Immunology Flashcards
(171 cards)
1
Q
Describe ‘Recognition of foreign molecules (non-self)’
A
- Resistance to infection
- Resistance to tumour
- Recognition of non-infectious foreign molecules
2
Q
Describe ‘Tolerance = specific inability to recognise antigens’
A
Means immune system does attack certain antigens (e.g. mother’s immune system tolerates antigen of foetus)
3
Q
Describe innate immunity
A
Occurs immediately with its response being non-specific. It provides immediate protection against infection and is stereotypical in response. It occurs in the same fashion every time.
- Cellular barriers (Epithelium and antibacterial chemicals)
- Cells (neutrophils,macrophages, dendritic cells, and NK cells)
- Plasma proteins
- Cytokines
4
Q
Describe ‘Adaptive immunity’
A
Develops over days to weeks, the adaptive immune system improves with repeated exposure. It also improves with exposure to wider range of antigens, as B and T memory cells will confer an improved repertoire of immune responses to different substances
- Cells (B cells and T cells)
- Plasma proteins (antibodies)
5
Q
Describe Haemopoietic stem cells
A
- Undifferentiated cells that differentiate to blood cells and immune cells
- In bone marrow
- Self renewing
6
Q
Describe macrophages (two types of phagocytic cells)
A
- Neutrophils: Grainy, multi-lobed nucleus
- Monocytes: bean-shaped nucleus
7
Q
List and describe the types of lymphocytes
A
T lymphocyte
- Mediate cell-mediated immunity
- CD4 and CD8 T cells
B lymphocyte
- mediate antibody immunity
8
Q
Describe natural killer cells
A
- large granular lymphocytes
- Part of innate immune response
- lack antigen specific receptor
9
Q
Describe dendritic cells
A
- Potent antigen presenting cells (APC)
- uptake antigen in peripheral sites and present to T-lymphocytes
10
Q
Describe eosinophils
A
- Bilobed nucleus with cytoplasmic granules
- defence against parasites
11
Q
Describe basophils
A
Heavily granulated
12
Q
Describe mast cells:
A
- Round nucleus
- involved in allergic reactions
- not usually in circulation; just beneath epithelia in blood vessel
13
Q
What are the functions of the primary lymphoid organs?
A
- Develop mature lymphocytes
- Generate receptor diversity
- Eliminates self-reactive cells
- MHC restriction for T cells
14
Q
What are the primary lymphoid organs?
A
- Bone Marrow
- Thymus
15
Q
Bone marrow is the site of:
A
- site of generation of all circulating blood cells
- site of B lymphocytes maturation
16
Q
The thymus is the site of:
A
- T lymphocytes maturation
17
Q
Describe functions of secondary lymphoid organs:
A
- Site for the generation of immune response
- Trap antigens
- Present antigens for T cell and B cell activation
18
Q
List the secondary lymphoid organs (3 of them)
A
- Lymph nodes
- Spleen
- Tonsils
19
Q
Describe differences between innate and adaptive immunity
A
Innate immunity:
- rapid response
- Independent of prior exposure. Same influence every time despite prior exposure
- Limited number of antigen-binding receptor
- General specificity for classes
- No self-reactivity
Adaptive immunity:
- Slow response
- Prior exposure causes retention of memory B cells and T cells makes subsequent responses faster and more potent
- Large number of antigen-binding receptor
- Very specific
- Self reactive cells are destroyed
20
Q
Name all the innate immunity components
A
- Cellular barriers: epithelium, anti-bacterial chemicals
- Cells: phagocytes (neutrophils and macrophages), NK cells, dendritic cells
- Plasma proteins
- Cytokines
21
Q
What are pathogen recognition receptors (PRR)
A
- PRRs recognise common structures shared by different pathogen but not structures found in host cells
- Receptors can be on cell surface or in cytotoxic endosomes
- E.g. toll-like receptors and NOD-like receptors
22
Q
Outline the properties of Pathogen associated molecular patterns (PAMP)
A
- Molecular structures on pathogen which are recognised and bound by the PRR
- E.g. lipopolysaccharides, mannose, dsRNA
23
Q
What is function of innate immunity?
A
- Early protection
- Activating and enhancing adaptive immunity
24
Q
What are toll-like receptors?
A
Cell surface receptors which bind proteins and lipoproteins
25
What does cell surface TLR bind to and name examples of this
- They bind to bacteria lipoproteins and proteins
TLR4 binds lipopolysaccharides (LPS)
TLR2 binds lipotechoic aic
TLR5 binds bacteria flagellum
26
What does cytotoxic endosome TLR bind to and name some examples
Bacterial and viral DNA and RNA
- TLR3 binds dsRNA
- TLR7 binds ssRNA
- TLR9 binds unmethylated DNA
27
List some common examples of C-type lectins, and their corresponding ligand and sources
C-type Lectins - cell surface protein that binds carbohydrates
- NOD binds peptidoglycan
- RIG binds RNA
28
Describe the cellular effects of activating TLR
- Cytokines production (inflammation)
- Chemokine production (cell recruitment)
- Activate bacterial killing mechanisms
- Activate dendritic cells
29
Describe the steps of Interleukin-1 and toll-like receptor pathways and their shared signalling pathway
1. TLR ligand binds to surface receptor
2. Adaptor molecule recruited (MyD88)
3. Enzymes activated (MAP kinase)
4. Transcription factors activated (NFkB)
30
Describe the difference between anti-specific and antigen non-specific immune responses
Antigen non-specific immune responses —> communication between cells
- Requires binding of general class of antigen
- Cytokines
- Chemokines
- Complement system
Antigen specific immune response —> long distance adaptive immunity
- Requires binding of a specific antigen
- Antibodies
31
Define cytokines, outline their properties and list common examples
Cytokines
- Antigen non-specific effector molecules
- Secreted by macrophages, T and B cells, and dendritic cells
- E.g. Interleukins (IL) and interferons (IFN)
Properties of cytokines:
- Potent in small quantities
- only produced when signal present
- mRNA rapidly degrades
- Bind to specific cell surface receptors
- Act locally
32
Describe the difference in function between cytokines and chemokines
Chemokines:
- “Chemoattractant cytokines” (type of cytokines)
- Attract cells to site of inflammation or lymph node
33
Describe the role of the innate vs the adaptive immune system in clearing an infection
Innate immune system mechanism of clearing infection
- Opsonization: proteins which bind to cover and increase phagocytic activity
- Complement system coats bacteria
- Neutrophils recruited to the site of infection to phagocytise the bacteria
- APC activate adaptive immune system
Adaptive immune system mechanism of clearing infection
- Adaptive immunity uses and amplifies innate immunity processes
- Antibodies coat the bacteria and enhance phagocytosis
- Antibodies activate the complement pathway
- Antibodies activate killing mechanisms in phagocytes
34
Describe the phagocytic role of neutrophils and macrophages in inflammation and bacterial killing
- Complement system and cytokines allow leukocytes to adhere to blood vessels walls
- Leukocytes leak through endothelium to inflammation site
- Neutrophils and macrophages engulf microbes
- Kill microbes: via lysosomal enzymes, via reactive oxygen species and nitrous oxide
35
Describe Clonal selection theory
Burnet’s clonal selection theory
- Lymphocytes acquire a unique, antigen receptor via gene recombination
- Foreign antigens select for specific receptor-bearing cell leading to clonal expansion of that specific cell
- Re-exposure to the same antigen induces a rapid ‘memory’ response due to the previously clonal-expanded population of cells that can bind that antigen
- Self-binding receptors are destroyed in the primary lymphoid organs during development
36
Describe clonal expansion
- Antigen binds one B cell
- Selected B cell proliferates
- Plasma cells and memory cells differentiate
37
Describe the phases of adaptive immune responses
- Antigen recognition
- lymphocyte activation
- Antigen elimination
- Contraction
- Memory
38
Describe the properties of dendritic cells and their role in linking innate and adaptive immunity
Immature dendritic cells
- surveillance cells in peripheral locations (e.g. skin, lungs, mucosa)
- Specialized in antigen uptake
- mature to be better antigen presenter
Mature dendritic cells
- mature dendritic cells up-regulate expression of MHC1 and MHC2 —> better presenters
- produce cytokines
- migrate to lymph nodes to activate T cells —> links innate immune with adaptive immune by bringing antigen from periphery to lymph node
39
Describe the function of dendritic cells as antigen presenting cells
Dendritic cells
- Antigen presenting cells
- phagocytise antigen and present antigen-peptide fragment on their MHC class 2 receptors: able to present pathogens that are inside host cells (e.g. viruses and intracellular bacteria
- MHC class 2 genetic makeup is unique to each person
- Must have antigen bound to the MHC peptide to present the antigen to the T-cell.
- Reside in tissues as immature cells and can regulate their MHC surface receptors
40
Describe the function of T cells as antigen presenting cells
T-cells:
- antigen receptors stay on the T-cell after activation
- secrete cytokines to recruit cells to the area where antigen binds T-cell receptors
- Only recognise presented antigen presented on self-MHC complex on the antigen-presenting cell
41
Explain the structure and function of the human leukocyte antigens (HLA) or ‘MHC’ complex 1
```
Structure of MHC class 1
- Two chains (heterodimer) —> alpha chain and beta chain
Beta chain: 1 domain, constant domain for binding CD8 of T cell
Alpha chain: 3 domains, alpha1 and alpha2 domains (variable) for antigen binding, alpha3 domain (constant) for binding CD8 of T cell.
```
- Domains held together with disulfide bonds
- Found in all uncleared cells
- Function = presents to CD8+ T cells
42
Explain the structure and function of the HLA or MHC Class 2
- Two chains (heterodimer) —> alpha chain and beta chain
- Both chains have a constant and variable domain
- Both chains bind with the antigen peptide
- Found in immune cells, mostly dendritic cells
- Function = Presents to CD4+ T cells
43
Explain how protein antigens are processed by the endogenous and exogenous antigen pathways to be presented by HLA class 1 molecules to CD8 and CD4 T cells
Presentation on MHC Class 1 molecules (Cytoplasmic antigen processing pathway):
1) Virus is IN cytoplasm of cell or virus phagocytised
2) Viral protein moved to cytoplasm where it’s ubiquitinated
3) Viral protein broken down to peptides
4) peptide binds with MHC class 1 in ER
5) MHC class 1 complex exported to surface from Golgi
44
Explain how protein antigens are processed by the endogenous and exogenous antigen pathways to be presented by the HLA class 2 molecules to CD8 and CD4 T cells
Presentation on MHC Class 2 molecules (Endogenous antigen processing pathway)
- protein uptake from the outside of the cell via endocytosis forms vesicles. Antigen protein never enters cytoplasm
1. Protein antigen endocytosed in vesicles
2. Lysosome fuses and digest antigen protein
3. Exocytotic vesicle containing MHC class 2 fuses with antigen peptide vesicle; complex forms
4. MHC Class 2 complex exported to surface
45
Explain how T lymphocytes are activated by antigen presenting cells
Activation of T-lymphocytes
- CD4 T cells are activated when an MHC Class 2 presents the corresponding antigen peptide for the TcR
- CD8 T cells are activated when an MHC Class 1 presents the corresponding antigen peptide for the TcR
46
Explain how T lymphocytes recognise an “infinite” variety of protein antigens from microbes
- T cells are developed in the thymus
- Rearrangement of TcR genes allow for 10^10 possible TcR combinations
- Positive selection = T cells that bind with self MHC and any peptide are kept
- Negative selection = T cell that bind with self peptides are deleted
47
Explain how the activation of T cells is regulated
CD4 T cells:
There are 2 signals required from APC for T-cell activation:
- Signal 1–> MHC complex and peptide must bind to TcR (I.e. same MHC gene content and matching antigen peptide fragment)
- Signal 2–> B7 on APC must bind with CD28 on T cell. B7 produced in presence of pathogens.
No activation if either signal is not present
CD8 T cells:
- Cross priming of CD8 T cells by dendritic cells
- Expansion of CD8 T cells requires CD4 T cell help
48
Explain the different processes of activation
CD4 T-cell activation - requires two signals from APC
CD8 T-cell activation - requires cross-pricing from APC and help from CD4 T cells
49
Summarise classes of antibodies and how they develop
5 classes: IgM, IgG, IgA, IgE, IgD
Development:
- B cells bind antigen at unique membrane receptors (B- cell receptors)
- Clonal expansion occurs
- B cells differentiate into plasma cells or memory B cells: Plasma cells release antigen-specific antibodies, memory cells remain in body to detect reinfection.
50
Describe structure of antibodies
Antibody structure contains heavy chain, light chain, hinge region, Fc region
Heavy chain:
- 3 constant regions and 1 variable region
- C- terminus inserts into membrane; N terminus responsible for antigen binding (variable region)
Light chain:
- 1 constant region and 1 variable region
- on N terminus on responsible for antigen binding
Hinge region: holds heavy chains together
Fc region:
- Region with only heavy chain
- Bind with effector cells and proteins to confer function: C1q to activate complement pathway, Opsonize phagocytosis - macrophages, recognition killing - Natural killer cells, sensitisation cell activation - mast cells.
51
Describe “Antigen binding region”
- N terminus binds antigen
- Composed of 3 loops of variable region of HC and LC
- Each monomer of antibody has 2 antigen-binding regions
52
Describe antibody IgM
- heavy chain ‘mu’
- 5 monomers
- Functions in primary response
- has C1q complement system
53
Describe Antibody IgG
- Heavy chain gamma
- 1 monomer
- secondary response
- has C1q complement system
- It does opsonize
54
Describe antibody IgA
- Heavy chain alpha
- it has two monomers
- functions in mucosal response
55
Describe antibody IgE
- Heavy chain epsilon
- 1 monomer
- For helminth parasites
56
Describe Antibody IgD
- heavy chain delta
- 1 monomer
- Naive B cell antigen receptor
57
Describe B-cell receptors
- Basically antibodies that are embedded in the cell membrane: light and heavy chain, variable regions bind antigen
- Signal transduction molecules next to BcR
- BcR binds to antigens
- Have CD19 proteins
58
Describe T-cell receptors
- Two chains, each with 1 constant domain and 1 variable domain
- CD3 proteins are next to TcR (all T-cells have CD3, then either CD4 or CD8)
- TcR binds to antigen-peptide fragments that are presented by antigen-presenting cells (I.e. dendritic cells): antigen-peptide fragment is bound to HLA (MHC)
59
Describe development of B-cell Receptor and T-cell receptor
- Variable regions of heavy and light chain are encoded by separate gene fragments that recombine to form a unique DNA sequence for the functional region
- There are multiple genes for the three domains (variable, diversity and junctions) that are combined together
- Bases are added and removed from the junctions between genes during RNA processing
60
Describe surface receptors on T-lymphocytes (4 of them)
T-cell receptor - generated from VDJ recombination, specific to one antigenic sequence
CD3 - complex or proteins that signals activation of T-cell from antigen specific TcR to nucleus
CD4+ - CD4+ is on T-helper cells and binds to MHC class 2 molecules to recognise antigen
CD8+ - CD8+ is on cytotoxic T cells and binds to MHC class 1 molecules to recognise antigen
CD4+ and CD8+ are like the specific Velcro that holds a T-cell to the antigen-presenting cell. T-cells can only have either CD4+ and CD8+ (mutually exclusive)
61
Describe T cell activation, including the role of co-stimulation and responses to activation
T-cells require two signals:
- Signal 1: TcR binds antigenic peptide-bound to MHC
- Signal 2: T-cell binds co-stimulator (B7 on APC)
Proliferation factors:
- cytokines (IL-2) must be present for proliferation
- IL-2 is released by activated dendritic cell and activated T-cell (autocrine stimulation)
62
Explain how the activation of T cells is regulated
T-cell activation is highly regulated because generated cytokines can be harmful to the host.
1) Stimulation via Co-stimulator from APC: binding of co-stimulator (B7) to CD28 receptor STIMULATES T-cell activation response
2) Inhibition via Co-stimulator from APC:
- B7 binds with greater affinity to another receptor termed CTLA4
- Binding to CTLA4 INHIBITS T-cell activation
- Expression of CTLA4 leads to cessation of signal to activate T-cells (no more binding to CD28)
3) Antibody Regulation
- Antibodies bind to receptors (CD28 or CTLA4) to block either inhibitory or activating signals
63
Summarise T-cell differentiation into effector and memory T-cells
Expansion and contraction of T-cells:
1) T-cells bind to APC via binding MHC molecules bound to peptide
2) In infection and pathogenic products, APC express B7 which binds to CD28 receptors on T-cells. Co-stimulation activates T-cell and IL-2 is secreted.
3) Activated T-cells are generated
4) T-cells bind interleukin-2 (IL-2) and promote cell proliferation
5) Cell death of expanding T-cell clones occurs due to lack of IL-2 growth factor, induced apoptosis via Fas-Fas ligand, or elimination of antigen
64
Describe the properties of cytokines and chemokines and the role of cytokines receptor expression in immune responses
T-cell activities are highly regulated by cytokines
- Cytokines are very short-lived and are only expressed for a few days
- Receptors for cytokines are also very short-lived and are also only expressed for a few days
- Different levels of different cytokines mediate the action of the T-cell
- The type of T-cell produced are dependent on the type of cytokines present around the T-cell
- E.g. IL-12 will cause differentiation into Th1 cells, IL-4 will cause differentiation into Th2 cells.
65
Summarise the migration of T-cells to sites of activation and infection or inflammation
Circulatory Path
- Heart pumps blood with T-lymphocytes in circulation: Blood —> interstitial fluid —> lymph vessels —> Thoracic duct —> Jugulosubclavian junction —> blood
- T cells exit the arteries in lymph nodes at the high endothelial venue (HEV)
- Afferent lymph vessels enter the lymph node and brings antigen presenting cells bound to antigen and activate T -cells
- Naive T-cells migrate to different lymph nodes until APC activates th T-cell
- Activation of the Naive T-cell will result in expression of L-selection which binds T-cell to lymph node
- Once sufficient T-cell clones are produced, they are released to the circulatory system to go to infection
- Once T-cells are activated, they need to migrate back to tissues where the antigen was originated
- Down-regulation of L-selection and production of VCAM-1 which binds activate T-cells to inflamed tissue
66
List the 4 functional types of CD4 T-cells
- Th1 T-cells
- Th2 T-cells
- Th17 T-cells
- Treg T-cells
67
What does Th1 T-cell respond to?
Intracellular pathogens
68
What does Th2 T-cells respond to?
Parasites and supports B-cells for production of antibodies
69
What are the functions of Th17 T-cells?
Mediate mucosal infections, bacterial infections, and fungal infections
70
Function of Treg T-cells?
Regulate T-cells thereby regulating overall immune response
71
What is the Nuclear Factor of Activated T-cell (NFAT)??
Transcription factors of activated Naive T-cells that can further differentiate into Th1, Th2, Th17 or Treg cells
72
Describe the activation of naive T-cells
Naive T-cells (Th0) are activated by:
- APC binds antigenic-peptide (forms peptide-MHC complex) and expressed B7 costimulator
- Naive CD4 T cells binds peptide-MHC Class 2 complex to T-cell receptor (TcR) and B7 co-stimulator to CD28 receptor (two-signal activation
- Activate APC and activated Th0 secretes IL-2 which binds to naive T cells
- IL-2 causes production of Nuclear Factor of Activated T-cells (NFAT)
- NFAT cause proliferation of attached Th0 cells and neighbouring Th0 cells
- Activated Th0 cells then differentiate based on present cytokines
- Th0 are activated in periphery during circulation and migrate to lymph nodes
73
Describe Th0 cell activation
- Naive CD4 T cells binds peptide-MHC Class 2 complex to T cell receptor (TcR) and B7 costimulator to CD28 receptor (two-signal activation)
- Activate APC and activated Th0 secretes IL-2 which binds to naive T-cells
- IL-2 causes production of Nuclear Factor of Activate T cells (NFAT)
- NFAT cause proliferation of attached Th0 cells and neighbouring Th0 cells
- Activated Th- cells then differentiate based on present cytokines
74
Describe Th1 Cell differentiation
- Activate APC secretes IL-12 which binds to activated naive T cells
- Transcription factor T-bet is expressed due to Il-12
- T-bet promotes differentiation of Th0 to Th1.
- Th1 secretes IFN-gamma, IL-12 and TNF (IFN-gamma release is hallmark of Th1)
- NOTE: Both IFN-gamma and IL-12 cause differentiation of Th0 to Th1 cells
75
Describe IL-12 activation of Natural killer cells
- IL-12 also activates natural killer cells to secrete IFN-gamma
- IFN-gamma stimulates Th1 cell differentiation and Th1 response
76
Describe Th1 cytokines profiles
- Th1 cells secrete IL-2, TNF and IFN-gamma
- IL-2: causes cell proliferation of Th0 cells
- IFN-gamma: macrophages and natural killer cell activation, differentiation of Th0 Cell to Th1 cell, inhibitory on Th2 cells, down-regulates B-cell synthesis of IgE and causes production of IgG2A
- TNF: activates macrophages
77
Function of Th1 cells
- Target: Intracellular parasites
- Activates macrophages
- Pro-inflammatory (e.g. Delayed Type Hypersensitivity (DTH) like in TB skin test)
- Promotes IgG production from B-cells (for opsonization and phagocyte activation)
78
Describe the response of activated macrophages
Activation of macrophages response:
- Increased production of reactive oxygen species (ROS), NO, and lysosomal enzymes: kill phagocytized microbes
- Secrete cytokines(TNF, IL-12) and chemokines: recruit WBC to inflammation site and promotes differentiation
- Activated macrophages increased the expression of B7 costimulators and MHC molecules: Increase T-cell activation
79
Describe the role of Th1 response in TB and granuloma formation and delayed type Hypersensitivity (DTH)
- People exposed to TB have high number of circulating memory Th1 cells reactivate to TB antigen
- Injection during TB test induces large swelling under skin due to large Th1 response
- Th1 secretes IFN-gamma to allow macrophages to engulf the TB-infected cells and form granulomas
- TB-infected cells that can’t be eliminated are contained by a “wall” (granuloma) of macrophages and T-cells
- Delayed type hypersensitivity is a purely cell-mediated response (no antibodies involved): Takes 2-3 days to develop
80
Explain the significance of Mendelian inherited susceptibility to mycobacterial infections
MSMD - Mendelian inherited susceptibility to mycobacterial infections
- Mutations of genes for signalling proteins between dendritic cells and macrophages causes immunodeficiencies: Individual is susceptible to mycobacterial infections, which wouldn’t normally be dangerous
- Proteins of Risk: IL-12, IL-12 receptor, IFN-gamma, IFN-gamma receptor
81
Describe the Th2 T cell actions:
```
Help B-cells mature:
- Switch Ig class (e.g. IgM to IgG)
- affinity maturation
- formation of memory B-cells
Allergic response and parasitic infections:
- stimulate eosinophils and mast cells
```
82
Describe differentiation of Th2 cells
Th2 cells is differentiated and developed from Th0 cells, stimulated by IL-4 secretion
83
Describe Th0 activation for Th2 cells
Same as Th1 differentiation for Th0 activation
- Naive CD4 T cells binds peptide-MHC Class 2 complex to T cell receptor (TcR) and B7 costimulator to CD28 receptor (Two-signal activation)
- Activate APC and activated Th0 secretes Is-2 which binds to naive T cells
- IL-2 causes production of Nuclear factor of Activate T-cells (NFAT)
- NFAT cause proliferation of attached Th0 cells and neighbouring Th0 cells
- Activated Th0 cells then differentiate based on present cytokines
84
Describe differentiation of Th0 cells into Th2 cells
IL-4 is secreted by multiple types of cells:
- Mast cells
- Basophils
- Natural killer cell
- Th2 cells
Binding IL-4 promotes differentiation of Th0 to Th2 cells
Binding IL-4 increases expression of GATA3 transcription factors
Increased GATA3 transcription increase production of:
- IL-4
- IL-4 receptors
- IL-5
- IL-13
85
Describe the roles of Th2 Cytokines
- IL-4 —> B cell help
- IL-5 —> eosinophils
- IL-13 —> B cell help + inflammation
86
Describe the pattern of Th2 response in B cells Ig formation and eosinophils and mast cell activation and recruitment
Eosinophils activation and recruitment:
- IL-5 recruit eosinophils to the site of parasitic infection
- Cause increase in the number of eosinophils
B-cell Ig formation
- IL-14 and IL-13 function help B-cells mature
- Maturation functions: switching Ig types (isotype switch) IgM to IgG, affinity maturation of IgG to high affinity antibody, memory B-cell formation
Mast cell activation and recruitment:
- IL-4 function to activate and recruit mast cells to the site of parasitic infection
Th2 response targets parasitic worms (e.g. intestinal worms) and responsible for Type 1 allergic reaction (IgE mediated reaction)
87
Explain the role of Th2 response in autopsy or “type 1” allergic reactions
Th2 response plays a large role in the activation/recruitment cells necessary in allergic responses:
- IgE antibody producing B-cells (IgE = antibody produce in an allergic reaction)
- Mast cells
- eosinophils
Th1 cells secrete IFN-gamma and TNF to inhibit the Th2 response.
Th2 cells secrete IL-10 to inhibit Th1 response.
88
Describe the activation and recruitment of eosinophils, their function and the role of IL-5
- Mature eosinophils circulate and are inactive
- IL-5 activates eosinophils to “Hypodense” tissue eosinophils: Triggers secretion of products, triggers cytotoxic effects on target
89
Describe the activation of Th0 cell proliferation
- Naive CD4 T cells binds to peptide-MHC Class 2 complex to T-cell receptor (TcR) and B7 co-stimulator to CD28 receptor (Two-signal activation)
- Activate APC and activated Th0 secretes IL-2 which binds to naive T cells
- IL-2 causes production of Nuclear Factor of Activate T cells (NFAT)
- NFAT cause proliferation of attached Th0 cells and neighbouring Th0 cells
- Activated Th0 cells then differentiate based on present cytokines
90
Describe differentiation of Th0 cells into Th17 cells
- IL-6 and TGF-beta is released by many sources: IL-6 —> Dendritic cells and macrophages (IL-6 is dominate signal), TGF-beta —> epithelial cells
- IL-6 and TGF-beta increases expression of RORyt
- RORyt increase IL-6R and TGF-BetaR receptor production and stimulates differentiation into Th17 cells
91
Describe overall function and effects of Th17 cells
- Th17 causes pro-inflammatory responses
- Th17 increases the secretion of anti-microbial peptides
- Th17 secretes chemokines to recruit neutrophils to the site of infection (chemotaxis)
- Th17 control fungal infections
- Th17 control bacterial infections especially gram-negative bacilli and gram-positive cocci
92
Describe cytokines profile and effector functions of Th17 cells
IL-17 family:
- Targets leukocytes and tissue cells
- Cause inflammation and attracts neutrophils
- cause production of anti-microbial peptides (e.g. Defensin which rips open bacteria membrane)
IL-22:
- targets tissue cells of breached epithelium
- causes increased barrier function
- cause anti-microbial peptides
93
Describe the type of bacterial infections that are controlled by Th17 T cells, I.e. Examples of extracellular bacterial infections
Th17 T-cells controls bacterial infection at mucosal sites:
- Gram-negative bacilli —> Klebsiella and pseudomonas
- Gram-positive cocci —> Staphylococcus aureus
94
Describe the function of Th17 cells including the role in release of chemokines, inflammation, neutrophil response, anti-microbial peptides and barrier function
- Stimulated anti-microbial peptides
- Stimulate inflammation
- Attract neutrophil to site
- Increase barrier function
95
Outline some clinical sequelae of defensins that illustrate their role in bacterial and fungal infections
- Short-charged peptides that burrow into bacterial cell walls
- Rips apart bacterial cell wall
- Released from neutrophils and epithelial cells
- Recruit neutrophils to infection site
96
Describe Th0 cell activation
- Naive CD4 T cells binds peptide-MHC class 2 complex to T-cell receptor (TcR) and B7 co-stimulator to CD28 receptor (two-signal activation)
- Activate APC and activated Th0 secretes IL-2 which binds to naive T-cells
- IL-2 causes production of Nuclear Factor of Activated T-cells (NFAT)
- NFAT cause proliferation of attached Th0 cells and neighbouring Th0 cells
- Activated Th0 cells then differentiate based on present cytokines
97
Describe differentiation of Treg from Th0
- Differentiation of Treg from Th0 occurs in the thymus (natural Treg) or in peripheral (induced Treg)
- TGF-beta and IL-6 bind to Th0
- FoxP3 transcription factor is upregulated (FoxP3 is marker of Treg)
- FoxP3 causes differentiation into Treg
98
Describe cytokine profile of Treg (secreted)
- TGF-beta
| - IL-10
99
Describe cytokine profile of Treg (secreted)
- TGF-beta
| - IL-10
100
Describe function of Treg (regulatory CD4 T cells)
- Prevent over-expansion of effector T cells: secretes inhibitory cytokines (IL-10 and TGF-beta), directly contacts CTLA4 inhibitory receptor on T cells
- Suppress self-reactive T-cells (since self-reactive Th0 are converted to Treg)
101
Describe the difference in Treg Natural and Treg inducible cells
Treg Natural
- Thymus derived T-cells
- Delete self-reactive T-cells
- Recognize MHC class-2 self peptides
Treg inducible cells:
- Treg cells derived in the periphery (lymph nodes) from naive Th0 cells
- Recognize MHC class 2-pathogen peptides
- induced during infection
102
Explain the clinical sequelae in the absence of T reg cells and give an example
Absence of Treg cells:
- Fatal autoimmune disease
- Abnormal Th1 and Th2 responses
103
Describe the pattern of response of the CD8 cells including their function and target
- CD8 T-cells only recognize MHC Class 1 presenters
- Also called cytotoxic T-cells
- Cause lysis or apoptosis of target cells
- Release inflammatory cytokines (IFN-gamma)
- Target virus-infected cells and tumours
104
Describe the viral activation of antigen presenting cells including the pattern recognition receptors and types of dendritic cells
- Toll-like receptors (TLR) of innate immune cells recognize viral nucleus acid
- Dendritic cells are activated by innate immune cells with bound viral nucleus acid: CD11c Myeloid Dendritic cells activates CD8 T cells (via TNF and IL-12), Plasmacytoid dendritic cells potent sources of IFN-alpha during virus infection
105
Outline the different type of interferons and the functions of Type 1 interferons
```
Type 1 Interferons:
- Interferon-alpha are secreted from monocytes and have nonspecific responses with antiviral function
- Interferon-beta are secreted from fibroblasts and have non-specific responses with anti-viral function
Functions:
- inhibit viral replication
- Activate natural killer cells
- Increase MHC class 1 expression
- Anti-proliferation
```
Type 2 Interferon:
- Interferon-gamma - secreted from T-cells and have specific responses with antiviral function
106
Describe the activation of CD8 T-cells naive and effector T-cells in terms of their MHC requirements, co-stimulators and site of activation
Infection and presentation of virus on APC surface:
1. Viral DNA/RNA enters cell
2. Protein is made by cell machinery
3. Protein is ground up
4. TAP transports peptide into ER
5. ER combines peptide with MHC Class 1 protein
6. Golgi packages MHC Class 1 + peptide with carbohydrate
7. Complex goes to surface
Activation of CD8 T-cells (two types):
- Naive CD8 T cell activation occurs at dendritic cells in secondary lymphoid tissues (lymph nodes, spleen, etc) requiring 3 signals: MHC Class 1/antigen-peptide binding with TcR, B7 binding with CD28 (co-stimulation), IL-2 (CD4 T cell help) —> CD4 helper T cell binds with DC and releases IL-2
- Effector CD8 T cell activation occurs at any MHC Class 1 positive cell at virus infect tissue: just requires 1 signal: MHC Class1/antigen-peptide binding with TcR
107
Explain how CD8 cells affect virus-infected or tumour cells
Function of CD8 T cells (also called Cytotoxic T cells when activated)
- Kill virus-infected cells or tumour cells: secrete performing and granzymes, contact infected cell via Fas ligand/Fas
- Secrete Cytokines (interferon-gamma) to activate inflammation, antiviral activity, and macrophages
108
Describe the process of CD8 performing/granzyme lysis of target cells
Secrete performing and Granzyme which trigger cytolysis and apoptosis:
- performing and granzyme enter target cell and trigger apoptosis
Contact infected cell via Fas ligand/Fas which triggers apoptosis
109
Outline the specific immune response to viruses in the short-term vs the long term - referring to CD8 cells and antibodies
- CD8 cells trigger early response to infection (short term): clear primary viral infection but can’t prevent reinfection
- Antibodies protect against reinfection (long term)
110
Describe the structure of antibodies of B-cells
- Two heavy chains and two light chains: Heavy chain = 3 constant and 1 variable region, light chain = 1 constant and 1 variable region
- Fab region = antigen binding region
- Fc region = constant region
- 5 types of heavy chains: alpha, delta, gamma, epsilon, mu
111
Describe the 5 classes of antibodies in humans
IgA: Mucosal immunity
IgD: Naive B cell antigen receptor
IgE: Mast cell activation and defence vs parasites
IgG: Most common; many functions
IgM: Naive B cell antigen receptor and complement activator
112
Describe the recognition of B-cell clone
Recognition of antigenic material on naive B-cells
- Naive B-cells express membrane bound antibodies, IgM and IgD, on their surface
- Antigen binds to specific IgM or IgD (BcR are membrane bound antibodies)
113
Describe the activation of B-cells
- Naive B cell expresses membrane bound IgM and IgD
- Antigen binds IgM or IgD (BcR)
- Clonal expansion occurs after binding (extent is dependent on T cell help): Thymus Independent activation; Thymus dependent activation
- Activated B cell differentiate into plasma cells that secrete antibodies with same antigen receptor
114
Describe clonal expansion of B-cell clone
- Activated B-cells will undergo clonal expansion and proliferate
- Clonal expansion will ensure increased numbers of B-cells with the same antigenic binding receptor on its surface
- Clonal expansion will lead to differentiation of B-cells into memory B-cells and plasma cells
115
Describe the characteristics of activated B cells
- Proliferation
- low levels of IgM secretion
- Increase expression of B7 co-stimulate
- Express cytokine receptors (for T cell help)
- Migrate to follicles
116
Describe Thymus-dependent antibody response
- Protein antigens are processed on APCs
- CD4 T helper cells play role in B-cell activation
- Two signals: antigen binding to BcR, CD40-CD40L co-stimulation (from T-helper cell)
- Induces heavy chain isotope switching, affinity maturation and memory: IFN-gamma: IgM —> IgG, IL-4: IgM —> IgE, TGF-beta: IgM —> IgA
117
Describe Thymus-independent antibody response
- Non-protein antigens bind to the B cell receptor (I.e. polysaccharides and lipids)
- T-cells do not help
- No heavy chain isotope class switching, affinity maturation, nor memory: weak antibody response
118
Describe primary antibody response
- First infection by antigen
- 5-10 day lag
- Smaller peak antibody response
- Mostly IgM
- Low binding affinity
119
Describe secondary antibody response
- Subsequent infection by antigen
- 1-3 day lag
- Large peak antibody response
- Mostly IgG
- High binding affinity
120
Describe activation of B-cells via binding of antigen to BcR - occurs within the lymph node primary/secondary follicles
1. Proliferation of B-cells require two signals:
- antigen binding to B-cell receptor
- Co-stimulation (CD40-CD40L) between B cell and CD4 T helper cell
2. Naive B cells encounter foreign antigens at secondary lymph nodes:
- Antigen cross-links IgM and IgD transmembrane receptor on B cell
- Signal is transducer via Ig-alpha and Ig-beta into B cell cytoplasm
3. Change in B cell phenotype (following B-cell activation)
- Increase survival and proliferation
- Increase B7 expression (activates Th cells)
- Expression of cytokine receptors
- Migration to follicles
121
Describe T-helper cell activation of B-cells - occurs in parafollicular cortex
- CD4 T-helper cells are activated by dendritic cells in T-cell zone of lymph nodes
- Activated T and B-cells meet at edges of follicles
- B cells can also engulf antigen peptides and present to naive T-cells.
- What is CD4 T-cell ‘help’:
1. T-cell is activated by signals 1 and 2 from B cells (antigen+MHC Class 2 and CD40 costimulation)
2. Activated T cells provides signals to further activate B cells
3. CD40 ligand on T-cell binds to CD40 molecule on B cell. Causes B cell effects: class switching, B-cell proliferation, antibody synthesis
122
Describe the molecular mechanisms of class switching
- Engagement of CD40 ligand on T-cell with CD40 on B cell is essential for class switching from IgM secretion to another Ig class
- Binding of cytokines determine outcome of class switching
- Different microbes are eliminated most efficiently by different immune responses: IFN-gamma promotes class switching to IgG, IL-4 and IL-5 promotes class switching to IgE
123
Describe mechanism of class-switching of immunoglobulins
- when helper T-cells and cytokines are present, switch regions are activated and gene recombination can occur for heavy chains
- Call “Switch recombination”
124
Describe affinity maturation and selecting the best antibodies
Affinity maturation - the affinity of antibodies to bind with antigens increases upon increased exposure and with time.
- Point mutations in VDJ gene regions occur which alter binding affinity
- Occurs in “Germaine centres” of follicles:
1. B cells expressing mutated receptors are given survival signal which bind to antigen-binding site (signals presented by follicular dendritic cells)
2. B cells clones that weakly bind antigen die
3. B cells clones are progressively selected until only high affinity B cells are left
125
Outline feedback inhibition of antibody secretion
- Secreted antibody forms complex with antigen
- Antigen-antibody complex binds to the B-cell Ig and Fc receptor
- Binding Fc receptor inhibits B-cell response
126
Describe effector functions of IgD
- Expressed on naive B-cells to recognize antigen and activate B-cell
- no known secreted forms
127
Describe effector functions of IgM
- Activate the complement pathway through the classical pathway
- synthesised in large amounts during primary exposure to antigen
- Indicate early immune response
128
Describe effector functions of IgA
- In mucosal lining
| - Secreted into gastrointestinal and respiratory tracts to neutralise microbes and toxins
129
Describe IgE effector functions
- Defence against helminths (parasites)
| - Cause mast cell degranulation (release of mediators): responsible for hypersensitivity
130
Describe IgG effector functions
Most common with most functions
- neutralise microbes and toxins
- opsonization of antigens
- Activate classical pathway of complement
- Attract NK cells
- Passed across placenta for neonatal immunity
- Feedback inhibition of B cells
131
Describe antibody neutralisation of microbes and toxins
Antibodies neutralise microbes and toxins by binding and preventing binding to host cell receptors
1. Binds to microbe so microbe can’t bind to host cells
2. Binds to microbes after released from infected cell; prevents infection of adjacent cells
3. Binds to toxins released by microbe so toxins can’t bind to cellular receptors
132
Describe antibody opsonization and phagocytosis of microbes
1. IgG binds and coasts surface of microbe
2. Fcgamma receptors on phagocyte bind Fc region (constant region) of IgG
3. Fc-gamma receptors Activate phagocytosis in macrophages and production of ROS and NO
4. Microbe phagocytized
5. Microbe killed by reactive oxygen species (ROS) and nitric oxide (NO)
133
Describe antibody dependent mediated cell-mediated cytotoxicity via IgG
- Infected host cell presents surface antigens
- IgG binds and coats surface of infected cells
- Fc-gamma receptors on NK cells bind with IgG
- NK cell releases toxic proteins to kill IgG-coated cell
134
Describe antibody dependent mediated cytotoxicity via IgE
- IgE binds and coats surface of helminth (too large to phagocytize)
- Eosinophils bind to IgE coated helminth (via Fc-epsilon receptors)
- Eosinophils release granules to kill helminth
135
Describe IgE-caused Hypersensitivity
- After initial exposure to an allergen, B cells makes excess IgE
- IgE binds to Fc-epsilon receptors on mast cells: “Sensitized mast cells” have IgE bound to surface with no antigen present
- When second exposure to antigen, the mast cell release granules causing hypersensitivity response
136
Explain how the complement pathway is activated
- Inactive proteins are activated via proteolytic cleavage
- Cascade of cleavage activates complement system
- Three activation pathways: Classical pathway, alternative pathway, lectin pathway
137
Describe the ‘Classical Pathway’
Activated by IgM and IgG binding to antigen
- Complement Activation:
1. IgG or IgM bind to microbe surface antigens
2. C1 binds to Fc
3. C1 cleaves to C4 and C2 (which both fragment to a/b parts)
4. C4b and C2a combine to make C3 convertase
5. C3 binds and fragments to make C5 convertase (C4b + C2a + C3b)
6. C5 converted to C5a and C5b
Goes to late steps of complement system
- C5 convertase + C5b attracts C6, C7, and C8
- Membrane attach complex (MAC) forms
- Cell lysis occurs
138
Describe “Alternative Pathway”
- C3 binds directly to microbe surface
- Factor B binds to make C3 convertase
- C3 binds to make C5 convertase (C3b + Bb + C3b)
139
Describe “Lectin pathway”
- Mannose-binding lectin binds to mannose in microbe surface
| - C4 and C2 bind to lectin (same steps as classical after)
140
Outline the properties and components of the complement pathway
Properties:
- Activation via proteolytic cleavage
- Tightly controlled
- Cascade amplifies activation
- All activation pathways lead to Membrane attach complex (MAC)
Regulation:
- DAF (decay accelerating factor) inhibits complement activation
- DAF stops binding of C3b with Factor B (alternate) and C4b2a (classical)
141
Explain using examples how microbes can evade humoral immunity
Pathogens can evade antibody-mediated immunity by:
- mutate surface antigens: during infection, between infections
- inhibit complement activation
- Resist phagocytosis
142
List the 3 lines of defence that protect against viruses
Physical barriers - prevent viruses from entering the body.
- Physical (air flow, tight functions, cilia)
- Chemical (pH, enzymes)
- Microbiological (normal flora)
Innate immune response - non-specific defence against virus
Adaptive immune response - specific defence against particular virus
143
Describe the broad difference between the innate immune response and the adaptive immune response
Innate response:
- same response every time; does not improve with exposure
- immediate response
- non-specific: pattern recognition receptors (PRR) recognize pathogenic associate molecular patterns (PAMP) on virus
Adaptive immune response:
- response improves with exposure
- initial response is slow, but future responses are faster
- specific to infecting pathogen
144
Describe the principle mediators of the innate immune response to virus infections
- Type 1 interferons
- Natural killer cells
- Cytokines
145
Explain how the innate immune response controls virus infection, including the function/role of Type 1 Inteferons, Natural killer cells and inflammatory mediators such as cytokines
Type 1 interferons - IFN-alpha and IFN-beta
- Type 1 IFN production is stimulated by virus infection
- Three functions of Type 1 IFN:
1. Inhibit viral replication —> stimulated uninflected cells to produces enzymes to inhibit viral replication
2. Enhance CTL response —> Increase MHC Class 1 expression of infected cells to enhance CTL response
3. Enhance NK cell activity
Natural killer cells:
- Recognize cells that fails to express MHC Class 1: MHC Class 1 bind to inhibitory receptor on NK cell, missing or altered MHC Class 1 allows active NK cells
- Early function in virus infection
Cytokines:
- Signal proteins secreted by cells involved immune response
- Mediators and regulators
146
Describe the principle mediators of the adaptive immune response to virus infections including antibodies, Cytotoxic T lymphocytes, Helper T cells:
Antibodies:
- recognize antigen
- can only bind with viruses in the extracellular phase of lifecycle (OUTSIDE cells)
- Bind to virus surface: prevents binding to cell-surface receptors on host cell
- Bind to infected cell surface: bind with Fc-gamma receptors on NK cells to activate NK cell (antibody dependent cell-mediated cytotoxicity)
Cytotoxic T-lymphocytes (CD8+ T lymphocytes):
- Elimination of viruses that are INSIDE cells
- Recognize antigen peptides presented on MHC Class 1 molecules
- Steps to CTL-mediated lysis:
1. Infect target cell displays antigenic peptide on MHC Class 1
2. CTL binds and activates
3. CTL granule exocytose
4. Apoptosis of target cell
Helper T cells (CD4+ T cells):
- Recognize MHC Class 2 molecules
- Provide “help” for antibodies and CTLs
- Release cytokines when activated
147
Explain how the adaptive immune response controls virus infection
- Antibodies coat the pathogen (opsonization) resulting in increased phagocytosis and NK cell activity
- MHC Class 1 binds intracellular pathogens and bind to CTL (CD8+) cells
- MHC Class 2 binds extracellular pathogens and causes activation of CD4+ cells to release cytokines
148
Summarise why viruses have evolved strategies to avoid the host immune response
- Viruses are dependent on host to provide replication machinery to make more viruses
- Host immunity has developed way to limit viruses’ reproduction
- Viruses have developed ways to evade host immunity:
1. Avoid antigen presentation and immune recognition
2. Latent “dormant” infection stage
3. Destroy host immune cells
149
Explain using examples how viruses can evade innate and adaptive immune responses
1. Infect “immune privilege” sites to avoid antigen presentation and immune recognition. E.g. Herpes simplex virus and Varicella Zoster virus hide in neutrons
2. Establish a dormant infection. E.g. Herpes simplex virus
3. Infect and destroy cell of host immunity. E.g. HIV kills CD4+ T cells
4. Viral gene products directly alter immune response
Viral encoded evasion of innate immune response:
- Modulation of Type 1 IFN response: Mimics IFN receptors, inhibit intracellular anti-viral response
- Modulation of cytokine networks
- Evasion of NK cell-mediated immunity: Produce MHC class 1 homolog that doesn’t present antigen, inhibits NK cells without triggering CTL cells
Viral encoded evasion of adaptive immune response:
- Modulation of antibody response: Antigen variability
- Modulation of MHC Class 1 antigen presentation:
1. Inhibit generation of antigenic peptides
2. Inhibit peptide transport via TAP complex (to ER)
3. Inhibit expression of MHC Class 1 complex to surface
- Modulation of MHC Class 2 antigen presentation: inhibition of surface expression, inhibition of MHC Class 2 molecule transcription
150
Outline the principles of vaccination and the criteria required for useful vaccines:
- Safe
- Effective at stimulating immune response
- Long-lasting immunity
- Cheap and available
- Stable
- Easy to administer
Herd immunity - community immunity; if most individuals (~95%) are immunised to a specific microbe, the microbe will not be able to spread through the community (i.e. even non-vaccinated people will be protected)
151
Explain the difference between passive and active immunisation
Passive:
- protective immunity by transfer of antibodies
- no specific immunological memory
- very short term protection
- natural passive immunization = through placenta or breastfeeding
- Artificial passive immunization = injection of antibodies
- Risks: serum sickness if injected antibodies are from other species, and patient’s body reacts, immune complexes can deposit in blood vessels
Active immunization:
- host’s immunity is activated to produce antibodies itself
- long lasting, protective immunity
- “herd immunity”
152
Describe the type of vaccines currently in use:
- Killed inactivated vaccine: microorganism is killed so not infective:
Adv: safe from virulence, safe for immunocompromised people, stable
Disadvantage: does not trigger T cell response (doesn’t last long enough), multiple doses needed, need adjuvants
Live attenuated vaccine: pathogenicity eliminated by retain capacity to grow in host
Adv: Better resemble microbe activity in body, long term protection, single dose, no adjuvants
Disadvantage: possible reversion to virulent form, limited shelf-life, complications similar to real disease
Subunit vaccines (purified macromolecules):
- Toxoids: exotoxins form organism is chemically inactivated, antibodies form which neutralise toxin
- Recombinant antigen: cloned genes expressed in bacteria and yeast, very safe
- Capsular polysaccharides: problem - polysaccharides aren’t presented on MHC proteins, solution: conjugate vaccines - polysaccharide is combined with tetanus toxoid, polysaccharide is bound to antibody, tetanus is presented on MHC Class 2 complex, antibodies for polysaccharide are produced
Virus-like particles:
- virus capsule with no nuclei acid inside
- not infectious
153
Describe the different classes of adjuvants and their capacity to boost immune responses
- Some proteins are not immunogenicity by themselves
- Adjuvants increase immune response and effectiveness of vaccine by: aggregating proteins, slowly release proteins over time (depot forming)
- Greatly improve T helper cell response (CD4+ T cell)
154
Describe three of the main classes of adjuvants approved for human use and their mode of action - Alum, MF59, MPL
Alum:
- antigens are adsorbed onto charged aluminium particles
- Depot of antigen releases antigen slowly
- promotes phagocytosis by APCs
- Boosts Th2 cell response
- Advantages: safe to use, stabilises antigen, augments the antibody responses, relatively simple formulation for large-scale production, cost-efficient
- Disadvantages: does not produce a strong Th1 response, loss of potency after freezing
ASO4:
- Alum + MPL, it works like Alum
- Forms depots to continuously release antigen
- Activates TLR4
- Downregulates Th2 response and unregulated Th1 response
155
Explain the new types of adjuvants currently in development and understand their mode of action e.g. targeting of pattern recognition receptors (PRRs)
New adjuvants include immune potentiators to fully stimulate the adaptive immunity
PAMPs (pathogen associated molecular patterns) will target different toll-like receptors. New adjuvants being developed will bind to TLR, and other molecules like PAMPs that target PRRs.
156
Explain the principle of self-tolerance and give clinical examples of the manipulation of tolerance
Tolerance - specific ability of the immune system n to to respond to antigens:
- neonatal tolerance: antigens encountered in the womb are seen as self-antigens
- autoimmunity: failure of self-tolerance leads to reactions with self-antigen, which is auto-immune disease
Self tolerance: inability of immune cells to attack self-antigens
- three mechanisms of self-tolerance:
1. Deletion of self reactive lymphocytes in thymus (t cells) and bone marrow (B cells)
2. Anergy = specific failure of self-reactive lymphocytes to respond to self-antigens
3. Suppression of self-reactive lymphocytes by T-reg
Tolerance manipulation:
- transplant tolerance: manipulate the immune response to treat foreign graft as self-antigens
- autoimmune disease: use mechanisms of auto-immune disease to design therapies and prevention
- usually need to give toxic immunosuppressive therapy for transplant and autoimmune disease
157
Summarise the mechanisms of central and peripheral tolerance for T-cells, including the role of Treg cells
Central tolerance: deletion of the auto-reactive lymphocytes occurring in primary lymphoid organs: T-cells in thymus, B-cells in Bone marrow
Peripheral tolerance:
- control of activation of T and B-lymphocytes in the secondary lymphoid organs (lymph nodes and spleen): T cells need co-stimulation (Antigenic peptide + MHC Class 2 and CD28-CD80); B cells need T cell help for antigen switching
- Suppression of T-cells by Treg
158
Describe the process of thymic involvement in T cell tolerance
Thymus:
- Generation of T-cell Diversity: T cell receptor genes are rearranged (antigen reactive and self-reactive)
- Selection of TcR:
1. Positive selection: only T cells that recognize self-MHC molecules are selected. Failure leads to death. Binding with MHC Class 1 shuts off the genes for CD4+ and vice versa for MHC class 2
2. Negative Selection: binding of self-peptides presented on self-MHC leads to cell death, only single positive cells make it to this step
159
How does the thymus express proteins from other organs?
- Thymus can present proteins that are expressed in thymus and plasma
- Self-peptides from other organs are produced by AIRE gene in thymus cells
- Mutation in AIRE gene reduces exposure to self-antigens in thymus. More self-reactive T cells escape
160
Describe the peripheral activation of T-Cells (in secondary lymphoid organ - lymph node or spleen)
- Dendritic cell presents non-self peptide to T cell
- Dendritic cell co-stimulates T cell with CD80-CD28 binding (CD80 = B7). CD28-CD80 response is absent if self-reactive T cell binds (CD80 is only present during infection)
- Only both recognition and co-stimulation leads to activation: Anergy - recognition of self-peptide in absence of co-stimulation leads to NO response
161
Describe control of T-cell expansion:
- T cell expansion is controlled by apoptosis
| - T-cell express Fas-ligand that bind and induce apoptosis in some T cells: Effector T cells and memory T-cell survive
162
Describe inhibition of T-cell
- negatively selected T-cells (bind to self-peptides) can result in development of Treg
- Treg are signalled via FoxP3 gene expression FoxP3 is characteristic of Treg
- Treg inhibit self-reactive T cells (more than one T cell can bind to an APC at once): direct contact inhibition via CTLA4, cytokine inhibition via IL-10 and TGF-beta
163
Explain the concepts of anergy and indifference
Anergy - If a self-reactive T-cell binds a self-peptide without the co-stimulators molecule it will enter a non responsive state
Indifference - Self-peptides that appear in very low levels are not recognised and are sequestered away from immune cells.
Antigens that occur so low in the periphery that the T-cells are indifferent, e.g. antigens of the eye. If damage to the eye occurs there are antigens that T-cells will then respond to can result in auto-immune T-cells.
164
Describe the breakdown of peripheral tolerance
If a self-peptide is recognised, and a co-stimulators signal is provided, a self-reactive T-cell become activated and will proliferate
165
Explain the mechanisms of central and peripheral tolerance for B-cells including bone marrow and secondary lymphoid organs, as well as the role of CD4, Th2, IL-4 and the production of antibodies
Central B cell tolerancing:
- Most self-reactive B cells are deleted in bone marrow.
Peripheral B-cell tolerancing:
- CD4 T cell differentiates to Th2 T cell in lymph node or spleen
- Th2 cell “helps” B cell which binds to same antigen peptide. *Th2 cell only bind to antigenic peptides): Direct contact help via CD40L-CD40, Cytokine help via IL-4
- T cell help is necessary for B cell to undergo Ig switching.
With no T-cell help, no Ig switching occurs, and B cell continues to produce low affinity IgM
166
Describe the basic features of auto-immunity, including the causes related to self-antigens and the immune system
Auto-immunity - break down of self tolerancing leading to immune responses against self antigens.
Causes:
- Self antigen related: mimicry of self-antigens by foreign antigens, drugs/virus causing self-antigen changes, sudden release of sequestered self-antigens
- immune system related: mutation in MHC gene, mutation in regulatory genes (AIRE, Fas-Fas ligand, FoxP3)
- Environmental (unknown causes)
167
Summarise the major manifestations of immune system dysfunction, with reference to underlying mechanism
Malignancy:
- The less mature an immune cell is when it turns malignant, the more aggressive the malignancy is in spreading
- Mature immune cells that turn malignant tend to be localised, structured growths
Lymphocyte infection:
- B cell infection (e.g. Epstein-Barr Virus)
- T-cell infection (e.g. HIV/AIS)
Immunodeficiency (under-active):
- Primary immunodeficiency: no external cause; may be genetic or acquired during life: antibody (B-cell) deficiency, T-cell deficiency
- Secondary Immunodeficiency: caused by external source: cytotoxic drugs, toxins, or radiations, HIV
Hypersensitivity (over-reactive):
- Allergy: hypersensitivity to foreign antigens
- Autoimmune disease: hypersensitivity to self-antigens
- Four types of hypersensitivity: Type 1 —> IgE and mast cells causes allergic reaction, Type 2 —> IgG/IgM and complement cause autoimmune disease, Type 3 —> Immune complexes cause vasculitis, Type 4 —> T cells cause contact dermatitis
168
Describe type 1 hypersensitivity (IgE and Mast cells)
Autopsy = genetic predisposition to make IgE antibody response to common, harmless environment antigens
Mechanism:
- Initial exposure to allergen:
1. Dendritic cells pick up and present allergen to T helper cells
2. Th cells cause B cells to produce IgE
3. IgE produced and bind to mast cells
- Future exposure:
1. Antigen bind to IgE on mast cells
2. Mast cells release mediators (mostly histamine) which cause allergic reaction
169
Describe Type 2 hypersensitivity (IgG/IgM autoimmune disease)
- IgG or IgM react with self-antigens
- Autoimmune disease
- Grave Disease: antibodies bind and stimulate to thyroid
- Myasthenia Gravis: antibodies bind and block ACh receptors which block neural transmission
170
Describe Type 3 hypersensitivity (serum sickness —> vasculitis)
Serum sickness: if the ratio of antibody and antigen in vaccines is just right, they form large complexes which deposit into blood vessel walls
Cutaneous vasculitis: blood accumulates under skin where immune complex broke blood vessel
171
Describe Type 4 hypersensitivity (delayed type hypersensitivity)
- T-cell mediated delayed type hypersensitivity
- Takes days to form
- CD4+ T cells recognize antigen and react
- E.g. TB skin test
