RESISTANCE OF THE BODY TO INFECTION:

I. Leukocytes, Granulocytes, the

Monocyte-Macrophage System, and
Inflammation
ROSE LILY V. BULOSAN-VALERIO
LEUKOCYTES (WHITE BLOOD CELLS)
 LEUKOCYTES OR WHITE BLOOD CELLS(WBC)
 Mobile units of the body’s protective system
 Formed partially in the bone marrow (granulocytes, monocytes, lymphocytes
and partially in the lymph tissue (lymphocytes and plasma cells)
 Most of them are transported to areas of serious infection and inflammation
providing rapid and potent defense against infectious agents
 Ability to “seek out and destroy” a foreign invader
General Characteristics of WBCs

TYPES OF LEUKOCYTES (WBC)

1. Polymorphonuclear neutrophils
2. Polymorphonuclear eosinophils
3. Polymorphonuclear basophils
4. Monocytes
5. Lymphocytes
6. Plasma cells
PLATELETS - fragments of another type of cell similar to WBCs found in
the bone marrow, the megakaryocytes
LEUKOCYTES (WBC)
 The polymorphonuclears have a granular appearance
 “granulocytes”
 “polys” because of multiple nuclei
 Granulocytes and monocytes protect the body against invading
organisms by
 Phagocytosis
 Releasing antimicrobial or inflammatory subtances that have multiple
effect that destroy the offending organism
 Lymphocytes and plasma cells function in connection with the
immune system
 Platelets activate the blood clotting mechanism
Concentrations of the different
WBC in the Blood
 Adult human has 7000 WBCs per microliter of blood
 5 million RBCs per ml
GENESIS OF WHITE BLOOD CELLS
GENESIS OF WHITE BLOOD CELLS

2 LINEAGES OF WBCS
A. Myelocytic – starts with the myeloblast
B. Lymphocytic –begins with lymphoblast

 Granulocytes and monocytes are formed ONLY in the BONE

MARROW
 Lymphocytes and plasma cells are produced in various
lymphogenous tissues
 Lymph glands, spleen, thymus, tonsils, lymphoid tissues (peyer’s patches)
GENESIS OF WHITE BLOOD CELLS
 WBCs formed in the BM are stored within the marrow until they are
released when need arises
 WBCs stored is 3x as much as the circulating WBCs in the blood
 Lymphocytes are stored in the lymphoid tissues
LIFE SPAN OF WBC
 After being released from the bone marrow, granulocytes stay for
 4-8 hrs in the blood
 4-5 days in the tissues
 In serious infections, life span is shorter
 Monocytes
 10-20 hours in the blood
 Once in the tissues, they become tissue macrophages
 Tissue macrophage system – continuing defense against infections

 Lymphocytes
 Continually enters the circulatory system along with draining of lymph from
LN and other lymphoid tissues
 They pass out of the blood back into the tissues by diapedesis
 Platelets
 replaced once every 10 days
NEUTROPHILS AND MACROPHAGES
DEFEND AGAINST INFECTIONS
 NEUTROPHILS
 Mature cells that can attack and destroy bacteria even in the
circulating blood
 TISSUE MACROPHAGES
 Begin as blood monocytes which are immature
 Once they enter the tissues, they swell increasing their size to 60-80 um
and are then capable of combating disease agents
 ‘macrophages”
NEUTROPHILS AND MACROPHAGES
DEFEND AGAINST INFECTIONS
 White blood cells and monocyte enter the tissue spaces by DIAPEDESIS
 Squeeze themselves through capillary pores
 White bloods cells move through tissue spaces by AMEBOID MOTION
 Some cells move at 40 um/min
 White Blood Cells are attracted to inflamed tissue areas by
CHEMOTAXIS
 When tissues become inflamed, different products/chemicals stimulate
chemotaxis
 1. bacterial or viral toxins
 2. degenerative products of the inflamed tissues
 3. products of complement complex
 4. reaction products of plasma clotting
PHAGOCYTOSIS
 It is the most important function of the neutrophils and macrophages
 PHAGOCYTOSIS – cellular ingestion of the offending agent
 Phagocytes must be selective of the materials to be phagocytized, otherwise, normal cells
might be ingested
 Selective Procedures
 1. Most natural structures in the tissues have smooth surfaces which resist phagocytosis
 2. Most naturel substances have protective protein coats that repel the phagocytes
 3. The immune system of the body develops antibodies against infectious agents
 Antibody combines with C3 which attaches to receptors on the phagocyte membrane
 OPSONIZATION – process by which a pathogen is selected for phagocytosis and destruction
Phagocytosis by Neutrophils

 Neutrophils are mature cells that can immediately begin

phagocytosis
 Attach to the particle and projects pseudopodia in all directions
enclosing the particle
 The enclosed chamber which contains the particle breaks away
from the outer cell membrane to form a free-floating phagocytic
vesicle (phagosome) inside the cytoplasm
 A neutrophil can phagocytize 3-20 bacteria before being
inactivated
Phagocytosis by Macrophages

 Macrophages are the end stage product of monocytes that enter

the tissues from the blood
 More powerful phagocytes
 Capable of phagocytizing 100 bacteria
 Ability to engulf larger particles (malaria)
 They often survive and function for many more months
Once phagocytized, most particles
are digested by intracellular enzymes
 Once a foreign particle has been phagocytized, lysosomes and
other cytoplasmic granules immediately come in contact with the
phagosome dumping many digestive enzymes and bactericidal
agents into the vesicle
 Phagocytic vesicle becomes a digestive vesicle
 Neutrophils and macrophages contain lysosomes filled with
proteolytic enzymes geared towards digesting bacteria and foreign
proteins
 Lysosomes of macrophages contain Lipases which digests thick lipid
membranes (m. tuberculosis)
Neutrophils and Macrophages can
kill bacteria
 Neutrophils and macrophages contain bactericidal agents
 Oxidizing agents formed by the enzymes in the membrane of the
phagosome or by a special organelle called Peroxisome
 1. Superoxide (O2-)
 2. Hydrogen Peroxide (H2O2)
 3. Hydroxyl ions (OH-)
 Myeloperoxidase catalyzes the reaction between H2O2 and chloride
ions to form hypochlorite (bactericidal)
Some bacteria have coats that are resistant to lysosomal digestion and
secrete substances that partially resist the killing effects of PMNs and
macrophages (chronic diseases like Tuberculosis)
MONOCYTE-MACROPHAGE CELL SYSTEM
(Reticuloendothelial System)

 Total combination of monocytes, mobile macrophages, fixed tissue

macrophages and specialized endothelial cells of the BM, spleen and
lymph nodes
 Almost all these cells originate from monocytic stem cells
 RES is synonymous with monocyte-macrophage system
 A generalized phagocytic system located in ALL tissues especially in areas
where large quantities of particles, toxins, and other unwanted substances must
be destroyed
MONOCYTE-MACROPHAGE CELL SYSTEM
(Reticuloendothelial System)

 Tissue Macrophages in the Skin and Subcutaneous Tissues

(Histiocytes)

 Macrophages in the Lymph Nodes

 No particulate matter can be absorbed directly through the capillary
membranes into the blood
 If particles are not destroyed locally in the tissues, they enter the lymph
and flow to the lymph nodes along with the lymph flow
 Foreign particles are then trapped in these nodes in a meshwork of
sinuses line by tissue macrophages
MONOCYTE-MACROPHAGE CELL SYSTEM
(Reticuloendothelial System)

 Alveolar Macrophages in the Lungs

 Tissue macrophages are present in the alveolar walls which
phagocytize particles in the alveoli
 If particles are digestible, macrophage digest them and release the
digestive products into the lymph
 If not digestible, a “giant cell’ capsule around the particle is formed
 Tuberculosis, silica dust particles, carbon particles
MONOCYTE-MACROPHAGE CELL SYSTEM
(Reticuloendothelial System)

 Macrophages (Kupffer Cells) in the Liver Sinusoids

 Bacteria may invade the body thru the gastrointestinal tract
 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
sinusoids lined with tissue macrophages called KUPFFER CELLS
 KUPFFER CELLS –effective particulate filtration system
 Phagocytosis of a single bacterium occurs in less than 0.01 sec
KUPFFER CELLS
 MONOCYTE-MACROPHAGE CELL
SYSTEM (Reticuloendothelial System)
 Macrophages of the Spleen and Bone Marrow
 Spleen is similar to the lymph node except that blood flows through the
tissue spaces instead of lymph
 a small artery penetrates from the splenic pulp and terminates into small
capillaries
 Capillaries (highly porous) allow whole blood to pass into the cords of the red
pulp
 Blood squeezes through these cords and returns to the circulation by way of the
venous sinuses
 Venous sinuses are lined by macrophages which phagocytize unwanted debris
(old and senescent RBCs)
INFLAMMATION: ROLE OF
NEUTROPHILS AND MACROPHAGES
 INFLAMMATION
 Characterized by
 1. vasodilation of local blood vessels
 2. increased permeability of the capillaries
 3. clotting of the fluid in the interstitial spaces (fibrinogen)
 4. migration of granulocytes and monocytes into the tissue
 5. swelling of the tissue cells
 Secondary to release of tissue products:
 Histamine, bradykinin, serotonin, prostaglandins, reaction products of
complement system, lymphokines (from sensitized T cells)
 The macrophage system is activated to devour the destroyed tissues but
may further injure the still-living tissue cells
INFLAMMATION
 “Walling –Off” Effect of Inflammation
 Fibrinogen clots block the inflamed area
 Fluid barely flows through the tissue spaces to delay the spread of bacteria
or toxic products
 Intensity of the inflammatory process is proportional to the degree of
tissue injury
 Staphylococcal infection release lethal cellular toxins so inflammation
develops rapidly (staph is walled off rapidly and prevented from spreading
throughout the body)
 Streptoccal infection do not cause an intense local tissue destruction
(walling off is slow, while strep continue to reproduce and migrate thus
have a greater tendency to spread and cause death than do staph)
MACROPHAGE AND NEUTROPHIL
RESPONSES DURING INFLAMMATION
 Tissue Macrophages Provide a First Line of Defense Against
Infection
 Within minutes of inflammation, macrophages are already present in
the tissues
 Once activated by products of infection and inflammation, there is
rapid enlargement of these cells
 Sessile/ fixed macrophages become mobile forming the first line of
defense during the first hour or so
MACROPHAGE AND NEUTROPHIL
RESPONSES DURING INFLAMMATION
 Neutrophil Invasion of the Inflamed Area is a Second Line of Defense
 Secondary to inflammatory cytokines (TNF, IL 1) and biochemical
products produced by the inflamed tissues
 1. Increased expression of adhesion molecules – selectins, intercellular
adhesion molecule 1 (ICAM 1)
 React with INTEGRIN on neutrophils
 the neutrophils stick to the capillary and venule walls in the inflamed area
(MARGINATION)

 2. Intercellular attachments between the endothelial cells of the

capillaries and small venules to loosen allowing openings large enough
for neutrophils to crawl through directly from the blood into the tissue
spaces (DIAPEDESIS)
 3. CHEMOTAXIS of neutrophils toward the injured tissue
Migration of Neutrophils from the
Blood to the Inflamed Tissues
MACROPHAGE AND NEUTROPHIL
RESPONSES DURING INFLAMMATION
 Acute Increase in the Number of Neutrophils in the Blood –
“Neutrophilia”
 Neutrophil count increases 4-5x the normal (4000-5000 to 15k to 25k per
microliter) – neutrophilia
 Caused by products of inflammation that enter the blood stream and
transported to the bone marrow and there act on the stored neutrophils
to mobilize them into the circulating blood
MACROPHAGE AND NEUTROPHIL
RESPONSES DURING INFLAMMATION
 Second Macrophage Invasion into the Inflamed Tissue is a Third Line
of Defense
 Together with the neutrophils, monocytes from the blood enter the
inflamed tissue and enlarge to become macrophages
 Low number of monocytes in the blood
 Build up of macrophages is slower (several days to weeks)
 Even after invading, monocytes are still immature cells requiring 8hrs or more
to enlarge and develop lysosomes (tissue macrophages)
 Macrophages can phagocytize more bacteria (5x more than
neutrophil) and far larger particles
 Macrophages play an important role in initiating antibody production
MACROPHAGE AND NEUTROPHIL
RESPONSES DURING INFLAMMATION
 Increased Production of Granulocytes and Monocytes by the Bone
Marrow is the fourth line of defense
 Results from stimulation of the granulocytic and monocytic progenitor
cells of the marrow
 Takes 3-4 days before they leave the bone marrow
 Continuous stimulus from inflamed tissue continue to produce
tremendous quantities of these cells for months and years (20-25x
normal)
FEEDBACK CONTROL OF THE MACROPHAGE
AND NEUTROPHIL RESPONSES
Factors implicated in control of macrophage response to inflammation:
 1. Tumor Necrosis Factor (TNF)
 2. Interleukin-1 (IL1)
 3. Granulocyte-monocyte colony stimulating factor (GM-CSF)
 4. Granulocyte colony stimulating factor (G-CSF)
 5. Monocyte colony stimulating factor (M-CSF)
Increased production of granulocytes and monocytes - GM-CSF, G-CSF,M-CSF
TNF, IL-1 and CSF – provide a feedback mechanism that begins with tissue
inflammation and proceeds to formation of large numbers of defensive WBCs
Formation of Pus
 A cavity formed in inflamed tissues containing varying portion of
necrotic tissue, dead neutrophils, dead macrophages and tissue
fluid
EOSINOPHILS
 Constitute 2% of all blood leukocytes
 Weak phagocytes
 Produced in large numbers in parasitic infections
1. releases hydrolytic enzymes from the granules which are modified
lysosomes
2. releases highly reactive forms of oxygen lethal to parasites
3. releases a larvicidal polypeptide (major basic proteins)
 Involved in allergic reactions
 Mast cells and basophils which participate in allergic reactions release an
eosinophilic chemotactic factor
 Causes eosinophils to migrate toward inflamed allergic tissue
 Eosinophils detoxify some of the inflammation inducing substances
 Phagocytize and destroy allergen-antibody complexes preventing excess spread
of the local inflammatory process
BASOPHILS
 Similar to the mast cells
 Roles of Basophils and Mast Cells
1. Liberate Heparin (prevents blood coagulation)
2. Release Histamine, bradykinin and serotonin
3. They play an important role in allergic reaction
 IgE has a special propensity to become attached to mast cells and basophil
 When the specific antigen for the specific IgE antibody reacts, the resulting
attachment of the antigen-antibody causes rupture of mast cells and basophils
to release histamine, bradykinin, serotonin, heparin, SRSA (a mixture of 3
leukotrienes) and lysosomal enzymes
 Release of these substances will cause local vascular and tissue reactions
(allergic manifestations)
LEUKOPENIA
 A clinical condition when the bone marrow produces very few
WBCs
 Decrease in disease fighting cells in the blood
 Factors which may lead to leukopenia
1. irradiation of the body
2. drugs and chemicals (benzene or anthracene)
3. common drugs (chloramphenicol, thiouracil, barbiturates)
4. cancer, autoimmune diseases – SLE, leukemia, lymphoma
5. Infections – HIV, hepatitis
LEUKEMIAS
 Uncontrolled production of WBCs caused by cancerous mutation of
a myelogenous or lymphogenous cell
 Characterized by increased number of abnormal WBCs in the
circulating blood
LEUKEMIAS
 TWO GENERAL TYPES
 1. Lymphocytic – caused by cancerous production of lymphoid cells
usually beginning in a lymph node or other lymphocytic tissue spreading
to other areas of the body
 2. Myelogenous – cancerous production of young myelogenous cells in
the bone marrow and then spreads through the body so that WBCs are
produced in many extramedullary tissues (lymph nodes, spleen, liver)
 Cancerous process produces partially differentiated cells
 Neutrophilic leukemia, eosinophilic leukemia ,basophilic leukemia or
monocytic leukemia
 Leukemia cells –bizarre and undifferentiated
 The more undifferentiated the cells are, the more acute is the leukemia
LEUKEMIA
 EFFECTS OF LEUKEMIA ON THE BODY
 Metastatic growth of leukemic cells in abnormal areas of the body
 Almost all leukemias spread to the spleen, lymph nodes, liver and vascular
regions
 Common effects are
 1. infections
 2. severe anemia
 3. bleeding tendency (thrombocytopenia)
 Excessive use of metabolic substrates by the growing cancerous cells
 “metabolic starvation”
 Leukemic tissues reproduce new cells rapidly so that tremendous demands are made
on the body reserves
 Patient’s energy is rapidly depleted, excessive utilization of amino acid by leukemic
cells lead to rapid deterioration of the normal protein tissues of the body