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BIOSCI 107 > Section 4: Blood and Immune > Flashcards

Section 4: Blood and Immune Flashcards

1
Q

Average person has ___L of blood

A

5L

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2
Q

_____L circulates through a person’s heart every 24 hours

A

14,000L

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3
Q

Large vs small vessels

A

Large vessels: High volume, low flow

Small vessels: Low volume, high flow

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4
Q

Vast network of small capillaries require…

A

Quite high pressures to force blood through

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5
Q

Muscular arteries and valves provide…

A

Pressurised directional flow from lungs to tissues and organs

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6
Q

Blood pressure ensures…

A

Even and efficient flow through small capillaries

Low enough to prevent capillary leakage but high enough to avoid coagulation

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7
Q

Why does blood move rapidly

A

Blood moves rapidly through tissues and small capillaries to ensure muscles and other organs are completely bathed in an oxygenated environment because tissue needs oxygen

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8
Q

Parts of heart

A

Right and left ventricles

Right and left atrium

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9
Q

Heart and lungs

A

Pulmonary artery extends from right ventricle to lungs where unoxygenated blood is bathed in oxygen and breathed in through the lungs
The blood is then drawn back in through the left atrium via the pulmonary vein
Left ventricle pumps blood out through the aorta and arterial system to tissues and organs

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10
Q

What is the source of haemopoietic stem cells

A

Bone marrow

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11
Q

Where do blood cells arise from

A

Tissue that resides inside bone

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12
Q

Is bone a small or large user of oxygen

A

Small

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13
Q

Is muscle a small or large user of oxygen

A

Small

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14
Q

Is the brain a small or large user of oxygen

A

Large/major

Generates lots of heat - hair prevents heat loss from skull, which is generated by the brain using/burning oxygen

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15
Q

Is the kidney a small or large user of oxygen

A

Large/heavy user

Filters blood

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16
Q

Liver - blood

A

Liver is a major recipient of blood via GI and spleen

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17
Q

How is blood divided across the body

A

Dependent on need

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18
Q

Pressure of arterial blood

A

Quite high, since arteries are muscular capillaries (thick muscular walls) so when left atrium pumps, those walls expand to carry pressure from the heart

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19
Q

How is pressure measured

A

Systolic and diastolic pressure

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20
Q

Normal blood pressure

A

Normal blood pressure is 120/80 (120mm of mercury = mercury of stigma monitor is 120mm high)

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21
Q

Systolic pressure

A

When blood is at full compression, i.e. left ventricle is squeezed at its tightest and arteries are expanded at their greatest

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22
Q

Diastolic pressure

A

Heart at complete rest

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23
Q

Too high and too low blood pressure

A

Too high: arteries are not expanding and contracting effectively, e.g. hardened or blocked (due to disease)
Too low: don’t have enough blood pumping through veins and arteries to supply tissues

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24
Q

Valves

A

Part of venous system
Prevent backflow because there is no pressure in the venous system - blood is draining back to the right ventricle that is not under as much pressure as the arterial system, i.e. ensures blood is always flowing in one direction

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25
Q

Major components of blood

A 
Cells
Proteins
Lipids
Electrolytes
Vitamins, hormones
Glucose
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26
Q

Blood - types of cells

A

RBC - carry haemoglobin
Erythroid
Myeloid (all white cells)
Lymphoid (B cells and T cells)

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27
Q

Haemoglobin contains…

A

Contains iron which carries oxygen

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28
Q

B lymphocytes come from … and provide …

A

Come from bone marrow and provide antibodies

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29
Q

Blood - types proteins

A 
Albumin - most abundant
Fibrinogen
Haemoglobin
Immunoglobins
Complement
Coagulation factors
Electrolytes
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30
Q

Blood - lipids

A

When you eat a fatty meal, those lipids are taken up and transported through blood by lipoproteins

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31
Q

Blood - lipids: lipoproteins

A

Signal susceptibility to diff forms of coronary heart disease
LDL (low density lipoprotein) - common, ‘bad’ lipoprotein
HDL and VLDL - ‘good’ lipoprotein’

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32
Q

Lipoproteins are based on…

A

Density; the only way to isolate them is to centrifuge them at high speed
Since they have low density, they will float to the top of a centrifuged tube of blood

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33
Q

Blood - electrolytes

A

Salts and minerals maintain isotonicity
Deviation from the norm of the normal ions will result in significant illness
K+ is most tightly regulated - regulates many cellular functions

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34
Q

Blood - vitamins, hormones

A

Transported to various organs by blood

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35
Q

Blood - glucose

A

Major source of carbon and energy (6C source used by muscle through glycolysis)

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36
Q

Blood separation: centrifugation

A

One of the simplest forms of separation of blood
Plasma, buffy coat, RBC
Test for health by looking at no. of red cells
- not enough red cells –> anemic
- too many red cells –> blood becomes viscous
- remove plasma and test

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37
Q

Centrifugation: Plasma

A

55% of blood V

Blood that still has fibrinogen in it that hasn’t been clotted

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38
Q

Centrifugation: Buffy coat

A

Layer of white cells

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39
Q

Types of blood cells

A

Erythrocytes: ~5-6 million / ml
Leukocytes: ~10,000 / ml
Platelets: ~400,000 / ml

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40
Q

Blood cells - erythrocytes

A

Anucleated
Form flat disc
Purpose: carry oxygen to tissue
Major protein: haemoglobin

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41
Q

Blood cells - leukocytes

A

Immune defense
Neutrophil: responds immediately to microbial challenge
Nucleated

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42
Q

Blood cells - platelets

A

Coagulation and tissue repair

Important for releasing factors which regulate homeostatic mechanism of tissue repair

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43
Q

Multiple myeloma

A

Mature B cell malignancy - produces an antibody in a very high amount
Person develops a monoclonal antibody in their blood
Shows on electrophoresis
Patients start to urinate the antibodies

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44
Q

Why don’t you typically see myeloma cells in blood

A

They typically reside in bone / bone marrow

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45
Q

Since walls of capillaries are very weak…

A

They leak easily, so osmotic walls on either side of the capillary vessels must be balanced carefully (albumin)

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46
Q

First cells to arrive at site of infection

A

Neutrophils

Driven to migrate from the capillaries to site of infection by activation of complement

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47
Q

Coagulation factors - haemophilia

A

Haemophilia’s result from a missing component

Factor VIII deficiency most common form of haemophilia

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48
Q

What are blood cells

A

Cells that circulate in blood

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49
Q

Origin of blood cells

A

A single multi-potent stem cell that resides in bone marrow

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50
Q

Multi-potential haemopoietic stem cell

A

Rare
Has capacity to differentiate into any mature haemopoietic stem cells that populate the body
High conc in umbilical cord
CD34 antigen - can isolate cells relatively easily

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51
Q

Multi-potential haemopoietic stem cell - CD34 antigen technique

A

Monoclonal antibody usually has fluorescent tag / magnetic bead attached to it –> added to patient’s blood
Hold magnet to side of tube so all CD34 cells bind to the side of the tube where the magnet is and wash away all other cells (leukemic cells) –> relatively purified pop of CD34 cells
Treat patient with high dose of radiation which destroys white cells and leukemic cells
Transplant back the isolated CD34 cells
Treat patient with other factors

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52
Q

Innate immune system contains…

A

Basophil
Neutrophil
Eosinophil
Monocyte (–> macrophages)

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53
Q

Adaptive immune system contain…

A

Small lymphocyte –> T lymphocyte and B lymphocyte

B lymphocyte –> plasma cell

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54
Q

Factors that drive haematopoiesis

A

GM-CSF: Granulocyte macrophage colony-stimulating factor
EPO: Erythropoietin
G-CSF: Granulocyte colony-stimulating factor

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55
Q

Receptors on myeloid progenitor cells bind to…

A

GM-CSF, and stimulates these cells to differentiate into myeloid cells

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56
Q

What is used to re-populate white cells in leukemia patients following radio-ablation

A

GM-CSF and G-CSF

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57
Q

Oxygen being transported to tissue allows…

A

Oxidative phosphorylation –> generate high energy ATP

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58
Q

Membrane of alveoli - thickness

A

Very thin - allows oxygen to diffuse across it

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59
Q

Blood colour

A

Pulmonary blood: bright red

Venous blood: dark red

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60
Q

Where is oxygen picked up

A

Lung alveolus

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61
Q

Haemoglobin - lobes

A

4 lobes within haemoglobin
Each lobe has a heme molecule, which contains 4 Ns which complex the Fe2+ –> allows oxygen to bind and dissociate under pressures that are normally found at atmospheric pressure / sea level –> oxygen readily associates with Fe2+

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62
Q

Atmospheric pressure / sea level pressure

A

160mm of mercury

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63
Q

Haemoglobin and oxygen molecules

A

4 molecules of oxygen per haemoglobin molecule

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64
Q

Haemoglobin - association and dissociation

A

Oxygen dissociates because partial pressure of oxygen has reduced significantly to ~10-40mm of mercury
While haemoglobin is there, it picks up CO2 (bi-product of respiration)
When it gets out to the lungs, the partial pressure of CO2 reduces and dissociates

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65
Q

What molecules might displace O2

A

CO and cyanide

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66
Q

Pathways used to activate complement

A

Classical, lectin, alternative activation - cascades

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67
Q

Complement - classical pathway

A

C1 –> C4 and C2 –> C3 (major component)

  1. Antibody binds to antigen on surface of microbe
  2. C1 complement binds to antibody
  3. C1 complement creates enzymes that cleaves C4 and C2 complements. C4 is cleaved into C4a + C4b. C2 is cleaved into C2a + C2b
  4. C4b and C2b collectively forms C3 convertase
  5. C3 convertase cleaves C3 complement into C3a + C3b. C3b is added onto existing C3 convertase to form C5 convertase. C3a leaves as an anaphylatoxin.
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68
Q

Complement - C5a, C4a, C3a

A

Anaphylatoxins, which are sensed by the macrophage

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69
Q

Convertase complex

A

Where proteins bind irreversibly to surface (covalent)

Attract macrophages and neutrophils to site of infection

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70
Q

Macrophages won’t recognise a bacteria until…

A

It’s coated with complement proteins

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71
Q

Complement - lytic pores

A

Can insert into some types of bacteria which then immediately kill the bacteria
Formed at end stage of complement
Membrane attack complex (MAC)

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72
Q

Coagulation pathways

A 
Intrinsic pathway (contact)
Common
Extrinsic pathway (tissue damage)

All are cascades

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73
Q

Coagulation pathway - enzyme thrombin

A

Exists as an inactive enzyme until activated by factor X

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74
Q

Coagulation pathway - enzyme plasminogen

A

Converted to active plasmin and cleaves the clot (thrombolysis)
Important for people who have had a thrombosis
Releases clot and saves patient from severe tissue damage

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75
Q

3 areas of immune response

A

Anatomical and physiological barriers
Innate immunity
Adaptive immunity

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76
Q

Anatomical and physiological barriers - examples

A

Intact skin - staforius
Cilary clearance
Low stomach pH - most pathogens don’t survive
Lysozyme in tears and saliva - good at disrupting surface of bacteria

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77
Q

Innate immunity - sub-types

A

Cellular component:
Myeloid lineage gives rise to WBC involved in cellular component

Humoral component:
Soluble proteins in blood designed to opsonise microorganisms as soon as they contact them

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78
Q

Innate immunity - examples

A

Cellular component:
Neutrophils and macrophages

Humoral component:
Complement
Lectin binding proteins that activate complement - recognises you need carbohydrates found on surface of bacteria –> anti-microbial peptides (e.g. guts, saliva) bind to surface of bacteria

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79
Q

Innate immunity vs adaptive immunity

A

Innate immunity doesn’t change / strengthen over time

Adaptive immunity strengthens / adapts the longer you are exposed to an antigen

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80
Q

Immune response - tolerance

A

In both innate and adaptive response, immune systems are said to be tolerant to self
If tolerance is broken, often leads to autoimmune disease

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81
Q

Main types of pathogens

A

Viruses
Bacteria, yeast, fungi
Protozoa and other parasites

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82
Q

Innate immunity provides…

A

Our first-line / immediate response to pathogen invasion

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83
Q

Innate immunity is highly developed with which 3 interlinked processes

A

Complement (C’)
Myeloid cells and phagocytosis (neutrophils and macrophages)
Pattern Recognition Receptors (PRR)

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84
Q

Innate immunity has no…

A

Memory

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85
Q

3 main types of pathogens require…

A

3 different defense strategies

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86
Q

Viruses

A

Intracellular pathogens
Defense relies on cellular immunity - must be able to distinguish infected from normal cells
Replicate on their own - carry genes that provide for enzymes that allow them to replicate once they use host machinery
Most viral infections onset within 24-48 hours and take 10 days from start to finish

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87
Q

Bacteria

A

Mostly extracellular pathogens
Defense primarily mediated by innate mechanisms and phagocytosis
Slightly higher order of pathogens

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88
Q

Protozoa and parasites

A

Complex multicellular organisms
Large - too big to be engulfed by phagocytic cells
Require direct killing by chemical mediators released by specialist myeloid cells (basophil, eosinophil, mast cell) - filled with cytotoxic chemicals released by degranulation (e.g. histamine)

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89
Q

Main bacteria distinguished by Gram stain

A

Gram positive bacteria

Gram negative bacteria

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90
Q

Gram positive bacteria

A

Thick peptidoglycan cell wall as defense –> lights up with Gram stain
Requires phagocytosis and aren’t killed directly by complement

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91
Q

Gram negative bacteria

A

Thin peptidoglycan layer surrounded by outer membrane –> doesn’t light up with Gram stain
Can often be lysed directly by complement membrane attack complex

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92
Q

Peptidoglycan wall

A

Present in most bacteria

Mechanism by which antibiotics work

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93
Q

Bacteria and antibiotics

A

Bacteria are able to develop resistance to antibiotics

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94
Q

Neutrophil extravasation

A

Ability of neutrophils to identify site of infection by recognising endothelial cells on inner wall of capillary that’s closest to infection
Whole process takes only minutes from first point of tissue injury

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95
Q

Neutrophil extravasation - steps

A
  1. Activation - chemokines from inflammation activates local endothelial cells lining an adjacent capillary wall
  2. Tethering - neutrophil tethers to inside capillary wall. Mediated by selectins unregulated on endothelial cells and sLe^x
  3. Adhesion - strong binding between neutrophil integrins and ICAM-1 on endothelium. Neutrophil immobilises and flattens
  4. Diapadesis - neutrophil squeezes between endothelial cells into interstitial space
  5. Chemotaxis - neutrophil migrates along a chemokine gradient to site of infection
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96
Q

sLe^x

A

Sialyl Lewis X

A carbohydrate antigen on neutrophils

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97
Q

Neutrophils phagocytosis of opsonised S aureus - colour

A

Neutrophils are phagocytosing opsonised S. aureus made green by a fluorescent dye

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98
Q

Neutrophils phagocytosis of opsonised S aureus - steps

A

Chemoattractants (e.g. C5a) are released that radiate away from bacteria and sensed by leading edge of neutrophil
Neutrophils migrate up chemoattractant gradient - polymerising actin filaments at leading edge and de-polymerising filaments at trailing edge

99
Q

Neutrophils - complement

A

Neutrophils have receptors that bind deposited complement proteins, mainly C3b on the surface

100
Q

Complement receptors

A

CR1, CR2, CR3, CR4
Myeloid cell receptors that bind activated complement components deposited on bacteria
CR1 is the main neutrophil receptor and binds to C3b
Cross-linking of surface CRs initiates phagocytosis

101
Q

FcR (antibody) mediates phagocytosis - steps

A
  1. Antibody (IgM and IgG) bind to bacterial antigens
  2. Exposes antibody Fc region
  3. Neutrophil FcR binds multivalent Fc
  4. Activates phagocytosis
102
Q

Phagocytosis - steps

A
  1. Ingestion - bacterium is captured by receptors, membrane invaginates into phagosome
  2. Fusion - phagosome and lysosome fuse to form a phagolysosome
  3. Acidification - phagolysosome acidifies with H+ pumped in
  4. Digestion - acidification activates protease and stimulates production of superoxides which kill bacteria (e.g. H2O2 and HOCl)
  5. Exocytosis - expulsion of digested microbe
103
Q

Molecular pattern recognition

A

Innate mechanism

Pattern recognition receptors (PRR) bind complex molecules that are unique to microbes

104
Q

Molecular pattern recognition - TLR

A

Toll-like receptors

Activation through TLR stimulates strong innate response through an important inflammation pathway

105
Q

Pathogen Associated Molecular Patterns (PAMPs)

A

Molecules unique to microbes recognised by PRRS
Structurally complex
Evolutionarily stable
Stimulate the ‘power’ switch for adaptive response

106
Q

LPS

A

Lipopolysaccharide
Membrane component of all gram negative bacteria
Type of PAMP
A ‘pyrogen’ - causes fever and inflammation when injected into bloodstream by binding and cross-linking of TLR4, stimulating an inflammatory response

107
Q

TLR4 and LPS

A

TLR4 is the receptor for LPS

108
Q

Septic shock

A

Release of LPS by Gram negative bacterial infections leads to life threatening septic shock

109
Q

B cells and T cells have ability to…

A

Rearrange a genetic locus to form 2 important molecules; cell surface receptor on surface of T cells and other starts off as cell surface receptor but then becomes a soluble antibody molecule
In B cells, it’s called immunoglobulin locus
In T cells, it’s called T cell receptor locus

110
Q

Immature B cell receptor

A

Has a receptor on surface, designed to recognise antigens

111
Q

Adaptive immunity

A

Fundamental feature of all higher organisms
Genes that regulate adaptive immune response are identical in all species
Relies on randomly produced antigen receptors
Memory - secondary response stronger and more rapid than primary response
Affinity of B cells towards antigen increases with time and persistence of antigen

112
Q

Adaptive immunity - vaccinations

A

When vaccinated, we generate an immune response which lasts almost our lifetime
Memory B cells are primed to recognise the toxin whenever we encounter it

113
Q

Adaptive immunity - repertoire of B and T lymphocytes

A

Born with large repertoire of B and T lymphocytes
Each lymphocyte represents a diff antigen specificity randomly produced by rearrangement of genes coding for the antigen receptors

114
Q

Adaptive immunity relies on…

A

Phenomenon of gene arrangement or recombination - the only genetic locus capable of this

115
Q

Affinity

A

The ability of molecules to recognise and bind tightly to antigens

116
Q

Immune repertoire developed before birth - problem and solution

A

Don’t know what antigens the individual will be exposed to throughout lifetime
Develops as many possible combinations of antigen-binding molecules as possible

117
Q

Antigen - lymph nodes

A

Antigen is taken up into lymph nodes and develop germinal centres and lymphoid follicles
Starts to produce lots of progeny that have similar but developing antibody molecules

118
Q

Features of transposon

A

Enzyme called transposase (does cutting and insertion)

Recognition sequences at end of transposal element

119
Q

Transposase - working in ‘trans’

A

Enzyme can work on bits of genes without affecting its own location

120
Q

RAG1 and RAG2

A 
Transposases
Recombination Activation Genes
If not present, no immune system will develop
Have a single exon
Responsible for rearrangement 
Only active in B and T lymphocytes
121
Q

Recognition sequences (RS)

A

Base pair sequences found at ends of any gene segment that rearranges
Substrate for RAG1 and RAG2 directed recombination

122
Q

Immunoglobulin (Ig) protein fold

A

Common fold
Repeated Ig domains form antibodies
Loops: where antigen binding site and rearrangement occurs
Loops at ends of strands are not constrained so can vary amino acid sequences without affecting stability of fold (but not all Ig domains vary amino acid sequences)

123
Q

Immunoglobulin (Ig) protein domain fold - β sheets

A

Ig protein domain fold is called a β-barrel of ~110 amino acids
Two stable anti-parallel β-pleated sheets joined in middle by a disulphide bond

124
Q

When is there affinity

A

When the sum of attractive molecular forces at two surfaces exceed the repulsive forces
The higher the affinity, the fewer molecules it takes per unit volume to associate and dissociate slowly

125
Q

Avidity

A

Results from multiple affinity contacts
Strength of binding can be orders of magnitude higher than individual affinities (avidity > sum of all affinities)
When an antibody binds to its antigen, it comes and stays together for a certain length of time

126
Q

Affinity - molar concentrations

A

Number of molecules needed of antibody and antigen to give 50% bound as an antigen-antibody complex

127
Q

Affinity - dissociation constant

A

How long it takes before the complex dissociates away from equilibrium after you remove the reactants

128
Q

Equilibrium constant

A

The conc of antibody and antigen where 50% remains bound to the complex

129
Q

Ig effector functions and associated Ig molecules

A

Activates complement: IgG, IgM
Secreted at mucosal surfaces: IgA
Placental transfer - foietal immunity: IgG
High affinity receptor on mast cells: IgE
Membrane bound form: IgM, IgD

130
Q

Ig molecule gene name / classes (greek)

A 
IgG: γ - most abundant
IgM: µ
IgA: α
IgD: δ
IgE: ε - least abundant
Gene codes for heavy chain
131
Q

B cells - Ig genes

A

Use µ gene first, resulting in a membrane bound IgM molecule - this is the B cell antigen receptor
After activation, B cell switches to using a heavy chain gene, typically γ

132
Q

Complementarity

A

An antibody can form complementarity to virtually anything because the potential amino acid diversity at the antigen binding site is vast

133
Q

Complementarity - affinity

A

Affinity arises when sum of attractive forces exceeds sum of repulsive molecular forces

134
Q

Somatic hypermutation

A

Occurs in germinal centres in lymph nodes
Start off with large repertoire
A few of those B cells will be involved in recognition of pathogen, which go to lymph nodes and undergo affinity maturation
2-3 months after immunisation boosting, you now have memory cells which have a higher affinity antibody against that specific pathogen –> strong protection

135
Q

Complementarity Determining Regions (CDR)

A

Amino acid variation is found in 3 discrete regions called CDR (1, 2, 3)
3 loops that connect strands in 1st domains of H and L chains
3 loops from V(H) and V(L) juxtapose in folded protein to form a roughly rectangular surface of ~800-1000 Å2
Loops form within beta strands
Where amino acid diversity occurs
2 identical antigen binding sites

136
Q

Recombination in Ig locus

A

Germ-line genes segmented into clusters: Variable (V), Diversity (D), Joining (J) and Constant (C) regions
Light chain locus has no D segments
D to J, then V to D
Intervening DNA is lost

137
Q

Recombination in Ig locus - precision

A

Joining is very imprecise, so base pairs are changed during repair
Leads to huge variation at VDJ joining
Most important mechanism for generating diversity in B and T cell repertoires at birth

138
Q

Recombination in Ig locus - which sections code for CDR 1, 2 and 3

A

CDR 1 and 2: V segment

CDR 3: VDJ region

139
Q

For every B cell…

A

There is one antigen specificity

140
Q

Clonal selection theory

A

When a baby, have naive repertoire of B cells
Encounter an antigen –> one of those B cells have a receptor which responds weakly to antigen –> undergoes mitosis
Migrates to a lymph node and produce progeny
Within those progeny, since that gene is undergoing somatic hypermutation, some of those B cells will have slightly higher affinity for antigen
Over time, end up with lots of B cells with higher affinity designed for that specific antigen than original clonal B cell
Results in higher affinity and reactive B cells that sit in lymphoid tissue for lifetime, waiting for next time you’re exposed to that antigen
When that happens, memory B cells rapidly produce plasma cells

141
Q

Lymph node follicle

A

Where clonal selection takes place
Occurs more often in exposed areas
Contains germinal centres
Contains T cells

142
Q

Lymph node follicles - T cells

A

Generate B cell progeny which develop higher and higher affinity
Eventually, some of those become high affinity memory cells that provide protection

143
Q

How cells become T cells

A

Haemopoietic lymphoid precursors migrate from bone marrow to thymus and mature into T lymphocytes (part of cellular adaptive response)

144
Q

T lymphocytes expression of co-factors

A

When they reach the thymus, they express co-factors CD4 and CD8 (referred to as double positive immature thymocytes)
This is the only time T cell expresses both receptors together

145
Q

T cells - learning in thymus

A

Go through a process of education in thymus, learning what ‘self’ looks like (MHC molecules expressed in thymic tissue)

146
Q

T lymphocytes - co-factors

A

CD4 helper T cell (~80% in blood)

CD8 cytotoxic T cell (~20% in blood)

147
Q

T lymphocytes - CD4 sub-factors

A

Treg - regulates immune response
Th1 - drive cellular response (when pathogen demands a cellular immune response)
Th2 - predominate when antibodies or humoral/B cell response required. regulates B cell response
Th17 - control of inflammatory response

148
Q

Thymus

A 
Primary lymphoid organ
Gland
Part of lymphoid tissue
Largest (most active) just before/after birth and shrinks with age
Sits at top of pericardium above heart
149
Q

T cells - survival in thymus

A

Only a small percentage of T cells survive thymus as mature T cells
Most die from neglect, either:
- didn’t recognise correct antigen to allow them to undergo mitosis - negative selection
- have recognised right ‘self’ antigen, but responded too strongly –> actively killed by apoptosis - positive selection

150
Q

MHC

A

Major Histocompatibility Complex
Polymorphic genes (diff in almost everyone except identical twins)
Genetic locus that regulates histocompatibility
Control tissue transplantation
Detect intracellular pathogens i.e. viruses and kills the cell
Code for HLA on cell surface

151
Q

T cells recognise

A
  • infected cells to either kill them or provide help to other cells that reduce ability for virus to replicate
  • antibodies (MHC) that actively present viral antigens to them
152
Q

Tissue / bone marrow transplantation - MHC match

A

Tissue transplanted from donor to recipient is as closely matched in MHC as possible, otherwise immune system of recipient will recognise donor cells as foreign and kill them - tissue rejection (learned)

153
Q

What is ‘nonself’

A

Anything that changes MHC

e.g. viruses, bacteria

154
Q

HLA

A

Human Leukocyte Antigens
Human version of MHC
Expressed on most cells
Present peptide antigens to T cells
Highly polymorphic
6 diff molecules expressed on human cells
Genes that encode for HLA molecules are diff across individuals

155
Q

CTL

A 
Cytotoxic T cells
React to own cells when there's a change in MHC class I molecules, i.e. when they express a neo-antigen picked up from inside the cell (viral or altered self-antigen)
Have ability to generate perforins / pore-forming molecules that are inserted into target cells to kill them - effective for anti-tumour activity
156
Q

Production of congenic mice

A

A skin transplanted to B
Backcross AxB with B
Repeated >20 times
AxB(20) is congenic with original B strain

157
Q

Congenic mice experiment

A

Infect mice with LCMV (brain virus)
Isolate lymphocytes from spleens after 1 week
Mix lymphocytes from strain A or B with virus infected epithelial cells from either A or B
Result: cytotoxic T lymphocytes only killed LCMV infected cells from same strain

158
Q

Viral immunity antigens

A

Self: antigen(s) encoded by MHC

Non-self: antigen(s) encoded by virus

159
Q

T cell receptor and MHC on target cell

A

T cell receptor recognises MHC on target cell which was changed because a new antigen was inserted
T cell receptor molecule makes physical contact

160
Q

T cell receptor

A

Membrane bound Ig-like molecule on T lymphocytes

161
Q

H2

A

Antigens on mouse cells

162
Q

Types of HLA

A

Class I: A, B, C
Class II: DR, DP, DQ
Serve diff roles

163
Q

How many diff antigens expressed on surface of cells?

A

12

164
Q

MHC class I HLA - A, B, C

A

Polymorphic region - alpha helices that sit along top of sheet are polymorphic - amino acid sequence vary between individuals
Peptide comes from virus
As MHC is produced on ribosome and moves into Golgi, it picks up peptides, folds, and is transported to cell surface where it remains for a length of time

165
Q

β2M (microglobulin) - purpose

A

Holds molecule in right conformation

166
Q

MHC class II HLA - DR, DP, DQ

A

2 chains - α and β
Polymorphic groove - allows peptide to bind to it
Peptide longer than in class I as it comes from a diff source (typically from antigens taken from extracellular pathogens)

167
Q

MHC restriction =

A

MHC + peptide

168
Q

CD4 and CD8 - differences

A 
CD4: helper T cells recognise antigens in MHC class II
CD8: cytotoxic T cells recognise antigens in MHC class I
169
Q

CD4 and CD8 - similarities

A

Accessory molecules that physically associate with TcR
Have intracellular tyrosine kinases associated with their cytoplasmic tails that initiate T cell signalling through phosphorylation
Crucial to immune activation

170
Q

CD4+ helper - function

A

HELP
Interacts with surface of macrophage
Huge production of cytokines and proliferation of T cells which form basis of T cell help

171
Q

CD8+ cytotoxic (CTL) function

A

KILLING
Recognises surface of infected cell
Complex forms, T cell become activated
Killing by introduction of perforins and granzyme that punch holes in target cell membrane and destroy cell viability

172
Q

Roles of MHC class I and II - summary

A 
MHC class I:
Peptide source - intracellular
Pathogen - viruses
Responding T cells - CD8
Effector function - cytotoxic
Capture short amino acid peptides generated by viral replication inside cell and presents them to cytotoxic cells
MHC class II:
Peptide source - extracellular
Pathogen - bacteria
Responding T cells - CD4
Effector function - help
173
Q

MHC polymorphism is restricted to…

A

The protein domains that form the peptide groove

174
Q

MHC polymorphism - co-dominance

A 
An individual expresses both maternal and paternal genes 2 x 3 MHC class I and 2 x 3 MHC class II molecules
Total of 12 polymorphic molecules expressed in cells
175
Q

Haplotype polymorphisms

A

Different variations of MHC

176
Q

Anchor amino acids

A

Where amino acid side chains point down into MHC molecules and anchor them

177
Q

Why is MHC so polymorphic

A

Diff in diff countries - haplotypes evolved to provide defense against particular pathogens those communities are likely to face
Polymorphism designed to create a broad capacity to provide protection for species as a whole

178
Q

MHC polymorphism - major consequences

A

Tissue transplantation is difficult except identical twins - requires careful matching and immunosuppressive drugs
MHC polymorphisms strongly linked to many autoimmune diseases

179
Q

When is tissue typing more/less important

A

Not as important in heart and lung tissue transport

Important if transplanting cells involved in immune recognition and defense (i.e. bone marrow)

180
Q

Heterologous bone marrow transplant

A

Relies on patients that are as closely matched as possible (unlike analogous bone marrow transplant)

181
Q

Most susceptibilities to a disease are of…

A

A strong MHC component

182
Q

Major types of type I allergies (examples)

A

Asthma (1/6 NZers)
Allergic rhinitis (seasonal hay fever)
Skin (dermatitis) eczema, urticaria (hives)
Insect allergies (house dust mite, bee stings)
Animal dander
Drugs (penicillin)
Large food proteins (gluten, peanut)
Nickel (metal induced contact dermatitis)
Anaphylaxis - may involve other organs

183
Q

Classifications of hypersensitivity

A

Type I:
Atopic allergy
IgE mediated
Immediate

Type II:
Complement mediated
Medium

Type III:
Serum sickness
Less common
Immune complexes
Medium

Type IV:
Delayed type (DTH) - involves adaptive immune response
Slow response

184
Q

Mast cells

A

Innate immune cells in the myeloid lineage that reside in skin
Provide protection against complex organisms that can’t be engulfed by phagocytosis

185
Q

Type I (atopic allergy) - mast cells

A 
Have Fc receptor on surface called Fc epsilon - receptor for IgE class of antibodies
Pre-coated with IgE that has been primed against a particular allergen; usually occurs early on in birth
186
Q

What does IgE regulate

A

Low conc, but regulates atopic allergies

187
Q

Type I hypersensitivity - pollen

A

Recognised and attaches to IgE
Lots of IgE on surface of mast cell –> cross-linking since pollen grains are large
Mast cells activate and degranulate, releasing chemicals, e.g. histamine, leukotrienes, prostaglandin, free radicals and substance P which work together to destroy the pollen

188
Q

Type I hypersensitivity can cause…

A

Smooth muscles to constrict
Blood vessels to constrict
Mucous glands to produce mucous/release fluid –> swelling
Platelets attracted to side –> platelet aggregation of clotting
Sensory nerve ending stimulation –> pain
Recruitment of other innate cells which also have granules released at sites of inflammation

189
Q

Type I hypersensitivity - CD4

A

Th1 or Th2

190
Q

What regulates type 1 hypersensitivity

A

Histamine

191
Q

Type II hypersensitivity

A

Involves FcR, complement and neutrophils
Antibody present in new-born baby that reacts to a protein on the surface of their RBCs basement membrane –> induces response by attracting neutrophils and complement
Neutrophil tries to digest membrane of RBC, resulting in lysis of RBCs
Causes hemolytic anemia AKA rhesus

192
Q

Rhesus anemia - parents must be…

A

Mother must be rhesus negative and father must be rhesus positive
Gene is dominant –> always expressed

193
Q

How does rhesus anemia affect babies

A

RhD from 1st baby may pass through placenta to mother, causing the mother to have B cells producing anti-RhD in her blood
First born not as affected
Anti-RhD passes onto next (2nd) baby through placenta, so when second baby is born, it succumbs to hemolytic anemia because antibody induces type II hypersensitivity

194
Q

Rhesus - treatment

A

Test mother and father
If mother negative and father positive, mother will receive an antibody which kills any RBCs that might have been transferred into her blood from the first baby –> prevents development of rhesus in following children

195
Q

Treatment of allergy by desensitisation - success rate

A

Works in approx 50% of patients

196
Q

Treatment of allergy by desensitisation - method

A

Skin scratch test to identify allergens

Increasing dose of allergen injected every week for 12-24 weeks
Drives B cells to produce IgG rather than IgE against the allergen
Goal is to have IgG bind to allergen before it binds to IgE
Note: IgG is more abundant than IgE

197
Q

Monoclonal antibodies - where was it first tested/observed

A

Spleens of mice to see if genes were changing over time, particularly if there were somatic mutations occurring in CR1, 2, and 3 that led to the higher affinity antibodies

198
Q

Define monoclonal

A

Single specificity and single binding affinity - can be highly specific and used for a range of purposes

199
Q

What is typically used when making monoclonal antibodies

A

Bacteria

Used to only use mouse genes, but now can use human genes –> humanised –> not rejected by body

200
Q

Making monoclonal antibodies - PEG

A

PEG fuses membranes of cells together; mix splenocytes and mouse myeloma line in correct ratio to get ~1:1 fusion between 1 B cell and 1 myeloma cell –> produces hybridoma

201
Q

Monoclonal antibodies - hybridoma

A

Hybrid between B cell and myeloma cell

Often still produces antibody the B cell was producing

202
Q

Making monoclonal antibodies - selection

A

Add a selective chemical that kills off myeloma cells that haven’t fused and put them on a plate
By 2 weeks, there are colonies of hybridomas that have grown out of a single cell and produce monoclonal antibodies
Take the hybridomas and put them in wells, then take supernatant (containing antibodies) and put on top of antigen that was coated to other microtiter plate
Add colour agent to show where there is an antibody

203
Q

Monoclonal antibodies - advantages

A

Highly specific for intended target, so no ‘off-target’ effects
Can be tailor-made with the right affinity
Humanised so stay in blood stream for months
No adverse reactions or toxicity to antibody
Can be modified to be bi-specific for great potency

204
Q

Monoclonal antibodies - disadvantages

A

Expensive to develop and make commercially

Side effects of functions can be serious

205
Q

What is serum

A

Plasma without the clotting factors

206
Q

Haematocrit

A

A measure of the percentage of whole blood occupied by erythrocytes

207
Q

The intrinsic and extrinsic pathways of blood clotting are identical after formation of _____

A

Prothrombin

208
Q

Major function of RBCs

A

Gas transport

209
Q

Blood functions

A

Transport heat
Protect against infectious disease
Transport nutrients
Regulate blood pH

210
Q

Which plasma protein plays a role in blood clotting?

A

Fibrinogen

211
Q

Which blood cell releases granules that intensify the inflammatory response and promote hypersensitivity (allergic) reactions?

A

Basophils

212
Q

An acute allergic response can lead to…

A

Anaphylactic shock

213
Q

Inability of the immune system to protect the body from a pathogen causes…

A

Immunodeficiency

214
Q

Function of C3 component of complement

A

Forms part of a convertase on the bacteria and is recognized by neutrophils through the receptor CR1

215
Q

An inflammatory response that occurs immediately upon exposure to an antigen is likely to be mediated by…

A

IgE and mast cells

216
Q

Coagulation - Many parasites and other microbes that rely on blood flow produce…

A

Powerful anti-coagulants that typically target the thrombin step

217
Q

Virulence factors

A

A protein produced by many microbes that inhibits the complement cascade

218
Q

Which cell is most associated with innate immunity

A

Myeloid

219
Q

CD34 antigen marker defines…

A

A small pop of cells giving rise to all blood cells

220
Q

Thrombin cleaves….

A

Fibrinogen to fibrin during coagulation

221
Q

What is a possible cause of cherry red blood

A

Poisoning

222
Q

What is unique to the adaptive immune system

A

Immunoglobulins

223
Q

What are essential components of gene recombination in Ig and TcR loci

A

RAG and recognition sequences

224
Q

Fc receptors activate phagocytosis upon….

A

Cross-linking

225
Q

Germ-line gene rearrangement involves…

A

imprecise joining of V, D and J segments, which are the most important part

226
Q

Viral immunity requires…

A

Dual recognition of self MHC and viral antigen (T cells)

227
Q

Maritoux skin test for tuberculosis - type

A

Type IV - delayed hypersensitivity response

228
Q

Affinity maturation

A

Takes place within germinal centre of lymph node follicles
Results from somatic hypermutation of rearranged Ig gene progressively producing higher affinity antibodies after B cell encounters the antigen

229
Q

Enzyme Factor Xa

A

Cleaves prothrombin to active thrombin

230
Q

Cb3 forms a principle component of..

A

Irreversibly bound convertase complex on bacterial surfaces

231
Q

What is the likely first event to happen when bacteria enters the skin

A

Complement proteins react and opsonise the bacteria

232
Q

TLR binds to…

A

A range of molecules unique to viruses and bacteria

233
Q

FcR

A

Myeloid cell receptors that bind antibodies coating a microbe, NOT to bacterial surfaces

234
Q

Which step leads to greatest amino acid diversity in CDR3 loop and TcR V domains

A

Random editing of base pairs prior to joining D to J and V to D segments

235
Q

Fcε (epsilon) receptor triggers…

A

Mast cell degranulation when bound to IgE and allergen

type I allergy

236
Q

Monoclonal antibodies have a single specificity towards … and are produced by…

A

1 epitope

Hybridoma

237
Q

Anaphylatoxins

A

Potent activators of neutrophil phagocytosis
Chemoattractants that recruit neutrophils to site of infection
Small polypeptides cleaved from complement C3, C4 and C5

238
Q

What components are common to both intrinsic and extrinsic pathway of coagulation

A

Factor X (10) and prothrombin

239
Q

Opsonisation - basic definition

A

Irreversible coating of bacteria by complement proteins

240
Q

Ig domain

A

A highly stable protein fold that allows amino acid variability in loops connecting its β-strands

241
Q

AIDS

A

Caused by depleting CD4 T-lymphocytes, preventing essential cytokine help to the immune system

242
Q

T-lymphocytes - class I and class II

A 
CD4 T cells recognise antigen presented by MHC class II
CD8 T cells recognise antigen presented by MHC class I
243
Q

Antibodies can…

A

Agglutinate and precipitate antigen
Neutralise antigen
Enhance phagocytosis

244
Q

Clonal selection of B-cells - antigens

A

Antigens are responsible for determining which cells eventually become cloned

BIOSCI 107 (7 decks)

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