⑧ 혈액

Chapter 32 Red blood cells, anemia, and polycythemia
혈액
경북대학교 의학전문대학원
생리학교실 홍 장 원
Chapter 33 Resistance to the body infection: Leukocytes, granulocytes,
monocyte-macrophage system, and inflammation
Chapter 34 Resistance to the body infection: immunity and allergy
Chapter 35 Blood types; Transfusion; Tissue and Organ transplantation
Chapter 36 Homeostasis and Blood coagulation

Chapter 33 Resistance to the body infection: Leukocytes,
granulocytes, monocyte-macrophage system, and
inflammation

1. Introduction
- innate immunity and adaptive immunity
2. Leukocytes
① general characteristics of leukocytes
ⓐ types of white blood cells
- polymorphonuclear cells (neutrophils, eosinophils,
basophils), monocytes, lymphocytes, plasma cells,
platelet
ⓑ concentration of different white blood cells in the
blood
ⓒ genesis of WBC
- derived from pluripotent hematopoietic stem cells
ⓓ life span of WBC
② Neutrophils and macrophages defend against infections
ⓐ white blood cells enter the tissue space by diapedesis
ⓑ white blood cells are attracted to inflamed tissue area
by chemotaxis
ⓒ Phagocytosis
ⓓ Once phagocytosed, most particles are ingested by
intracellular enzymes
ⓔ Both neutrophils and macrophages can kill bacteria
③ Mnocyte-macrophage cell system (RES system)
ⓐ Tissue macrophages in the skin and subcutaneous
tissues (histiocytes)
ⓑ Macrophages in the lymph nodes
ⓒ Macrophages in the lungs
ⓓ Macrophages in the liver sinosouid
ⓔ macrophages of the spleen and bone marrow
Chapter 33 Resistance to the body infection: Leukocytes, granulocytes, monocyte-macrophage
system, and inflammation ④ Inflammation; the role of neutrophils and macrophages
- vasodilation, increased permeability of the capillaries,
swelling of the tissues, migration of ganulocytes and
monocytes, clotting of the fluid in the interstitial space
ⓐ Walling-off effect of inflammation
ⓑ Macrophage and neutrophil response during
inflammation
㉠ Tissue macrophage is a first line of defense against
infection
㉡ Neutrophil invasion of inflamed area is second line
of defense
㉢ Acute increase in number of neutrophils in the blood
- neutrophilia
㉣ Second macrophage invasion into the inflamed
tissue is a thrid line of defense
㉤ Increased production of granulocytes and
monocytes by the bone marrow
㉥ Feedback control of the macrophage and neutrophil
responses
㉦ formation of pus
3. Eosinophil
① parasitic infection
② allergic reactions
4. Basophils & mast cells
① allergic reactions
5. Leukopenia
6. Leukemia

1. introduction
- our bodies are exposed continually to bacteria, viruses, fungi, and parasites
- Many of these infectious agents are capable of causing serious abnormal
physiologic function or even death if they invade the deeper tissues
- Our bodies have a special system for combating the different infectious and toxic
agents
- This system is composed of blood leukocytes (white blood cells) and tissue cells
derived from leukocytes
- These cells work together in two ways to prevent disease
① by actually destroying invading bacteria or viruses by phagocytosis (innate
immunity)
② by forming antibodies and sensitized lymphocytes, which may destroy or
inactivate the invaders (adaptive immunity)
- Immune recognition - self/nonself

1. introduction
- These cells work together in two ways to prevent disease

2. Leukocytes (white blood cells)
- Leukocytes; white blood cells, mobile units of body’s protective system
- formed partially in the BM (granulocytes, monocytes, lymphocytes)
- formed partially in the lymph nodes (lymphocytes and plasma cells)
- after formation, they are transported in the blood to different parts of the body
- most of them are specifically transported to areas of serious infection and
inflammation, thereby providing a rapid and potent defense against infectious
agents; seek out and destroy

① General characteristics of leukocytes
ⓐ Types of white blood cells
- polymorphonuclear cells (neutrophils, eosinophils, basophils), monocytes,
lymphocytes, plasma cells, platelets (derived from megakaryocytes)
- polymorophonuclear cells (neutrophils, eosinophils, basophils)
- granular appearance; hence called granulocytes
- poly-; multiple nuclei
- Granulocytes and monocytes; protect the body against invading organism by
ingesting them (phagocytosis), comprise innate immunity
- lymphocytes and plasma cells function mainly in connection with the immune
system, comprise adaptive immune system
- platelet; activate blood clotting system

ⓑ concentration of the different white blood cells in the blood
- adult human; 7000 WBCs/㎕
ⓒ Genesis of WBC
- differentiated from pluripotent hematopoietic stem cells
- two major lineage of WBCs; myelocytic and lymphocytic lineage
- stems from either myeloblast or lymphoblast

ⓒ Genesis of WBC
Myeloblast Lymphoblast
Promyelocyte
megakaryocyte
MonocyteBasophileosinophilNeutrophil
band
neutrophil
metamyelocyte
myelocyte

ⓒ Genesis of WBC
- granulocytes and monocytes are formed only in the BM
- lymphocytes and plasma cells are produced mainly in the various
lymphogenous tissues (lymph nodes, spleen, thymus, tonsils, various pockets
of lymphoid tissues such as payer’s patch)
- WBCs formed in the BM/Ln are stored within the marrow/Ln until they are
needed in the circulatory system. Then various factors cause them to be
released
ⓓ Life span of WBC
- Life of granulocytes released from BM is normally 4 to 8 hrs in the circulation
and another 4 to 5 days in tissues where they are needed
- In serious tissue infection, this total life span is often shortened to only a few
hours because granulocytes proceed even more rapidly to the infected area,
perform their functions, and are destroyed
- monocytes also have a short transit time (10-20 hrs in the blood). Once in the
tissue, they swell much larger sizes to become tissue macrophages, can live for
month unless destroyed. These tissue macrophages are the basis of tissue
macrophage system

ⓓ Life span of WBC
- lymphocytes enter circulatory system continually, along with drainage of lymph
from the lymph nodes and other lymphoid tissues. After few hours, they pass
out of the blood back into the tissues, they renter the lymph and return to the
blood again and again. Lymphocytes have life spans of wks to months,
depending on the body’s need
- platelet in the blood are replaced about once every 10 days; 30,000 platelets
are formed each day for each ㎕ of blood

- attack and destroy invading bacteria, viruses, other injurious agents
- Neutrophils are mature cells that can attack and destroy bacteria even in the
circulating blood
- Tissue macrophages begin life as blood monocytes (immature cells with little
ability to fight infectious agent at that time). When they enter tissues, they begin
to swell to 60-80 μm, extremely capable of combating disease agents in the
tissues
- Tissue macrophages
Location Name
adipose tissue adipose tissue macrophage
Liver kupffer cells
Lymph node histiocyte
Lung alveolar macrophage
skin/mucosa largerhans cells
CNS microglia
Kidney mesangial cells
Bone osteoclast
Peritoneal cavity peritoneal macrophages

Taken from a 16-mm movie made in the 1950s by the late David Rogers at Vanderbilt University.

ⓐ White blood cells enter the tissue space by diapedesis
- WBCs can squeeze through the pores of blood capillaries by diapedesis

ⓑ White blood cells are attracted to inflamed tissue area by chemotaxis
- many different chemical substances cause both neutrophils and macrophages
to move toward source of the chemical; chemotaxis
- when a tissue becomes inflamed, at least a dozen different products that can
cause chemotaxis toward the inflamed tissue are formed
㉠ some of the bacterial or viral toxins (PAMPs, pathogen-associated molecular
patterns)
㉡ degenerative products of inflamed tissues themselves (DAMPs, damage-
associated molecular patterns)
㉢ several reaction products of complement complex (e.g. C5a)
㉣ several reaction products caused by plasma clotting in the inflamed area

ⓑ White blood cells are attracted to inflamed tissue area by chemotaxis

Free circulating
neutrophils
Trends Immunol 2011; 32:452–60
Nat Rev Immunol 2013; 13:159–75
Nat Immunol 2014; 15:602–11
Tethering Slow rolling Full arrest
Firm adhesion
L-selectin
PSGL
P-selectin
E-selectin
LFA-1 PSGL
ChemR
ICAM-1
E-selectin
Chemokine
LFA-1 VLA-4
ChemR
ICAM-1
VCAM-1
Chemokine
LFA-1 VLA-4
Mac-1 ChemR
ICAM-1/2
VCAM-1
Chemokine
Transmigration
Extravasated
Neutrophils
Chemotaxis
Necrotaxis
Macrophages
Induce adhesion
molecules
CXCL2 ligand
IL-8 CXCL1 (GROα)
CXCL2 (GROβ) CXCL3 (GROγ)
CXCL5 (ENA78) CXCL6 (GCP21)
Priming of neutrophils
Assembly of NADPH oxidase
Prime for degranulation
enhanced phagocytosis, chemotaxis
DAMP PAMP
Necrotaxis-associated
molecules
LTB4 fMLP
Chemotaxis
IL-1

ⓒ Phagocytosis
- The most important function of neutrophils
- Whether phagocytosis occurs depends on three selective procedure
㉠ most natural structures of the tissues have smooth surface, which resist
phagocytosis. If the surface is rough, the likelihood of phagocytosis is
increased
㉡ most natural substances of the body have protective protein coats that repel
phagocytosis. Most dead tissues and foreign particles have no protective
coats, which makes them subject to phagocytosis
㉢ The immune system of the body develops antibodies against infectious
agents such as bacteria. Abs then adhere to bacterial membrane and make
the bacterial especially susceptible to phagocytosis (opsonization). To do this,
the antibody molecule also combines with C3 products of the complement
cascade. The C3 molecule attach to the receptors on the phagocytic
membrane, thus initiating phagocytosis

ⓒ Phagocytosis
- phagocytosis by neutrophils
- the neutrophils entering the tissue are already mature cells that can
immediately begin phagocytosis
- neutrophils first attaches itself to the particle and then projects pseudopodia
in all directions around the particles, the pseudopodia meet one another on
the opposite side and fuse → create enclosed chamber that contains the
phagocytized particle. then, the chamber invaginates to the inside of the
cytoplasmic cavity and breaks away from the outer cell membrane to form a
free-floating phagocytic vesicle (phagosome)

ⓒ Phagocytosis
- phagocytosis by macrophages
- more powerful phagocytes than neutrophils
- also have ability to engulf much larger particles, even whole blood cells,
occasionally malarial parasites, whereas neutrophils care not capable of
phagocytizing particles much larger than bacteria
- after digesting particles, macrophages can extrude the residual product and
often survive and function of many more years
- present pathogen-derived antigens (antigen-presenting cells)

ⓓ Once phagocytized, most particles are digested by intracellular enzymes
- lysosomes and other cytoplasmic granules in the neutrophil or macrophages
immediately come in contact with phagocytic vesicle, their membrane fuses,
thereby dumping many digestive enzymes and bactericidal agents to the
vesicle; Thus, the phagocytic vesicle now becomes digestive vesicles.
- Both neutrophils and macrophages contain an abundance of lysosomes filled
with proteolytic enzymes especially geared for digesting bacteria and other
foreign protein matter. The lysosomes of macrophages also contain large
amount of lipase, which digest the thick lipid membranes possessed by bacteria
such as the tuberculosis bacillus.

ⓓ Once phagocytized, most particles are digested by intracellular enzymes

ⓔ Both neutrophils and macrophages can kill bacteria
- neutrophils and macrophages contain bactericidal agents that kill mot bacteria
even when lysosomal enzymes fails to digest them.
- Much of the killing effects results from several powerful oxidizing agents
formed by enzymes in the membrane of the phagosome by a special organelle
called the peroxisome. These oxidizing agents include large quantities of
superoxide (O2
-), hydrogen peroxide (H2O2), hydroxyl ion (OH-)
- Also one of the lysosomal enzyme, myleoperoxidase, catalyzes the reaction
between H2O2 and chloride ions to form hypochlorite, which is exceedingly
bactericidal

Neutrophil
Phagosome
Phagocytosis
NOX2
gp91 phox
p22phox
p67
phox
p47
phox
p40
phox
NADPH oxidase
complex
Fc receptor
Complement R
Opsonized
bacteria
Nat Chem Biol 2008; 4; 278-286
Actin polymerization
→ protrusion of memb.
O2
O2- H2O2
H+
O2
HOCl
MPO
ROS-mediated
bactericidal activity
Azurophil granules
Myeloperoxidase, Elastase
Cathepsin G, Proteinase 3
Defensins, BPI
Speciﬁc granules
Lactoferrin, Cathelicidin
Lysozyme, Collagenase
Leukolysin, Cyt b558, NGAL
Gelatinase granules
Gelatinase, Leukolysin
Lysozyme, NRAMP1
Secretory granules
CR1, CR3 (CD11b-CD18)
FPR, CD14, CD16
Depolimerization
of actin
Granule-mediated
bactericidal activity
Neutrophil Extracellular Traps
DNA + Histone + Granule
→ traps bacteria, kills
extracellularly
{Fused with
phagosome

Azurophil granule DAPI Histone Science 2004; 303:1532

③ Monocyte-macrophage cell system (reticuloendothelial system)
- monocyte-macrophage system
- After entering the tissues and becoming macrophages, another large portion of
monocytes becomes attached to the tissues and remains attached for months or
even years until they are called on to perform specific local protective functions
- they have same capabilities as the mobile macrophages to phagocytize large
quantities of bacteria, viruses, necrotic tissue, or other foreign particles in the
tissue. When they are appropriately stimulated, they can break away from their
attachment and once again become mobile macrophages that respond to
chemotaxis and other inflammatory process.
- Reticuloendothelial system (monocyte-macrophage system)
- total combination of monocytes, mobile macrophages, fixed macrophages,
and a few endothelial cells in the bone marrow, spleen, and lymph nodes
- All these cells originate from monocytic stem cells

ⓐ Tissue macrophages in the skin and subcutaneous tissues (Histiocytes)
- when infection begins in a subcutaneous tissue and local inflammation
ensures, local tissue macrophages can divide in situ and form still more
macrophages → perform usual functions of attacking and destroying bacteria
- histiocyte; tissue macrophage or dendritic cells or lagerhans cells in the skin

ⓑ Macrophages in the lymph nodes
- If the pathogens are not destroyed locally in the tissue, they enter the lymph
and flow to the lymph nodes located intermittently along the course of the
lymph flow → then, pathogens are trapped in those nodes in a meshwork of
sinuses lined by tissue macrophages
- large numbers of macrophages line the lymph sinuses, and if any particles 
enter the sinuses, the macrophage phagocytize them and prevent  
general dissemination throughout the body

ⓒ Macrophages in the lungs
- Another route by which invading organisms frequently enter the body is
through the lungs
- large numbers of tissue macrophages are present as integral components of
alveolar walls. They phagocytize particles that become entrapped in the alveoli
→ digest them and release the digestive products into the lymph. If the
particles are not digestible, the macrophage form a “giant cell” capsule around
the particle until they are slowly dissolved

ⓓ Macrophages (Kupffer cells) in the liver sinusoid
- GI tract is an another route by which bacteria invade
- large numbers of bacteria from ingested food constantly pass through the GI
mucosa into the portal blood
- Before this blood enters the general circulation, it passes through the liver
sinusoid, which are lined with tissue macrophages called Kupffer cells
- effective particular filtration system that almost none of the bacteria from the
GI tract passes from the portal blood into the general system circulation

ⓔ Macrophages of the spleen and bone marrow
- If an invading organism succeeds in entering the general circulation, there are
other lines of defense by the tissue macrophage system, especially in the
spleen and bone marrow.
- The spleen is similar to lymph nodes, except the blood, instead of lymph, flow
through the tissue spaces of the spleen
B-cells
Tissue macrophages

ⓔ Macrophages of the spleen and bone marrow
- If an invading organism succeeds in entering the general circulation, there are
other lines of defense by the tissue macrophage system, especially in the
spleen and bone marrow.
- The spleen is similar to lymph nodes, except the blood, instead of lymph, flow
through the tissue spaces of the spleen

④ Inflammation: role of neutrophils and macrophages
- when tissue injury occurs (whether caused by bacteria, trauma, chemical, heat, or
any other reason), multiple substances are released by the injured tissue and
cause dramatic changes secondary changes in the surrounding uninjured tissues
- This entire complex of tissue changes is called inflammation
- inflammation is characterized by
㉠ vasodilation of the local blood vessels → subsequently excess local blood flow
㉡ increased permeability of the capillaries; leakage of fluid into interstitial space
㉢ Clotting of the fluid in the interstitial space because of increased amounts of
fibrinogen and other proteins leaking from the capillaries
㉣ migration of large numbers of granulocytes and monocytes into the tissue
㉤ swelling of the tissues; some of the tissue products that cause these reactions
are histamine, bradykinin, serotonin, prostaglandin, reaction products of
complement system, reaction products of blood clotting system, lymphokines

㉠ vasodilation ㉡ increased permeability of the capillaries → ㉤ swelling of the tissues
㉣ migration of large numbers of granulocytes and monocytes into the tissue
㉢ Clotting of the fluid in the interstitial space (walling-off)

ⓐ Walling-off effect of inflammation
- “wall off” the area of the injury from the remaining tissue
- The tissue spaces and the lymphatics in the inflamed area are blocked by
fibrinogen clots so that after a while, fluid barely flows through the space

ⓑ Macrophage and neutrophil response during inflammation
㉠ Tissue macrophage is a first line of defense against infection
- RES provides a first line of defense
- histiocytes in the subcutaneous tissue, alveolar macrophages in the lung,
microglial in the brain, kupffer cells in the liver immediately begins their
phagocytic actions
㉡ Neutrophil invasion of inflamed area is second line of defense
- within first hours or so after inflammation begins, large numbers of
neutrophils begin to invade the inflamed area from the blood. This is
caused by inflammatory cytokines (TNF, IL-1) and other biochemical
products
→ induce expression of adhesion molecules (selectin, ICAM-1 on the
endothelial cells) → react with integrin on neutrophils; margination of
neutrophils → cause intercellular attachment between the endothelial cells
of the capillaries and small venules to loosen, allowing openings of large
enough for neutrophils to crawl via diapedesis → They then cause
chemotaxis of neutrophils toward the injured tissues

㉢ Acute increase in number of neutrophils in the blood - neutrophilia
- within a few hours after the onset of acute, severe inflammation, the
number of neutrophils in the blood sometimes increases 4-5 fold;
neutrophilia
- neutrophilia is caused by products of inflammation that enter the blood
stream, are transported to the bone marrow, and act on the stored
neutrophils of the marrow to mobilize these into the circulating blood
Marginated pool Circulating pool
Normal physiologic state
Inﬂammation (Early)
Inﬂammation (Late)
BloodBone marrow, Spl
Liver, Lung, Intestine
Lymph node
Myeloblast Promyelocyte Myelocyte Metamyelocyte Band-form
Neutrophil
Mature
Neutrophil
Stem cell
Pool
Mitotic pool Post mitotic pool

㉣ Second macrophage invasion into the inflamed tissue is a third line of defense
- monocytes from blood enter the inflamed tissue and enlarge to become
macrophages. However, the number of monocytes in the circulating blood is
low; also, the storage pool of monocytes in the BM is much less than that of
neutrophils.
- therefore, buildup of macrophages in the inflamed tissue area is much slower
than that of neutrophils, requiring several days. Also, differentiation of
monocytes into macrophages take several hours.
- After several days-wks, the macrophage finally dominates the phagocytic cells
of the inflamed area.

㉤ Increased production of granulocytes and monocytes by the BM is a fourth
line of defense
- results from stimulation of granulocytic/monocytic progenitor cells of BM
- takes 3-4 days before newly formed granulocytes and monocytes reach
Marginated pool Circulating pool
Normal physiologic state
Inﬂammation (Early)
Inﬂammation (Late)
BloodBone marrow, Spl
Liver, Lung, Intestine
Lymph node

㉥ Feedback control of the macrophage and neutrophil responses
- TNF (tumor necrosis factor), IL-1 (interleukin-1), GM-CSF (granulocyte-
monocyte colony-stimulating factor), G-CSF (granulocyte colony-stimulating
factor), M-CSF (monocyte colony-stimulating factor)
→ formed by activated macrophage

㉦ Formation of pus
- Neutrophils and macrophages eventually die after phagocytosis
- cavity is excavated in the inflamed tissue, contains varying portions of
necrotic tissue, dead neutrophils, dead macrophages, tissue fluid; pus
- pus gradually autolyze over a period of days, end products are absorbed into
the surrounding tissues and lymph

3. Eosinophils
- 2% of all leukocytes, weak phagocytes. exhibit chemotaxis
① parasitic infection
- often produced largely in parasitic infection. Although most parasites are too
large to be phagocytized by eosinophils, eosinophils attach themselves to the
parasite.
- release hydrolytic enzymes from granules, highly reactive oxygen metabolites,
granules a highly lavacidal polypeptide major basic proteins
Caenorhabditis elegans
eosionphils
(from mouse)

3. Eosinophils
- accumulate in peribronchial tissues in asthma pts.
- mast cells and basophils release eosinophil chemotactic factors → cause
eosinophil migrate toward the inflamed allergic tissues
- believed to detoxify some of the inflammation-inducing substances released by
the mast cells and basophils, and probably phagocytize and destroy allergen-
antibody complexes, preventing excess spread of the local inflammatory process

3. Eosinophils

4. Basophil & Mast cells
- similar to the large tissue mast cells
- Both mast cell and basophil liberate heparin into the blood, a substance that can
prevent blood coagulation
- they both release histamine, bradykinin, and serotonin
- Indeed, it is mainly the mast cells in inflamed tissues that release these substances
during inflammation

① Allergic reaction
- IgE has a special propensity to become attached to mast cells and basophils
- allergen binds to pre-formed IgE → IgE Ab-Ag complex → cause mast cell/basophil
rupture and release large amounts of histamine, bradykinin, serotonin, heparin,
slow-reacting substances of anaphylaxis, and lysosomal enzymes → local vascular
and tissue reactions that cause allergic manifestation

① Allergic reaction

5. Leukopenia
- bone marrow produce very few white blood cells → body unprotected against many
bacteria and other agents that might invade the tissues
- normally, the human body lives in symbiosis with many bacteria because all the
mucous membranes of the body are constantly exposed to large numbers of
bacteria → any decrease in WBC results in invasion of adjacent tissues by normal
flora
- within 2 days after bone marrow stops producing WBCs, ulcer may appear in the
mouth and colon, or the person develop some form of severe respiratory infection.
- irradiation of the body by x-ray or gamma-ray, or exposure to drugs and chemicals
that contain benzene or anthracene nuclei, is likely to cause aplasia of the BM.

6. Leukemias
- uncontrolled production of blood cells can be caused by cancerous mutation of
myelogenous or lymphogenous cells. Greatly increased numbers of abnormal WBCs
in the circulating blood
ⓐ Types of leukemia
- lymphocytic leukemia, myelogenous leukemia
- classified according to differentiation stages, acute/chronic
ⓑ Effects of leukemia on the body
- Leukemic cells from BM may reproduce so greatly that they invade surrounding
bone, causing pain, and eventually a tendency for bones to fracture easily
- Almost all leukemias eventually spreads to the spleen, lymph nodes, liver and
other vascular regions, regardless of origin
- development of infection, severe anemia, a bleeding tendency caused by
thrombocytopenia (a lack of platelet)
- Excessive use of metabolic substances by growing cancerous cells → the energy
of the patient is greatly depleted, and eventually die due to metabolic starvation

Chapter 34 Resistance to the body infection: immunity
and allergy

1. Introduction
- innate immunity and adaptive immunity
2. Adaptive immune system
- acquired, highly-speciifc, unable to dintinguish self/non-self → allergies, autoimmune disease, tolerance to
tumors
⑤ T cells and B cell antibodies react highly specifically
against specific antigen
ⓐ millions of specific types of lymphocytes are
stored in the lymphoid tissues
ⓑ origins of many clones of lymphocytes
ⓒ Mechanism for activating a lone of lymphocytes
㉠ role of macrophages in the activation
process
㉡ Role of T cells in activation of B cells
ⓓ Specific attributes of B lymphocyte system -
humoral immunity and Abs
㉠ Formation of antibodies by plasma cells
㉡ Formation of memory cells
⑥ Nature of antibodies
ⓐ Specificity of antibodies
ⓑ classes of antibodies
ⓒ mechanism of action of antibodies
㉠ agglutination
㉡ precipitation
㉢ neutralization
㉣ lysis
㉤ opsonization
① basic types of acquired immunty - humoral and
cell-mediated immunity
② Both types of acquired immunit are initiated by
antigen
③ Lymphocytes are responsible for acquired
immunity
ⓐ Two types of lymphocytes promote cell
mediated or humoral immunity - T lymphocytes, B
lymphocytes
④ Preprocessing of the T and B lymphocytes
ⓐ Thymus gland preprocess the T lymphocytes
- positive selection
- negative selection
ⓑ Liver and bone marrow preprocess the B
lymphocytes

1. introduction
- Immunity; ability to resist almost all types of organisms or toxins that tend to
damage the tissues and organs
- Innate immunity and adaptive immunity
① Innate immunity
- non-specific, in-born immunity system
- The cells of the innate system recognize and respond to pathogens in generic way
- major functions of innate immune system include;
ⓐ recruiting immune cells to sites of infection, through chemical factors
(cytokines)
ⓑ complement cascade to identify bacteria, and promote clearance of antibody
complexes or dead cells
ⓒ identification and removal of foreign substances by specialized WBCs
ⓓ activation of the adaptive immune system through a process known as antigen
presentation
ⓔ acting as physical and chemical barrier to infectious agents
② Adaptive immune system

- acquired, adaptive immunity
- highly specific to a particular pathogen, provide long-lasting protection.
- sometimes the adaptive immune system is unable to distinguish self/non-self →
allergies, autoimmune disease, tolerance to tumors
- Immunization; most of vaccines use adaptive immune response
① Basic types of acquired immunity - humoral and cell-mediated
- Humoral immunity (B-cell immunity); body develops circulating antibody, which
are globulin molecules in the plasma that are capable of attacking the invading
pathogens
- cell-mediated immunity (T-cell immunity); formation of large numbers of T
lymphocytes that are specifically crafted in the lymph nodes to destroy the
foreign agents
② Both types of acquired immunity are initiated by antigens
- acquired immunity does not develop until the invasion by foreign organism or
toxin → our body must recognize this invasion
- Each toxin or organism always contains one or more specific chemical
compounds

① Basic types of acquired immunity - humoral and cell-mediated

② Both types of acquired immunity are initiated by antigens
- antigens
- a molecule capable of inducing an immune response on the part of the host
organism. may originate from within the body (“self-antigen”) or from the
external environment (“non-self”)
- usually peptides, polysaccharides, or lipids
- for a substances to be antigenic, must have a high molecular weight (> 8,000)
- The process of antigenicity usually depends on regularly recurring molecular
groups, called epitopes, on the surface of large molecules.

③ Lymphocytes are responsible for acquired immunity
- lymphocytes are located most extensively in the lymph nodes, spleen, submucosal
areas of GI tract, thymus, bone marrow
- invading agents first enters the tissue fluids and then is carried by lymph vessels
to the lymph node or other lymphoid tissue

ⓐ Two types of lymphocytes promote “cell-mediated” or “humoral” immunity - the
T and B lymphocytes
- T lymphocytes; responsible for forming the activated lymphocytes that provide
“cell-mediated” immunity
- B lymphocytes; responsible for forming antibodies that provide “humoral”
immunity
- Both types of lymphocytes are derived from pluripotent hematopoietic stem
cell that form common lymphoid progenitor cells
- all of the lymphocytes that are formed eventually end up in the lymphoid
tissue, but before doing so, they are further differentiated or preprocessed

T and B lymphocytes

T and B lymphocytes
- T-lymphocytes; lymphoid progenitor cells (destined to T lymphocytes) migrate
to thymus, and preprocessed. Thus they are called T lymphocytes
- B-lymphocytes; lymphoid progenitor cells (destined to form antibodies) are
preprocessed in the liver during mid-fetal life and in the bone marrow in late
fetal life and after birth (first identified in the bursa of fabricius)

- although all lymphocytes in the body originate from lymphocyte-committed stem
cells of the embryo, these stem cells themselves are incapable of forming directly
either activated T lymphocytes or antibodies. Before they can do so, they must be
further differentiated in appropriate processing areas as flows
- T lymphocytes, after origination in the BM, first migrate to thymus glands
- They divide rapidly and at the same time develop extreme diversity for reacting
against different specific antigens; one thymic lymphocytes reactivity against
one antigen
- this continues until there are thousands of different types of thymic
lymphocytes with specific reactivities against many thousands of different
antigens
- These different types of preprocessed T lymphocytes now leave the thymus
and spread by way of the blood throughout the body to lodge in lymphoid
tissue everywhere

- T cell diversity = TCR (t-cell receptor) diversity
- TCR binds to Ag-bound MHC (major histocompatibility complex)
- positive selection; T cells which binds to MHC survive

- The thymus also makes certain that any T lymphocytes leaving thymus will not
react against proteins or other antigens from host; otherwise, T cells would be
lethal to the host itself.
- Thymus selects which T lymphocytes will be released by first mixing them with
virtually all the specific “self-antigens” from the body’s own tissues. If T cell
reacts, it is destroyed. Thus, only the cells finally released are those that are
nonreactive against body’s own antigen.
- Most of the preprocessing T lymphocytes in the thymus occurs shortly before
the birth and for a few month after birth.
- negative selection; T cells which does not react 
with self-antigen survive → establish the “Tolerance”

ⓑ Liver and bone marrow preprocess the B lymphocytes
- B cells are preprocessed in the liver during mid-fetal life and in the BM during
late fetal life and after birth
- B lymphocytes are different from T lymphocytes  
in two-ways
㉠ instead of whole cell developing reactivity against  
the antigen (T cells), B cells actively secrete antibodies 
that are reactive agents; large protein molecules that 
are capable of combining with and destroying  
antigenic substances.
㉡ B cells have even greater diversity than the T cells →  
forming many millions of types of B-lymphocytes  
antibodies with different specific reactivities.
- After preprocessing, B cells migrate into the lymphoid  
tissue throughout the body.

⑤ T cells and B cells antibodies react highly specifically against specific antigen
- When specific antigen come in contact with T/B cells in lymphoid tissues → T cells
become activated to form activated T cells, B cells become activated to form
antibodies → activated T cells and antibodies in turn react highly specifically
against the particular types of the antigens that initiated their development
ⓐ Millions of specific types of lymphocytes are stored in the lymphoid tissues
- each of preformed diverse lymphocytes is capable of forming only one type of
antibody or one type of T cells with a single type of specificity.
- Once the specific lymphocyte is activated by its antigen, it reproduces wildly,
forming tremendous numbers of duplicate lymphocytes; a clone of
lymphocytes
- If it is a B cells, its progeny will eventually secrete specific types of antibodies
- If it is a T cells, its progeny are specific sensitized T cells
a clone of  
antigen-specific
lymphocytes

ⓑ Origins of many clones of lymphocytes
- The whole gene for forming each type of T/B cells is never present in the
original stem cells. Instead, there are hundreds of “gene segments”
- During preprocessing of the respective T/B cells, these genes segments become
mixed with one another in random combination, finally form whole gene of
specific T/B cells.

ⓒ Mechanism for activating a clone of lymphocytes
㉠ Role of macrophages in the activation process
- macrophages phagocytize and digest pathogens → process and liberate
antigenic molecules on the surface through MHC II (HLA II) → the
macrophages present these antigen by cell-to-cell contact directly to the T
lymphocytes (or directly to the B cells), thus leading to activation of specified
lymphocyte clones.
- During antigen presentation, macrophages release a special activating
substance, interleukin-1, that promotes still further growth and reproduction
of the specific lymphocytes

ⓒ Mechanism for activating a clone of lymphocytes
㉡ Role of T cells in activation of B cells
- Most antigens activate both T/B cells at the same time. Some of the T cells
that are formed, called helper T cells, secrete specific substances
(lymphokines) that activate specific B cells. Indeed, without the aid of these
helper T cells, the quantity of antibodies formed by the B cells is usually slight

ⓓ Specific attributes of the B-lymphocyte system - humoral immunity and Abs
㉠ Formation of antibodies by plasma cells
- On entry of a foreign antigen, macrophages present antigen to B cells → +Th
cells → B lymphocytes enlarge and take on the appearance of lymphoblast →
differentiate into plasma cells (cytoplasm expand and the ER vastly
proliferate) → produces gamma-immunoglobulin (IgG) which are extremely
specific for specific antigen

ⓓ Specific attributes of the B-lymphocyte system - humoral immunity and Abs
㉡ Formation of memory cells - difference between 1’ and 2’ responses
- a few of the lymphoblasts formed by activation of a clone of B cells do not
go on to form plasma cells but instead form moderate number of new B cells
similar to those of the original clone; memory cells
- They are dormant until activated once again by a new quantity of the same
antigen; subsequent exposure to same antigen will cause a much more rapid
and potent antibody response.
- increased potency and duration of the 2’ response explain why immunization
is usually accomplished by injecting in multiple doses with period of several
weeks or several months between  
injections

- immunoglobulin (Ig), MW 160,000 - 970,000, constitute 20% of plasma protein
- composed of light and heavy chains
- combination of two light and two heavy polypeptide chains
- each heavy chain is paralleled by light chain at one of its ends, forming a heavy-
light pair
- variable portion; heavy/light chain, different for each specificity of antibody,
attaches specifically to particular type of antigen
- constant portion; determines other properties of antibody, establishing
diffusivity of antibody, adherence of antibody to specific structure within the
tissue, attachment to complement complex
ⓐ Specificity of antibodies
- each antibody is highly specific for a  
particular antigen

ⓑ Classes of antibodies
- Ig G, Ig A, Ig M, Ig E, Ig D
- IgG; constitute 75% of all antibodies of the normal person, highly specific
- IgM; forms a large complex, less specific, eliminate pathogens in the early
stages of B cell-mediated (humoral) immunity before there is sufficient Ig G
- IgE; Binds to allergen, triggers histamine release from mast cell and basophil,
involved in allergy. Also protects against parasitic worm
- IgA; mucosal area (gut, respiratory tract, urogenital tracts), saliva, tears,
breast milk, prevent colonization by the pathogens
- IgD; functions mainly as an antigen receptor on B cells that have not exposed
to antigen. shown to activate basophil, mast cells to produce antimicrobial
factors

ⓒ Mechanisms of action of antibodies
㉠ by direct attack on the invader
㉡ By actions of the complement system
ⓓ Direct action of antibodies on invading agents
- bivalent nature of antibodies and multiple antigen sites on most invading
agents, the antibodies can inactivate the invading pathogens
㉠ Agglutination; pathogens are bound together into a clump
㉡ Precipitation; due to high molecular weight of antibodies, molecular
complex of soluble antigen and antibody becomes insoluble and precipitate
㉢ Neutralization; antibodies cover the toxic sites of the antigenic agent
㉣ Lysis; some potent antibodies are occasionally capable of directly attacking
membranes of cellular agents, resulting in 
rupture of the agent
㉤ Opsonization; mark pathogen for ingestion 
and elimination by a phagocytes

ⓓ Direct action of antibodies on invading agents
㉠ Agglutination
㉡ Precipitation
㉢ Neutralization
㉣ Lysis
㉤ Opsonization

•Does bacteria has adaptive immune system against virus? - development of
CRISPR/CAS9 system in bacteria

•Memory of innate immune cells? - Trained immunity

- acquired, highly-speciifc, unable to dintinguish self/non-self → allergies, autoimmune disease, tolerance to
tumors
⑦ Complement system
ⓐ classical pathway; initiated by antigen-antibody
complex
ⓑ common functions of complement system
㉠ opsonization and phagocytosis ㉡ lysis ㉢
agglutination ㉣ neutralization ㉤ cheomtaxis
㉥ activation of mast cells and basophils ㉦
inflammatory effects
ⓒ Alternative pathway
⑧ Special attributes of the T-lymphocyte system -
activated T cells and T-cell mediated immunity
ⓐ release of activated T cells from lymphoid tissue and
formation of memory cells
ⓑ antigen presenting cells, MHC proteins, and antigen
receptor on T cells
ⓒ several types of T cells and their different functions
㉠ helper T cells
- stimulate growth/proliferation of Th, Tc, Treg
- stimualtion of B cell growth and differentiation
into B cells
- activation of macrophage systems
㉡ Cytotoxic T cells vs NK cells
㉢ suppressor T cells
ⓓ Tolerance of the acquired immune system to
one's one tissue - the role of preprocessing in the
thymus and bone marrow
㉠ main tolerance results from clone selection
during preprocessing
㉡ failure of the tolerance mechanism causes
autoimmune disease
- rheumatic fever, glomerulonephritis,
myasthenia gravis, lupus erythematosis,
rheumatoid arthritis
⑨ Immunization by injection of antigens
ⓐ injection of dead organism
ⓑ immunity against toxins
ⓒ attenuated organism
⑩ passive immunity
3. Allergy and hypersensitivity
① allergy caused by activated T cells; delayed-
reaction allergy
② Allergies in the "allergic" person who has excess
IgE antibodies
㉠ anaphylaxis
㉡ urticaria
㉢ allergic rhnitis (hay fever)
㉣ asthma

- “complement” is a collective term that describes a system of about 20 proteins,
many of which are enzyme precursor
- C1-C9, B, D; all these are present normally among the plasma proteins in the
blood. The enzyme precursors are inactive, but they can be activated

ⓐ Classical pathway; initiated by antigen-antibody complex
- C1 complex; composed of C1q (pathogen sensor), C1s and C1r (serine
proteases)
- C1q interact with pathogen surface or with antibodies bound to surface →
conformational changes, which leads to the activation of autocatalytic
enzyme C1r → active form of C1r cleave C1s → activated C1a cleave C4 →
C4b then binds with C2 → C2 is cleaved by C1s to produce C2a → C4b2a
complex (classical C3 convertase); convert C3 into C3b/C3a → C3b then
convert C5 into C5a/C5b → C5b then convert C6, C7 → C5b67 then convert
C8, C9 → formation of C5b6789 (membrane attack complex)

ⓐ Classical pathway; initiated by antigen-antibody complex

ⓑ Common functions of complement system
㉠ Opsonization and phagocytosis; C3b strongly activate phagocytosis by both
neutrophils and macrophages. This process is also called opsonization.
㉡ Lysis; formation of membrane attacking complex (C5b6789) → direct
rupture of the cell membranes of bacteria or other invading organisms.
㉢ Agglutination; the complement products also change the surfaces of the
invading organisms, causing them to adhere to one another, thus promoting
agglutination.
㉣ Neutralization of viruses; the complement enzymes and other complement
products can attack the structures of some viruses.
㉤ Chemotaxis; C5a initiate the chemotaxis of neutrophils and macrophages,
thus causing large numbers of these phagocytes to migrate into the tissue
area adjacent to the antigenic agents
㉥ Activation of mast cells and basophils; C3a, C4a, C5a activate mast cells/
basophils, causing them to release histamine, heparin → cause increased
local blood flow, increased leakage into the tissue.
㉦ Inflammatory effect; increased blood flow, increased capillary leakage,
interstitial fluid proteins to coagulate in the tissue space, limiting bacterial
spreading

ⓑ Common functions of complement system
㉠ Opsonization and phagocytosis ㉡ Lysis; formation of MAC (C5b6789)
㉢ Agglutination ㉣ Neutralization of viruses ㉤ Chemotaxis
㉥ Activation of mast cells and basophils ㉦ Inflammatory effect

ⓒ Alternative pathway
; does not rely on pathogen-binding antibodies, initiated by spontaneous C3
hydrolysis; C3(H2O) binds to factor B allowing it to be cleaved by factor D
into Ba/Bb → C3(H2O) complex is a C3 convertase → more C3 into C3a and
C3b
; normally C3 activation is limited by endogenous complement regulatory
protein. Pathogens do not have complement regulatory proteins →
spontaneous activation of C3 on the surface of pathogen
; distinguish self, non-self

ⓓ Lectin pathway
; homologous to classic pathway, binds to mannose residue on the pathogen
surface → activate complement cascade
; mannose-binding lectin (MBL), ficolin, MBL-associated serine protease
(MASP)
; MASP associated with MBL or ficolin cleaves C4 to C4a/C4b, which binds to
microbial surface → C4b binds C2a, which is cleaved by MASP-2 to C2a/C2b
→ forming C4b2a complex; active C3 convertase

ⓓ Lectin pathway
Lectin pathway

⑧ Special attributes of the T-lymphocyte system - activated T cells and T cell-
mediated immunity
ⓐ Release of activated T cells from lymphoid tissue and formation of memory cells
- Once exposure to proper Ag → specific T cells proliferate and release large
numbers of T cells → some T cells last for months or even years; memory T cell
- T-lymphocyte memory cells are formed in the same way that B memory cells
are formed
ⓑ Antigen-presenting cells, MHC proteins, and antigen receptor on T cells
- T cells respond to antigen only when they are bound to specific molecules
called MHC protein on the surface of APC (antigen-presenting cells)
- The three major types of APC; macrophage, B cells, dendritic cells (DC)
- The DC, the most potent APC, are located throughout the body, their only
function is to present antigen to T cells
- MHC class I; expressed in all kinds of cells, present  
self-antigen to cytotoxic T cells,
- MHC class II; expressed in APC, present non-self  
antigen to T helper cells

mediated immunity
ⓒ Several types of T cells and their different functions
- Three types of T cells; helper T cell, cytotoxic T cell, suppressor T cells
㉠ Helper T cells
- CD4, the most numerous of the T cells
- major regulatory functions of immunity
- they release a series of protein mediators 
(lymphokines); IL-2,3,4,5, GM-CSF, IFN-γ
- specific regulatory function of Th
- in the absence of Th, the immune system 
is paralyzed
- AIDS (acquired immunodeficiency syndrome)
- Th are inactivated by HIV →  
host is totally unprotected against  
infectious disease

mediated immunity
㉠ Helper T cells
Stimulation of growth/proliferation of Th, Tc, Treg
- IL-2 has a strong stimulatory effects in 
growth of Th, Tc (cytotoxic T cell),  
Treg (regulatory T cell, suppressor T cell)
Stimulation of B cell growth and differen- 
tiation to form plasma cells/antibodies
- IL-4,5,6 → induce differentiation and 
growth of B cells into plasma cells and 
antibodies production
Activation of the macrophage system
- lymphokines induce arrest of macrophage 
migration, causing them to be accumulated  
in the inflamed tissue
- activate phagocytosis of macrophages, 
enhance bactericidal activity

mediated immunity
- CD8 T cells, direct-attack cell that is capable of killing microorganisms; killer
cells
- inspect the self-derived antigen which are presented through MHC I
- when pathogen-derived antigen is presented, they kill infected host cells
through hole-forming protein (perforin) → punch holes in the cells
- NK cells mainly detect “missing self (absence of MHC I expression)”

mediated immunity

mediated immunity
㉢ Suppressor T cells
- regulatory T cells (Treg), suppressor T cells
- suppress the function of both cytotoxic and helper T cells
- prevent autoimmune responses or excessive immune reactions
- maintain immune tolerance

mediated immunity
ⓓ Tolerance of the acquired immune system to one’s own tissues - role of
preprocessing in the thymus and bone marrow
- If a person should become immune to his/her own tissues → acquired immunity
would destroy the individual’s one body; immune mechanism normally
“recognize” a person’s own tissue as being distinctive from bacteria or viruses
㉠ Main tolerance results from clone selection during preprocessing
- during preprocessing of lymphocytes in the thymus and bone marrow, almost
all clones of lymphocytes that are specific to damage the body’s own tissues
are destroyed
㉡ Failure of the tolerance mechanism causes autoimmune 
disease
- sometimes people lose their immune tolerance of  
their own tissues. Usually occurs after destruction of 
some of the body’s own tissues, which releases  
considerable amounts of “self antigens”

mediated immunity
㉡ Failure of the tolerance mechanism causes autoimmune disease
- several specific diseases that result from autoimmunity
- rheumatic fever; exposure to specific type of streptococcal toxin that has a
molecular structure similar to the structure of host tissue

mediated immunity
- glomerulonephritis; the person become immunized against the basement
membrane of glomeruli

mediated immunity
- myasthenia gravis; autoimmunity against acetylcholine receptors

mediated immunity
- lupus erythematosus; person becomes immunized against many different
body tissues including autoantibody against dsDNA
- rheumatoid arthritis; autoimmunity against joint tissues including
autoantibody against dsDNA

⑨ Immunization by injection of antigens
- immunization used to produce acquired immunity against specific diseases
ⓐ A person can be immunized by injecting dead organism that are no longer
capable of causing disease but still have some of their chemical antigen
- typhoid fever, whooping cough, diphtheria, many other types of bacterial
disease
ⓑ Immunity can be achieved against toxins
- immunizing against tetanus, botulism
ⓒ a person can be immunized by being  
infected by live organism that are  
“attenuated”
- small pox, yellow fever, poliomyelitis,  
measles, other viral disease

⑩ Passive immunity
- Active immunity; persons’ own body develops either antibodies or activated T cells
in response to invasion of body by a foreign antigen
- Passive immunity; deliver antibodies or activated immune cells directly to the
recipient

① Allergy caused by activated T cells; delayed-reaction allergy
- caused by activated T cells and not by antibodies
- In the case of poison ivy; repetitive ivy toxin exposure → development of activated
Th and Tc → subsequent exposure result in activated T cell-mediated immune
reactions, as well as extensive invasion of tissues by macrophages.
- The damage normally occurs in the tissue area where instigating antigen is
present
② Allergies in the “allergic” person who has excess IgE antibodies
- Some people has allergic tendency, and are often called atopic allergies.
- The allergic tendency is genetically passed from parent to child, and is
characterized by the presence of large quantities of IgE antibodies
- These antibodies are called reagins or sensitizing antibodies
- When allergen (Ag that react with specific IgE) enters body → allergen-IgE
reaction occurs → mast cell/basophil releases histamine, proteases, leukotriene,
chemotactic substances, heparin, platelet activating substances → dilation of the
local blood vessels; attraction of eosinophil/neutrophils; increased permeability of
capillaries, edema formation; contraction of local smooth muscle

㉠ Anaphylaxis
- widespread allergic reactions, whole-body vasodilation, increased permeability
of the capillaries. Leukotriene induces spasm of the smooth muscle of the
bronchioles, eliciting asthma-like attack
- Occasionally, people dies of circulatory shock or suffocation
㉡ Urticaria
- histamine-induced local vasodilation (red flare), increased local permeability
causes swelling of skin (hives) → generalized hives; urticaria

㉢ Allergic rhinitis (hay fever)
- in hay fever, the allergen-reagin reactions occurs in the nose
- histamine → local intranasal vascular dilation → increased capillary permeability
→ rapid fluid leakage into the basal cavities → nasal linings become swollen
and secretory
㉣ Asthma
- allergen-reagin reaction occurs in the bronchioles of the lung → mast cell-
derived slow-reacting products → spasm of bronchiolar smooth muscle →
difficulty breathing

Dendritic cells
- largerhans cells (discovered in late 19th century)
- the term “dendritic cells” were coined in 1973 by R. Steinman
- connect innate and adaptive immunity, professional APC
Name Description Secretion
Toll-like
receptors
Conventional dendritic cell
(previously called Myeloid dendritic
cell) (cDC or mDC)
Most similar to monocytes. mDC are
made up of at least two subsets:
(1) the more common mDC-1, which is a
major stimulator of T cells
(2) the extremely rare mDC-2, which may
have a function in ﬁghting wound
Interleukin 12 (IL-12)
TLR 2, TLR
4
Plasmacytoid dendritic cell (pDC)
Look like plasma cells, but have certain
characteristics similar to myeloid
dendritic cells.[6]
Can produce high amounts of interferon-
alpha[7] and were previously called interferon-
producing cells.[8]
TLR 7, TLR
9

Tumor Antigen
DC Maturation
Dendritic cell
Ag uptake
Ag processing
Immunization
Ag presentationLymph node
Effector T-cell Response
cytotoxic T cell
Tumor
Ag presentation to T/NK cells  
NK cell
B-cell
TAM/TAN
종양에 대한 정상 면역감시체계

Ag presentationLymph node
cytotoxic T cell
NK cell
B-cell
종양 관련 인자들
(TGF-β, IL-1,6,8,10, ROS, VEGF
etc.), hypoxia, high adenosine
Immunoediting/ escape of immunosurveillance
MHCIIlow DC (immaturity of DC)
TGF-b, IL-10, IDO/arginase expression, etc.
Natural Treg 의 증식/ naive T cells 을
Treg (CD4+ CD25+ Foxp3+)로 분화 유도
TGF-β, IL-10, CTLA4
및 여러 기전
정상 분화의 억제
tolerogenic program
M-MDSC, G-MDSC
Tumor-associated Macrophage (TAM)
Tumor-associated Neutrophils (TAN)
Effector phase
의
억제
priming 과정의 억제
종양 성장 촉진
X
X
X X
X
Treg 분화 유도
수지상세포의 교란
1. 수지상세포 기능저하
↓ DC motility
↓ Ag processing
↓ Ag presentation
↓ DC-T cell contact
2. 수지상세포의 양 저하
↓ DC generation
↓ number of DC
immaturity of DC at Tum
effector T 림프구의 억제
Effector phase 의 억제
종양의 면역감시체계 회피기전

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