Phys Chapter 33
Leukocytes
 Granulocytes, monocytes, and few lymphocytes produced in bone marrow, and lymphocytes and plasma cells
formed in lymph tissue
 Granulocytes occasionally called “polys” because of multiple nuclei (polymorphonuclear)
 Granulocytes and monocytes ingest invaders, and lymphocytes and plasma cells function in connection with
immune system
 Early differentiation of pluripotential hematopoietic stem cell – 2 major lineages of WBCs (myelocytic and
lymphocytic lineages)
1. Myeloblast
2. Promyelocyte
3. Megakaryocyte
4. Neutrophil myelocyte
5. Young neutrophil metamyelocyte
6. “Band” neutrophil metamyelocyte
7. Polymorphonuclear neutrophil
8. Eosinophil myelocyte
9. Eosinophil metamyelocyte
10. Polymorphonuclear eosinophil
11. Basophil myelocyte
12. Polymorphonuclear basophil
13-16 – stages of monocyte formation
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Granulocytes and monocytes only formed in bone marrow – stored within marrow until needed
Lymphocytes and plasma cells produced mainly in various lymphogenous tissues, especially lymphy glands,
spleen, thymus, tonsils, and various pockets of lymphoid tissue elsewhere in body, such as bone marrow and
Peyer’s patches underneath epithelium in gut wall
o Lymphocytes mostly stored in various lymphoid tissues, except for small number temporarily being
transported in blood
 Life of granulocytes after being released from bone marrow is normally 4-8 hours circulating in blood and
another 4-5 days in tissues where they are needed; in times of serious tissue infection, total lifespan shortened
to only a few hours because granulocytes proceed more rapidly to infected area, perform their functions, and in
the process are destroyed themselves
 Monocytes have short transit time (10-20 hours in blood) before wandering through capillary membranes into
tissues, where they swell to much larger sizes and become tissue macrophages, where they can live for months
unless destroyed while performing phagocytic functions
 Lymphocytes enter circulatory system continually, along with drainage of lymph from lymph nodes and other
lymphoid tissue; after few hours, they pass out of blood back into tissues by diapedesis and reenter the lymph
and return to the blood again; have life spans of weeks or months depending on body’s need for these cells
 Platelets replaced once every 10 days or so
Neutrophils and Macrophages Defend Against Infections
 Mainly neutrophils and macrophages attack and destroy invading bacteria, viruses, and other injurious agents
 Neutrophils and monocytes can squeeze through pores of blood capillaries by diapedesis
 Both neutrophils and macrophages can move through tissues by ameboid motion
 Many different chemical substances in tissues cause both neutrophils and macrophages to move toward source
of chemical (chemotaxis)
o When tissue becomes inflamed, products that cause chemotaxis toward inflamed area are
 Some bacterial or viral toxins
 Degenerative products of inflamed tissues themselves
 Several reaction products of “complement complex” activated in inflamed tissues
 Several reaction products caused by plasma clotting in inflamed area
o
Chemotaxis depends on concentration gradient of chemotactic substance (concentration is greatest
near source, which directs unidirectional movment of WBCs)
 Most important function of neutrophils and macrophages is phagocytosis; whether they will phagocytose or not
depends on selective procedures
o Most natural structure in tissues have smooth surfaces that resist phagocytosis, but if surface is rough,
likelihood of phagocytosis increased
o Most natural substances of body have protective protein coats that repel phagocytes, but dead tissues
and foreign particles usually have no protective coats, which makes them subject to phagocytosis
o Immune system of body develops antibodies against infectious agents; antibodies adhere to bacterial
membranes and make bacteria especially susceptible to phagocytosis
 Antibody molecule combines with C3 product of complement cascade, and C3 molecules attach
to receptors on phagocyte membrane, initiating phagocytosis
 Above mechanism called opsonization
 Neutrophils attach themselves to particle to be phagocytized and project pseudopodia in all directions around
particle, then pseudopodia meet one another on opposite side and fuse, creating chamber that encloses
particle; chamber invaginates to inside of cytoplasmic cavity and breaks away from outer cell membrane to form
free-floating phagocytic vesicle (phagosome) inside cytoplasm; single neutrophil can usually phagocytize 3-20
bacteria before neutrophil becomes inactivated and dies
 Macrophages much more powerful phagocytes than neutrophils, often capable of phagocytizing as many as 100
bacteria; also have ability to engulf much larger particles including RBCs and malarial parasites; after digesting
particles, macrophages can extrude residual products and survive and function for many more months
 Once foreign particle phagocytized, lysosomes and other cytoplasmic granules in neutrophil or macrophage
immediately come in contact with phagocytic vesicle and their membranes fuse, dumping digestive enzymes
and bactericidal agents into the vesicle (phagocytic vesicle now digestive vesicle)
o Both neutrophils and macrophages contain abundance of lysosomes filled with proteolytic enzymes
especially geared for digesting bacteria and other foreign protein matter
o Lysosomes of macrophages (not neutrophils) contain large amounts of lipases, which digest thick lipid
membranes possessed by some bacteria
 Phagosomes of both neutrophils and macrophages contain bactericidal agents that kill most bacteria even when
lysosomal enzymes fail to digest them – important because some bacteria have protective coats or other factors
that defend against digestive enzymes
o Much of killing effect results from powerful oxidizing agents formed by enzymes in membrane of
phagosome or by peroxisomes – oxidizing agents include superoxide (O2-), H2O2, and hydroxyl ions (OH-),
all of which are lethal to most bacteria, even in small quantities
o Myeloperoxidase – lysosomal enzyme that catalyzes reaction between H2O2 and Cl- to form hypochlorite
(ClO-), which is exceedingly bactericidal
o Some bacteria, notably tuberculosis, have coats resistant to lysosomal digestion and also secrete
substances that partially resist killing effects of neutrophils and macrophages – responsible for many
chronic diseases
Monocyte-Macrophage Cell System (Reticuloendothelial System)
 Some macrophages attach to tissues and remain there for months or years until called on to perform specific
local protective functions; have same capabilities as mobile macrophages to phagocytize large quantities of
bacteria, viruses, necrotic tissue, or other foreign particles; when appropriately stimulated, they break away
from attachments and become mobile macrophages that respond to chemotaxis and all other stimuli related to
inflammatory process – monocyte-macrophage system that exists in virtually all tissue areas
 Total combination of monocytes, mobile macrophages, fixed tissue macrophages, and few specialized
endothelial cells in bone marrow, spleen, and lymph nodes is reticuloendothelial system (monocyte-macrophage
system) and is a generalized phagocytic system located in all tissues, especially in those areas where large
quantities of particles, toxins, and other unwanted substances must be destroyed
 When infection begins in subcutaneous tissue of skin and local inflammation ensues, local tissue macrophages
can divide to multiply, then perform their usual functions of attacking and destroying infectious agents
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Essentially no particulate matter that enters tissues, such as bacteria, can be absorbed directly through capillary
membranes into blood; if particles not destroyed locally in tissues, they enter lymph and flow to lymph nodes,
where they are trapped in a meshwork of sinuses lined by tissue macrophages
o Lymph enters lymph node by way of afferent lymphatics, then flows through nodal medullary sinuses,
and passes out hilus into efferent lymphatics
o Large numbers of macrophages line lymph sinuses, and if any particles enter sinuses by way of lymph,
macrophages phagocytize them and prevent general dissemination throughout body
 Large numbers of tissue macrophages present as integral components of alveolar walls; can phagocytize
particles that become entrapped in alveoli; if particles digestible, they are digested and released into lymph, and
if not, macrophages form “giant cell” capsule around particle until such time (if ever) it can be slowly dissolved
 Large numbers of bacteria from ingested food constantly pass through GI mucosa into portal blood; before
blood enters general circulation, it passes through liver sinusoids lined with tissue macrophages (Kupffer cells)
that form effective particulate filtration system (almost none of bacteria get through)
 If invading organism succeeds in entering general circulation, macrophages of spleen and bone marrow are next
line of defense; in spleen and bone marrow, macrophages become entrapped by reticular meshwork of organs
and when foreign particles come in contact with macrophages, they are phagocytized
 Spleen has small arteries that penetrate from splenic capsule into splenic pulp and terminate in small capillaries
that are highly porous, allowing whole blood to pass out of capillaries into cords of red pulp
o Blood gradually squeezes through trabecular meshwork of cords and eventually returns to circulation
through endothelial walls of venous sinuses
o Trabeculae of red pulp lined with vast numbers of macrophages, and venous sinuses also lined with
macrophages
Inflammation: Role of Neutrophils and Macrophages
 When tissue injury occurs, multiple substances released by injured tissues and cause dramatic secondary
changes in surrounding uninjured tissues (inflammation)
o Characterized by vasodilation of local blood vessels with consequent excess local blood flow, increased
permeability of capillaries allowing leakage of large quantities of fluid into interstitial spaces, often
clotting of fluid in interstitial spaces because of increased amounts of fibrinogen and other proteins
leaking from capillaries, migration of large numbers of granulocytes and monocytes into tissues, and
swelling of tissue cells
o Tissue products that can cause inflammation include histamine, bradykinin, serotonin, prostaglandins,
several different reaction products of complement system, reaction products of blood clotting system,
and multiple substances (lymphokines) that are released by sensitized T cells
 One of first results of inflammation is to wall off area of injury from remaining tissues by blocking tissue spaces
and lymphatics with fibrinogen clots so that after a while, fluid barely flows through spaces – delays spread of
bacteria or toxic products
 Intensity of inflammatory process usually proportional to degree of tissue injury
 Within minutes after inflammation begins, macrophages already present in tissues, whether histiocytes in
subcutaneous tissues, alveolar macrophages in lungs, microglia in brains, or others, immediately begin their
phagocytic actions
o First effect when activated by products of infection and inflammation is rapid enlargement of
macrophage
o Then many previously sessile macrophages break loose from attachments and become mobile, forming
first line of defense against infection during first hour or so
o Within first hour or so, large numbers of neutrophils begin to invade inflamed area from blood (caused
by inflammatory cytokines like TNF and IL-1 and other biochemical products produced by inflamed
tissues that initiate:
 Increased expression of adhesion molecules, such as selectins and intracellular adhesion
molecules-1 (ICAM-1) on surface of endothelial cells in capillaries and venules; adhesion
molecules, reacting with complementary integrin molecules on neutrophils, cause neutrophils to
stick to capillary and venule walls in inflamed area (margination)
 Intercellular attachments between endothelial cells of capillaries and small venules loosen,
allowing openings large enough for neutrophils to crawl through by diapedesis
 Chemotaxis of neutrophils toward injured tissues
o Within several hours after tissue damage begins, area becomes well supplied with neutrophils
 Within a few hours after onset of acute inflammation, number of neutrophils in blood increases 4-5x
(neutrophilia) caused by products of inflammation that enter blood stream, are transported to bone marrow,
and there act on stored neutrophils of marrow to mobilize into circulating blood
 Monocytes from blood enter inflamed tissue and enlarge to become macrophages, but number of monocytes in
circulation is low and storage pool of monocytes in bone marrow much less than that of neutrophils, so buildup
of macrophages in inflamed tissue area much slower than that of neutrophils, requiring several days to become
effective
o Monocytes require 8 hours or more to become macrophages (swell and develop lots of lysosomes)
o After several days to several weeks, macrophages finally dominate phagocytic cells of inflamed area
because of greatly increased bone marrow production of new monocytes
 Fourth line of defense is greatly increased production of both granulocytes and monocytes by bone marrow,
resulting from stimulation f granulocytic and monocytic progenitor cells of marrow – takes 3-4 days before
newly formed granulocytes and monocytes reach stage of leaving bone marrow; if stimulus from inflamed tissue
continues, bone marrow can continue to produce cells in tremendous quantities for months or years
(sometimes rate is 20-50x normal)
 Factors that play dominant role in control of macrophage response to inflammation – formed by activated
macrophage cells in inflamed tissues and in smaller quantities by other inflamed tissue cells
o Tumor necrosis factor (TNF)
o Interleukin-1 (IL-1)
o Granulocyte-monocyte colony-stimulating factor (GM-CSF)
o Granulocyte colony-stimulating factor (G-CSF)
o Monocyte colony-stimulating factor (M-CSF)
 Cause of increased production of granulocytes and monocytes by bone marrow mainly the colony-stimulating
factors; combination of TNF, IL-1, and colony-stimulating factors provides powerful feedback mechanism that
begins with tissue inflammation and proceeds to formation of large numbers of defensive WBCs that help
remove cause of inflammation
 Essentially all neutrophils and many, if not most, of macrophages that engulf particles die; after several days, a
cavity often excavated in inflamed tissues that contains varying portions of necrotic tissue, dead neutrophils,
dead macrophages, and tissue fluid (pus)
o After infection has been suppressed, dead cells and necrotic tissue in pus gradually autolyze over period
of days, and end products eventually absorbed into surrounding tissues and lymph until most of
evidence of tissue damage gone
Eosinophils
 Weak phagocytes that exhibit chemotaxis, often produced in large numbers during parasitic infections and
migrate in large numbers to tissues diseased by parasites
 Eosinophils attach themselves to parasites by special surface molecules and release substances that kill many
parasites
o Schistosomiasis – parasite can invade any part of body; eosinophils attach themselves to juvenile forms
of parasite and kill many of them
o Kill parasites by releasing hydrolytic enzymes from granules (modified lysosomes), releasing highly
reactive forms of oxygen especially lethal to parasites, and releasing from granules highly larvacidal
polypeptide (major basic protein)
o Trichinosis (from trichinella parasite in undercooked pork) causes eosinophilia
 Eosinophils have propensity to collect in tissues in which allergic reactions occur, such as in peribronchial tissues
of lungs in people with asthma and in skin after allergic skin reactions
o Mast cells and basophils release eosinophil chemotactic factor that causes eosinophils to migrate
toward inflamed allergic tissue
o Eosinophils detoxify some of inflammation-inducing substances released by mast cells and basophils and
phagocytize and destroy allergen-antibody complexes, preventing excess spread of local inflammatory
process
Basophils
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Similar to mast cells located immediately outside many capillaries of body – both liberate heparin into blood
Mast cells and basophils release histamine and smaller quantities of bradykinin and serotonin (mainly released
by mast cells)
 Type of antibody that causes allergic reactions (IgE) has special propensity to become attached to mast cells and
basophils; then when specific antigen for specific IgE subsequently reacts with antibody, resulting attachment of
antigen to antibody causes mast cell or basophil to rupture and release large quantities of histamine, bradykinin,
serotonin, heparin, slow-reacting substance of anaphylaxis, and lysosomal enzymes – causes local vascular and
tissue reactions that cause many, if not most, allergic manifestations
Leukopenia
 Bone marrow produces very few WBCs, leaving body unprotected against many bacteria and other invaders
 Any decrease in number of WBCs immediately allows invasion of adjacent tissues by bacteria already present
(even those that belong in mouth, colon, urethra, etc.)
 Within 2 days after bone marrow stops producing WBCs, ulcers may appear in mouth and colon, or person
might develop some form of severe respiratory infection
 Bacteria from ulcers rapidly invade surrounding tissues and blood, and death can ensue in less than a week
 Irradiation of body by x-rays or gamma rays or exposure to drugs and chemicals that contain benzene or
anthracene nuclei likely to cause aplasia of bone marrow
o Some common drugs such as chloramphenicol (antibiotic), thiouracil (used to treat thyrotoxicosis), and
various barbiturate hypnotics on rare occasions cause leukopenia
 After moderate irradiation injury to bone marrow, some stem cells, myeloblasts, and hemocytoblasts may
remain undestroyed in marrow and are capable of regenerating bone marrow, provided sufficient time
 Patient properly treated with transfusions, plus antibiotics and other drugs to ward off infection, usually
develops enough new bone marrow within weeks to months for blood cell concentrations to return to normal
Leukemias
 Uncontrolled production of WBCs can be caused by cancerous mutation of myelogenous or lymphogenous cells,
causing leukemia, which is usually characterized by greatly increased numbers of abnormal WBCs in circulation
 Leukemias divided into lymphocytic leukemias and myelogenous leukemias
o Lymphocytic leukemias – caused by cancerous production of lymphoid cells, usually beginning in lymph
node or other lymphocytic tissue and spreading to other areas of body
o Myelogenous leukemia – begins by cancerous production of young myelogenous cells in bone marrow
and then spreads throughout body so WBCs produced in many extramedullary tissues (especially lymph
nodes, spleen, and liver)
 Cancerous process occasionally produces partially differentiated cells, resulting in neutrophilic
leukemia, eosinophilic leukemia, basophilic leukemia, or monocytic leukemia
 More frequently, leukemia cells bizarre and undifferentiated and not identical to any normal
WBC; the more undifferentiated the cell, the more acute the leukemia is, often leading to death
within a few months if untreated
 With more differentiated cells, process can be chronic, developing slowly over 10-20 years
 Leukemic cells, especially very undifferentiated cells, usually nonfunctional for fighting infection
 First effect of leukemia is metastatic growth of leukemic cells in abnormal areas of body
o Leukemic cells from bone marrow may reproduce so greatly they invade surrounding bone, causing pain
and tendency of bones to fracture easily
 Almost all leukemias eventually spread to spleen, lymph nodes, liver, and other vascular regions, regardless of
whether origin of leukemia is in bone marrow or lymph nodes
 Common effects are development of infection, severe anemia, and bleeding tendency caused by
thrombocytopenia (lack of platelets); result mainly from displacement of normal bone marrow and lymphoid
cells by nonfunctional leukemic cells
 Excessive use of metabolic substrates by growing cancerous cells – leukemic tissues reproduce new cells so
rapidly that tremendous demands made on body reserves for foodstuffs, specific amino acids, and vitamins;
consequently, energy of patient is greatly depleted, and excessive utilization of amino acids by leukemic cells
causes especially rapid deterioration of normal protein tissues of body
o While leukemic tissues grow, other tissues become debilitated
o
After metabolic starvation has continued long enough, this alone is sufficient to cause death