serve as sentinel cells when opportunity arises.
121. The most important sentinel cells are macrophages. Macrophages
scattered throughout the body can capture, kill, and destroy microbial invaders.
Macrophages have multiple other functions and so consist of multiple different
subpopulations.
122. Macrophages express many different pattern-recognition receptors
(PRRs) and readily detect and respond to invading bacteria and viruses. In addition to
effective phagocytosis, they respond by producing complex cytokine mixtures. The
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most important of these are interleukin-1 (IL-1), IL-6, IL-12, IL-18, and tumor
necrosis factor- (TNF) (Figure 5-6).

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123.

Infla

mmation
Macrophages
recognize
tissue
damage,
promote

the

recruitment
of
neutrophils,
and regulate
the processes by which neutrophils recruit monocytes. As sentinel cells,
macrophages promote neutrophil emigration from blood vessels. The release
of high-mobility group band protein-1 (HMGB1) and other damageassociated molecular patterns (DAMPs) from damaged tissues stimulates
resident macrophages to produce TNF- and IL-6 as well as neutrophil
chemotactic chemokines, CXCL8, CCL3, and CCL4 and reactive oxygen
species. Exosomes are small cytoplasmic vesicles, about 50 to 100 nm in
diameter, that can transmit signals between cells. They are released by
stimulated macrophages, dendritic cells, and B cells. These exosomes carry
with them a mixture of immunostimulatory and proinflammatory molecules.
They can spread through the extracellular fluid, where they interact with
nearby cells. Thus exosomes from macrophages containing bacteria can
express bacterial cell wall components such as glycopeptidolipids and other
pathogen-associated molecular patterns (PAMPs) on their surfaces. As a
result, the exosomes can bind to PRRs on nearby neutrophils and
macrophages, leading to MyD88-dependent release of TNF-, CCL5, and
iNOS and promoting more inflammation.

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124. Phagocytosis when microbial invasion occurs and inflammation


develops, blood monocytes respond by binding to vascular endothelial cells in a
manner similar to neutrophils. Thus adherence and rolling are triggered by selectin
binding, and the cells are brought to a gradual halt by integrins binding to ligands on
vascular endothelial cells. The monocytes bind to endothelial cell intracellular
adhesion molecule 1 (ICAM-1), using 2-integrins and then emigrate into the tissues.
Within the tissues these cells are called macrophages. Several hours after neutrophils
have entered an inflammatory site, the macrophages arrive. These macrophages are
attracted not only by bacterial products and complement components such as C5a but
also by DAMPs from damaged cells and tissues. Once neutrophils have emigrated
into tissues, they also attract macrophages. Thus neutrophil granules contain
macrophage chemoattractants such as azurocidin, defensins, and cathelicidins.
Activated neutrophils and endothelial cells produce monocyte chemoattractant
protein-1 (CCL2) under the influence of IL-6. Neutrophils are the martyrs of the
immune system: they reach and attack foreign material first, and in dying they attract
macrophages to the site of invasion. Phagocytosis by macrophages is similar to the
process in neutrophils. Macrophages destroy bacteria by both oxidative and
nonoxidative mechanisms. In contrast to neutrophils, however, macrophages can
undertake sustained, repeated phagocytic activity.
125. In addition, macrophages release collagenases and elastases that destroy
nearby connective tissue. They release plasminogen activator that generates plasmin,
another potent protease. Thus macrophages can soften up the local connective
tissue matrix and permit more effective penetration of the damaged tissue.
Macrophages phagocytose both apoptotic neutrophils and their exosomes. The
contents of neutrophil granules are not always destroyed but may be carried to
macrophage endosomes where they can continue to inhibit the growth of bacteria.
Thus neutrophils can enhance the effectiveness of macrophages in host defense.
126. Generation of Nitric Oxide In some mammals, especially rodents, cattle,
sheep, and horses (but not in humans, pigs, goats, or rabbits), microbial PAMPs

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trigger macrophages to synthesize inducible nitric oxide synthase (iNOS or NOS2).


Not all macrophages generate nitric oxide. Those that do are called M1 cells, and
their primary function is host defense. A second population of macrophages, called
M2 cells, does not produce NO but instead converts arginine to ornithine using the
enzyme arginase. These two macrophage populations play different roles in defending
the body. M1 cells defend against microbial invaders and produce proinflammatory
cytokines. M2 cells have opposite effects: they reduce inflammation and produce
cytokines that suppress immune responses. M2 cells thus promote blood vessel
formation, tissue remodeling, and tissue repair. M1 cells are produced early in the
inflammatory process when inflammation is required. M2 cells, on the other hand,
tend to appear late in the process when healing is required.
127.

2.6 Role of Macrophages in Phagocytosis

128. The macrophage accomplishes its ongoing cleanup task by engulfing


unwanted particles and 'eating' them. As mentioned before, a macrophage is an
amoeba-type cell. Imagine a jelly-like blob oozing along, surrounding its prey, and
swallowing it. This is essentially how a macrophage works.
129. Phagocytosis is a type of endocytosis. Endocytosis is a process through
which a cell absorbs a particle, molecule, bacterium, or other type of matter by
engulfing it. Phagocytosis refers to the engulfing of larger, solid particles. Often the
engulfed particle is another cell, like when a white blood cell, which is a part of the
immune system, engulfs a bacterium to destroy it.
130. Macrophages are professional phagocytes and are highly specialized in
removal of dying or dead cells and cellular debris. This role is important in chronic
inflammation, as the early stages of inflammation are dominated by neutrophils,
which are ingested by macrophages if they come of age.
131. A macrophage uses a process called phagocytosis to destroy and get rid
of unwanted particles in the body. Phagocytosis literally means 'eat cell.' The process
works like this: as the macrophage engulfs the particle, a pocket called a phagosome

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is formed around it. Then, enzymes are released into the phagosome by an organelle
within the macrophage called a lysosome. Much like the enzymes in our own
stomach are released to digest our food, the enzymes released by the lysosome digest
the particle. The remaining debris, or what is left of the particle, exits the macrophage
to be absorbed back into the body.
132. The neutrophils are at first attracted to a site, where they proliferate,
before they are phagocytized by the macrophages. When at the site, the first wave of
neutrophils, after the process of aging and after the first 48 hours, stimulate the
appearance of the macrophages whereby these macrophages will then ingest the aged
neutrophils.
133. The removal of dying cells is, to a greater extent, handled by fixed
macrophages, which will stay at strategic locations such as the lungs, liver, neural
tissue, bone, spleen and connective tissue, ingesting foreign materials such as
pathogens and recruiting additional macrophages if needed.
134. When a macrophage ingests a pathogen, the pathogen becomes trapped
in a phagosome, which then fuses with a lysosome. Within the phagolysosome,
enzymes and toxic peroxides digest the pathogen. However, some bacteria, such as
Mycobacterium tuberculosis, have become resistant to these methods of digestion.
Typhoidal Salmonellae too induce their own phagocytosis by host macrophages in
vivo, and inhibit digestion by lysosomal action, thereby use macrophages to replicate
and cause macrophage apoptosis. Macrophages can digest more than 100 bacteria
before they finally die due to their own digestive compounds.
135. Macrophages do not distinguish between the different types of bacteria,
viruses, or other outsiders, they do recognize that those particles do not belong in the
body by detecting the different outer proteins. Macrophages even have the ability to
detect signals sent out by bacteria, allowing them to travel to the site of infection.
136.

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137.

Parts:

138.

1. Pathogens

139.

2. Phagosome

140.

3. Lysosomes

141.

4. Waste material

142.

5. Cytoplasm

143.

6. Cell membrane

144.
145.

Steps of a macrophage ingesting a pathogen:

a. Ingestion through phagocytosis, a phagosome is formed


b. The fusion of lysosomes with the phagosome creates a phagolysosome; the
pathogen is broken down by enzymes
c. Waste material is expelled or assimilated (the latter not pictured)
146.
147.

2.7 Macrophage Recruitment and Chemotaxis

148.
Monocytes are recruited into tissues in response to a very
wide range of different stimuli. Where a pathogen is involved, they are commonly
preceded by neutrophils, which release a range of toxic agents designed to kill
extracellular pathogens. The macrophage then has the task of clearing both the dead
pathogens and the dead neutrophils. To enter a tissue, the monocyte in peripheral
blood must adhere to the vessel wall, cross the endothelial cell barrier, and then
migrate towards the stimulus; a process known as chemotaxis. The process of
recruitment of neutrophils and macrophages involves the resident macrophages which
act as sentinels. They responds to local stimuli by producing cytokines that make the
endothelial cells more sticky (through the increased expression of cell adhesion
molecules such as P-selectin) and so-called chemokines, that promote the directed
migration of inflammatory cells. Monocytes may also migrate towards increasing
concentrations of molecules that produced by microorganisms themselves, by
damaged tissues, or by the activation of the complement or clotting cascades which
release bioactive peptides such as C5a. One example of a microbial chemoattractant
is N-formyl-methionyl peptides; which are unique to bacteria because this is the
initiating amino acid at the N terminus of all bacterial proteins.
149.

2.8 Role of Macrophages in Necrosis

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150.

Necrosis is the death of body tissue. It occurs when too little blood

flows to the tissue. This can be from injury, radiation, or chemicals. Necrosis
cannot be reversed.There are some kinds of necrosis :
1. Coagulative
2. Liquefactive
3. Caseous
4. Fat necrosis
5. Gangrenous necrosis
151.

Cells that die in these physiological or sometimes phatological contexts

typically are removed rapidly by phagocytic cells, including macrophages.


152.
153.
154.
155.
156.
157. Macrophages in necrotic cells usually found internalized only as small
cellular particles after loss of membrane integrity. Macrophages can be activated by
cytokines such as interferon-gamma (IFN-gamma) and bacterial endotoxins, such as
lipopolysaccharide (LPS). Necrotic cells induce proinflammatory cytokine production
in macrophages. The activation of macrophages leads to the production of a widerange of hormone-like molecules called cytokines, that are important for orchestration
of an appropriate inflammatory and acquired immune response, but can also initiate
much of the pathology of disease. These molecules include tumor necrosis factor-a,
interleukin-1 and interleukin-6. Together they contribute to initiation of systemic
responses including fever, known collectively as the acute-phase response. These
responses contrive to initiate sickness behaviour and to make the body less conducive
to pathogen replication. In extremus, they are themselves the cause of life-

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threatening complications seen in septic shock; multiple organ failure and


disseminated intravascular coagulation. For this reason, cytokines have been
attractive targets for therapeutic interventions.

158.
159.

2.9 The Role of Macrophages in Apoptosis

a Apoptosis
160.
Apoptosis is a physiological process and a type of
programmed cell death whi
ch is important for embryologic
development, maintenance of homeostasis and elimination of damaged cells.
This is a controlled, energy dependent process and involves a number of
different morphological changes. These changes are a result of the action of
efficient cysteinyl aspartate-specific proteases called caspases, and includes
reduced cell volume, chromatin condensation, nuclear fragmentation, and
membrane blebbing.
161.
Apoptotic death can be triggered by a wide variety of
different stimuli, which induce either the extrinsic or the intrinsic apoptotic
pathways. The extrinsic pathway is induced by the activation of proapoptotic
receptors on the cell surface. Specific molecules such as Apo2L/TRAIL and
Fas- Ligand, which are known as pro-apoptotic ligands, bind to the death
receptors (DR)4/DR5 and Fas, respectively, and thereby induce activation of
apoptosis.
162.
In contrast to the extrinsic pathway, the intrinsic pathway
is initiated from within the cell in response to stress signals, such as DNA
damage, hypoxia, or the loss of survival signals. Both pathways are however
interconnected with other signalling proteins, such as NK-B and p53MDM2, and also converge at the level of effector caspases. Caspases are
proteolytic enzymes that mediate apoptosis by cleavage of a number of
different substrates that are vital for cell survival.

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163.
Apart from morphological changes during apoptosis,
changes on the apoptotic cell surface also occur. These changes are mainly
important to stimulate efficient removal of apoptotic cells by phagocytosis.
However, apoptosis is a dynamic process, during which cell surface molecules
are continuously changing. Phosphatidylserine (PS), a phospholipid that is
normally present on the inner leaflet of the plasma membrane, flips to the
outer leaflet early in the apoptotic process. Increased PS expression has been
found to stimulate phagocytosis.
164.
As a result of both oxidative and non-oxidative stressinduced apoptosis, expression of oxidized PS, in conjunction with the nonoxidized PS, serves as an important phagocytosisstimulatin signal. Other cell
surface changes are alterations in the pattern of 10 glycosylation of
glycoproteins and glycolipids, changed expression levels of specific
molecules, and non-specific changes such as surface charge possibly due to
changes in glycosyl groups. Alterations in sugar chains, surface charge and
oxidation result in the generation of sites resembling oxidised lipoprotein
particles, thrombospondin (TSP) binding sites, sites capable of binding lectins
or the complement proteins C1q and C3b, as well as various collectin-binding
sites. These surface alterations, resulting in new binding sites for receptors,
have important implications for the removal of the apoptotic cell.
165.
b Elimination of apoptotic cells an overview
166.
Elimination is accomplished by professional phagocytes
like macrophages and dendritic cells (DCs), but also by nonprofessional
phagocytes such as fibroblasts, epithelial and stromal cells to name a few cell
types (Fig.1). To recruit professional phagocytes, that are not always located
in immediate proximity, apoptotic cells have been found to secrete soluble
molecules that act as chemotactic factors, find me signals, to phagocytes.
Following recruitment of phagocytes, the elimination of apoptotic cells
consists of two central elements: 1) the apoptotic cell has to be tethered to the
phagocyte, and 2) induction of phagocytosis-stimulating signals upon cellcell
contact. These interactions between the apoptotic cell and the phagocyte are
key events for proper removal. Generally it is suggested that these interactions
induce phagocytosis stimulatory (eat me) or inhibitory (dont eat me)
signals and that the relative contribution of these signals determines whether

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the cell should be eliminated or not.

167.
168.

Figure 1. Phagocytosis of apoptotic cells

169.
Adopted figure from Molecular Cell, Vol 14, 277-287, May 7, 2004. Lauber K.
et. Al. Clearance of apoptotic cells: Getting rid of the corpses
170.

c The calreticulin/LRP1 interaction


171.
Calreticulin (CRT) is a Ca2+-binding endoplasmatic
protein and a molecular chaperone. As such, it is a multifunctional protein that
mainly functions in the endoplasmic reticulum (ER). However, by still
unknown mechanisms, CRT is transported to the plasma membrane and is
detectable on the cell surface. As a cell surface protein CRT has been
implicated in antigen presentation and complement activation,
immunogenicity of cancer cell death, wound healing, thrombospondin
signalling, and clearance of apoptotic cells.
172.
d The CD47/SIRP interaction
173.
CD47, or integrin-associated protein (IAP), is a
ubiquitously expressed transmembrane cell surface glycoprotein and a
member of the immunoglobulin (Ig) superfamily.

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174.

e Immunological consequences of defective apoptotic clearance


175.
In contrast to pathogen elimination, apoptotic cell
clearance does not result in an inflammatory response. This is due to more
than a passive avoidance; instead apoptotic cells are actively
immunosuppressive.
176.
Failure of eliminating apoptotic cells, due to a clearance
defect or an overload of apoptotic cells, allows the cells to proceed into
secondary necrosis. This results in cell swelling and eventually bursting,
leading to uncontrolled leakage of noxious contents and autoantigens.
177.
f Senescent erythrocytes
178.
Old erythrocyte will be die trough phagocytosis process.
Aged erythrocyte shows membrane alteration which enable binding of natural
IgG antibodies and subsequent phagocytosis. Researchers write that specific
erythrocyte alteration is in Band 3.
179.
g

Dentritic cells

180.
DCs are professional antigen presenting cells with the
ability to activate T cells and thereby exert immune-regulatory functions.
Immature DCs are present in most tissues and have a high endocytic capacity
to capture a number of different antigens, such as peptides, bacteria, viruses,
and dying cells.
22

181.
In their mature state, DCs activate T cells and thereby
stimulate T cell immunity. Similar to macrophages, DCs also have the ability
to eliminate apoptotic cells with beneficial immunological effects, where DC
uptake is important for peripheral tolerance. Central tolerance is achieved in
the thymus where autoreactive T cells are eliminated.
182.
However, all self-antigens are not represented in the
thymus since many proteins dont have access to the thymus during
development (e.g. growth of new tissues such as breast during puberty),
making it possible that some self-reactive T cells escape selection in the
thymus.
183.
DCs phagocytose apoptotic cells, degrade them, and cross
present the digested self peptides from apoptotic cells on MHC class I on their
surface. By migrating to secondary lymphoid organs and presenting the
engulfed self-antigens to T cells, self-reactive T cells will become deleted or
anergic to achieve peripheral tolerance.
184.
Both non-professional and professional phagocytes can
eliminate apoptotic cells. Immature monocyte-derived DCs (iMoDC),
granulocyte-macrophage colony-stimulating factor (GMCSF)- driven
macrophages (M1s), and IL-10-producing M-CSF-driven macrophages
(M2s), are three professional phagocytes derived from the same monocyte
population.
185.
In a situation of apoptotic overload, other subsets of
phagocytes, such as the pro-inflammatory M1, might act as backups.
186.

2.10 The Role of Macrophage in Natural Resistence to Virus

Infections
187. By their position at sites of initial infection (e.g., the respiratory tract)
and their wide distribution in major organs of the body (e.g., the liver), macrophages
may be decisive in determining the susceptibility or resistance of an animal to virus
infections. The uptake or clearance of a virus particle from the circulation or
extracellular fluids has been shown first of all to depend on the particle size, as is the
case with inert particles, larger particles being cleared more rapidly than smaller ones.
However, other factors, such as the presence of virus specific receptor sites on
macrophages and the presence of opsonizing antibody, are also important. By uptake
and digestion of virus particles, macrophages may delay or even prevent the spread of
the infection to susceptible cells. However, if the virus can replicate in macrophages,
the infection may go further, and widespread destruction of organs and tissues may
occur. Furthermore, infected monocytes in the circulation can, provided they support
virus replication, be a source of dissemination of the infection by their migration
through the body. It thus seems clear that virus-macrophage interactions may be of
23

crucial importance for the outcome of the infection. Much information on the
importance of macrophages in resistance to virus infections has been gained by
studying experimental infections in which differences exist between the interactions
of macrophages with different strains or types of the same virus. Likewise, models in
which differences in handling a certain virus are found among macrophages from
animals of different ages or different strains of the same species have been
extensively studied.
188.
189. Besides constituting an immediate, "ready to function" barrier to virus
penetration and dissemination in the body, macrophages participate in the defenses
mounted by an infected host and directed against the invading pathogen. During the
courses of many infections, macrophages become hyperactive and activated with
increased microbicidal capacity. This process is immunologically mediated by
specifically sensitized T lymphocytes, presumably via the secretion of soluble
lymphokines, and macrophages are now recognized as important ultimate effectors of
both antiviral and antibacterial cell-mediated immunity. The increased antimicrobial
activity is at least partly nonspecific in that activated macrophages arising during an
infection with one microorganism show increased activity against other, unrelated
agents as well. In addition to increased microbicidal capacity, activated macrophages
have been shown to exhibit a number of other distinctive features: increased
phagocytic ability, accelerated "spreading" on glass surfaces, increased lysosomal
enzyme content, augmented metabolic functions, and antitumor activity. Many of
these properties are shared by nonspecifically stimulated macrophages elicited in vivo
or in vitro by various irritants, such as mineral oil, glycogen, proteose-peptone,
thioglycolate, etc., and it has been speculated that activated and stimulated
macrophages are fundamentally alike. It is well documented that specific macrophage
recruitment and activation occurring in the course of a virus infection are of crucial
importance for recovery. Much more open questions are the significance of
nonspecific macrophage activation and stimulation in the natural resistance of the
host to virus infections and the prospects of nonspecific macrophage activating
immunomodulation in the prophylaxis and treatment of virus infections. In vitro, both
stimulated and immunologically activated macrophages have shown great antiviral
potentials. Thus, Hirsch et al demonstrated by an infectious center assay that
proteose-peptone-stimulated peritoneal macrophages from adult mice were
considerably more restrictive in the replication of HSV-1 than were unstimulated
cells. Suckling mice, on the other hand, did not respond to proteose-peptone
stimulation with the production of a macrophage population with these
characteristics, a fact that might partly explain the inefficiency of suckling mouse
macrophages to restrict replication of viruses in vivo and in vitro.
24

190.
191. Aspects of the importance of the mononuclear phagocyte system as a
barrier to the establishment and dissemination of virus infection in the body have
been presented. From an anatomical point of view, cells of the mononuclear
phagocyte system are well suited for this function. They are strategically placed at the
portals of entry of many viruses and are widely distributed in close contact with the
circulating blood in most organs of the body, thus encountering the virus early in the
infection. From a functional point of view, the ability of macrophages to take up and
destroy invading virus particles may be of the utmost importance in the race between
the destructive growth of thevirus and the induction of a specific immune response.
If, on the other hand, the virus is able to multiply more or less freely in macrophages,
the "viral burden" and the destruction may have proceeded beyond the limit of the
capacities of the specific immune responses, when they eventually turn up.
Polymorphonuclear leukocytes do not constitute a fixed barrier system in the body,
and they are generally not a very conspicuous feature in the pathological lesions
produced by viruses. Although they are capable of taking up virus particles, there is
no evidence that they play a very prominent role, if any, in the antiviral defense
mechanisms of the body. The collaboration of macrophages with other host defense
mechanisms against virus infections is a subject of current interest. For example,
macrophages have been shown to be of importance in the production by specifically
sensitized lymphocytes ofimmune (type II) interferon. However, the role of
macrophages seems more important in the immune response. Thus, macrophages are
recognized as important ultimate effectors of antiviral cell-mediated immunity.
Probably, macrophages also play a role in the inductive phase of the immune
response by capturing the virus and by processing the viral antigens and presenting
them to lymphocytes for immune recognition. As previously stated, the basic nature
of the capacity of macrophages to restrict the replication of viruses is at present
unknown. A better understanding of this question, together with more insight into the
collaboration of macrophages with other host defense mechanisms, might open new
fields of specific immunomodulation. This could be of importance in the prophylaxis
and treatment of virus infections in persons with increased susceptibility, for example,
premature infants and persons with genetically determined or induced immune
deficiencies.
192.
193.

2.11 The Role of Macrophage in Haemodynamic Disorders

194.

Hemodynamic

is

the fluid

dynamics of blood

flow.

The circulatory system is controlled by homeostatic mechanisms, much


as hydraulic

circuits are

controlled

by control

systems. Hemodynamic
25

response continuously monitors and adjusts to conditions in the body and its
environment. Thus hemodynamic explains the physical laws that govern the
flow of blood in the blood vessels. The relationships can be challenging
because blood vessels are complex, with many ways for blood to enter and
exit under changing conditions. Hemodynamic disorder such as : edema,
hyperemia, congestion, hemorrhage, hemostasis, thrombosis, embolism,
infark, and shock.
195.
1. EDEMA
196.

Edema is condition when the bodies tissue (interseluler tissue) and body

cavity swelled by fluid from blood plasma. Without any vascular damage
2. HYPEREMIA
197.
Hyperemia is an active process resulting from augmented tissue inflow
because of arteriolar dilation, as in skeletal muscle during exercise or at sites
of inflammation. The affected tissue is redder because of the engorgement of
vessels with oxygenated blood.
3. CONGESTION
198.
Congestion is a passive process resulting from impaired outflow from a
tissue. It may occur systemically, as in cardiac failure, or it may be local,
resulting from an isolated venous obstruction. The tissue has a blue-red color
(cyanosis), particularly as worsening congestion leads to accumulation of
deoxygenated hemoglobin in the affected tissues
4. HEMOSTASIS
199.

Hemostasis is arrest of bleeding, that physiologically result in response

to vascular
200.
damage and provides a mechanism to seal an injured vessel to prevent
blood loss.
5. HEMORRHAGE
201.

Condition of bodies tissue when hemostasis happen so the blood in

vessel come out and make the tissue bleeding.

26

202.

Hemostasis
hemorrhage

1.1 Hemorrhage cause


203.
204.
6. THROMBOSIS
205.

Thrombosis is an inapropriate thrombus formation of fibrin and platelet

with other blood elements on the wall of a blood or lymphatic vessel or heart
or free in their lumen [thrombo-emboli].
206.

Hemorrhage

Trhrombus

7. EMBOLISM
207.

Is a part of thrombus or a piece of free-floating material wihin the blood

8. INFARK
208.

Necrosis of tissue cause lack of oxygen, and make tissue become lot of

connective tissue. Infark is causing by the thrombus.


9. SHOCK

27

209.

Shock, or cardiovascular collapse, is the final common pathway for a

number of potentially lethal clinical events, including severe hemorrhage,


extensive trauma or burns, large myocardial infarction, massive pulmonary
embolism, and microbial sepsis.
210. So, from the hemodynamic disorder, the role of macrophage
(Monocytes because still in blood vessels) are just for the healing (Phagositosis
bacteria or some foreign thinks outside the blood vessels) and can removed the plug
on the wall of blood vessels, so the accumulation it will disappeared and any further
problems like shock, infark, and embolism can be decreased.
211.
212.
213.
214.

2.12 The Role of Macrophage in Acute Inflammation

215.
216.
217.
218.
219.
220.
221.
222. Acute inflammation is a rapid response to an injurious agent that serves
to deliver mediators of host defense leukocytes and plasma proteins to the site of
injury. Acute inflammation has three major components: (1) alterations in vascular
caliber that lead to an increase in blood flow; (2) structural changes in the
microvasculature that permit plasma proteins and leukocytes to leave thecirculation;
and (3) emigration of the leukocytes from the microcirculation, their accumulation in
the focus of injury, and their activation to eliminate the offending agent.

28

223. Macrophages recognize microbial products and secretemost of the


cytokines important in acute inflammation. These cells are stationed in tissues
torapidly recognize potentially injurious stimuli and initiate the host defense reaction .
Adhesion molecules in endothelial tissues cause mediators such as histamine,
thrombin, and plateletactivating factor (PAF) to stimulate the redistribution of Pselectin from its normal intracellular storesin granules (Weibel-Palade bodies) to the
cell surface. Macrophages, mast cells,and endothelial cells respond to injurious agents
by

secreting

the

cytokines

TNF,

IL-1,

andchemokines

(chemoattractant

cytokines).TNF and IL-1 act on the endothelial cells of postcapillary venules adjacent
to theinfection and induce the expression of several adhesion molecules.
224. Phagocytosis and the release of enzymes by neutrophils and
macrophages are responsible foreliminating the injurious agents and thus constitute
two of the major benefits derived from theaccumulation of leukocytes at the
inflammatory focus.
225.
226.
227.

2.13 Role of Macrophage in Chronic

Inflamation
228.

The macrophage is the characteristic

cell type in chronic inflammatory reactions, in the rheumatoid synovium, as in


other sites. When macrophages are activated, considerable synthesis of
enzymes and other proteins occurs. Macrophages can be activated by (i)
products of activated lymphocytes, (ii) immune complexes and (iii) the
complement cleavage product C3b. Among the many consequences of
macrophage activation are (i) secretion of hydrolytic enzymes, (ii) cleavage of
C3 into C3a, which is cytolytic, and C3b, (iii) production of tissue
thromboplastin, a powerful procoagulant, and (iv) formation of polyamine
oxidase, which in the presence of appropriate substrates generates factors that
lyse or limit the proliferation of tumour cells, lymphocytes and microorganisms.

29

229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
239.
240.
241.
242.
243.

Macrophages contribute to tumor growth

and progression. Attracted to oxygen-starved (hypoxic) and necrotic tumor


cells they promote chronic inflammation. Inflammatory compounds such as
tumor necrosis factor (TNF)-alpha released by the macrophages activate the
gene switch nuclear factor-kappa B. NF-B then enters the nucleus of a tumor
cell and turns on production of proteins that stop apoptosis and promote cell
proliferation and inflammation. Moreover, macrophages serve as a source for
many pro-angiogenic factors including vascular endothelial factor (VEGF),
tumor necrosis factor-alpha (TNF-alpha), granulocyte macrophage colonystimulating factor (GM-CSF) and IL-1 and IL-6 contributing further to the
tumor growth. Macrophages have been shown to infiltrate a number of
tumors. Their number correlates with poor prognosis in certain cancers
including cancers of breast, cervix, bladder and brain.Tumor-associated
macrophages (TAMs) are thought to acquire an M2 phenotype, contributing to
tumor growth and progression. Recent study findings suggest that by forcing
IFN- expression in tumor-infiltrating macrophages, it is possible to blunt

30

their innate protumoral activity and reprogram the tumor microenvironment


toward more effective dendritic cell activation and immune effector cell
cytotoxicity.
244.
245.

2.14 Role of Macrophage in Wound Healing

246. Macrophages have been described to have many functions in wounds,


including host defense, the promotion and resolution of inflammation, the removal of
apoptotic cells, and the support of cell proliferation and tissue restoration following
injury. Recent studies suggest that macrophages exist in several different phenotypic
states within the healing wound, and that the influence of these cells on each stage of
repair varies with the specific phenotypes. While the macrophage is beneficial to the
repair of normally healing wounds, this pleotropic cell type may promote excessive
inflammation and/or fibrosis in certain circumstances. Due to advances in the
understanding of this multi-functional cell, the macrophage continues to be an
attractive therapeutic target both to reduce fibrosis and scarring, and to improve
healing of chronic wounds.
247. The inflammatory response following tissue injury plays important roles
both in normal and pathological healing. Immediately after injury, the innate immune
system is activated, setting in motion a local inflammatory response that includes the
recruitment of inflammatory cells from the circulation. This rapid response begins
with the degranulation of platelets that arrive at the site as well as the injury-induced
degranulation of resident mast cells. Local immune cells, including resident
macrophages, are activated by proinflammatory mediators released in response to
injury, as well as Damage Associated Molecular Pattern molecules (DAMPs). The
hypoxic environment of the wound also promotes inflammation, as hypoxia
stimulates numerous cell types, including macrophages, to produce mediators
important to inflammation.
248. Resting macrophages produce only low levels of pro-inflammatory
mediators. Upon exposure to pro-inflammatory cytokines, interferons, LPS or other
microbial products, or DAMPS such as heat-shock proteins, high mobility group box

31

proteins, and molecular fragments of the extracellular matrix, macrophages acquire a


pro-inflammatory, or

classically activated phenotype. Following activation,

proinflammatory macrophages themselves produce a large number of mediators and


cytokines including interleukin-1, interleukin-6, interleukin-12, TNF, and inducible
nitric oxide synthase (iNOS). Because many of these mediators have been shown to
be present in the early wound environment, macrophages seem a likely source.
Macrophages also produce chemoattractants, including chemokines, that recruit
additional leukocytes .
249. One critically important function of wound macrophages is the capacity
to facilitate the nonphlogistic removal of neutrophils. Neutrophils are abundant in
early wounds, and are essential for effective decontamination. Yet a large body of
evidence suggests that neutrophils negatively influence repair, probably because this
cell type is capable of destroying normal tissue. Neutrophil proteases, such as elastase
and cathepsin G, can degrade most components of the extracellular matrix as well as
proteins as diverse as clotting factors, complement, immunoglobulins, and cytokines.
Since the extracellular matrix serves as a supporting scaffold for infiltrating cells,
modification of the extracellular matrix by neutrophils could have important
consequences for repair. Neutrophils also produce a large number of free oxygen
radicals, and thus are capable of inducing considerable oxidative stress on the wound.
Mediators such as superoxide and hydrogen peroxide can cause additional tissue
damage, delaying the repair process and modifying healing outcomes. The large load
of neutrophils is removed primarily by apoptosis. The removal of the apoptotic cells
by phagocytosis, a process that is termed efferocytosis, prevents secondary necrosis
of these cells, and is thought to be essential for complete repair.
250. Macrophages are unique in wounds, as they represent the single most
effective means of neutrophil removal. Macrophages assist in the removal of
neutrophils from sites of injuries in several ways. Macrophages respond to
neutrophils and their products, and can induce apoptosis in neutrophils. Perhaps more
importantly, macrophages recognize and actively ingest apoptotic neutrophils, thus
helping to resolve wound inflammation. Several studies suggest that the phagocytosis

32

of neutrophils influences macrophage phenotype, causing a switch from proinflammatory to a growth promoting, reparative phenotype.
251. Macrophages influence wound healing through the generation of growth
factors that promote cell proliferation and protein synthesis, as well as by the
production of proteases and their inhibitors that influence ECM content and
remodeling. A multitude of factors that are known to be present in healing wounds
have been shown to be produced by macrophages.
252. During this final phase, capillary regression and collagen remodeling
are dominant features. Macrophages can produce factors that are anti-angiogenic
(such as thrombospondin-1 and IP-10), and others, including CXCR3 ligands, that
direct the termination of the repair response in multiple ways. Other cells within the
wound may also produce these concluding signals,but since macrophages can
theoretically be a major source of these types of factors, these cells may play an
active role in the termination of the wound healing process.
253.
255.

256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.

254.

Figure 1. The pattern of leukocyte


infiltration into wounds
Inflammatory cells are present during
each of the phases of wound repair,
represented here as hemostasis (yellow
panel), early inflammation (light pink
panel), late inflammation (medium pink
panel) and resolution/remodeling (blue
panel). The relative density of the four
most prominent types of leukocytes in
wounds
(mast
cells,
neutrophils,
macrophages, and lymphocytes) is
depicted.
While
neutrophils
and
lymphocytes disappear, low numbers of
resident mast cells and macrophages are
present
during
lengthy
remodeling
Figure
2. Thethe
likely
pattern
of
phase.
macrophage function during the
course of wound healing
In the early wound, monocytes and
resident macrophages become activated,
undertake phagocytosis of microbes and
perhaps early neutrophils, and produce
proinflammatory
mediators
and
chemoattractants. Macrophages also
assist in the induction of apoptosis in
neutrophils, thus turning the wound
towards a non-inflammatory, reparative
state. In the later phases of wound repair,
macrophages
ingest
apoptotic
neutrophils, producing growth factors to
support tissue restoration. In the very late
stages, as the wound resolves,
macrophages
may
guide
tissue
remodeling by producing factors to
33
promote capillary regression and
collagen remodeling.

267.

2.15 Role of Macrophages in Adaptive Immunity

268. Macrophages is to alert the immune system to microbial invasion. After


ingesting a microbe, a macrophage presents a protein on its cell surface called an
antigen, which signals the presence of the antigen to a corresponding T helper cell.
269. After digesting a pathogen, a macrophage will present the antigen (a
molecule, most often a protein found on the surface of the pathogen and used by the
immune system for identification) of the pathogen to the corresponding helper T cell.
The presentation is done by integrating it into the cell membrane and displaying it
attached to an MHCclass II molecule, indicating to other white blood cells that the
macrophage is not a pathogen, despite having antigens on its surface.
270. Eventually, the antigen presentation results in the production of
antibodies that attach to the antigens of pathogens, making them easier for
macrophages to adhere to with their cell membrane and phagocytose. In some cases,
pathogens are very resistant to adhesion by the macrophages.
271. The antigen presentation on the surface of infected macrophages (in the
context of MHC class II) in a lymph node stimulates TH1 (type 1 helper T cells) to
proliferate (mainly due to IL-12 secretion from the macrophage). When a B-cell in
the lymph node recognizes the same unprocessed surface antigen on the bacterium
with its surface bound antibody, the antigen is endocytosed and processed.
272. Macrophages provide yet another line of defense against tumor cells and
somatic cells infected with fungus or parasites. Once a T cell has recognized its
particular antigen on the surface of an aberrant cell, the T cell becomes an activated
effector cell, producing chemical mediators known as lymphokines that stimulate
macrophages into a more aggressive form.
273.
274.
275.
276.
277.

34

278.
279.

CHAPTER III

280.

CONCLUSION
281.

3.1 Macrophage is a large white blood cell that is an important part of our immune
system
3.2 Macrophage plays a lot of roles in immune system. But mostly, macrophage
recognizes the foreign agents that invade the bodies and secreting several types of
chemical mediator to destroy the foreign agent, then finally, eliminating the debris
of foreign agents by phagocytosis.
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
292.
293.
294.
295.
296.
297.
298.
299.
300.
301.

35

302.
303.
304.
305.

REFERENCES

306.
307.
308.

https://en.m.wikipedia.org/wiki/Macrophage

309.

http://www.news-medical.net/life-sciences/Macrophage-Function.aspx

310.

www.ncbi.nlm.nih.gov/pmc/articles/PMC3596046

311.

https://www.diva-portal.org/smash/get/diva2:278362/FULLTEXT01.pdf

312.

https://en.wikipedia.org/wiki/Macrophage

313.

http://study.com/academy/lesson/macrophages-definition-function-

types.html
314.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC281459

315.
316. Yohnston RB. Monocytes and macrophages. Dalam: Lachman PJ, Keith DP, Rosen FS,
Walprot MJ, penyunting. Clinical aspects of immunology, vol 1; edisi ke-5, Oxford:
Blackwell Scientific, 1993. Veterinary Immunology 9t, Ian Tizard

36