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BOD MVST 1b > Immunology > Flashcards

Immunology Flashcards

1
Q

IFN1alpha and beta

A

Produced by virus infected cells
Interferon response
Induce resistance to viral replication in surrounding cells
Induce expression of ligands recognised by NK receptors
Activate NK cells to kill

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2
Q

CXCL8/IL8

A

Secreted by local Mphage
Recruit and activate neutrophils, basophils and T cells to site of infection
Causes LFA-1 integrin to change to high affinity binding state + forms gradient for neutrophil in migration by sticking to extracellular matrix

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3
Q

IL-12

A

Produced by local Mphage
Activates NK cells and causes their proliferation
Induces CD4+ to differentiate into Th1 cells

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4
Q

IFN-gamma

A

Produced by activated NK cells and CD8+ T
Activates macrophages and upregs killing capacity
Th1 promoter
Induces expression of vascular adhesion molecules

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5
Q

IL6

A

Lymphocyte activation
Increased antibody production
Feber
Stim hepatocytes to release acute phase proteins including CRP and fibrinogen
Induces differentiation of CD4 cells into Th17 or Tfh

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6
Q

CRP

A

Opsonin and complement activation

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7
Q

Fibrinogen

A

Fibrin clot formation

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8
Q

Prostaglandins

A

Made by COX pathway

Induce vascular permeability, vascular dilation, neutrophil chemotaxis

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9
Q

Thromboxane

A

Made by COX pathway

Induce platelet aggregation and blood vessel constriction

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10
Q

PAF

A

Platelet activating factor
Lipooxygenase pathway from arachidonic acid
Induce platelet activation, eosinophil chemotaxis, neutrophil activation

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11
Q

Leukotrienes

A

Lipooxygenase pathway from arachidonic acid

Induce bronchial smooth muscle contraction, neutrophil chemotaxis, slow reacting substance of anaphylaxis SRS-A

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12
Q

How do you induce phagocytosis?

A
  1. C3b binds to CR1 (or CR3) and

2. C5a binds to C5AR1

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13
Q

What clinical condition do you get from low CR1 levels and why?

A

Immune complex disease

Normally highly expressed on erythrocytes, where they bind immune complexes and take them to be cleared by the liver

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14
Q

What is MBL?

A

Mannose binding lectin
Collectin with collagen and lectin domains
Soluble PRR - binds mannose and fucose round on microbial surfaces of pathogen
Activates complement via lectin pathway

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15
Q

Which complement components are involved in the alternative pathway?

A

C3
C3H2OBb = fluid phase C3 convertase
C3bBb = alternative pathway C3 convertase

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16
Q

Which complement components are involved in the lectin pathway?

A 
MBL, MASP1 and 2
C4
C2
C3
C4bC2a = classical C3 convertase
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17
Q

Which complement components are involved in the classical pathway?

A 
C1 (q, then r and s)
C4
C2
C3
Uses C4bC2a = classical C3 convertase
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18
Q

Which complement components are involved in the membrane attack complex?

A

C3b2Bb = alternative C5 convertase
C4bC2aBb = classical pathway c5 convertase
C5b
C5b67
C5b678
C5b6789
Used against gram - bacteria and enveloped viruses

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19
Q

Properdin

A

Positive regulator alternative pathway

Stabilises C3bBb and C3b2Bb (MAC formation)

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20
Q

Factor I

A

Negative regulator
Constitutively active serine protease that degrades C3b and C4b
Requires MCP and factor H cofactors

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21
Q

Membrane cofactor protein

A

Induces dissociation of C4bC2a (lectin and classical pathways) and C3bBb (alternative) by factor I

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22
Q

Complement receptor 1

A

Negative regulator of complement cascades
Decay accelerating capacity and factor I cofactor activity
Induces dissociation of C4bC2a (lectin and classical pathways) and C3bBb (alternative) by factor I

Mediates phagocytosis

Immune adherence (to clear Ab-Ag complexes)

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23
Q

Factor H

A

Main control factor to PROTECT THE HOST
Soluble cofactor for factor I
Attaches to sialic acid present on host membranes, but absent from most bacteria
Causes dissociation of C3bBb and makes C3b susceptible to cleavage by factor I

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24
Q

DAF

A

Decay accelerating factor
Present on host cells
Dissociates the classical and alternative C3 convertases (Bb leaves)

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25
Q

Protectin

A

Cell surface protein, binds MAC intermediate C5b678, prevents insertion into membranes
Also interacts with C9 and prevents its recruitment to the MAC complex

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26
Q

C1-4 defects?

A

Immune-complex disese, infection

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27
Q

C3 defect?

A

Susceptibility to infection by pyogenic bacteria (encapsulated bacteria) as C3 is an important opsonin
e.g. Staph or strep

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28
Q

C5-9 defect?

A

MAC component defects
Lack of complement mediated lysis
Recurrent Neisseria infections

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29
Q

Factor D/properdin defect?

A

Can’t make C3b. Less opsonisation and phagocytosis. So control of encapsulated/pyogenic bacteria compromised, especially N. meningitides

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30
Q

Factor I, Factor H defect?

A

Depletion of C3 due to uncontrolled alternative pathway activation leads to susceptibility to pyogenic infections especially N. meningitides

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31
Q

DAF/protectin defect?

What can it be due to?

A

GPI-anchored proteins so due to reduced GPI synthesis
On RBCs
Causes paroxysmal nocturnal hemoglobinuria - complement mediated lysis of RBCs

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32
Q

How does S. Aureus evade complement?

A
  1. Protected by polysaccharide capsule to prevent opsonisation
  2. SCIN Staphylococcus Complement Inhibitor binds and inactivates C3 convertases if they do assemble, so opsonins aren’t generated
  3. Secretes proteins that bind or degrade and inactivate C3
  4. Secretes staphylococcal protein A that binds the Fc region of IgG blocking complement recruitment and activation
  5. Recruit host inhibitor factor I to bacterial surface by clumping factor A
  6. Chemotaxis inhibitory protein blocks C5a chemotactic receptor on neutrophils limiting their recruitment
  7. Other proteins interfere with neutrophil extravasation to the site of infection
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33
Q

What are TLRs and how many do we have?

A

They are pattern recognition receptors
We have 10
First PRRs to be discovered

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34
Q

What do TLRs trigger?

A
  1. Signalling adaptor molecule MyD88
  2. Downstream signalling events - BACTERIA activate NF-kappaB, AP-1 (a TF) - PRO INFLAMMATORY, and VIRUSES IRFs interferon-regulatory factors - ANTI-INFLAMMATORY
  3. Release of products including inflammatory cytokines, IFN-1, chemokines, antimicrobial peptides
  4. Dendritic cell maturation
  5. Induction of adaptive immune response
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35
Q

Which TLRs are on the cell surface? What do they recognise in general?

A

1245610
Microbial lipids EXCEPT TLR5 - flagellin
–> NF-kappaB, AP-1 pro-inflammatory

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36
Q

Which TLRs are in endosomes? What do they recognise in general?

A

3789

Nucleic acids - dsRNA, ssRNA, DNA –> viral IRF interferon response anti-inflammatory

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37
Q

What does TLR1 recognise?

A

TLR1/2 heterodimer

PAMP: Triacyl lipoproteins (on gram - bacteria)

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38
Q

What does TLR2 recognise?

A 
and TLR2/6 and TLR2/1 heterodimer
PAMP: Peptidoglycan (gram +)
Zymosan (yeast, fungi)
Diacyl lipoproteins, GPI-linked proteins (trypanosomes)
DAMP: HSP, HMGB-1, urate crystals
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39
Q

What does TLR3 recognise?

A

PAMP: dsRNA viral
DAMP: mRNA necrotic cells

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40
Q

What does TLR4 recognise?

A

PAMP: LPS
DAMP: HSP, HMGB-1, oxidised LDL from chronic inflammation of arterial wall in atherosclerosis

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41
Q

What does TLR5 recognise?

A

PAMP: Flagellin

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42
Q

What does TLR6 recognise?

A

TLR2/6 heterodimer
PAMP: Diacyl lipopeptides (gram +)
Zymosan (yeast/fungi)
DAMP: oxidised LDL from chronic inflammation of arterial wall in atherosclerosis

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43
Q

What does TLR7 recognise?

A

PAMP: ssRNA virus
DAMP: ssRNA

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44
Q

What does TLR8 recognise?

A

PAMP: ssRNA virus, phagocytosed bacterial RNA
DAMP: ssRNA, microRNA

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45
Q

What does TLR9 recognise?

A

PAMP: unmethylated CpG-DNA (bacterial DNA)
DAMP: Self-DNA, HMGB-1

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46
Q

What does TLR10 recognise?

A

????

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47
Q

Name some PRRs and what they detect.

A

TLRs - bacterial and viruses that replicate in endosomes mainly
CLR C-type lectin receptors (fungal infections)
RLRs RIG-I-like receptors (viral RNA in the cytoplasm)
NLR Cytosolic NOD-like receptors (cytoplasmic receptors that recognise both PAMPs and DAMPs)
NOD1 NOD2 = recognise fragments of peptideoglycan from bacteria
NOD2 = muramyl dipeptide released from gut microbiota, role in gut homeostasis. Mutations associated with Crohn’s disease
NLRP3/NALP3 - peptidoglycan, bacterial DNA, ATP, toxins, dsRNA. Part of inflammasome

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48
Q

What is the inflammasome?

A

Large cytosolic structure
Linked to diseases - atherosclerosis, gout, Type 2 diabetes
NLRP3 involved - detect peptidoglycan, bacterial DNA, ATP, toxins, dsRNA
Induce inflammation by causing caspase 1 –> IL-1beta
Triggered by cholesterol, monosodium urate (Gout) TXNIP (related to hepatic glucose production in T2Diabetes)

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49
Q

IL-1beta?

A

Formed by caspase 1 caused by inflammasome
Activates lymphocytes, local tissue destruction, increases access of effector cells
Activates vascular endothelium - induces E-selectin
Leads to fever and production of IL6

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50
Q

Examples of DAMPs?

A

HMGB-1, ATP, DNA, RNA, ECM components uncovered by tissue damage, HSPs

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51
Q

Purpose of the acute inflammatory response?

A

Basically = recruit exudate

  1. Dilate blood vessels (Histamine, TNF-alpha, prostaglandins, leukotrienes)
  2. Increase permeability of vessel wall
  3. Recruit cells (leukocytes, neutrophils initially, then monocytes, some infections eosinophisl and plasma cells)
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52
Q

What are the endogenous pyrogens?

A

IL-1, IL-6, TNF-alpha, IFN-gamma

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53
Q

Which cytokines promote cellular immunity/Th1?

A

IFN-gamma, IL-12

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54
Q

Which cytokines promote humoral immunity/Th2?

A

IL4, IL10

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55
Q

Which cytokines are non-inflammatory?

A

TGF-beta, IL4, IL10

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56
Q

What do macrophages secrete?

A
  1. Cytokines - IL-1beta, TNF-alpha, IL-6, CXCL8, IL-12

2. Prostaglandins and leukotrienes

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57
Q

TNF-alpha

A

Triggered by IgE and IgG cross-linking
1. Activates vascular endothelium
2. Increases vascular permeability
Increased IgG, complement and cell entry to tissues
3. Increased platelet adhesion to blood vessel wall
4. Fever,
5. Mobilisation of metabolites
6. E-selectin appears
7. Induce prostaglandin synthesis in the hypothalamus8. Can result in shock

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58
Q

Which receptors on neutrophils help their recruitment and what do they bind to?

A
  1. Sialyl-Lewis X (to P and then E selectin - vessel) for rolling/weak tethering
    CXCL8 receptor -nphil
  2. LFA-1 - nphil to ICAM-1 for tight adhesion - wall
  3. then CD31 on endothelium for diapedesis NB also elastase
  4. follows CXCL8 gradient
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59
Q

What is LAD?

A

Leukocyte adhesion deficiency
Rare immunodeficiency caused by defect in the recruitment of neutrophils due to CD18 defect (beta chain of LFA-1).
Results in recurrent life threatening bacterial infection in infants

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60
Q

How are monocytes recruited?

A

24h later VLA4, the monocyte integrin binds to VCAM1 (endothelial adhesion molecule upreg more slowly)

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61
Q

What is the pathophysiology of septic shock?

A

Burns/widespread endotoxins like LPS –> macrophages in liver and spleen release TNF alpha –> widespread vasodilation –> loss of blood pressure and heart failure (septic shock) and disseminated intravascular coagulation (blood clotting in the small vessels) –> loss of perfusion so major organ failure
Also massive consumption of clotting proteins –> lack of clotting capacity in the blood and bleeding

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62
Q

Why might chronic inflammation occur?

A
  1. Injurious agent endogenous e.g. stomach acid
  2. Injurious agent may be non-degradable e.g. silica
  3. Injurious agent may evade host defences e.g. TB
  4. Host may attack itself e.g. RA autoimmunity
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63
Q

How does an antibody work?

A
  1. Neutralisation
    Blocking biological activity of a target molecule e.g. a toxin
  2. Opsonisation
    Ab coated Ag interact with specific receptors, e.g. on macrophages, allowing them to recognise an Ag more efficiently.
  3. Complement activation
    Ab coated Ag may cause direct lysis by recruiting complement - classical pathway
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64
Q

How do lymphocytes enter lymph nodes?

A

Through specialised endothelia called high endothelial venules

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65
Q

How do follicular dendritic cells trap antigen in B cell area?

A

In complexes of Ag/Ab/C3b

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66
Q

How do dendritic cells enter the lymph node?

A

Afferent lymphatic

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67
Q

How many constant domains do each type of antibody have?

A

IgG, A, D = 3

IgM, E = 4

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68
Q

Where is the flexibility of an antibody?

A

Hinge region and V-C junction (like a ball and socket joint)

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69
Q

How do antigen binding sites vary?

A

3 complementarity determining regions CDRs

CDR3 most variable

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70
Q

How are CDR1, 2 and 3’s variations generated in heavy chains?

A

Somatic recombination of 38-46 genes for variable region - CDR 1 and 2
23 for diversity, 6 for joining - together = CDR3, plus the junctions between rearranged V D and J

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71
Q

How is diversities generated in light chains?

A

Somatic recombination for V then J of first kappa (34-38 V and 5 J) then lambda (29-33 V then 4-5J)

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72
Q

How is antibody diversity achieved?

A
  1. Different light and heavy chain combinations
  2. Different VDJ segments
  3. Junctional diversity
  4. Somatic hypermutation
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73
Q

How is junctional diversity achieved and what is the point?

A

Terminal deoxynucleotide transferase (TdT) addition, addition due to recombination mechanism, deletion
Point = variation! can change between reading frames, add stop codons etc.

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74
Q

How does the B cell undergo somatic hypermutation and where does it do it?

A

Antigen driven so in lymph nodes
Daughter cells of B cells undergo numerous (1/1000) point mutations, including C –> U deamination by AID activation induced cytidine deaminase
If new receptor isn’t an improvement, doesn’t get T cell help

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75
Q

What does the enzyme AID do?

A

Somatic hypermutaiton, isotype switching

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76
Q

What does alternative splicing offer to Ab generation?

A
  • produces IgM and IgD initially

- can choose different polyA sites to either generate soluble or membrane bound Ig

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77
Q

Which Ig has the highest serum level?

A

IgG1

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78
Q

Which Ig has the longest and shortest half life?

A

Longest = IgG1, IgG4

Shortest - IgE

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79
Q

Which Ig can transfer across the placenta?

A

IgG

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80
Q

Which Ig activate complement?

A

IgM IgG123, IgA

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81
Q

Which Ig bind to the Fc of the macrophage?

A

IgG1, IgG3, IgG4, IgA, IgE

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82
Q

Which Ig mainly binds to mast cells?

A

IgE

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83
Q

What are the different subsets of Fc receptor and what is their function?

A

Effector function of Ab, deliver antibody to different sites and link antigen to molecules or cells
1. High affinity

RI Kd 10^-9, bind monovalent Ab/Ag complexes
2. Low affinity FcgammaRI or II, Kd 10^-6, bind multivalent Ab/Ag complexes

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84
Q

FCgammaRI?

A

High affinity for IgG
On macrophage, activated PMN
phagocytosis and respiratory burst neutrophil

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85
Q

FcGammaRIIa?

A

Low affinity for IgG
Macrophages neutrophil
Phagocytosis

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86
Q

FcGammaRIIb?

A

Low affinity for IgG
B lymphocytes
Ab regulation

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87
Q

FcGammaRIIIA?

A

Low affinity for IgG
Only recognises Ab/Ag complexes - ADCC cannot be triggered by free Ig
NK cells, macrophage
ADCC
Signal v strong, one is enough to trigger

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88
Q

FcgammaRIIIb?

A

GPI linked
Low affinity for IgG
Neutrophils
Phagocytosis

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89
Q

Which antibody receptor on NK cells mediates ADCC?

A

FCgammaRIIIa

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90
Q

What does the C3b receptor recognise? What does it do?

A

IgM
Activates complement
Binding delivers complexes to the liver and spleen for removal by macrophages

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91
Q

How are helminths targeted?

A

IgE binds, recognised by FCepsilonRI (high affinity for IgE), triggers eosinophil to release granules containing proteins toxic to helminths

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92
Q

What are the effector functions of Ab?

A
  1. Opsonisation
  2. ADCC (virally infected cells, and via eosinophils for helminths)
  3. Mobilisation of inflammatory mediators
  4. Antibody transport
  5. Antibody feedback to regulate responses
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93
Q

FCepsilonRI

A

On eosinophils for IgE helminth ADCC
On mast cells and basophils, cross linked to cause degranulation and release of inflammatory mediators
Also triggered during allergic reactions when allergens bind IgE on mast cells

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94
Q

Which receptors are on mast cells and basophils?

A

FcepsilonRI and FcgammaRIII

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95
Q

Which Ig protect the mucosal surfaces from infection?

A

IgA and to a lesser extent IgM

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96
Q

How is IgA transported across epithelia?

A

Receptor recognises J chain region and transports it across.

J chain is the disulphide link region of IgM and IgA

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97
Q

How is the baby protected?

A

IgA in milk,

IgG that had been transported across the placenta

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98
Q

How is the humoral response regulated?

A

Ab produced in response to Ag will form immune complexes
B cells specific for the same Ag that have FcgammaRIIB and the BCR bind
acts as a negative signal and terminates the response

99
Q

What is affinity?

A

Interaction between a single antibody binding site and a single monovalent epitope on an antigen

100
Q

What is avidity?

A

Measure of the strength of interaction due to recognition of the polyvalent epitopes

101
Q

Which chromosome is the MHC locus on?

A

6

102
Q

What is the structure of MHC Class I?

A

MHC I: alpha chain non covalently linked to beta2 globulin. Heavy alpha chain has 3 extracellular domains
alpha 1 and 2 form the peptide binding groove, that accommodates peptides 8-9aa long
Base of groove = beta pleated sheet, alpha helices form the sides
Binds to CD8+ cells on alpha3 region

103
Q

What is the structure of MHC Class II?

A

2 similarly sized transmembrane domains - alpha 1 and 2, beta 1 and 2
Peptide binding groove between alpha 1 and beta 1 domains
Binds to CD4+ cells on beta2 region

104
Q

How many peptides do the grooves of MHC class I and II hold? What specifies which can bind apart from length?

A

Class I = 9, 10 if it bends in the middle
Class II = 13-25 as open ended
Certain positions are conserved as these anchor residues have to make specific contacts with pockets in the binding groove
Determine the peptide-binding motif
Means many different peptides can be presented

105
Q

What generates MHC diversity?

A
  1. Polygeny
    3 class I HLA-A, HLA-B, HLA-C
    3 class II HLA-DP, HLA-DQ, HLA-DR
  2. Polymorphism (most polymorphic gene known to man)
  3. Express co-dominantly so twice as many
106
Q

How does the TCR rearrange?

A
  1. Rearrange beta chain D –> J, V –>DJ
  2. Surface expression with Pre-T-alpha (can try lots of times)
  3. Stops beta-chain rearrangement
  4. Cell proliferates
  5. CD4+ CD8+
  6. Alpha chain rearrangement V –> J
  7. Check against MHC Class I and II to see if either recognised
  8. Positive and negative selection begins!
107
Q

How many chances do the heavy chain of the BCR/ the beta chain?

A

BCR: two tries
TCR: many tries

108
Q

Do B or T cells have a higher total diversity?

A

T! not v different Variable region pairs, but much larger junctional diversity in TCR, giving 10^18 potentials, while B 5x10^13 (this is theoretical, there are about that many cells in the whole body)

109
Q

What are T cells selected for?

A
  1. Successful beta chain rearrangement
  2. Positive selection - deletes useless cells that don’t bind to self MHC
  3. Negative selection - deletes autoreactive cells
110
Q

Where does the T cell undergo positive selection?

A

Cortical epithelial cells
Moderate interaction = signal to continue maturing
Lack of interaction = death by neglect
Expression of CD4 and CD8 altered to match MHC restriction

111
Q

Where does the T cell undergo negative selection?

A

Thymus - cells that have a high affinity for MHC/self peptide die by apoptosis
Periphery - MHC/self peptide combinations not expressed in the thymus

112
Q

What pressures are there on peptide binding stringency to MHC?

A

Too low stringency - a large number of different peptides bind, which results in only a few copies of any particular peptide-MHC allele
Too high stringency - many copies of same peptide-MHC on the surface for some pathogens, and also may miss all peptides of pathogens with a small genome
Each MHC can bind 1/1000-1/10000 random peptides
And approx. 100 individual peptide-MHC complexes per cell

113
Q

Summarise the MHC Class I antigen processing pathway

A

Endogenous peptides e.g. viral proteins, present to CD8+

  1. Antigen degraded by proteasome into peptide
  2. moved from cytosol into ER by TAP transporter associated with antigen processing
  3. Peptides of a suitable length and sequence loaded onto partly folded class I molecules assisted by chaperones
  4. Fully fold, released from chaperones
  5. Pass through Golgi
  6. Follow secretory pathway to cell surface
114
Q

Summarise the MHC Class II antigen processing pathway

A

Exogenous proteins, present to CD4+

  1. MHC Class II synthesis passes though ER, to prevent binding peptides they associate with invariant chain Ii (blocks peptide groove, acts as a folding chaperone, targets II/Ii to the endocytic pathway)
  2. II/Ii pass from ER through Golgi
  3. Endocytic pathway
  4. Partly remove Ii, leaving CLIP (a small protein) in the peptide binding groove
  5. Ag uptaken by endocytosis degraded into peptides by proteases
  6. Fuse with MIIC compartments (peptide loading compartments)
  7. CLIP removed, Ag derived peptides with appropriate binding motifs loaded onto class II
  8. Transport to cell surface
115
Q

TCR structure?

A

Like a single Fab
2 polypeptide chains, each domain similar to Ig fold domain (so TCR a member of the immunoglobulin superfamily)
Alpha chain similar to light chain, beta chain similar to heavy chain

116
Q

Difference BCR TCR?

A

TCR monovalent (BCR at least bivalent)
Membrane bound with no secreted counterpart
Doesn’t undergo somatic hypermutation
Only antigen recognition, not linked to effector function

117
Q

How do T cells develop?

A

In the thymus
1. Precursors enter outer sub-capsule
2. Progress through cortex, contact cortical epithelial cells which mediate positive selection
3. Get to medulla, Mphage and dendritic cells trigger negative selection.
Macrophages remove thymocytes that fail to mature

118
Q

What is the major cause of thymocyte death?

A

Lack of positive selection

119
Q

How is the T Cell activated?

A

Co-stimulation
1. TCR binding to MHC
2. Co-stimulatory molecules CD28 on T cell with B7.1/CD80 and B7.2/CD81
and CD40L on T cell with CD40 on APC
(3. Cytokines IL-2 autocrine, TNF alpha, IL1)

120
Q

How is the B cell activated?

A
  1. Binds and internalises Ag
  2. Presented on surface on MHC Class II complexes (endocytic pathway)
  3. Cross linking of MHC with TCR, B7 with CD26, CD40 with CD40L
  4. CD40 binding stim B cell proliferation + class switching

NB!! Certain thymus-independent interactions have an intrinsic ability to stimulate naïve B cells without the need for T cells. These TI Ag are microbial products composed of repetitive elements (PS and LPS) - cross-link membrane Ig and induce B cell proliferation

121
Q

IL-2?

A

Cytokine released by T cells
Acts in autocrine manner to kick the T cell back into the cell cycle
Tregs CD25+/IL2+

122
Q

What are Th1 cells?

A 
Stim by: IL12, IFNgamma
CD4+
Pro-inflammatory - support inflammation and cell-mediated responses
Activate mainly mphage, NK and CTLs
Intracellular pathogens
TF: Tbet
Release: IFNgamma
123
Q

What are Th2 cells?

A 
Stim by: IL10 IL4
CD4+
Aimed in elimination of parasitic infections
Characteristic TF: GATA3
Release: IL4,5,10,13
124
Q

What are Th17 cells?

A

Stim by TGFbeta, IL6
Characteristic TF = RORgamma3
Defence against extracellular bacteria and some fungi. Enhance neutrophil response
Release: IL-17

125
Q

What affects which type of CD4+ cell develops?

A 
Cytokine milieu
Antigen conc (high --> Th1)
MHC/peptide conc
TCR receptor affinity (high --> Th1)
Then self-reinforcing
126
Q

IL4?

A

Induces differentiation of CD4 cells into Th2 cells - promotes humoral immunity
stimulates isotype switching into IgE

127
Q

Which cytokines activate macrophages?

A

IL-12, IFN-gamma

128
Q

What is the danger hypothesis?

A

The immune system recognises infectious non-self

Injection of a protein can result in tolerance, or not on the context

129
Q

What is adjuvant?

A

Mixture that cues the immune system that an infection is taking place
Convert soluble protein into particulate material, contain bacterial products to stimulate PRRs
Complete Freund’s Adjuvant contains ground up mycobacteria

130
Q

What is AIRE?

A

Autoimmune regulator

Expresses many peripheral antigens in the thymus so more negative selection can take place

131
Q

Mutations in AIRE result in what?

A

APECED autoimmune disease

132
Q

How is central tolerance of B and T cells effected?

A
  1. Positive
  2. Negative selection T cells (AIRE)
  3. B cells need T cells to develop, so this should tolerise them
  4. Imperfect, so B cells that react to abundant Ag on self cells eliminated as they develop (apoptosis, or remain attached to Ag in bone marrow - anergy) - clonal selection
133
Q

Why is central tolerance imperfect?

A
  1. Not all antigens are expressed centrally

2. Some Ag aren’t expressed until the immune system is matured

134
Q

What are the mechanisms of peripheral tolerance?

A
  1. Ignorance
    - Ag in immunologically privileged sites
  2. Split tolerance
    - Pathways are interdependent, so don’t need to tolerise all, i.e. leave autoreactive B cells that won’t mature without T cell help
  3. Anergy
    - Induced in T cells if TCR bound by MHC, but second signal not present. T cell anergised. In bone marrow or just after enters peripheral tissue. In B cells too (if large amounts of soluble Ag but not cross-linked at the surface)
  4. Suppression
    - Autoreactive T prevented from reacting by Tregs
135
Q

What are Tregs?

A 
Stim by: TGFbeta, IL4
CD25 - IL-2 receptor +ve
Maintain T cell homeostasis and tolerance, suppress effector T cells
TF: Foxp3
Release: IL10 TGFbeta
136
Q

What are the categories of Tregs?

A

Natural - educated in thymic selection. Intermediate affinity for self Ag and not deleted by negative selection.
Inducible - unsure! Prob due to cytokine profile, chronic-low-dose Ag exposure, lack of costimulation, presentation by immature DCs (i.e in GALT), microenvironment rich in TGFbeta

137
Q

How do Tregs act?

A
  1. Contact self antigen
  2. Suppress proliferation of naïve T cells on the same APC
  3. Maybe via cell contact, or
  4. Non-inflammatory cytokines IL4 IL10 TGF-beta
  5. Activation of an enzyme (IDO) required for T cell growth (lose tryptophan)
  6. Inhibit proinflammatory cytokines
  7. Absorb IL2
  8. Signal to APC to decrease B7 cofactor expression
138
Q

Which disease results from a loss of the TF characteristic of Tregs?

A

FoxP3
IPEX syndrome - profound systemic autoimmunity
Immune dysregulation, polyendocrinopathy, entropathy X-linked (just means intestinal pathology)

139
Q

What does Medawar’s experiment show?

A

Neonatal tolerance depends on timing, dose of Ag, amount of costimulation and location
Mice A injected at birth with B bone marrow accepted a graft from B at 6 weeks, but not from mouse C
If injected with B a week after birth, tolerance is not achieved
B at birth –> chimerism of bone marrow –> some differentiate to APC and migrate to thymus –> tolerise thymocytes
B later –> number and maturity of peripheral T cell pool sufficient to destroy the donor stem cells before they can engraft

140
Q

Tolerance mechanisms in the placenta?

A

Physical barrier to mother’s T cells
Lack of MHC Class I expression on trophoblast cells
Produce immunosuppressive factors like alpha-fetoprotein and IDO (a tryptophan catabolising enzyme)

141
Q

Examples of experimentally induced tolerance?

A
  1. Inhalation tolerance/peptide sniffing: aerosolise MHC-binding peptidesa nd inhaled
  2. Co-receptor blockade: MAb to CD4/8, B7, CD40 can lead to tolerance. Maybe future use to tolerise for tissue grafts
142
Q

What are fungal spores coated with to make them immunologically inert?

A

Hydrophobin

143
Q

How does streptococcus pneumonia evade the immune system?

A

Different strains/serotypes with antigenically different capsular polysaccharides

144
Q

How do trypanosomes evade the immune system?

A

Gene rearrangements frequently

145
Q

How do flu viruses evade the immune system?

A

Antigenic drift and shift (recombination with bird or pig viruses)

146
Q

What on earth is original antigenic sin?

A

Special case of tolerance
Primary response to a pathogen constrains the further activation of naïve cells during a secondary response (via antibody feedback - FCgammaRIIB immune complexes?)
Only common epitopes thus stimulate antibody production if infected by different strains
Host doesn’t respond to new epitopes on reinfecting virus

147
Q

How does herpes evade the immune system?

A

Herpesvirus goes into a latent state and remains dormant within cells, especially neurons as they express very little MHC class I

148
Q

How do staphylococci evade the immune system?

A

Make superantigens which activate large numbers of T cells by bridging between MHC Class II and TCR, masking any specific response

149
Q

How does EBV evade the immune system?

A

Blocks presentation by MHC Class I

Resists degradation by proteasome

150
Q

How does CMV evade the immune system?

A 
Blocks presentation by MHC Class I
Blocks TAP transporter (peptide into ER)
Block and degrade MHC class I
151
Q

How does Kaposi virus evade the immune system?

A 
Blocks presentation by MHC Class I
Remove class I from surface
152
Q

How does cancer evade the immune system?

A

Lose MHC Class I expression by mutation or loss of fragment of chromosome

153
Q

What is autoimmunity?

A

Failure of self tolerance meaning that the immune system attacks host components, causing pathological change

154
Q

Why are some organs more likely to be affected in organ-specific immunity?

A

Well vascularised, and make organ-specific proteins

Thyroid = Hashimoto’s thyroidosis, Grave’s disease. Adrenals. Stomach (pernicious anemia). Pancreas (Type ! diabetes)

155
Q

Discuss Grave’s disease

A

Autoimmune organ-specific condition
Direct Ab mediated effects
AutoAb IgG to TSH receptor. Doesn’t undergo feedback inhibition like TSH, so overproduction of thyroxine and hyperthyroidism –> goitre, bulging eyes, heat intolerance
Th2 response

156
Q

Discuss Hashimoto’s thyroidosis

A 
Autoimmune
Direct Ab mediated effects
AutoAb block hormone production so hypothyroidism. 
Th1 response
Goitre, intense lymphocyte infiltration
157
Q

Discuss myasthenia gravis

A

Autoimmune disease
AutoAb to AChR block NMJ transmission from cholinergic neurons by first blocking ACh binding and subsequently causing downregulation of the receptor
Progressive weakness

158
Q

What is the mechanism of rheumatic fever’s autoimmune pathology?

A

Direct Ab mediated

159
Q

Discuss autoimmune haemolytic anaemia

A

Direct Ab mediated

Rh blood group antigens AutoAb lead to destruction of Th RBCs

160
Q

Discuss Goodpasture’s syndrome

A

Direct Ab mediated effects

AutoAb to Type IV collagen –> glomerulonephritis

161
Q

List autoimmune diseases mediated directly through Ab

A
  1. Graves
  2. Hashimoto’s thyroidosis
  3. Myasthenia gravis
  4. Rheumatic fever
  5. Goodpasture’s syndrome
162
Q

Discuss pathophysiology of SLE

A 
SLE = systemic lupus erythematosus
Auto-Ab-Ag complexes
Anti-cytoplasmic and anti-nuclear autoAb
Leads to butterfly rash on face, glomerulonephritis, vasculitis, arthritis, complement depletion
Most common in African and Asian women
163
Q

What mechanism underlies the pathophysiology of vasculitis?

A

Immune complexes of Auto-Ab-Ag

164
Q

Which autoimmune diseases are mediated by immune complexes?

A

SLE

Vasculitis

165
Q

Name a predisposing factor of SLE

A

Complement deficiency

166
Q

Discuss the pathophysiology of Type I diabetes

A

T cell mediated damage
Doesn’t require AutoAb
CD8+ cells, direct destruction by TNFalpha, recruitment of macrophages and bystander killing, induction of apoptosis by FasL
T cell against pancreatic beta cell Ag

167
Q

Discuss the pathophysiology of rheumatoid arthritis

A

T cell against synovial joint Ag –> joint inflammation and destruction

168
Q

Discuss the pathophysiology of multiple sclerosis

A

T cell against myelin basic protein proteolipoprotein –> brain degeneration and paralysis

169
Q

Name autoimmune conditions mediated by T cells

A

Type II diabetes
RA
MS

170
Q

What is EAE and what does it show?

A

Model of MS - autoimmune encephalitis
If inject MBP myelin basic protein with an adjuvant a Th1 response to MBP develops
If the T cells are isolated and injected, without Ab or adjuvant, they can cause disease in another rat

171
Q

What amino acid polymorphism can result in an increased relative risk of T1Diabetes?

A

LA-DQb chain position beta 57 form -ve asp (creates a salt bridge ) to val/ser/ala (hydrophobic, salt bridge disrupted)
Affects binding of different diabetogenic peptides

172
Q

What is ankylosing spondylitis?

A

Rheumatic disease
90% express the HLA-B27 genotype
T cell mediated TNFalpha and IL-1 implicated (inflammasome)

173
Q

What proportions are the different factors contributing to type 1 diabetes meant to play?

A

Environmental 50%
MHC peptide presentation 25%
Other genes affecting tolerance 25%

174
Q

What triggers autoimmune conditions?

A
  1. Release of sequestered antigen
  2. T-cell tolerance bypass
    i. Modification (neoantigen recognised by T cells) e.g. by binding of a pathogen to self protein, citrullination by environmental factors like smoking
    ii. Inflammation - activates pAPC, may activate anergic/ignorant Ts
    iii. Molecular mimicry - Ab or T cells generated in the response to an infectious agent cross-react with self-antigens
175
Q

How do you create spontaneous autoimmune disease models?

A

Inbreed strains of animals for characteristics like prevalence of autoimmune disease

176
Q

How do you create induced autoimmune disease models?

A

Require:

  1. Presence of genetic susceptibility factors
  2. Treatment of animal to trigger disease e.g. inject spinal chord extract + powerful adjuvant –> EAE
177
Q

Discuss the NOD mouse

A

Create NOD mouse non-obese diabetic
Transfer of CD4+ CD25+ Treg from normal mice delays or suppresses disease
Germ-free environment provides some protection

178
Q

How do you treat autoimmune diseases?

A

If organ-specific replace whatever is missing eg Hashimoto’s thyroidism give thyroxine
otherwise broad immunosuppressive drugs e.g. anti-TNF Ab
Theory - give NOD mice schistosomiasis. The overall response is biased to Th1 or Th2, treatments to stimulate the opposite state may help

179
Q

What are Tfh?

A

Stim: IL6, IL21
TF: BCL6
Help locate B cells to follicles, activate B cells, trigger isotype switching and affinity maturation
Release: CXCR5

180
Q

What are the four types of hypersensitivity reaction?

A 
I = allergic reaction
II = Ab mediated cytotoxic
III = immune complex mediated
IV = T cell mediated/Delayed type
181
Q

How does Type I hypersensitivity work?

A

Mediated by IgE
Cause is contact with Ag to which the host has pre-existing Ab
Mast cells activated by cross linking of FcepsilonRI receptors by Ag binding to prebound IgE.
Rapid response = mast cells degranulate and release histamine and serotonin
6h later = late response. secondary inflammatory mediators released

182
Q

What is the pathophysiology of asthma?

A

Type I hypersensitivity
Chronic inflammation of airways characterised by increased Th2 lymphocytes, eosinophils, neutrophils, basophils. Amplify inflammation and airway remodelling.
Genetic predisposition can be caused due to factors affecting Th1/2 balance: TBet loss, IL4, IgEReceptor, smooth muscle cell behaviour, bronchial physiology

183
Q

What conditions can be caused by type I hypersensitivity?

A

Asthma
Hayfever
Allergic rhinitis

184
Q

What are allergens?

A

Normally proteases, low MW, highly soluble (so readily diffuse into mucus)

185
Q

How do you test for an allergen?

A

Skin-prick test
Few mins: wheal and flare reaction
6h late reaction: swells to spread to surrounding tissue

186
Q

Who are atopic individuals?

A

Individuals who have multiple allergies: hayfever and asthma
Have serum IgE 10-100x normal levels
May have a selective advantage to protect against parasites where muscular contractions are needed to expel them from the GI tract

187
Q

Treatment of allergies?

A

Antihistamine and corticosteroids to suppress leukocyte function
Identification and avoidance of the antigen

188
Q

How do you test for asthma?

A

Inhale an allergen
Test breathing rate
Decrease after a few mins due to degranulation of mast cells
Decrease after several hours due to leukotrienes (bronchoconstrictors) and other inflammatory mediators

189
Q

What is type II hypersensitivity?

A

Antibody-mediated cytotoxic
After 5-8h
IgM or IgG binds to cells or tissue Ag
Triggers clearance by Mphage bearing Fcgamma receptors, in the spleen, or by complement lysis
Caused by altered components of human cells - e.g. penicillin makes a novel epitope by binding to RBCs

190
Q

Where is there pre-existing antibody even when the antigen hasn’t been contacted yet?

A

ABO blood groups

191
Q

Where is there pre-existing antibody even when the antigen hasn’t been contacted yet?

A

ABO blood groups

Ab already induced by natural exposure to similar antigenic determinants on microorganisms in the gut.

192
Q

What are A, B and O antigens?

A 
Core H antigen
O = unmodified H 45%
A = + terminal N-acetylgalactosamine 40%
B = terminal galactose 11%
AB = both 4%
AB = universal recipient, O = universal donor
193
Q

What is haemolytic disease of the newborn?

A

Occurs when mother Rh- baby Rh+. Some Rh+ blood leaks into maternal circulation at birth. Mother makes IgG against Rh+. Can cross placenta, so subsequent Rh+ babies can be compromised. Can be countervented by giving anti-Rh Ab to the mother before she reacts to her child’s RBCs as cross linking to the FcgRIIB prevents activation of naïve B cells.

194
Q

Which diseases are caused by Type II hypersensitivity?

A

Haemolytic anemia
Thrombocytopenia
Penicillin allergy

195
Q

What is type III hypersensitivity?

A

2-8h

Results when Ag is soluble and in high quantities

196
Q

What do different concentrations of Ag lead to within the context of hypersensitivity?

A

Low –> Type III

High –> Type I

197
Q

What is type III hypersensitivity?

A 
2-8h
Results when Ag is soluble and in high quantities
Immune complexes form
Deposited in tissues
Trigger mast cells via FcgammaRIII receptor
Activates complement
PMNrecruited to site of deposition
Local damage and inflammation
198
Q

Pathophysiology of arthritis?

A

Immune complex mediated hypersensitivity

199
Q

Pathophysiology of glomerulonephritis

A

Immune complex mediated hypersensitivity

200
Q

Pathophysiology of arthus reaction?

A

Immune complex mediated hypersensitivity on the skin of sensitised individuals who have Ab against the sensitising Ag

201
Q

Pathophysiology of arthus reaction?

A

Immune complex mediated hypersensitivity on the skin of sensitised individuals who have Ab against the sensitising Ag
Binds to FcgammaRIII on mast cells
Degranulation
Local inflammatory response, increased vascular permeability
Protein release, phagocytosis
Blood vessel occlusion

202
Q

Pathophysiology of Serum sickness

A

Immune complex mediated hypersensitivity

When high doses of horse serum were used to treat pneumonia

203
Q

Which diseases trigger a type III hypersensitivity reaction?

A 
Arthritis
Glomerulonephritis
Arthus reaction
Pigeon fancier's disease/farmer's lung
Serum sickness
204
Q

Causes of arthritis?

A 
Hypersensitivity = type III
Autoimmune = type IV/T cell mediated. T cell against synovial joint Ag --> joint inflammation and destruction
205
Q

Causes of Type IV hypersensitivity?

A

Delayed type/
Cell mediated hypersensitivity
24-72hrs
Mediated by memory Th1 that release cytokines –> recruit monocytes –> mphages

206
Q

Causes of Type IV hypersensitivity?

A

Delayed type/
Cell mediated hypersensitivity
24-72hrs
Mediated by memory Th1 that release cytokines –> recruit monocytes –> mphages
10-100 times more Ag required for antibody-mediated hypersensitivity

207
Q

Physiology of Tb mantoux test

A

Cell mediated hypersensitivity via Th1 cells sensitive to Tb Ag

208
Q

Pathophysiology of contact sensitivity?

A

Similar to Type IV hypersensitivity
A cutaneous reaction to haptens that complex with host proteins
e.g Poison ivy, metal salts, small reactive chemicals
Th1 cells activate mphages

209
Q

Causes of Type IV hypersensitivity?

A

Delayed type/
Cell mediated hypersensitivity
24-72hrs
Mediated by memory Th1 that release cytokines –> recruit monocytes –> mphages
10-100 times more Ag required for antibody-mediated hypersensitivity

210
Q

Physiology of Tb mantoux test

A

Cell mediated hypersensitivity via Th1 cells sensitive to Tb Ag

211
Q

Pathophysiology of contact sensitivity?

A

Similar to Type IV hypersensitivity
A cutaneous reaction to haptens that complex with host proteins
e.g Poison ivy, metal salts, small reactive chemicals
Th1 cells activate mphages

212
Q

IL3?

A

Released by Th1 cells

Stimulates monocyte production by bone marrow stem cells

213
Q

What is the significance of Abacavir?

A

Can displace peptides from MHC

T cell mediated drug hypersensitivity in people who have HLA-B57

214
Q

What does iatrogenic mean?

A

Caused by medical treatment

215
Q

What are the 4 possible relationships between transplanted material and the recipient?

A
  1. Autologous
  2. Syngeneic i.e twins
  3. Allogeneic i.e same species
  4. Xenogeneic i.e different species
216
Q

What is immunological memory?

A

A recipient who has already received a graft from a donor will reject a skin graft from the donor more rapidly second time round

217
Q

Why do memory T cells respond faster than effector T cells?

A

They are more numerous and more readily activated

218
Q

What are the mechanisms of rejection?

A
  1. Hyperacute rejection
  2. Acute Graft Rejection (direct and indirect recognition)
  3. Chronic rejection
219
Q

What is hyperacute rejection?

A

Very rapidly
Like Type II hypersensitivity
From pre-existing antibody e.g ABO incompatible, ABO Ag also on endothelium so rejection v fast
Tissue damaged by complement activation, leakage of fluids and platelet aggregation that blocks the microvasculature
Takes place in xenotransplants

220
Q

What does discordant mean?

A

Xenotransplants where recipient makes natural IgM and IgG to sugars on the tissue of the donor

221
Q

What are the problems of xenografts?

A

Discordant - humans make natural IgM and IgG against sugars on the donor tissue
Complement - DAF etc protect self-tissues but this doesn’t transfer well across tissues, so human complement attacks the graft

222
Q

What is acute graft rejection?

A

Barrier to allotransplantation
Caused by T cell recognition of the transplanted tissue - type of IV hypersensitivity as involves CD8+ cells and CD4+ cells
Can be either direct recognition of allo MHC, or indirect recognition of allo MHC

223
Q

What type of rejection blocks each type of transplant?

A

Xenotransplant - hyperacute
Allotransplant - acute rejection
Isogenic - even this can be rejected by acute rejection e.g. if donor male recipient female

224
Q

How do recipient T cells directly recognise allografts?

A

Recognise donor MHC
Recipient’s naïve T cells contain clones of alloreactive T cells that recognise allotypes of HLA that the recipient doesn’t have.
Some are memory type alloreactive T cells.
naïve individuals have a high frequency of TCRs that react to allo-MHC products. May not need to bind with a particularly high affinity to result in activation of the T cell as could potentially engage with every MHC on a cell.
Recipient sensitised by migration of allogeneic dendritic cells from the inflamed donor organ –> lymph –> secondary lymphoid tissue. Settle in T zones and present donor MHC with donor peptide to activate host circulating T cells. Alloreactive T cells travel back to graft where they attack through allorecognition. Mainly CD8 cytotoxicity, but also activate resident mphages via Th1.

225
Q

How do recipient T cells recognise allografts indirectly?

A

Uptake of allogeneic proteins by recipient’s APCs, and presentation to T cells by self MHC
Can get some of the donor Ags as some of donor dendritic cells will migrate to lymphoid tissue and die by necrosis or apoptosis
May present the donor MHC, and some non-MHC or minor Ag - mostly on Class II MHC (as taken up by endocytosis)
T cells activated are specific for host HLA with donor peptide
Destroy graft by:
1. Cross react with donor HLA plus peptide (so MHC sharing may increase reactivity as donor + recipient dendritic cells can prime recipient T for minor peptides)
2. IFN-gamma Activate mphage –> lytic enzymes
3. IL456 Activate B cell –> Ab (–> immune complex formation)
4. IL-2 activate Cytotoxic T cell –> ADCC

226
Q

What is a minor antigen?

A

Proteins that vary in sequence where at least one of the allomorphs is found in a peptide which binds to the MHC of the recipient.

227
Q

What are the forms of macrophage?

A

M1 and M2
M1 = classically activated by LPS and IFN-gamma
Secrete high levels of IL-12, low levels IL-10
M2 = repair. Wound healing and repair. Produce anti inflammatory cytokines like IL-10. Phenotype of resident tissue macrophages. Can be further elevated by IL4.

228
Q

How does chronic rejection work?

A 
Years after transplant
May occur due to immune responses against blood vessels --> blood supply compromised --> ischaemia --> loss of function
May occur due to type III hypersensitivity due to IgG against allogenic HLA class I molecules depositing on the blood vessels of the transplanted organs
229
Q

Which form of rejection corresponds to each type of hypersensitivity?

A 
Hyperacute = II
Chronic = III
Acute = IV
230
Q

Why is the cornea easy to transplant (immunologically speaking)?

A

Immunoprivileged site

Lack of lymphatic drainage and some sites also lack vascularisation

231
Q

Why do you sometimes do multiple organ transplants?

A

Kidney has immunosuppressive effects? So do a combined kidney, lung, liver, heart, pancreas

232
Q

What are the sources of stem cells?

A

In order of decreasing mature T cell contamination

  1. Peripheral blood (give cytokines to enrich)
  2. Bone marrow
  3. Cord blood
233
Q

What is graft-versus-host rejection used for?

A

In leukaemia treatment - donor cells reject the host tissue

234
Q

How important is HLA-matching on allograft survival in the kidney, the liver, the heart and haematopoietic stem cells?

A

Very = haematopoietic stem cells
Significant = kidney, heart
No effect = liver

235
Q

How do you HLA match?

A

Microcytoxicity used
Use sera with known anti-HLA Ab that recognise allomorphs of particular HLA loci.
Make this from multiparous women who had produced Ab to their babies initially, now use MAb.
See which of these the donor blood cells, when added complement is added, osmotically lyse (the ones that lyse are the HLA class) and so take up a dye called trypan blue.
Now many use tissue typing

236
Q

What is important to check for a transplant?

A

HLA type

See if there are any pre-formed Ab in recipient to donor alloantigens

237
Q

How do you check for preformed alloantigens?

A

Screen recipient serum against panels of microbeads, each coupled with a specific HLA protein
Add secondary antibody (anti IgG) which is fluorescent
Basically do an ELISA

238
Q

What immunosuppression is used in a kidney transplant currently?

A
  1. Steroids - systemic immunosuppression e.g. prednisolone
  2. Cytotoxic drugs - kill dividing cells i.e. T cells, especially on entry to cell cycle e.g. azathioprine
  3. Immunosuppressive - target cell signalling in lymphocytes e.g. cyclosporine, FK506, rapamycin
239
Q

Prednisolone

A

Steroid
Systemic immunosuppressive effects
Use for kidney transplant

240
Q

Azathioprine

A

Cytotoxic drug
Kills dividing cells, especially on entry to cell cycle
Use for kidney transplant

241
Q

Cyclosporin

A

Block signal transduction for activation of T cells
Immunosuppressive
Treatment of kidney transplant

242
Q

Sirolimus/rapamycin

A

Reduces IL2 production, so inhibits activation of B and T cells
Treatment of kidney transplant

243
Q

What are potential future immunosuppressive therapies?

A
  1. Possibly in future use MAb against CD4 and CD8 (or other cofactors)
  2. Antibody blocking -perform graft under cover of anti-CD4 non depleting antibodies (favour Th2)
  3. Use TReg to tolerise

BOD MVST 1b (9 decks)

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