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Physiology - Veterinary > Blood, coagulation and immunity > Flashcards

Blood, coagulation and immunity Flashcards

1
Q

Describe the major functions of the red blood cells

A
  • Oxygen delivery to tissues
  • Acid-base buffer of the whole blood
  • Delivery of CO2 to the lungs for expiration
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2
Q

Describe the basic enzymes and processes that enable the red blood cell to act as an acid-base buffer for the whole blood

A
  • RBCs contain large quantities of carbonic anhydrase
    • This enzyme catalyses the reversible reaction

H20 + CO2 ⇔ H2CO3 (carbonic acid) ⇔ H+ + HCO3-

  • The reaction catalysed by carbonic anhydrase is extremely rapid
  • This reaction allows rapid transfer of excessive tissue CO2 to the lungs where expiration of CO2 reduces the concentration and drives the equation to the left
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3
Q

Describe the role of cobalamin and vitamin B12 in the production of RBCs.

What RBC abnormality results from deficiency of Vit B12 and cobalamin

A
  • Vitamin B12 and cobalamin are essential for DNA synthesis
  • Both are required for the adequate formation of thymidine triphosphate
    • Thymine is one of the purine bases that is an essential DNA building block
  • As the RBC production is rapid and turnover constant, reduction in the available DNA building blocks reduces the rate of RBC cell division and maturation
  • This leads to reduced RBC production and the RBCs that are produced have not matured sufficiently
  • Poorly matured red blood cells are large, fragile, oval shaped macrocytes
  • These macrocytes have a short life - 1/3 - 1/2 of normal
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4
Q

What are the major functions of the tissue macrophages

A

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5
Q

What is the defined role of the reticuloendothelial system?

A
  • The reticuloendothelial system (RES) is a heterogeneous population of phagocytic cells in systemically fixed tissues that play an important role in the clearance of particles and soluble substances in the circulation and tissues
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6
Q

What are the components of the reticuloendothelial system and where are they located

A
  • The RES is primarily composed of tissue macrophages
    • Monocytic cells that have migrated into the tissues, expanded / increased in size become adapted to form specific functions based on their location
  • Specialised endothelial cells, especially liver sinusoidal endothelial cells also actively participate in the clearance of small particles from the body
  • The macrophages of the RES are located in most organs, but are particularly dense in the following:
    • Skin / subcutaneous tissue
    • Lymph nodes
    • Lungs - alveolar macrophages
    • Liver - Kupffer cells
    • Spleen - within the trabecular network and venous sinuses of the red pulp
    • Bone marrow
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7
Q

Describe the broad complex of tissue changes that occurs during inflammation

A
  1. Vasodilation of the local blood vessels
    • Increased local blood flow
  2. Increased vascular permeability
    • Allows for leakage of fluid into the interstitial space
  3. +/- Clotting of the fluid within the interstitial space
    • primarily due to increased amounts of fibrinogen and other proteins
  4. Migration of granulocytes and monocytes
    • Driven largely by chemotactic factors released during inflammation
    • Activation of the phagocytic system of both neutrophils and macrophages
  5. Swelling of the tissue cells
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8
Q

List the major important mediators of inflammation and the basic role of each

A
  1. Histamine
    • Increases capillary permeability
  2. Bradykinin
    • Primary effect is vasodilation, but also contributes to increases in vascular permeability
  3. Serotonin
    • Released from platelets during inflammation and at small quantities stimulates vasodilation
    • With increased release, vasoconstriction and platelet aggregation occurs
  4. Prostaglandins
    • PGI2 is a vasodilator and inhibits platelet aggregation
  5. Complement system - several reaction products
  6. Coagulation system - several reaction products
  7. Lymphokines
    • Activate and regulate the immune response
    • Stimulate chemotaxis
    • Aid B cells to produce antibodies
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9
Q

Briefly describe the process whereby neutrophils migrate out of the blood into inflammed tissue

A
  • Neutrophil invasion of an inflammed site begins within the first hour or so
  • Inflammatory cytokines attract neutrophils to the site
    • IL-1, TNF and other inflammatory products
  • Increased endothelial cell expression of adhesion molecules
    • iCAM - intercellular adhesion molecule - 1
    • Selectin
  • Integrin molecules on the neutrophil interact and bind to the adhesion molecules on the endothelium
    • This causes margination of the neutrophil
  • The inflammatory cytokines increase vascular wall permeability
    • Increased space between the endothelial cells allows for diapedesis of the neutrophils into the tissue
  • Inflammatory mediators then cause chemotaxis and neutrophils migrate via ameboid movement within the interstitial space
  • The mature neutrophils are ready primed to begin their scavenging function
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10
Q

Describe the first line defence systems offered by macrophages during inflammation

A
  • The initial macrophage response is carried out by the tissue macrophages
    • ie. the macrophages that are already mature and ready to perform their scavenging function
  • The macrophages enlarge during inflammation
  • Previously sessile macrophages can break away from their tissue attachment and move more freely through the tissue
  • There are limited numbers of macrophages in the tissues to provide this first line of defence
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11
Q

Describe the third line of defence that macrophages provide during tissue inflammation

A
  • Monocytes enter an inflammed area in a similar manner to the neutrophils
    • Circulating and storage pool of monocytes is smaller than the neutrophils
  • Once in the tissues, monocytes take ~8 hours to swell and produce abundant lysosomes to enable their phagocytic actions
  • It takes several days to weeks for the bone marrow to produce more monocytes such that they can predominate in the inflammatory response
  • These macrophages can also initate the development of antibodies
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12
Q

What is a neutrophil extracellular trap?

What are the known roles of the NETs?

A
  • Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens.
    • NETs are formed by release of granule proteins and chromatin to form an extracellular fibril matrix

​

  • The NETs comprise a high concentration of antimicrobial proteins such as elastase, cathepsin G and histones
  • May serve as a physical barrier to microbial migration
  • They serve to trap and prevent widespread diffusion and damage from the proteases released by the neutrophils
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13
Q

Describe the known role of NETs (neutrophil extracellular traps) during sepsis

A
  • With overwhelming infection such as seen with sepsis, NETs have been shown to form within the capillaries
    • This occurs specifically within the liver sinusoids and the alveolar capillaries
  • The formation of intravascular NETs is tightly controlled by platelets
    • Platelets sense severe infection with TLR-4
    • They then bind to and activate neutrophils
    • Platelet activated neutrophil NET formation is rapid, occurring within minutes
  • Intravascular NETs have been documented to trap intravascular bacteria as they pass through the vessels
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14
Q

Describe the activation pathway for NETosis

A
  • Thought to begin with activation of the NADPH oxidase ensyme in the plasma membrane
  • This activates protein-arginine deiminase 4 (PAD4) via ROS
  • PAD4 alters the histones in DNA by citrullination
    • This results in decondensation of the nuclear DNA
  • Azurophilic granule proteins then enter the nucleus resulting in further decondensation and rupture of the nuclear envelope
  • Chromatin enters the cytoplasm and additional granule and cytoplasmic proteins are added to the NET
  • The next process depends on the activation trigger - suicidal or vital NETosis ensues
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15
Q

Describe the process of suicidal NETosis

A
  • Neutrophils form the NET intracellularly followed by rupture of the plasma membrane.
  • This results in release of the NET and death of the cell
    • This cell death is different from both apoptosis and necrosis
  • Activated when ligands such as antibodies bind with TLR’s, Fc receptors and complement receptors
    • This activation triggers the influx of calcium and activation of the NETosis pathway
  • The process can take hours even with potent stimulation
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16
Q

Describe the process of vital NETosis

A
  • Stimulated by bacterial LPS, other bacterial products and TLR4-activated platelets or complement proteins in tandem with TLR2
  • Vital NETosis results in bledding of the nucleus and formation of a DNA filled vesicle
  • This DNA filled vesicle is exocytosed leaving the plasma membrane intact
  • This process does not result in cell death, but there is a reduction in the cell DNA volume
    • The neutrophil can continue performing phagocytosis and kill microbes after vital NETosis
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17
Q

List the 5 most important factors that help stimulate the bone marrow response in the face of persistent inflammation

A
  1. Tumour necrosis factor
  2. IL-1
  3. Granulocyte-monocyte colony stimulating factor
  4. Granulocyte colony stimulating factor
  5. Monocyte colony stimulating factor
18
Q

Describe the mechanisms by which eosinophils can mitigate a parasitic infection

A
  • Eosiniphils display chemotaxis to areas of parasitic infestation
    • IL-5 and eotaxin enhance eosinophil chemotaxis
    • This occurs as a part of a Th2 driven immune response
  • They are only weak phagocytes and predominantly exert their effect by endocytosis of vesicular material
  • They are able to attach to the larval parasite surface in the presence of antibody or complement proteins
  • They help to kill larvae by:
    • Release of hydrolytic enxymes (from their granules / lysosomes)
    • Production of reactive oxygen species
    • Releasing major basic protein from their granules
19
Q

Briefly describe the role of mast cells and basophils in the development of an IgE mediated allergic response

A
  • Allergens and antigens can stimulate the production of IgE by B cells and activated plasma cells
    • This production requires activation or exposure to the allergen, such that there is time for this response
  • IgE can then bind to FceRI receptors on the mast cell
    • This IgE binding essentiall primes the mast cell to react to the antigen specific for that IgE production
  • If the same antigen presents again it can bind directly with the IgE coated mast cell
    • Binding of antigen allows for activation of the mast cell and release of granules via exocytosis
  • The substances released include histamine, bradykinin, serotonin, heparin, leukotrienes and lysosomal enzymes
    • ​These substances mediate the majority of the clinical manifestations of an allergic response
    • Vasodilation, localised swelling (increased vascular permeability, pain (bradykinin mediated), increased heat etc.
20
Q

Describe the major components of the innate immune system

A
  1. Phagocytosis
    • neutrophils and macrophages have the ability to engulf, digest and destroy invading bacteria etc
  2. Digestion
    • Destruction of ingested organisms by the acid environment of the stomach and other digestive enzymes
  3. Barrier
    • The skin prevents invasion directly
  4. Chemical systems and cells within the blood
    • Lysosyme - can attack and dissolve bacteria
    • basic polypeptides - can interact and inactivate certain types of gram-positive bacteria
    • Complement
    • Natural killer lymphocytes - can identify and destroy foreign cells, tumour cells and infected cells
21
Q

Describe the basic components of the adaptive immune system

A
  • The adaptive immune response is generated in response to antigens from a foreign toxin or organism​
    • This response is highly specific and targeted
  • Humoral immune response
    • The production of antibodies by B-lymphocytes
    • Antibodies are specific for a partigular antigen or allergen
  • Cell-mediated immunity
    • Development of activated T-lymphocytes that can specifically target a foreign agent
22
Q

Describe briefly the role of macrophages in the development of the adaptive immune response

A
  • Tissue macrophages are primarily responsible for sampling and presentation of antigens to the B- and T-lymphocytes
  • The macrophages phagocytose and partially digest the invading pathogen / antigen (in phagolysosomes)
  • The antigen products are then liberated into the cytosol
  • They are then combined with antigen presenting proteins (eg. MHC II - activate T lymphocytes)
  • The antigens are moved the the cell surface of the macrophage (or endothelial cell) to present to or contact the local lymphocytes
  • Macrophages also produce IL-1 - promotes growth and division of the activated lymphocytes
23
Q

Describe briefly the role of T cells in the development of humoral immunity

A
  • Humoral immunity is provided by the development of antibodies by activated B lymphocytes and plasma cells
  • Antigen is presented to both T and B lymphocytes.
  • Presentation of the same antigen to these lymphocytes causes the following (one they are already primed):
    • B lymphocytes start to produce antibodies
    • T helper cells produce lymphokines
      • These lymphokines provide further marked stimulation to the developing B cells
      • Marked increase in antibody production in the presence of concurrent T-helper cell activation
24
Q

Describe the process of plasma cell differentiation and memory cell formation

A
  • B lymphyocytes initially differentiate to become highly specific for a particular antigen
  • Once exposed to their specific antigen, the B lymphocyte with expand taking on the appearance of a lymphoblast
    • Some of these lymphoblasts differentiate to form plasma blasts
  • The RER in the plasmablast expands rapidly and the cells divide each ~ 10 hours
    • Each plasmablast will divide ~ 9 times to form ~ 500 cells in less than 4 days
  • The lymphoblasts will also divide and mature to form clones of the originally stimulated lymphocyte - memory cells
    • Thus, increased numbers of specific lymphocytes are produced to migrate around the body
25
Q

Descirbe the role of memory cells in the development of a stong antibody response

A
  • The initial exposure to an antigen will result in the development of a primary immune response
  • This primary response results in clonal expansion of the specific B lymphocyte for the specific antigen
  • These clonal lymphocytes are called memory cells
  • With a second exposure to the same antigen, there are vastly increased numbers of the specific B lymphocyte clone for expansion and differentiation into antibody producing plasma cells
  • This response is utilised by vaccination programs that require a second injection of antigen for development of a strong and sustained immune response
26
Q

All immunoglobulins contain both heavy and light polypeptide chains with a variable and constant portion.

Describe the functional characteristics of the vairable and constant portions of the immunoglobulins

A

Variable Portion:

  • The variable portion is the segment that is different for each specific antigen type.
  • The binding of antigen occurs within the variable portion of each Ig

Constant Portion:

  • This portion of the antibody conveys distinctive properties and is similar accross all antibodies of a given class
    • eg. IgE, IgA, IgG, IgM, IgD
  • This region conveys properties such as:
    • Diffusion within tissues
    • Adhesion to specific structures
    • Attachment to complement
    • Membrane diffusion properties
27
Q

Describe the 4 main direct actions that enable of antibodies to neutralise invading pathogens

A
  1. Agglutination
    • multiple large particles are bound together in a clump
  2. Precipitation
    • Molecular complex of soluble antigen (eg. tetanus toxin) becomes so large that it is rendered insoluble
  3. Neutralisation
    • Antibodies cover the toxic site of the agent
  4. Lysis
    • Some potent antibodies can directly attack and rupture the cell membrane on pathogens
28
Q

Describe the components and primary action of the complement system

A
  • The complement system is a complex of ~20 proteins, most of which are enzyme precursors
  • The proteins of the complement system are a normally present within the plasma
  • The principle protines are designated C1-C9, B and D.
  • The role of the complement system is to enhance the actions of antibodies and phagocytic cells in destroying pathogen, removing damaged cells from the body and promoting inflammation
29
Q

Describe the basic pathway to activation of the complement system

A
  • Initiation begins following binding of an antibody to its target antigen
  • Antigen binding uncovers a reactive site on the constant portion of the antibody
  • This reactive site / activated site then directly binds with the C1 molecule of the complement system
  • This binding activates the proenzyme C1, setting into motion the cascade of reactions of the complement system
30
Q

Note the end effects of the various end products produced by activation of the complement system

A
  1. Opsinisation and phagocytosis
    • C3b strongly activates phagocytosis of the bacteria to which the antibody-antigen complex is adhered
  2. Lysis
    • C5b6789 - a combination of complement proteins is called the membrane attack complex
    • This product inserts itself into the lipid bilayer and creates pores that allow ion transfer
      • Leads to osmotic rupture of the cells
  3. Agglutination
    • Alteration of the invading cell surface occurs such that they adhere to one another
  4. Neutralisation
    • Direct damage to virulence components of invading viruses
  5. Chemotaxis
    • Factor 5a is a strong chemotactic factor for neutrophils and macrophages
  6. Activation of mast cells and basophils
    • C3a, C4a, C5a all activate mast cells and basophils
    • Stimulates granule release - strong mediators of the inflammatory response
  7. Inflammatory effects
    • Directed inflammatory effects occur over and above that generated by mast cells and basophils
      • Enhanced vasodilation
      • Enhanced capillary permeability
      • Interstitial fluid coagulation
31
Q

List the three major groups of T cells

A
  1. T helper cells (CD4+)
  2. Cytotoxic T cells (CD8+)
  3. Regulatory T cells
32
Q

List and describe the major actions of the T helper cells on the other components of the immune system

A

The produced lymphokines essentially regulate the remainder of the immune system

  1. Stimulation of growth and proliferation of the cytotoxic and regulatory T cells
    • Predominantly regulated by IL-2
  2. Stimulation of B cell growth and differentiation to form plasma cells and antibodies
    • IL-4, IL-5, IL-6 - such a strong effect they have been called B cell stimulating factors
  3. Activation of the macrophage system
    • The lymphokines help to stop/slow the migration of macrophages once they have reached the target
    • They activate the macrophages for more efficient phagocytosis
  4. Positive feedback onto the T-helper cells
    • Especially IL-2 - direct positive feedback effect on stimulation of the T-helper cells
33
Q

Briefly describe the mechanism of action of the cytotoxic T cells

A
  • The receptor proteins expressed by cytotoxic T cells allow them to bind avidly to specific organisms or cells
  • After binding they secrete proteins called perforins
    • ​Perforins punch round holes in the cells membranes allowing easy passage of ions and fluid into the cell
  • The cytotoxic T cell also secretes cytotoxic substances directly into the attacked cell/organism
  • The T cells can then detach from the attacked cell and move to another
  • They are especially lethal to viral infected cells and also play an important role in the destruction of neoplastic cells
34
Q

Describe the major role of the T regulatory cells

A
  • While their role not fully ellucidated, they predominantly suppress the immune response
  • By supressing or regulating the effects of the T helper cells and the cytotoxic T cells, they can limit the potential damage caused by an activated immune system
  • They play a major role in limiting the ability of the immune system to attack self antigen
  • Largely responsible for immune tolerance
35
Q

List the contents of the platelets and note the major function of each product

A
  1. Actin and myosin molecules and thrombosthenin
    • Enable platelets to contract
  2. ER and golgi residues
    • Synthesise the enzymes and proteins
    • Storage of calcium ions
  3. Mitochondria
    • Energy generation
  4. Enzyme systems
  5. Fibrin-stabilising factor - FXIII
    • Enzyme responsible for the formation of fibrin crosslinks
  6. Vascular endothelial growth factor (VEGF)
    • Stimulates endothelial and smooth muscle cells together with fibroblasts - help repair damaged endothelium
36
Q

Describe the processes that occur during the formation of a normal platelet plug

A
  • Exposure of the subendothelial collagen is the initial stimulation for platelet plug formation - ie. from vascular damage
  • The platelets swell and develop numerous pseudopods
    • The cell surface becomes more adhesive
  • Cell surface Gp1b receptors bind to vWF attached to the subendothelial collagen
  • The contractile elements in the platelets activate and granules are released
    • ADP and platelet activating factor (PAF)
    • Thromboxane is produced
  • More platelets are recruited and adhere to the original activated platelets
37
Q

Describe the production, metabolism and action of prothrombin

A
  • Continually produced in the liver
  • 68.8 kDa in size (similar to albumin)
  • Can be cleaved by extrinsic or intrinsic tenase (FVII+TF, FXa+FVIII)
    • Prothrombin is split to liberate thrombin
  • Prothrombin is being continually used and there are no significant body stores
    • Halted production as with acute liver insufficiency will lead to low blood levels within ~1 day
  • Prothrombin cleavage and activation is vitamin K dependent
  • Thrombin, produced rapidly during coagluation, catalyses cleavage of 4 peptides from each fibrinogen molecule
    • This allows the individual fibrinogen monomers to polymerise to for long fibrin fibres
38
Q

Briefly describe the process of clot retraction

A
  • A blood clot is a cluster of platelets, red and white blood cells together with plasma.
  • The blood clot is held together by an extensive network of fibrin strands that are cross-linked by the action of Factor XIIIa (released by the platelets - and activated by thrombin)
  • Within minutes of clot formation, contraction of platelet elements helps to extrude the excess fluid - serum
  • Platelet contractile elements are responsible for the contraction
    • Actin, myosin and thrombosthenin
    • Require calcium which is released from the golgi, ER and mitochondria
  • Tight adhesions between the platelets, fibrin and the underlying subendothelial tissues help to bring the damaged vascular endothelium together
  • Retraction also enables strengthening of the clot and the meshwork becomes more dense
39
Q

Describe the factors that prevent blotting in a normal vascular system

A
  • Smooth endothelial surface prevents contact activation
    • Subendothelial collage and vWF remain hidden
  • Glycocalyx - mucopolysaccharide layer adsorbed to the endothelial cells
    • repels clotting factors and platelets preventing their activation
  • Thrombomodulin
    • Bound within the endothelial membrane - binds and removes thrombin
  • Thrombin-thrombomodulin complex
    • Activates Protein C
      • Protein C inactivates FV and FVIII
  • ​Production of PGI2 (prostacyclin) and NO by endothelial cells​
    • Both inhibit platelet aggregation and cause vasodilation
40
Q

Describe the action of the major anticoagulats within the blood

A
  1. Antithrombin III circulates within the blood
    • ATIII initially blocks the action of thrombin on fibrinogen
    • Secondarily inactivates the thrombin
  2. The fibrin formed during the coagulation process
    • The majority of thrombin formed in adsorbed within the developing fibrin matrix
    • This process ensures that the majority of the thrombin formed during coagulation remains local and prevents excessive spread of the clot.
41
Q

Describe how endogenous heparin contributes to the anticoagulation balance within the body

A
  • Heparin is produced and stored within basophils and mast cells predominantly
    • Heparin is continually produced and released
    • It is present in the largest quantities in the basophilic mast cells in the precapillary connective tissue
      • Especially within the lungs and liver
  • Heparin by itself has minimal anti-coagulant properties and remains in low concentration within the body
  • Heparin acts by markedly increasing the activity of antithrombin III (ATIII)
  • ATIII+heparin removes:
    • Thrombin
    • FIX through FXII
  • Heparin therefore reduces the concentrations of some of the activated coagulation factors and thrombin.
  • Heparin is contstantly produced to ensure minimal growth of the tiny clots formed continually within the body
42
Q

Describe the activation of plasmin and its mechanism of action

A
  • Plasmin circulates in the blood in the inactive state called plasminogen
  • Plasminogen is bound within newly formed blood clots
  • Damaged tissue including the vascular endothelium very slowly release tissue plasminogen activator (t-PA) which slowly converts plasminogen to plasmin within a few days of clot initiation
  • Plasmin is a proteolytic enzyme with a similar structure to trypsin
  • Plasmin digests fibrin fibres helping to remove the formed clots
    • This process can re-establish blood flow within the tiny capillaries which would otherwise be occluded by the clot
  • Plasmin also digests / inactivates fibrinogen, FII, FV, FVIII, FXII
    • This helps to minimise clot formation and can cause localised hypocoagulability

Physiology - Veterinary (9 decks)

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