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M- Pathology > 2 - Adrian kelly > Flashcards

2 - Adrian kelly Flashcards

1
Q

Components of innate immune system

A

Anatomical barriers
Physiological barriers
Phagocytic cell
Inflmmation

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2
Q

Important feature of innate immunity

A

No memory of encounter with foreign antigen

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3
Q

Activation of B lymphocytes

A 
Differentiation into plasma cells
Secrete antibody (soluble version of BCR)
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4
Q

Antibodies interact with …

A

Epitopes
Linear epitopes
Conformational epitopes (protein in native structure)

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5
Q

Antibody regions

A

Variable - bind antigen

Constant - recruit effector function (macrophage,neutrophil,basophil,mast cell, complement)

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6
Q

Antibodies work in 3 ways;

A

Neutralisation - block activity
Opsonisation - enhanced phagocytosis
Complement activation - recruited to antibody coated antigen, cause lysis

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7
Q

Gene rearrangement for TCR occurs

A

When they mature in the thymus

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8
Q

T cell receptor

A

Only recognises degraded proteins (peptides) complexes with MHC, presented by APCs

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9
Q

MHC

A

Major histocompatability conplex

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10
Q

APC

A

Antigen presenting cell

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11
Q

MHC class 1 molecules

A

Expressed on most cells
Associate with peptides produced in cytosol (internal protein antigen)
T cells express co receptor CD8, mature into cytotoxic T cells

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12
Q

MHC class II

A

T cells express CD4 co receptor
Mature into t helper cells
External protein antigens

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13
Q

Central lymphoid organs

A

Bone marrow and thymus

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14
Q

Mature or naive cells

A

T and B cells with successfully rearranged receptors, not yet exposed to particular antigen

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15
Q

Professional APC

A

First time naive T cell sees peptide-MHC complex it must be presented by professional APC

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16
Q

Lymph nodes and spleen are designed to

A

Optimise interaction between APC and B and T lymphocytes

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17
Q

High endothelial venules

A

Specialised endothelia that lymphocytes enter node through

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18
Q

Dendritic cells with captured antigen

A

Enter T cell area
Naive T cells survey antigen-MHC on dendritic cells
Retained if have complementary receptors
Stimulated to differentiate into effector T cells

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19
Q

FDCs

A

Follicular dendritic cells
B cells concentrate around, in B cell areas
FDCs trap antigen/antibody/c3d complex

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20
Q

Affinity maturation

A

FDCs trap antigen/antibody/c3d complex
Hold antigen to be screened by B cells
Internalise, process and present it to T helper cells
Activate B cell to produce antibody
Cells with highest affinity receive T help and are preferentially induced to proliferate

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21
Q

No. Of epitopes on antigen

A

Can have many different, recognised by different antibodies

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22
Q

Fab

A

Fragment of antigen binding

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23
Q

Fc

A

Fraction crystallisable

Binds receptor

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24
Q

Different light chains

A

K kappa or lambda

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25
Q

Changing Fc

A

Different antibody, so different effector funvtion

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26
Q

Immunoglobulin fold domains

A

Light chain has one variable and one constant

Heavy chain has one variable and three constants

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27
Q

Which antibodies have four heavy constant domains?

A

IgM

IgE

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28
Q

Hinge region

A

Flexibility to interact with antigen

Flexibility also at V-C junctions

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29
Q

CDR

A

Three Complementarity determining regions
CDR3 is most variable
Appear as loops at surface

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30
Q

Somatic recombination

A

Gene segments rearrange during B cell development
65 variable gene segments
27 diversity gene segments
6 junctional segments

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31
Q

CDR1 and CDR2 variation

A

By variable gene segments

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32
Q

CDR3 variation

A

By diversity and junction all gene segments

In junctions between V-D-J

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33
Q

Order of heavy chain rearrangement

A

1- D –> J

2- V –> DJ

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34
Q

Allelic exclusion

A

Rearrangement on both chromosomes

But if a functional heavy chain is generated, rearrangement on other chromosome is prevented

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35
Q

Light chain rearrangement

A

No diversity segments

K chain first, if unproductive, lambda chain next

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36
Q

Rearrangement controlled by

A

Recombinases that recognise conserved heptamer and nonomer sequences adjacent to VD+J sequences

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37
Q

Generation of antibody diversity (4 processes)

A

Different heavy and light combinations
Different heavy VD+J segments
Junctional diversity
Somatic hypermutations

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38
Q

Junctional diversity

A

Addition and loss of nucleotides at VDJ junctions

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39
Q

Somatic hypermutation

A

Point mutations in variable regions

Increased affinity selected by affinity maturation

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40
Q

B cells initially expressed with

A

Mu and sigma constant regions
Produce IgM and IgD antibodies
Coexpressed and generated by alternative splicing

41
Q

Isotope/class switching

A

B cell can change constant region isotype

42
Q

Generation of BCR and soluble antibody

A 
Alternative splicing (multiple exons)
Different polyadenylation sites
43
Q

Five immunoglobulin isotypes

A 
IgM
IgG
IgA
IgD
IgE
44
Q

Different Fc receptors

A

Fc gamma RI - High affinity, bind monovalent

FcgRII and III - Low affinity bind multivalent antigen/antibody complexes

45
Q

Macrophages and neutrophils express what type of receptor?

A

Fc gamma

46
Q

Binding of antigen/antibody by C3b receptors on RBCs…

A

Delivers complexes to liver and spleen for removal by phagocytes

47
Q

NK cells FcgRIII receptor

A

Ligation by antigen/antibody complex releases cytoplasmic granules, lytic enzymes
(ADCC)

48
Q

ADCC

A

Antibody dependent cell mediated cytotoxicity

49
Q

Functions mediated by Fc domains of antibodies

A 
Opsonisation
ADCC
Mobilise inflammatory mediators
Active antibody transport
Regulate antibody production
50
Q

Fc binds to mast cells and basophils ..

A

Release of inflammatory mediators

51
Q

Allergic reactions - allergen binds to

A

IgE on mast cells

52
Q

Transport across epithelial cell

A

A receptor for polymeric Ig recognises j chain region of IgA and transports

53
Q

B cells negative feedback system

A

B cells specific for same antigen can bind by FcgammaRIIB and BCR
Negative signal that terminates B cell response

54
Q

Affinity

A

Interaction between single antibody binding site and single epitope

55
Q

Avidity

A

Strength if interaction due to recognition of polyvalent epitopes

56
Q

MHC

A

Major histocompatability complex
Gene locus on chromosome 6
Codes for MHC1 and MHC2 molecules

57
Q

MHC molecules

A

Glycoproteins

Present peptides to T cells

58
Q

MHC Class 1

A

Transmembrane a (a1,a2,a3)
Non covalently linked to B2-microglobulin
a1 and a2 form peptide binding groove (8-9aa)
Groove base is Bpleated sheet, sides are a helices

59
Q

MHC Class 2 molecules

A

2 similar sized transmembrane chains, a and B
Peptide binding groove formed by a1 and B1
Open ended - can bind 13-25aa

60
Q

Polygeny of MHC molecules

A 
Expression of multiple independent loci
3 isotypes
1- HLA-A, HLA-B, HLA-C
2- HLA-DP, HLA-DQ, HLA-DR
HLA=human leukocyte antigens
61
Q

Polymorphism of MHC

A

Many alternative forms of same gene
250 alleles
Extensive allelic polymorphism is pathogen driven

62
Q

How are MHC genes inherited?

A

As haplotypes
Co-dominantly expressed (maternal and paternal)
Heterozygotes can present more peptides

63
Q

MHC restriction

A

T cell sees a combination of a particular MHC molecule associated with a particular peptide

64
Q

Anchor residues

A

Conserved amino acids at certain points on the peptide, to make contact with pockets in binding groove

65
Q

Anchor residues determine the …

A

Peptide binding motif for that MHC molecule

66
Q

Endogenous proteins are presented on…

A

MHC class 1 molecules

67
Q

Exogenous proteins are presented on …

A

MHC class 2 molecules

68
Q

MHC class 1 antigen processing pathway:

A

Proteins in cytosol degraded by proteasome
Peptides moved into ER by TAP
Suitable peptides loaded onto class 1 molecules
MHC peptide complexes released from chaperones, pass through Golgi, secretory pathway to cell surface
Presented to CD8 cytotoxic cells

69
Q

TAP

A

Transporter associated with antigen processing

70
Q

MHC class 2 antigen processing pathway

A

Class2 a/B chains bind with invariant chain Ii (prevent binding peptides in ER)
ER to Golgi to endocytic pathway
Ii partially removed, leaving CLIP in groove
Antigens degraded by proteases
In MIIC peptide loading compartments CLIP is removed
Peptides loaded onto class 2 molecules
Cell surface for presentation to CD4 helper T cells

71
Q

Invariant chain

A

MHC class 2 pathway

  • blocks peptide binding groove
  • folding chaperone
  • targets II/Ii complexes to endocytic pathway
72
Q

TCR structure

A 
Related to single Fab fragment
2 polypeptides, with constant and variable region
Monovalent
Membrane bound
No somatic hypermutation
Antigen recognition-no effector function
73
Q

TCR rearrangement

B chain

A 
B chain
- D-->J 
- V-->DJ
Surface expression with surrogate a chain
Stops B chain rearrangement
Proliferation
CD4-CD8- double negative
74
Q

TCR rearrangement

a chain

A

a chain
- V–>J
CD4+CD8+ double positive

75
Q

Which region of TCR is most variable?

A

CDR3
Due to VDJ junctions
Makes major contact with peptide in groove

76
Q

T cells are selected for:

A

Successful B chain rearrangement
Positive selection
Negative selection

77
Q

Positive selection

A

Tested against self MHC/peptide
Moderate affinity - positive signal to continue maturation
Low affinity - death by neglect
CD4+ single positive selected against MHC class1/peptide
CD8+ single positive selected against MHC class2/peptide

78
Q

Negative selection

A

Auto reactive thymocytes
High affinity for MHC/self peptide
Eliminated by apoptosis
Can only eliminate cells recognising combinations expressed in the thymus

79
Q

Cells mediating positive selection

A

Cortical epithelial cells

In cortex of thymus

80
Q

In cortex, thymocytes rearrange…

A

a chain, giving multiple opportunities for +ve selection

Lack of +ve selection –> cell death

81
Q

Cells triggering negative selection

A

Dendritic cells

Macrophages - remove thymocytes that fail to mature

82
Q

Mature naive T cells

A

Have survived selection

Activated by professional APC to become functional

83
Q

T cell activation - 2 signal hypothesis

A

Signal 1 - TCR engagement

Signal 2 - co-stimulatory molecules

84
Q

T cell co-stimulatory molecules

A

T cell:
CD28 interacts with B7.1 and B7.2 (CD80 and CD86) on APC
CD40L interacts with CD40 on APC

85
Q

Defining feature of professional APC

A

Expression of co-stimulatory molecules

86
Q

How do naive T cells enter lymphoid organs?

A

From blood through High Endothelial Venules

87
Q

Binding of naive T cell to professional APC

A

Naive T cell proliferates and differentiates into a population of armed effector T helper cells

88
Q

Maturation of naive B cells…

A

Bind and internalise antigen (signal 1)
Present peptide on surface as MHC2/peptide complex
Complex is recognised by T helper
Co-stimulatory molecules (CD28/B7 and CD40L/CD40)
Cross linking CD40 (signal 2)

89
Q

Cross linking of CD40 on B cell promotes…

A

B cell proliferation
B cell survival signals
Immunoglobulin class switching

90
Q

B-T cell cooperation

A

Interaction with co-stimulatory molecules leads to mutual activation

91
Q

After activation, B cells bind to

A

Follicular dendritic cells (present in B cell follicles)

Enable B cell to form germinal centres

92
Q

Thymus independent antigens

TI antigens

A

Stimulate naive B cells without B-T cell interaction

93
Q

Naive CD4 cells differentiate into

A

TH1/TH2 bias is self reinforcing
Depends on cytokines present during proliferation
Cytokines released by dendritic cells, macrophages, NK cells, focus immune response

94
Q

TH1

A

Cell mediated immunity
TH1 - produce cytokines, which activate macrophages, NK cells, CTLs, intracellular pathogens
Stimulated by abundant antigen and high affinity TCR interactions

95
Q

TH2

A

Humoral pathway
TH2 - cytokines activate B cells (antibodies) (IL4, IL5, IL6)
IgG, igA, IgE, eosinophils and mast cells
Stimulated by low peptide abundance or weak affinity TCR

96
Q

What cytokines promote B cell growth?

A

IL4

IL6

97
Q

What cytokine causes production of
IgG?
IgA?
IgE?

A

IL4
IL5
IL4

98
Q

What cytokines stimulate
Eosinophils?
Mast cells?

A

IL5

IL4

M- Pathology (7 decks)

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