Physiology Ch 33 p423-432
Resistance of the Body to Infection: Leukocytes, Granulocytes, Monocyte-Macrophage, Inflammation
Leukocytes – white blood cells (WBC) that are the mobile units of body’s immune system
-formed in bone marrow (granulocytes and monocytes) and lymph tissue (lymphocytes/plasma cells)
-There are six types of WBCs: polymorphonuclear neutrophils, eosinophils, basophils, monocytes,
lymphocytes, and plasma cells (platelets come from megakaryocytes)
-granulocytes are granular cells with multiple nuclei, and protect the body from invading organisms by
ingesting them by phagocytosis. (monocytes do this as well)
-Lymphocytes and plasma cells – function with the immune system
-human body has 7000 WBC/uL of blood (neutrophils 62%, lymphocytes 30%, monocytes 5.3%)
Genesis of WBC – pluripotent hematopoietic stem cells differentiate early to committed stem cells for
WBCs, the myelocytic (begins with myeloblast) and lymphatic (begins with lymphoblast) lineage
-granulocytes and monocytes are formed only in the bone marrow
-lymphocytes produced in lymph glands, spleen, thymus, tonsils, bone marrow, and Peyer’s Patches
-WBC in bone marrow are stored until needed, when factors are secreted to release WBC into blood
-3x the needed WBC compared to circulating WBC stored in marrow
-Lymphocytes stored in lymphoid tissues
-Megakaryocytes formed in bone marrow and bud into platelets or thrombocytes
Lifespan of WBC – granulocytes live for 4-8 hours after being released from bone marrow and 4-5 days
in tissues where they are needed. In serious infection, they survive for only a few hours and destroyed
-Monocytes live 10-20 hours in the blood before wandering through capillaries into tissues, where they
swell and become tissue macrophages and live for months until destroyed
-Lymphocytes continually enter circulation and lymphatic system and live for weeks or months
-Platelets replaced once every 10 days, and 30,000 platelets are formed each day per microliter
Neutrophils and Macrophages Defend against Infections – neutrophils and tissue macrophages attack
and destroy invading bacteria, viruses, and other infectious agents
-neutrophils are mature WBC that destroy bacteria even in circulation
-tissue macrophages begin as monocytes (immature cells in blood and cannot fight infection) but swell
in tissues to increase their size 5x to be called macrophages and capable of fighting disease
WBC Enter Tissue Spaces by Diapedesis – neutrophils and monocytes squeeze through pores of
capillaries by diapedesis, where a small portion of a cell slides through a smaller pore slowly
WBC Move through Tissue Spaces by Ameboid Action – both neutrophils and macrophages move
through tissues by ameboid action
WBC are Attracted to Inflamed Tissue Areas by Chemotaxis – several chemicals in tissues cause
neutrophils/macrophages to move toward source of chemical, known as chemotaxis. A dozen different
products that cause chemotaxis are formed:
1. Bacterial/toxins
2. Degenerative products of inflamed tissues
3. Reaction products of the complement complex in inflamed tissues
4. Several reaction products caused by plasma clotting
-chemotaxis depends on concentration gradient of chemotactic source which directs unidirectional
movement of WBC (up to 100um away)
Phagocytosis – cellular ingestion of the offending agent by phagocytic cells. Three things occur before
phagocytosis can happen:
1. Most surfaces have smooth surfaces that resist phagocytosis, rough surface increases likelihood
2. Most natural substances of body have protein coats to resist phagocytosis – dead tissues and
foreign particles have no protective coats and are subject to it
3. Immune system develops antibodies against infectious agents that adhere to membranes and
make bacteria susceptible to phagocytosis
a. Antibody has to combine with C3 product of complement cascade which attaches to
receptors on phagocyte membrane to initiate phagocytosis
b. This selection by antibodies and phagocytosis is called opsonization
Phagocytosis by Neutrophils – neutrophils entering tissues are mature cells that can begin phagocytosis
-neutrophil first attaches itself to foreign particle and projects pseudopodia in all directions around it
-the pseudopodia meet on another on opposite sides and fuse  chamber invaginates to the inside of
the cytoplasmic cavity and breaks away from outer membrane to form free floating phagocytic vesicle
also called a phagosome inside cytoplasm
-can ingest 3-20 bacteria before neutrophil inactivates and dies
Phagocytosis by Macrophages – macrophages are monocytes that have entered tissues, and are much
more powerful than neutrophils, capable of ingesting up to 100 bacteria and much larger particles (RBC,
malarial parasites)
-after ingestion, macrophages can extrude residual products and survive to function longer
Once Phagocytized, Most Particles Digested by Intracellular Enzymes – lysosomes and other granules in
neutrophil or macrophage come in contact with phagocytic vesicle, membranes fuse, and digestive
enzymes are dumped into vesicle
-both neutrophils and macrophages contain abundance of lysosomes with proteolytic enzymes geared
for digesting bacteria and other matter
-macrophages also contain lipases to digest thick lipid membranes some bacteria have (tuberculosis
bacillus)
Both Neutrophils and Macrophages can Kill Bacteria – these cells contain bactericidal agents that can
kill most bacteria even if lysosomes fail to digest them. This is important if bacteria have protective
coats that prevent proteolytic digestion
-results from oxidizing agents formed by enzymes in membrane of phagosome or by peroxisome, and
include superoxide ion (O2-), hydrogen peroxide (H2O2), and hydroxyl ions (OH-), which are lethal to
most bacteria
-lysosomal enzyme myeloperoxidase catalyzes reaction between H2O2 and chloride to form
hypochlorite, which is bactericidal
-tuberculosis resistant to all this jazz
Monocyte-Macrophage Cell System (Reticuloendothelial System) – large portion of monocytes can
become attached to tissues and remain attached for months or years until called upon to perform
specific function in tissue.
-Same function (phagocytosis of bacteria, viruses, necrotic tissue) as circulating cells, and when
stimulated, can break away from attachments to become mobile
-total combination of monocytes, mobile macrophages, fixed tissue macrophages, specialized
endothelial cells in bone marrow, spleen and lymph nodes called reticuloendothelial system, better
known as the monocyte-macrophage system and is a generalized phagocytic system in all tissues
Tissue Macrophages in Skin and Subcutaneous Tissues (Histiocytes) – if skin is broken, infection can
begin in subcutaneous tissue, in which case local tissue macrophages divide in-situ and attack infectious
agents
Macrophages in Lymph Nodes – no particulate matter that enters tissue can be absorbed through
capillaries and into the blood, but instead they enter the lymph and flow to nodes along the course of
lymph flow, and trapped by nodes lined by tissue macrophages
-lymph enters through lymph node capsule through afferent lymphatics and flows through nodal
medullary sinuses to pass out the hilus into efferent lymphatic to empty into venous blood
-macrophages line lymph sinuses to phagocytize particulates and prevent body dissemination
Alveolar Macrophages in Lungs – invaders can enter body through the lungs, but tissue macrophages
exist in alveolar walls to phagocytize particles that are trapped in alveoli and release digestion products
into lymph
-if particle is indigestible, macrophage forms big cell capsule around particle and waits for it to dissolve
Macrophages (Kupffer Cells) In the Liver Sinusoids – bacteria can invade through GI tract from ingested
food and travel through portal blood into the liver sinusoids, which are lined with Kupffer Cells
-these cells form effective particulate filtration so that no bacteria from GI reach systemic circulation
Macrophages in Spleen and Bone Marrow – if invading organism enters circulation, macrophages in
spleen and bone marrow exist to phagocytize the particles
-spleen similar to lymph nodes except blood flows instead of lymph
-small artery penetrates splenic pulp and terminates in small capillaries which are porous and allow
blood to pass into cords of red pulp  after which it squeezes through trabecular mesh to return to
circulation
-trabeculae are lined with macrophages
Inflammation – when tissue injury occurs for any reason, substances are released by injured tissues and
cause secondary changes in surrounding non-injured tissues called inflammation, characterized by:
1. Vasodilation of local blood vessels with increased blood flow
2. Increased permeability of capillaries to allow leakage of fluid into interstitial spaces
3. Clotting of fluid in interstitial spaces because of increased fibrinogen leaking through
4. Migration of granulocytes and monocytes to tissue
5. Swelling of tissue cells
-some of the substances that cause inflammation are: histamine, bradykinin, serotonin, prostaglandins,
reaction products of complement system, reaction products of clotting system, and lymphokines
released by sensitized T cells
Walling-Off Effect of Inflammation – inflammation ‘walls-off’ the area of injury from remaining tissues
through fibrinogen clots so that fluid barely flows through the spaces after a while to delay spread of
bacteria
-intensity of inflammatory response proportional to degree of tissue injury (if infection is fast growing,
walling off is quicker, and vice-versa), if infection grows slower  higher risk of spreading beyond wall
Macrophage and Neutrophil Response to Inflammation – macrophages are in the tissues within
minutes of inflammations and begin phagocytic actions (first line of defense)
-when activated by products of infection and inflammation, they enlarge and break loose from
attachments to become mobile
Neutrophil Invasion of Inflamed Area is Second Line of Defense – within 1st hour after inflammation,
neutrophils invade the area from blood caused by inflammatory cytokines (TNF, IL-1) and biochemical
products to initiate the following reactions:
1. Increase expression of adhesion molecules such as selectins and intracellular adhesion
molecule -1 (ICAM-1) on the surface of endothelial cells in capillaries
a. These cause neutrophils to stick to capillary walls and is called margination
2. They cause intercellular attachements between endothelial cells to loosen to allow neutrophils
to crawl through in a process known as diapedesis directly from blood into tissue space
3. They then cause chemotaxis of neutrophils toward injured tissues
-several hours after damage begins, the area becomes well supplied with neutrophils
Acute Increase in Number of Neutrophils in Blood (Neutrophilia) – within few hours of acute, severe
inflammation, neutrophil count increases 4-5x from 4000 to 15000/uL, which is called neutrophilia
-caused by inflammatory products that travel to bone marrow to act on stored neutrophils
Second Macrophage Invasion into Inflamed Tissue is Third Line of Defense – alone with neutrophils,
monocytes from blood enter the inflamed tissue and enlarge to become macrophages, but because
number of monocytes is low, buildup isn’t as high as neutrophils
-require 8 hours to mature to macrophages and develop many lysosomes
-after several days-weeks, macrophages dominate the phagocytic cells in the area and kill many bacteria
Increased Production of Granulocytes and Monocytes by Bone Marrow is 4th Line of Defense – results
from stimulation of granulocytic and monocytic progenitor cells of marrow, which takes 3-4 days before
newly formed granulocytes or monocytes mature enough to leave marrow
-if inflammation continues, bone marrow continues to produce these for years at 20-50x normal rate
Feedback control of Macrophage and Neutrophil Responses – five factors predominate control of
macrophage response to inflammation:
1. Tumor necrosis factor (TNF)
2. Interleukin-1 (IL-1)
3. Granulocyte-monocyte colony-stimulating factor (GM-CSF)
4. Granulocyte colony-stimulating factor (G-CSF)
5. Monocyte colony-stimulating factor (M-CSF)
-all of these are formed by active macrophages in inflamed tissues
-the three CSF are main feedback regulators of granulocyte and monocyte production in bone marrow
-GM-CSF can regulate both, while the other two only regulate their own, respectively
Formation of Pus – after neutrophils and macrophages engulf bacteria and necrotic tissue, they
essentially all end up dying, and a cavity is excavated in the inflamed tissues containing necrotic tissue,
dead neutrophils and macrophages and tissue fluid. This combination is called pus. Once infection has
been suppressed, everything drains into lymph
Eosinophils – constitute 2% of all WBC and are weak macrophages exhibiting chemotaxis but not
significant in protecting against infections
-produced in large numbers of people with parasitic infections and migrate in large numbers to tissues
affected by the parasite
-Eosinophils attach to parasites by surface molecules and release substances that kill the parasites
-Schistosomiasis is a parasitic infection found in 1/3 of the population in Asia, Africa, and South America
and can invade any part of the body.
-Eosinophils attach to juvenile forms of the parasite and kill them in many ways:
1. Releasing hydrolytic enzymes from granules containing lysosomes
2. Releasing highly reactive forms of O2 that are lethal to parasites
3. Releasing from granules a larvacidal polypeptide called major basic protein
Trichinosis – parasitic disease that causes eosinophilia resulting from invasion of muscles by Trichinella
parasite after person eats undercooked, infested pork
-Eosinophils also collect in tissues where allergic reactions occur such as peribronchial tissues of lungs in
people with asthma and skin after allergic skin reactions
-mast cells and basophils release eosinophil chemotactic factor to cause eosinophils to migrate
toward inflamed tissue
-believed to detoxify some of inflammation-inducing substances released by mast cells and
basophils and phagocytize allergen-antibody complexes to prevent spread of local inflammation
Basophils – basophils in circulation are similar to mast cells located immediately outside capillaries and
liberate heparin into the blood to prevent blood coagulation
-both mast cells and basophils release histamine, bradykinin, and serotonin, but it is mainly mast cells
that release these during inflammation
-mast cells and basophils play important role allergic reactions because antibody that causes allergic
reactions, immunoglobulin E (IgE) binds to mast cells and basophils
-when IgE binds to antigen and subsequently binds mast cell/basophil, it causes the cell to
release large quantities of histamine, bradykinin, serotonin, heparin, slow-reacting substance of
anaphylaxis, and lysosomal enzymes
Leukopenia – condition where bone marrow produces very few WBC which leaves body unprotected
against bacteria and other agents
-body normally contains bacteria living throughout mucous membranes, and so any decrease in WBC
would cause invasion of adjacent tissues by these bacteria
-2 days after bone marrow stops producing WBC, ulcers appear in mouth and colon or person develops
respiratory infection, death can ensue
-irradiation by x-rays or gamma rays, drugs containing benzene or anthracene can cause bone marrow
aplasia
-chloramphenicol, thiouracil, and barbiturate hypnotics can cause leukopenia
Leukemias – uncontrolled production of WBC caused by cancerous mutation of myelogenous or
lymphogenous cell causes leukemia
-types of leukemias include lymphocytic leukemia and myelogenous leukemia, where lymphocytic is
caused by cancerous production of lymphoid cells beginning in lymph node or lymphocytic tissue
-myelogenous leukemia begins by cancerous production of young myelogenous cells in bone marrow
that spread throughout body so WBC are produced in many extramedullary tissues such as lymph
nodes, spleen, and liver
-myelogenous leukemia has cancerous process producing partially differentiated cells resulting in
neutrophilic leukemia, eosinophilic leukemia, basophilic leukemia, or monocytic leukemia
-most often, leukemia cells are bizarre and undifferentiated and not identical to any of the normal white
blood cells
-the more undifferentiated, the more acute it is, often leading to death soon
-the more differentiated, the more chronic it is and develops over 10-20 years
Effects of Leukemia on the Body – first effect is metastatic growth of leukemic cells in abnormal areas
of the body, and can invade surrounding bone to cause pain and tendency for fracture
-almost all leukemias spread to spleen, lymph nodes, liver, and other vascular regions
-common effects are infection, severe anemia, and bleeding tendency caused by thrombocytopenia
-may result from displacement of normal bone marrow
-big effect is excessive use of metabolic substrates by growing cancer cells, so energy of patient is
greatly depleted and excessive utilization of AA by leukemic cells causes rapid deterioration of normal
proteins of the body, can cause death