Guyton ch 34 - 9.1

• The body is constantly exposed to bacteria, viruses, fungi, and parasites that can cause serious illness or death if they invade deeper tissues.
• The body has a defense system composed of blood leukocytes (white blood cells, WBCs) and tissue cells derived from leukocytes.
• This system works by:
  • Destroying invaders through phagocytosis
  • Forming antibodies and sensitized lymphocytes to neutralize invaders

Leukocytes (White Blood Cells)

• Leukocytes, or white blood cells (WBCs), are the mobile units of the body's protective system.
• WBCs are formed in the bone marrow (granulocytes, monocytes, some lymphocytes) and lymph tissue (lymphocytes, plasma cells).
• After formation, WBCs are transported in the blood to different parts of the body.
• WBCs are valuable because they are specifically transported to areas of serious infection and inflammation, providing a rapid defense.
• Granulocytes and monocytes can "seek out and destroy" foreign invaders.

Types of White Blood Cells

• Six types of WBCs are normally present in the blood:
  • Neutrophils (polymorphonuclear)
  • Eosinophils (polymorphonuclear)
  • Basophils (polymorphonuclear)
  • Monocytes
  • Lymphocytes
  • Plasma cells (occasionally)
• Platelets are also present, which are fragments of megakaryocytes from bone marrow.
• Polymorphonuclear cells (neutrophils, eosinophils, basophils) have a granular appearance and are called granulocytes.
• Granulocytes and monocytes protect against invaders by phagocytosis or releasing antimicrobial/inflammatory substances.
• Lymphocytes and plasma cells function in the immune system.
• Platelets activate the blood-clotting mechanism.

Concentrations of White Blood Cells in Blood

• An adult human has about 7,000 WBCs per microliter of blood, compared to 5 million RBCs per microliter.
• Normal percentages of different WBC types:
  • Neutrophils: 62.0%
  • Eosinophils: 2.3%
  • Basophils: 0.4%
  • Monocytes: 5.3%
  • Lymphocytes: 30.0%
• The number of platelets is normally between 150,000 and 450,000 per microliter of blood, averaging about 300,000.

Genesis of White Blood Cells

• Multipotential hematopoietic stem cells differentiate into committed stem cells.
• Two major WBC lineages are formed: myelocytic and lymphocytic.
• Granulocytes and monocytes are formed only in the bone marrow.
• Lymphocytes and plasma cells are produced mainly in lymphogenous tissues (lymph glands, spleen, thymus, tonsils, lymphoid tissue in bone marrow, Peyer’s patches in the gut wall).
• WBCs formed in the bone marrow are stored there until needed in the circulatory system.
• About three times as many WBCs are stored in the marrow as circulate in the entire blood, representing a 6-day supply.
• Lymphocytes are mostly stored in lymphoid tissues.
• Megakaryocytes are formed in the bone marrow and fragment into platelets (thrombocytes), which are important for blood clotting.

Life Span of White Blood Cells

• Granulocytes circulate for 4-8 hours in the blood and then spend another 4-5 days in tissues.
• In serious tissue infection, the lifespan is shortened to a few hours.
• Monocytes transit in the blood for 10-20 hours.
• Once in tissues, monocytes become tissue macrophages and can live for months.
• Tissue macrophages provide continuing defense against infection.
• Lymphocytes circulate continually through the body, passing from blood to tissues and back to blood via lymph.
• Lymphocytes have life spans of weeks or months.
• Platelets are replaced about once every 10 days, with about 30,000 platelets formed daily per microliter of blood.

Neutrophils and Macrophages Defend Against Infections

• Neutrophils and tissue macrophages attack and destroy invading bacteria, viruses, and harmful agents.
• Neutrophils are mature cells that can attack and destroy bacteria in the circulating blood.
• Tissue macrophages originate from blood monocytes, which are immature cells with limited ability to fight infection while in the blood.
• Once monocytes enter the tissues, they enlarge to become macrophages.
• Macrophages can grow up to 60-80 micrometers in diameter and combat disease agents in the tissues.

Diapedesis and Ameboid Motion

• Neutrophils and monocytes enter tissue spaces by diapedesis, squeezing through gaps between endothelial cells of blood capillaries and postcapillary venules.
• Both neutrophils and macrophages move through tissues by ameboid motion.

Chemotaxis

• Neutrophils and macrophages are attracted to inflamed tissue areas by chemotaxis, moving toward the source of chemical substances.
• Substances causing chemotaxis include bacterial/viral toxins, degenerative products of inflamed tissues, complement complex reaction products, and plasma clotting reaction products.
• Chemotaxis depends on the concentration gradient of the chemotactic substance.
• It is effective up to 100 micrometers away from inflamed tissue, facilitating the movement of WBCs from capillaries into the area.

Phagocytosis

• Phagocytosis is a major function of neutrophils and macrophages, involving cellular ingestion of the offending agent.
• Phagocytes are selective of the material that is phagocytized.
• Factors influencing phagocytosis:
  • Smooth surfaces resist phagocytosis, while rough surfaces increase it.
  • Protective protein coats repel phagocytes; dead tissues and foreign particles lack these coats.
  • Antibodies developed by the immune system against infectious agents make bacteria susceptible to phagocytosis (opsonization).
• Opsonization involves antibodies adhering to bacterial membranes and combining with the C3 product of the complement cascade, which then attaches to receptors on the phagocyte membrane.
• Neutrophils can phagocytize 3 to 20 bacteria before becoming inactivated and dying.
• Macrophages, when activated by the immune system, can phagocytize up to 100 bacteria.
• Macrophages can engulf larger particles, such as RBCs or malarial parasites.
• After digesting particles, macrophages can extrude residual products and survive longer.
• Once phagocytized, particles are digested by intracellular enzymes from lysosomes and cytoplasmic granules.
• Lysosomes contain proteolytic enzymes for digesting bacteria and foreign protein matter.
• Macrophages also contain lipases to digest lipid membranes of some bacteria (e.g., tuberculosis bacillus).

Killing Bacteria

• Neutrophils and macrophages contain bactericidal agents that kill bacteria, even when lysosomal enzymes fail to digest them.
• Oxidizing agents like superoxide (O2−), hydrogen peroxide (H2O2), and hydroxyl ions (OH−) are lethal to bacteria.
• Myeloperoxidase catalyzes the reaction between H2O2 and chloride ions to form bactericidal hypochlorite.
• Some bacteria, like the tuberculosis bacillus, resist lysosomal digestion and killing effects.

Monocyte-Macrophage Cell System (Reticuloendothelial System)

• Monocytes become attached to tissues and remain there for months or years, performing local protective functions.
• They can phagocytize bacteria, viruses, necrotic tissue, and foreign particles.
• Appropriately stimulated macrophages can detach and become mobile, responding to chemotaxis.
• The body has a widespread monocyte-macrophage system in virtually all tissue areas.
• The reticuloendothelial system includes monocytes, mobile macrophages, fixed tissue macrophages, and specialized endothelial cells in bone marrow, spleen, and lymph nodes.
• It is a generalized phagocytic system located in tissues where large quantities of unwanted substances must be destroyed.

Tissue Macrophages

• Tissue macrophages in skin and subcutaneous tissues (histiocytes) divide in situ and attack infectious agents during inflammation.
• Macrophages in lymph nodes trap foreign particles in sinuses lined by tissue macrophages.
• Particles enter lymph nodes via afferent lymphatics, flow through medullary sinuses, and exit via efferent lymphatics.
• Macrophages phagocytize particles, preventing dissemination throughout the body.
• Alveolar macrophages in lungs phagocytize particles entrapped in alveoli, digesting them or forming giant cell capsules around indigestible particles.
• Macrophages (Kupffer cells) in liver sinusoids filter bacteria from the gastrointestinal tract, preventing them from entering the general systemic circulation.
• Macrophages in the spleen and bone marrow trap and phagocytize foreign particles in the blood.
• The spleen filters blood through porous capillaries, with macrophages lining the trabeculae and venous sinuses to phagocytize debris and old/abnormal RBCs.

Inflammation: Role of Neutrophils and Macrophages

• Inflammation occurs in response to tissue injury, caused by bacteria, trauma, chemicals, or heat.
• Inflammation is characterized by:
  • Vasodilation with increased local blood flow
  • Increased capillary permeability, leading to fluid leakage into interstitial spaces
  • Clotting of fluid in interstitial spaces
  • Migration of granulocytes and monocytes into the tissue
  • Swelling of tissue cells
• Tissue products causing inflammation include histamine, bradykinin, serotonin, prostaglandins, complement system reaction products, blood clotting system reaction products, and lymphokines.
• These substances activate the macrophage system, which devours destroyed tissues.

Walling-Off Effect of Inflammation

• Inflammation walls off the injured area from the remaining tissues.
• Tissue spaces and lymphatics are blocked by fibrinogen clots, delaying the spread of bacteria or toxins.
• The intensity of inflammation is proportional to the degree of tissue injury.

Macrophage and Neutrophil Responses During Inflammation

• Tissue macrophages provide the first line of defense, becoming enlarged and mobile within minutes of inflammation.
• Neutrophil invasion is the second line of defense, occurring within the first hour due to inflammatory cytokines.
• Inflammatory cytokines cause:
  • Increased expression of adhesion molecules on endothelial cells
  • Loosening of intercellular attachments between endothelial cells
  • Chemotaxis of neutrophils toward the injured tissues
• Neutrophils adhere to capillary and venule walls (margination) and crawl through the capillaries by diapedesis (extravasation).
• The area becomes well-supplied with neutrophils, which immediately begin killing bacteria and removing foreign matter.

Neutrophilia and Macrophage Invasion

• Neutrophilia, an acute increase in the number of neutrophils in the blood, occurs within a few hours of severe inflammation.
• Neutrophilia mobilizes stored neutrophils from the bone marrow, making more available to the inflamed tissue.
• Monocytes from the blood enter the inflamed tissue and enlarge to become macrophages, forming the third line of defense.
• Macrophage buildup is slower than that of neutrophils, requiring several days to become effective.
• Monocytes mature into macrophages, developing quantities of lysosomes.
• Macrophages can phagocytize more bacteria and larger particles than neutrophils and initiate antibody development.

Increased Production of Granulocytes and Monocytes

• Increased production of granulocytes and monocytes by the bone marrow is the fourth line of defense.
• This results from stimulation of granulocytic and monocytic progenitor cells.
• It takes 3-4 days for newly formed cells to reach the stage of leaving the bone marrow.
• The bone marrow can continue to produce these cells in large quantities for months or years.

Feedback Control of Macrophage and Neutrophil Responses

• Five dominant factors control the macrophage response to inflammation:
  • Tumor necrosis factor (TNF)
  • Interleukin-1 (IL-1)
  • Granulocyte-monocyte colony-stimulating factor (GM-CSF)
  • Granulocyte colony-stimulating factor (G-CSF)
  • Monocyte colony-stimulating factor (M-CSF)
• These factors, formed by activated macrophages, stimulate granulocyte and monocyte production by the bone marrow, providing a feedback mechanism for removing the cause of inflammation.

Formation of Pus

• When neutrophils and macrophages engulf bacteria and necrotic tissue, they die.
• A cavity forms in the inflamed tissues, containing necrotic tissue, dead neutrophils, dead macrophages, and tissue fluid (pus).
• Pus is gradually autolyzed and absorbed into surrounding tissues after the infection has been suppressed.

Eosinophils

• Eosinophils constitute about 2% of all blood leukocytes.
• They are weak phagocytes and exhibit chemotaxis.
• Eosinophils are produced in large numbers in people with parasitic infections and migrate into diseased tissues.
• Eosinophils attach to parasites and release substances that kill them:
  • Hydrolytic enzymes
  • Reactive forms of oxygen
  • Major basic protein
• Examples of parasitic diseases where eosinophils play a role include schistosomiasis and trichinosis.
• Eosinophils also collect in tissues where allergic reactions occur, detoxifying inflammation-inducing substances and phagocytizing allergen-antibody complexes.

Basophils

• Basophils in the circulating blood are similar to tissue mast cells.
• Both mast cells and basophils liberate heparin (prevents blood coagulation) and histamine, as well as smaller quantities of bradykinin and serotonin.
• Mast cells in inflamed tissues release these substances during inflammation.
• Mast cells and basophils play a role in allergic reactions.
• Immunoglobulin E (IgE) antibodies attach to mast cells and basophils.
• When the specific antigen reacts with the IgE antibody, the mast cell or basophil releases histamine, bradykinin, serotonin, heparin, slow-reacting substance of anaphylaxis (leukotrienes), and lysosomal enzymes.
• These substances mediate local vascular and tissue reactions, causing allergic manifestations.

Leukopenia

• Leukopenia is a clinical condition in which the bone marrow produces very few WBCs.
• This leaves the body unprotected against invading bacteria.
• Ulcers may appear in the mouth and colon, or severe respiratory infection develops.
• Bacteria from the ulcers rapidly invade surrounding tissues and the blood.
• Causes include irradiation, drugs/chemicals (benzene, anthracene), chloramphenicol, thiouracil, and barbiturates.
• Treatment involves transfusions, antibiotics, and other drugs to ward off infection.

Leukemias

• Leukemia is caused by cancerous mutation of a myelogenous or lymphogenous cell, leading to uncontrolled production of WBCs.
• There are two general types of leukemia:
  • Lymphocytic: cancerous production of lymphoid cells
  • Myelogenous: cancerous production of young myelogenous cells in the bone marrow
• In myelogenous leukemia, the cancerous process may produce partially differentiated cells (neutrophilic, eosinophilic, basophilic, or monocytic leukemia).
• Leukemia cells, especially undifferentiated cells, are usually nonfunctional for providing normal protection against infection.

Effects of Leukemia on the Body

• The first effect is metastatic growth of leukemic cells in abnormal areas of the body.
• Leukemic cells may invade surrounding bone, causing pain and fractures.
• Almost all leukemias spread to the spleen, lymph nodes, liver, and other vascular regions.
• Common effects are infection, severe anemia, and a bleeding tendency caused by thrombocytopenia.
• The displacement of normal bone marrow and lymphoid cells by nonfunctional leukemic cells causes these effects.
• Leukemia leads to excessive use of metabolic substrates by growing cancerous cells.
• The rapid reproduction of leukemic tissues creates high demands for foodstuffs, amino acids, and vitamins.
• The patient's energy is depleted, and normal protein tissues of the body deteriorate.
• Metabolic starvation can eventually cause death.