HEMATOLOGY AND THE NONSPECIFIC IMMUNE RESPONSE Physiology Unit 3
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HEMATOLOGY AND THE NON-‐SPECIFIC IMMUNE RESPONSE
Physiology Unit 3
Hematocrit
• Percentage of blood volume that is erythrocytes – 45% in men – 42% in women
• Average blood volume in is 5 L
Plasma
• Large amounts of organic/inorganic substances dissolved in water
• Serum – Plasma with fibrinogen and other cloCng factors removed
• Plasma proteins are made in the liver – Albumins
• Most abundant
– Globulins • Different categories • Some made by immune cells
– Fibrinogen • CloCng
Human Blood Formed Elements
Erythrocytes • Contain hemoglobin (Hb)
– Transport O2, some CO2 – O2 binds to Fe3+ in Hb molecules – Average [Hb]
• Women 14 g/100 mL • Men 16g/100 mL
• 7 μm in diameter • High SA/V
• Life span 120 days • Erythropoiesis
– Erythrocytes produced by red marrow
– Iron, Vitamin B12, folic acid necessary
Iron • Iron lost per day needs to be
replaced by dietary intake • Total iron
– 50% total iron in Hb – 25% in cytochromes – 25% in liver ferri]n
• Iron recycling is very efficient – Transferrin
• Iron transport protein • Delivers iron to bone marrow
Vitamin B12 and Folic Acid
• Vitamin B12 – Required in small amounts (1 millionth of a gram/day)
– Required for the ac]on of folic acid
– Found only in animal products
– Intrinsic factor is necessary for vitamin B12 absorp]on • A protein secreted by the stomach
• Folic Acid – Found in leafy plants, liver, yeast
– Essen]al for DNA forma]on • Required for thymine synthesis
• Causes impairment of cell division when not present in adequate amounts
• Fewer erythrocytes produced
Regula]on of Erythrocyte Produc]on
• Erythropoie>n – Secreted by kidney, liver – Acts on bone marrow to s]mulate produc]on of erythrocytes
– Increased secre]on when less O2 delivered to kidneys
– Testosterone also s]mulates release of erythropoie]n
Leukocytes
• Produced by bone marrow • Monocytes and many lymphocytes undergo further development outside the bone marrow
Platelets
• Fragments of large cells called megakaryocytes
• Involved in blood cloCng
• Clot forma>on can not occur without platelets
Stem Cells
• To]potent stem cells – Can give rise to any extra-‐embryonic (chorion, amnion, placenta) AND embryonic (adult) cells
• Pluripotent stem cells – Can give rise to any embryonic (adult) cell
• Mul]potent stem cells – Can only give rise to certain cell lines (i.e. bone marrow
stem cells) – Adult stem cells – Umbilical cord stem cells
Blood Cell Produc]on
Hemostasis
• Preven]on of blood loss (stoppage of bleeding) • Injuries to small vessels (arterioles, capillaries, venules) • Immediate response to injury is vasoconstric]on – Reduces flow to the area – Presses together the sides of the endothelium
• Induces s]ckiness • “glues” the endothelium together
• Requires 2 processes 1. Platelet plug forma]on 2. Blood coagula]on (cloCng)
Forma]on of a Platelet Plug 1. Platelet adhesion
– Exposed collagen in connec]ve ]ssue
– von Willebrand factor • Secreted by endothelial cells and platelets
2. Triggers platelet ac>va>on – Release contents of secretory
vesicles that act locally
3. Triggers platelet aggrega>on – Forma]on of platelet plug
Platelet Plug Localiza]on
• Adjacent, undamaged endothelial cells release prostacyclin (PGI2) – Strong inhibitor of platelet aggrega]on
• Adjacent, undamaged endothelial cells also release NO – Vasodilator – Inhibits platelet adhesion, ac]va]on and aggrega]on
Blood Coagula]on Clot Forma]on
• The transforma]on of blood into a solid gel called a clot or thrombus – Consists mainly of fibrin
• CloCng occurs locally around the platelet plug • Func]on is to support and reinforce the platelet plug and to solidify blood that remains in the wound channel
CloCng Pathway Role of Thrombin
• Cascade of events leads to the conversion of prothrombin (plasma protein) to thrombin
• Thrombin catalyzes the split of fibrinogen to loose fibrin – Fibrin network then becomes stabilized
• Thrombin also s]mulates platelet ac]va]on
CloCng Pathway
CloCng Pathway Role of Platelets
• CloCng can not occur in the absence of platelets
• Ac]vated platelets are essen]al because several of the cascade reac]ons take place on the surface of ac]vated platelets
• Ac]vated platelets display specific membrane receptors that bind several of the cloCng factors which permits the reac]ons to occur
CloCng Pathway
• Intrinsic pathway – Everything necessary for this pathway is in the blood
• Extrinsic pathway – A cellular element outside the blood is needed
– Tissue factor • Not a plasma protein • Located on the outer plasma membrane of fibroblasts Thrombin Burst
Dissolving the Clot Fibrinoly]c System
• A fibrin clot is a temporary fix un]l the blood vessel is repaired
• Plasminogen is ac]vated to plasmin
• Plasmin digests fibrin which dissolves the clot
Resistance to Disease
• Body defenses against infec]ous disease • Immune system has 2 arms: – Innate or non-‐specific immunity – Adap]ve or specific immunity
Immune Cells
• Diverse collec]on of cells that are found in blood, lymph and ]ssues throughout the body
• Cytokines – Chemical messengers secreted by immune cells
• Cells – Leukocytes – Plasma cells – Macrophages – Dendri]c cells – Lymphocytes – Mast cells
Immune Cells
• Leukocytes – Use blood primarily for transport and migrate to the ]ssues where they func]on
• Plasma cells – Found in ]ssues (lymph nodes) where they differen]ate from B lymphocytes
– Synthesize and secrete an]bodies
Immune Cells
• Macrophages – Found in all organs and ]ssues strategically placed where they will encounter their targets • Epithelia in contact with the outside of the body
– skin, lining of diges]ve and respiratory tract – Line blood and lymph vessels
– Tissue specific resident popula]ons – Derived from monocytes, transform into macrophages
– Pass through walls of capillaries to enter ]ssues • Diapedesis and extravasa]on
Macrophage
• Kupfer Cells (liver) • Mesangial Cells (kidney) • Satellite Cells (PNS) • Microglia (CNS) • Dendri]c Cells (skin) • Monocytes • Dust Cells (lungs) • Histocytes (c.t.) • Osteoclasts (bone)
• Macrophage are long lived
• APC role • Removal of cellular debris
• Inflammatory response • Tissue repair • Wound healing
Diapedesis or Extravasa]on
Immune Cells
• Dendri>c cells – Epithelium in contact with the external environment, lymph nodes
– Macrophage func]on – APC’s – Messengers between innate and adap]ve immunity
• Lymphocytes – Recogni]on cells in specific immune defenses and are essen]al for all aspects of specific immune responses
Immune Cells
• Mast cells – Found in connec]ve ]ssues (especially below epithelial surfaces of the body)
– Move into ]ssues where they differen]ate and divide
– Contain vesicles that contain histamine and heparin
Cytokines
• Immune cells secrete more than 100 protein messengers that regulate host cell division
• Involved in non-‐specific and specific immune defenses
• Most of their ac]ons act locally – Paracrine/autocrine agents – Some will circulate in blood and act as hormones on distant organs
• Allow communica]on between different immune cells and ]ming of cascade reac]ons
Nonspecific Immune Defenses Innate Immune Response
• Against all “non-‐self” cells • Recognize some general property marking the invaders as foreign – Anitgens
• Not dependent upon exposure to disease • Include: defenses at the body surfaces, the inflammatory response, interferons
Defenses at the Body Surface Physical Barriers
• Skin – Water ]ght barrier – Kept clean and dry – Sweat glands secrete an]bodies, lysozyme – Mostly impermeable to microbes
• Certain microbes drill through (syphillis, hook worms, many arthropod borne pathogens)
• Cough and sneeze reflex • Hairs at the entrance of the nose
Defenses at the Body Surface Physical Barriers
• Mucus membranes • Nonkera]nized epithelial membranes, omen ciliated
• Lined with mucus • Contain an]microbial chemicals
• Excellent for trapping microbes for expulsion
Defenses at the Body Surface Physical Barriers
• Serous membranes • Lubricated with serum from
“leaky capillaries” • Internal physical barrier to infec]on of vital organs
• Heart, lungs, and abdominal viscera • Similar protec]on by the meninges of the brain and spinal cord
Nonspecific Chemical Defenses
• pH levels – Gastric juice, vaginal secre]ons, urine
• Lysozyme – In tears, saliva, sweat – Binds to microbes and punches holes in the cell wall
– Found in granules of neutrophils and macrophages
Nonspecific Cellular Defenses
• Neutrophils • First WBC at an infec]on site
• Voracious phagocytes • Microphage • Use lysozymes and oxygen radicals to dissolve microbes
Nonspecific Cellular Defenses
• Eosinophils • Slightly phagocy]c • Major role in infec]ons involving eukaryo]c parasites (worms)
• Also involved in certain allergies, dissolving clots, detoxifying foreign substances
Nonspecific Cellular Defenses
• Basophils • Similar to mast cells of loose connec]ve ]ssue
• Granules contain – Heparin – Histamine
• vasodilator, increases capillary permeability
• Important to inflamma]on, especially related to allergies
Nonspecific Cellular Defenses
• Monocytes • Transform when ac]vated to macrophages
• Eat microbes cellular debris
• Stored in the red pulp of the spleen
• Link nonspecific body defenses to the specific immune responses
Nonspecific Cellular Defenses
• Natural Killers • NK Cells • “lymphocyte like cell”, but not immunologically specific
• Performs tumor surveillance
Inflamma]on
• Local response to infec]on or injury • Func]ons – To destroy foreign invaders – Prepare for ]ssue repair
• Key mediators are phagocy]c cells – Neutrophils, macrophages, dendri]c cells
Inflamma]on
1. Infec]on or injury causes release of chemicals 2. Local vasodila]on 3. Increase in protein permeability resul]ng in
diffusion of protein and filtra]on of fluid into inters]]al fluid
4. Diapedesis: movement of leukocytes from venules into inters]]al fluid of infected/injured area
5. Destruc]on of bacteria 6. Tissue repair
• A “suite” (or family) of plasma proteins • Extracellular killing of bacteria without phagocytosis • Sequen]ally bind to bacteria, forming a pore, causing lysis
• AnEbodies acEvate the first complement protein (C1)
• Some form opsonins – Make microbes “tasty” – Chemical aoractant for phagocytes – Molecule that enhances phagocytosis
Complement Pathway
Complement
Complement
Interferons
• Nonspecific chemical defenses in plasma • Interferon family of cytokines • Nonspecifically inhibit viral replica]on in cells – Protec]on for healthy cells against newly released viruses
– Host (]ssue) specific, not virus specific • Released by virus infected body cells
Interferon Ac]on
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