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Biology 107 > Blood and Immune > Flashcards

Blood and Immune Flashcards

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1
Q

Major Components of Blood

A
  1. Red Blood Cells (40%)
  2. Buffy Coat, containing white cells (10%)
  3. Plasma, containing soluble proteins, lipids, platelets (50%)
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2
Q

Plasma

A

Liquid fraction of uncoagulated blood

  • Serum remains after coagulation and is normally straw yellow
  • Fibrinogen is absent
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3
Q

Serum Separation

A

Serum separates in an electric field into:

  1. Albumin (50%)
  2. Alpha 1
  3. Alpha 2
  4. Beta
  5. Gamma
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4
Q

Albumin

A
  • 50%
  • Functions to maintain colloidal osmotic pressure
  • Binds and transports small molecules and proteins
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5
Q

Fibrinogen

A
  • 17%

- Involved in clotting in the coagulation cascade

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6
Q

Immunoglobulin

A
  • 10%
  • Found in gamma fraction and are responsible for humeral immunity
  • Produced by plasma cells
  • Elevated in diseases such as multiple myeloma
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7
Q

Complement (C’)

A
  • Group of zymogens (inactive substance which is converted into an enzyme when activated by another enzyme)
  • Essential for phagocytosis
  • Stable as zymogens but break down quickly when cleaved
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8
Q

Coagulation

A
  • Set of 13 protein that initiate cleavage of Fibrinogen to Fibrin
  • Thrombin is central enzyme
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9
Q

Myeloid Cells

A

Provide innate immunity

  • Neutrophils
  • Basophils
  • Monocytes (macrophages)
  • Eosinophils
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10
Q

Lymphoid

A
  • Provide adaptive immunity

Produces B-lymphocytes (antibodies) and T-Lymphocytes (cellular)

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11
Q

Haematopoiesis

A
  • All blood cells begin as Hematopoietic stem cell (HSC) food in bone marrow - characterised by CD34 marker antigen
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12
Q

CD34+ HSC

A

Gives risk to myeloid or lymphoid progenitors

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13
Q

Myeloid Progenitor

A

Gives rise to:

  • Erythrocytes
  • Mast Cells
  • Megakaryocytes (To Throbocytes)
  • Myeloblasts (give rise to myeloid cells)
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14
Q

Lymphoid Progenitor

A

Gives rise to:

  • Natural Killer Cells (Large granular lymphocytes)
  • Small Lymphocytes (give rise to lymphoid cells)
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15
Q

Erythropoietin (EPO)

A
  • Drives production of RBC

- Mainly in Kidneys in adulthood (liver in perinatal)

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16
Q

Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF)

A
  • Stimulates production of myeloid cells
  • Produced by macrophages, T-Cells, endothelial cells, fibroblasts
  • Administered to repopulate WBC in cancer patients
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17
Q

Granulocyte Colony-Stimulating Factor (G-CSF)

A
  • Stimulates production of granulocytes
  • Acts to mature neutrophils
  • Produced by multiple cells
  • Administered to repopulate WBC in cancer patients
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18
Q

Complement Cascade

A

Set of 9 plasma proteins that lead to opsonisation and phagocytosis of foreign organisms
- Proteolytic activation cascade

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19
Q

Classical/Antibody Mediated Complement Cascade

A
  1. Antibody (IgM, IgG) binds to an antigen on the microbe thus recruiting C1 to bind to the antibody
  2. Activation of C2 and C4 molecules which are cleaved (forming C4a, C2a) forming a convertase
  3. Convertase is covalently bound to the surface of the microbe and recruits C3 which is cleaved to C3b
  4. More C3 is generated and the surface of the microbe is covered with C3 Convertase forming opsonins
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20
Q

Lectin Complement Cascade

A

Lectins are carbohydrate binding proteins that bind unusual carbohydrates to the microbe and this activates the convertase pathway

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21
Q

Alternative Complement Cascade

A

Complement C3 is activated and cleaved just by being close to the surface of the microbe, activating another type of C3 Convertase to form opsonins

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22
Q

End Stage Complement

A

Convertase activates C5 to cleave and for C5b to form a lytic pore with C6, 7, 8, and 9.

  • Pore inserts into a bacterial membrane causing its lysis
  • Membrane Attack Complex (MAC)
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23
Q

Anaphylatoxins

A

Small polypeptides C2a, C4a, C5a which are powerful chemoattractants that recruit and activate phagocytes to engulf the bacteria
- Neutrophils and Macrophages rapidly engulf opsonised bacteria but ignore ones without

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24
Q

Coagulation Cascade

A
  • Proteolytic activation cascade

- Calcium ion essential for clotting

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25
Q

Intrinsic Coagulation Cascade

A
  • Caused by blood contact with surfaces other than the body

- Uses Factor XII, XI, IX, VIII along with the common factor X to form Factor Xa

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26
Q

Extrinsic Coagulation Cascade

A
  • Caused by tissue damage

- Uses Tissue Factor, V, VII along with common factor X to form Factor Xa

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27
Q

Factor Xa

A
  • Factor Xa assists the cleavage of Prothrombin to Thrombin
  • Thrombin cleaves Fibrinogen to form Fibrin monomers
  • Fibrin monomers cross link together to form a clot
28
Q

Plasminogen

A
  • Plasminogen is a zymogen which is converted to the active Plasmin that can dissolve a clot by breaking Fibrin polymers back down to its monomers
  • Thrombolysis
  • Plasminogen activators are TPA (Tissue Plasminogen Activator) or Streptokinase (used to thin blood)
29
Q

Innate Immunity

A
  • Does not strengthen with time

- First line of defence against pathogens

30
Q

Pattern Recognition Receptors (PRR)

A

Receptors found on many cells that recognise complex molecules that are unique to microbes

  • Cross-linking of PRR’s stimulates an inflammatory response which enhances immunity
  • Toll-Like Receptors
31
Q

Virus

A

Intracellular pathogen that will use the host machinery for replication

32
Q

Bacteria/Yeast/Fungi

A

Predominately extracellular pathogen that typically require engulfment and destruction by phagocytic cells

33
Q

Gram Positive Bacteria

A
  • Thick cell walls
  • Resistant to direct complement MAC lysis
  • Must be phagocytosed
34
Q

Gram Negative Bacteria

A
  • Thinner layer and outer membrane

- More sensitive to MAC lysis

35
Q

Protozoa/Parasites

A
  • Complex, often multicellular and highly developed
  • Can live inside or outside of cells
  • Too big to be engulfed by macrophages
  • Need a means of secreting inflammatory mediators and cytotoxic chemicals which kill (Basophils, Eosinophils, Mast Cells)
36
Q

5 Steps to Recruit Neutrophil to the Site of Infection

A
  1. Activation
    - Anaphylatoxins from injury activate local endothelial cells lining adjacent capillary
  2. Tethering
    - Neutrophil tethers to the inside of the capillary wall
    - Mediated by selectins (cell adhesion molecule ICAM-1) unregulated on endothelial cells and Sialyl-Lewis X a carbohydrate antigen on neutrophils
  3. Adhesion
    - Binding between neutrophil interns and ICAM-1 on the endothelium
    - Neutrophil immobilises and flatterns out
  4. Diapedesis
    - Neutrophil squeezes between endothelial cells of the blood vessel
  5. Chemotaxis
    - Neutrophil migrates along the chemoattractant gradient to site of infection
    - Polymerising actin filaments at leading edge and depolymerising filaments at trailing edge
37
Q

Complement and Fc Receptor Mediated Phagocytosis

A

Myeloid cells express CR1, CR2, CR3 and CR4 receptors for complement

  1. Antibody (IgM, IgG) binds to a bacterial antigen
  2. This exposes the antibodies Fc region
  3. Neutrophils Fc receptor binds multivalent Fc region of antibodies
  4. Phagocytosis is activated
  5. Membrane invaginate forming a phagosome
  6. Phagosome fuses with a lysosome forming a phagolysosome
  7. Phagolysosome acidifies and superoxides kill the bacteria
38
Q

Fc Receptors

A

Expressed on myeloid cells and bind the Fc region of antibodies bound to a bacterias surface
- Fc Epsilon receptor on Mast Cells bind to the IgE which is responsible for atopic allergy

39
Q

Phagocytosis

A
  1. Ingestion
    - Bacterium held on the surface of a myeloid cell is invaginated into a phagosome
  2. Fusion
    - Phagosome and lysosome fuse
  3. Acidification
    - Phagolysosome acidifies as H+ is pumped in
  4. Digestion
    - Acidification activates protease and stimulates the production of superoxides which are highly toxic
    - Powerful proteases eat the microbe
  5. Exocytosis
    - Expulsion of digested microbe
40
Q

Pathogen Associated Molecular Patterns (PAMP’s)

A
  • Molecules associated with groups of pathogens that are recognised by cells of the innate immune system
  • Recognised by PRR’s
  • E.g Lipopolysaccharide (LPS)
41
Q

Toll-Like Receptors (TLR)

A
  • A type of PRR
  • Has coiled leucine rich repeat domains
  • Bind to different types of unusual PAMP’s
  • Binding causes TLR to aggregate on the surface signalling a powerful response through the NFKB pathway
42
Q

Lipopolysaccharide (LPS)

A
  • PAMP which is a component of Gram negative bacteria
  • Is recognised by TLR in conjunction with MD2 (serum protein - LPS binding protein)
  • Lipid portion binds to TLR4
  • Binding stimulates receptor cross-linking to signal an inflammatory response
  • Very powerful pyrogen
43
Q

Origins of Adaptive Immunity

A
  • Ig and T-Cell Receptors (TCR) gene recombinations use the same mechanism as transposons (Jumping)
  • RAG 1 and RAG 2 (Recombination Activation Genes) are still present and are a form of the ancient transposase
  • Recombination Sequences are also present and located at the end of all Ig and TcR gene segments
  • RS and RAG are identical in species with adaptive immunity - only present in B and T Lymphocytes
44
Q

Adaptive Immunity Overview

A
  • Secondary response is stronger and faster than the primary naive response - IgG las much longer
  • Born with many B and T Lymphocytes which have randomly produced antigen receptors
45
Q

Affinity

A

How strongly two molecules are attracted to each other to bind

46
Q

Avidity

A

Results from multiple affinity contacts (weak or strong)

- Strength of avidity binding can be order of magnitude stronger than the affinity contacts that make it up

47
Q

Primary Naive Response

A

1st immunisation is characterised by a rise in antigen specific, low affinity serum IgM peaking 2 weeks post immunisations and diminishing rapidly

48
Q

Secondary Response

A

Boosting generates a rapid burst of antigen specific high affinity IgG which can last up to years
- Best vaccines are inactive variants of the bacteria/virus

49
Q

Lymphatic System

A
  • Circulatory system for immune cells connecting lymph nodes
  • Carriers lymph and drains fluid from interstitial space
  • Bone marrow and thymus are the primary lymphoid organs
  • Lymph node and spleen are secondary tissues - filled with lymphocytes where B-Cells undergo affinity maturation
50
Q

B-Cells

A
  • Begin in the bone marrow and mature in secondary tissue

- Produce antibodies and form soluble (humoral) arm of the immune response

51
Q

B-Cell Receptor

A

Antigen receptor is a membrane bound IgM that associates with intracellular molecules
- Transmit signals via phosphorylation

52
Q

T-Cells

A

Begin as immature lymphocytes and then move to the thymus where they mature into cells with cellular adaptive immunity

53
Q

T-Cell Receptor

A

Immunoglobulin like surface molecule on T-Cells

  • Goes under gene rearrangement like Ig
  • Either CD4 or CD8
  • Alpha and Beta chain
  • Recognises self MHC
  • Monovalent and does not undergo affinity maturation
54
Q

Immunoglobulin Fold

A
  • Two antiparallel Beta pleated sheets made up of 7-9 Beta strands forming a barrel structure
  • Strands are conserved and are connected to loops which provides the variable antigen binding site - also imprecise joining creates versatility
  • Extreme amino acid diversity on loops
  • 6 loop regions connecting Beta strands
  • Loops are known as Complementarity Determining Regions (CDR)
55
Q

IgG Structure

A
  • Two heavy and two light chains
  • N-Terminus of the light chains bind to the antigen (bivalent) FAB (Fragment Antigen Binding)
  • Heavy chains form the effector function and bind the Fc (Fragment Crystalline) Receptor (C1 can bind)
  • Heavy chains have 4 domains - 1 variable and 3 constant
56
Q

IgM Structure

A
  • Default made by all B-Cells (Primary surveillance antibodies)
    Has two forms:
    1. Membrane bound (monomer) - B-Cell antigen receptor
    2. Soluble (pentamer) - 10 antigen binding sites and reacts strongly with surfaces through avidity binding
  • 5 Fc regions that bind C1
57
Q

Ig and TcR gene segments

A
  • Variable
  • Diversity
  • Joining
  • Constant
58
Q

Heavy Chain Recombination of Ig and TcR gene

A
  • D segment joins to a J segment
  • V segment then joins to the D segment
  • Forms pre mRNA which is then splices with one of the 5 constant segments (gamma, epsilon, etc)
  • CD1 and CD2 are encoded in the V segment
  • CDR3 Loop is encoded by the VDR junction which is very imprecise and thus created a huge amino acid and this antigen binding diversity
59
Q

Light Chain Recombination of Ig and TcR gene

A
  • Has no D segments

- V joins to J and only have one constant region to choose from

60
Q

Clonal Selection

A

Before you are born immune system produces 10(11) different B-Cell antigen specificities through random rearrangement

  • Individual clines are then selected to mature by the antigens within germinal centres in the lymph node
  • Begin with low affinity IgM then through affinity maturation B-Cells can produce high affinity IgG
61
Q

Affinity Maturation

A
  • B-Cells encounter antigen in the lymph node and B-Cell will produce clines that posses this antigen receptor (low affinity)
  • Somatic hypermutation of the H and L chains of Ig will introduce random mutation into the VDJ segments
  • Some of these will generate higher affinity antigen receptors that are selected by lower antigen concentrations
  • After successful rounds of the affinity maturation, mature B-Cell will become a plasma cell and secrete soluble IgG (high affinity), others will remain in lymph nodes as long term memory cells
62
Q

Cellular Immunity - T-Cells

A

T-Cells initially are double positive as express both CD4 and CD8 antigens

  • CD4 and CD8 are co-receptors associated with TcR and carry intracellular tyrosine kinases that initiate signalling in T-Cells through phosphorylation
  • T-Cells encounter MHC Class 1 and 2 which are expressed on thymic epithelium
  • If they respond to class 1 they become CD8 Cytotoxic Cells (CTL)
  • If they respond to class 2 they become CD4 Helper Cells
  • Antigen specific T-Cells activate antigen specific B-Cells
63
Q

Cytotoxic CD8 Cells

A
  • 20% of blood T-Cells
  • Can ‘kill’ other cells
  • Produces granzyme and Perforin which punch holes in the target cell membrane and destroy cell viability
64
Q

Helper CD4 Cells

A
  • 80% of blood T-Cells
  • HIV virus replicates itself in these cells
  • Secrete cytokines to alert CD8 cells where pathogens are:
  • Treg - suppress immune response
  • Th1 - promote cell mediated immunity
  • Th2 - promote antibody mediated immunity
  • T17 - drive inflammation
65
Q

MHC Restriction

A
  • ## T-Cells recognise foreign antigens from virus and bacteria via MHC

Biology 107 (5 decks)

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