Immune 1

• Humoral Theory


  Postulated by Hippocrates, states that an imbalance in blood, phlegm, black bile & yellow bile causes disease
• Galen


  Formalized the relationship between humoral medicine & Greek natural philosophy
• 4 humours


  • Blood
  • Phlegm
  • Black bile
  • Yellow bile
• 4 qualities


  • Hot
  • Cold
  • Dry
  • Wet
• Body humours & physical world elements

  Shared a common qualitative nature
• Microcosm


  Little world of human body
• Macrocosm


  Greater world
• Microcosm (little world of human body)

  Related to macrocosm (greater world)
• 4 main liquids in the body

  • Blood
  • Phlegm
  • Black bile
  • Yellow bile
• Combination of hot & wet

  Produces air element & blood humour
• Blood predominated in Spring


  Person with natural excess of blood had a sanguine physical & psychological humoral constitution or temperament
• If unhealthy, key to restore balance

  1. Lifestyle (diet & exercise)

  2. Medication (herbs)
• "Opposites cure opposites"


  E.g. cold remedy cures hot illness
• Illness


  Seen as internal disorder of body, not the result of a specific agent like bacteria
• Humoral vision of body lasted until late seventeenth century in Europe
• By middle ages this was seen as "quackery"
• New science of Galileo, Descartes, Newton, & Boyle replaced Aristotelian, qualitative, natural philosophy with a mechanical, chemical, & mathematical vision of the world & body
• Developments in medicine before the 17th century

  • Notions of pulmonary circulation (1200-1500s)
  • Valves in veins (1600s)
  • Blood circulates body & is pumped by the heart (1600s)
  • First description of red blood cells (RBCs) by a 21 year old microscopist (1658)
  • The capillary system (1661)
  • First recorded blood transfusion (dog to dog) (1665)
  • First human blood transfusion (lamb to boy) (1667)
  • Anton van Leeuwenhoek discovered that RBCs are 25,000 times smaller than a grain of sand (1674)

  
• Developments in medicine from 1700-1984


  • Transfusions still failing (1700-1800s)
  • Properties of blood emerge (coagulation factors, platelets in clots, etc.) (1800-1900s)
  • Successful human blood transplants (1800-1900s)
  • Red Cross organized civilian blood donor service during WWI & II leading to new developments in storing & using blood (1917)
  • Optimized glucose-citrate solutions (prevent coagulation & allow for viable storage) (1917)
  • X ray crystallography reveals hemoglobin structure (protein in RBCs that carries oxygen) (1959)
  • Slowly thawing frozen plasma precipitated factor VIII (antihemophilic factor) which has great clotting power (1965)
  • Adding factor VIII via replacement therapy helps to stop & prevent bleeding (1965)
  • Hepatitis B discovered through infected donors (1971)
  • First cases of AIDS (1981)
  • AIDS virus identified (1983 & 1984)

  
• Functions of the circulatory system

  • Transportation of all substance essential for cellular metabolism (Respiratory, Nutritive, Excretory)
  • Regulation (Hormonal, Temperature)
  • Protection (From injury, From pathogens)
• Buffy layer


  Thin, light interface between RBCs and plasma
• Hematopoiesis


  Formation of blood cells, Hematopoietic stem cells originate in the embryo & migrate to different tissues, Liver is the major hematopoietic organ of the fetus, Bone marrow is the major hematopoietic organ after birth, Cytokines play important roles in hematopoiesis

  
• Blood samples after centrifugation have RBCs packed at the bottom, WBCs and platelets in the thin, light "buffy coat" interface, and plasma fluid at the very top

  
• Normal ranges


  • Hematocrit (Female: 35-46%, Male: 41-53%)
  • Hemoglobin (Female: 12-16g/100mL, Male: 13.5-17.5g/100mL)
  • RBC count (4.5-5.9 million/mm3)
  • WBC count (45,000-11,000/mm3)

  
• Erythropoiesis


  1. Uncommitted stem cells go through a series of stages in the bone marrow

  2. Once the nucleus is expressed, leading to the formation of the reticulocyte, the cell is released into circulation where it becomes a mature RBC (erythrocyte)

  3. Once the nucleus is expelled, the reticulocyte moves into circulation & becomes a RBC

  
• Red blood cells do not have a nucleus

  
• Erythropoiesis


  Iron is really important in the oxygen offloading and loading with hemoglobin
• Red Blood Cells (Erythrocytes)


  • Cytoskeleton creates unique, concave shape
  • Flexible – swell in hypotonic medium, shrink in hypertonic medium
  • Some illnesses can affect RBC shape e.g. Sickle Cell Anemia

  
• Erythrocytes & Hemoglobin


  • Function to aid in O2 delivery to tissues
  • Most O2 found in blood is bound to Hb in RBCs
  • Hb gives blood its red colour
  • RBC made up of 4 globin proteins (2 alpha, 2 beta), each with a heme group binding an iron molecule
  • Heme iron combines with oxygen in the lungs & releases oxygen into tissue

  
• Each RBC can carry over a billion molecules of oxygen (280 million Hb molecules/RBC x 4 heme groups)

  
• Total arterial O2 carrying capacity in blood

  O2 bound to Hb + unbound = 197 mL HbO2/L blood + 3 mL dissolved O2/L blood = 200 mL O2/L blood

  
• Oxygen saturation


  • Blood entering tissues contains 200 mL O2/L blood, Blood leaving tissues contains 155 mL O2/L blood, i.e. 45 mL O2 unloaded to the tissues
  • In systemic arteries, ~97% of hemoglobin in form saturated with oxygen (oxyhemoglobin), Blood leaving in systemic veins has an oxygen-hemoglobin saturation of ~75%, i.e. ~22% of the oxygen is unloaded to tissues

  
• Physiologic factors that change Hb conformation

  • Decrease in pH decreases Hb affinity for O2 i.e. more offloaded into tissues (opposite for increase in pH)
  • Increase in temperature decreases Hb affinity for O2 i.e. more offloaded into tissues (opposite for decrease in temperature)

  
• 2,3-Diphosphoglyceric Acid (2,3-DPG)


  Mature RBC lack nuclei, mitochondria, & ER, Cannot respire aerobically i.e. the cells that carry O2 cannot use it, RBCs must obtain energy through anaerobic metabolism of glucose, At a certain point in the glycolytic pathway, a side reaction occurs that results in the production of 2,3-DPG, Enzyme that produces 2,3-DPG is inhibited by oxyhemoglobin i.e. when oxyhemoglobin levels decrease (e.g. hypoxia, anemia), 2,3-DPG production is increased, Increased 2,3-DPG concentration increases O2 unloading (shifts curve right)
• Oxygen reserve


  • Oxyhemoglobin remaining in venous blood
  • Enough to sustain brain & heart for ~4-5 minutes without breathing or CPR
  • Can also be used when tissue requirements increase e.g. exercise

  
• Oxyhemoglobin decreases by ~22% as the blood passes through the tissues from arteries to veins


  Oxygen unloading increases

  
• Oxyhemoglobin levels decrease (e.g. hypoxia, anemia)


  2,3-DPG production increases

  
• Increased 2,3-DPG concentration


  Increases O2 unloading (shifts curve right)
• Mature RBCs


  • Lack nuclei, mitochondria, & ER
  • No protein/enzyme synthesis, or ability to repair membrane
  • Cannot respire aerobically i.e. the cells that carry O2 cannot use it
  • Must obtain energy through anaerobic metabolism of glucose
• 2,3-Diphosphoglyceric Acid (2,3-DPG)


  • Side reaction in the glycolytic pathway that results in the production of 2,3-DPG
  • Enzyme that produces 2,3-DPG is inhibited by oxyhemoglobin