Immunology Flashcards
1
Q
What is the immune system?
A
Complex cellular and protein network that has evolved to protect the host from pathogenic microbes
2
Q
What are the two major types of immunity?
A
Innate and Adaptive (acquired)
3
Q
In terms of the innate immune system:
- When does it arise?
- How fast is the reponse?
- Does it give rise to immunological memory?
- What kind receptors are invovled?
- What are the infection barriers?
A
- Present from birth
- Response time – minutes to hours (i.e. immediate response to threat)
- No long term memory – cannot be used for vaccination
- Uses germ-line encoded receptors (i.e. already encoded in the genome – there is a limited number of them, around 100) to recognise patterns associated with pathogens or tissue damage
- Includes barriers to infection – physical, chemical, commensal flora
4
Q
In terms of the acquire immune system:
- When does it arise?
- How fast is the reponse?
- Does it give rise to immunological memory?
- What kind receptors are invovled?
A
- Develops only after exposure to foreign antigen
- Response time – days (over 96 hours after infection – more rapid if secondary response)
- Long lasting immunological memory – basis of vaccination
- Uses a huge diversity of antigen-specific receptors derived by gene-segment rearranged during lymphocyte development
5
Q
What is clonal selection?
A
this is the idea that each lymphocyte, with its specific receptor, will recognise a specific antigen
6
Q
What is clonal expansion?
A
The antigen binding stimulates clonal expansion (i.e. the proliferation of effector lymphocytes)
7
Q
What is the difference between primary and secondary lymphoid tissues?
A
- Primary lymphoid organs are where lymphocytes are produced in a process called lymphopoiesis
- Secondary lymphoid organs are where lymphocytes can interact with antigen and with other lymphocytes
*
8
Q
Give examples of (a) primary and (b) secondary lymphoid tissues
A
- Primary = Bone Marrow, Thymus
- Secondary = Spleen, Lymph nodes, Mucosal associated lymphoid tissues (MALT)
9
Q
What is the thymus?
A
- The thymus (a primary lymphoid organ)– a bi-lobed organ situated at the level of the trachea
- Each lobe has a medulla and a cortex
- Filled with T lymphocytes (or thymoytes)
10
Q
What is the role of the spleen?
A
The spleen (a secondary lymphoid organ) filters for antigens in the blood
11
Q
Explain the immunological structure of the spleen
A
The spleen can be divided into two key areas:
- Red pulp – where the red blood cells are filtered
- White pulp – where the white blood cells are filtered
- Further split into a B cell and T cell area
12
Q
Within the white pulp of the spleen, where do the B and T cells reside?
A
13
Q
What is one consequence of a splenectomy
A
Individuals who do not have a spleen are highly susceptible to infections with encapsulated bacteria
14
Q
What is haematopoiesis and where does it occur?
A
Bone marrow is the site of haematopoiesis (the formation of blood cells)
15
Q
Outline the major stages involved in haematopoiesis
A
- Stem Cell Stage – pluripotent, self-renewing. Give rise to all blood cell types, do not express specific marker proteins (such as CD4)
- Progenitor Cell Stage – semi-committed cells (i.e. committed to particular lineage). Stem cells become progenitor cells in the presence of specific growth factors
- Mature Cell Stage – completely committed, mature cells. Progenitor cells become mature cells as part of one of two lineages, common lymphoid cells or common myeloid cells (specific growth factors determine which)
16
Q
How many litres of lymph are drained each day?
A
2-3 L
17
Q
Within lymph nodes, where to B and T cells reside?
A
There is physical segregation of T and B cells:
- T cells stay within the parafollicular cortex
- B cells reside in the lymphoid follicle
18
Q
How do lymphocytes within nodes recognise an infection has occured?
A
Within the nodes, HEV (high endothelial venules) signal to the lymphocytes that there is an infection so that they leave the node and enter circulation
19
Q
What is the purpose of epithelium
A
It is the first line of defence
20
Q
What is the purpose of mucosae/skin?
A
- Mucosae and skin form a physical barrier
- It has a very large surface area, in large part a single layer of cells
- Heavily defended by the immune system
21
Q
What is the cutaneous immune system?
A
There is a dense network of immune system cells in the skin to prevent the penetration of infection through this primary barrier
22
Q
What problems does lymphocyte recirculation solve?
A
- There are a very large number of T cells with different specificities
- There are a very large number of B cells with different specificities
- There may only be limited amounts of antigen
- How does the body ensure that the antigen meets lymphocyte with specific receptor?
23
Q
What are lymphocytes?
A
Lymphocytes are small cells with agranular cytoplasm with a large nucleus
24
Q
What are the two types of lymphocytes? How are they classified?
A
Can be subdivided into 2 groups depending on where they were produced
- B lymphocytes (Bone Marrow)
- T lymphocytes (Thymus)
25
What are clusters of differentiation (CDs)?
* An internationally recognised systematic nomenclature for cell surface molecules
* Used to discriminate between cells of the haematopoietic system
* There are more than 350 CD markers (eg: CD4)
26
What are the two subtypes of T lymphocytes?
**CD4+ = T helper cells, regulatory T cells**
* Secrete cytokines
**CD8+ = cytotoxic T cells**
* Lyse infected cells, secrete cytokines
* Important for viral infections
27
What is the function of B lymphocytes?
Produce antibodies
28
What is expressed by B lymphocytes?
* Express CD markers CD19 & CD20
* Express MHC Class II (can present antigen to helper T cells)
29
What are antigen presenting cells?
APCs are cells that can present processed antigen (peptides) to T lymphocytes to initiate an acquired (adaptive) immune response
30
Give some examples of APCs
* B lymphocytes
* Dendritic cels
* Macrophages
31
List and Explain the various recognition strategies employed by the innate immune system
**PAMPs (pathogen-associated molecular patterns)**
* Detect conserved microbial structures
* Recognised by various cell receptors collectively known as **PRRs (pathogen recognition receptors)** (inc. **TLR**s, **NLR**s, CLRs and RLRs)
* PAMPs are produced ‘inadvertently’ by pathogens during replication
* PAMPS are detected by immune cells with **PRR**s causing release of cytokines & chemokines
**DAMP **
* Recognised by **NLR**s
* Detect metabolic consequences of cell infection or injury
**NK Cells **
* **MHC Class I **receptors
* Decrease MHC and have a balance between inhibitory and activatory signals (so you shift the balance to effect a response
32
What is the general response of innate immune system cells?
## Footnote
*(Hint - remember it is the same in everyone)*
* Express receptors to allow detection and migration to sites of infection,
* Express pattern recognition receptors, which are genetically encoded, that allow pathogen detection
* Have phagocytic capability
* Secrete cytokines and chemokines to regulate the immune response
33
What are NK Cells?
Large granulated lymphocytes: cytotoxic, lyse target cells and secrete the cytokine interferon-g
34
Do NK cells require previous exposure to the pathogen?
No - NK cells do not require previous exposure to activate killing ability
35
What kind of receptors are expressed by NK cells?
No antigen-specific receptor, but express both activating and inhibitory receptors: balance of signals
Have receptors which bind to antibody-coated cells (ADCC)
36
What is a neutrophil?
Neutrophil (polymorphonuclear leukocyte) – make up 50-70% of leukocytes (most abundant white blood cell)
* Short lived cells,
* Circulate in blood then migrate into tissues;
* First cells to be recruited to a site of tissue damage/infection
37
Outline the process involved in neutrophil-assoicated pathogen destruction
1. Move from circulation into tissues to site of infection
2. Bind pathogen
3. Phagocytose pathogen
4. Kill pathogen
38
What two terms are given for the movement of neutrophils?
The movement of neutrophils into tissues is **diapedesis** and **chemotaxis **
39
What is opsonisation
* The process of coating of micro-organisms with proteins to facilitate phagocytosis
* Opsonins are molecules that bind to antigen, and also can be bound by phagocytes
* Antibody and complement function as opsonins
40
What two types of neutrophil-mediated killing mechanisms are there?
* **Oxygen dependent -** involves toxic metabolites, superoxide anion, hydrogen perioxide, reactive nitrogen intermediates, NO
* **Oxygen independent -** involves enzymes, lysosymes, hydrolytic enzymes and AMPs
41
What are macrophages?
* Phagocytic cells
* Macrophage less abundant than neutrophils
* Dispersed throughout the tissues;
* Signal infection by release of soluble mediators
42
What are cytokines?
* Small secreted proteins
* Involved in cell-to-cell communication
* Seen as “messengers” of the immune system
* Tend to act locally
* Biological effects at very low concentrations
* Short-lived
43
List the various types of cytokines
* interleukins (IL-x): between leukocytes (around 35 sub-types)
* interferons (IFN): anti-viral effects (3 sub-types: alpha, beta & gamma)
* chemokines chemotaxis, movement (around 50 sub-types, each with their own receptors)
* growth factors
* cytotoxic tumor necrosis factor (TNF)
44
What are the general types of cytokine action?
* Autocrine Action - the cytokine can attach to the cell that produced it (this is the case with IL-2)
* Paracrine Action – the cytokine attaches to nearby cells
* Endocrine Action – the cytokine attaches to nearby cells having travelled through systemic circulation
45
What is septic shock?
Result of excessive cytokine production and release due to dysregulation in the system (usually due to bacterial infection)
46
What are the functions of the following innate immune system cells?
* Neutrophils
* Macrophages
* Dendritic cells
* Basophils
* Eosinophils
* Mast cells
* Natural killer (NK) cells
* Neutrophils = Phagocytosis, Acute inflammation (1st cells to arrive to site of injury)
* Macrophages = Phagocytosis, Longer lived (arrive after neutrophils), Can be resident in healthy tissues.
* Dendritic cells = Antigen presentation
* Basophils = Parasitic infections and allergies, bind IgE, release heparin and histamine
* Eosinophils = Parasitic infections and allergies, bind IgE, release prostaglandins and leukotrienes.
* Mast Cells = Allergies, bind IgE, release histamine and heparin
* NK Cells = Kill virally or tumour infected cell, secrete IFN-γ Antibody dependent cell cytotoxicity,
47
What is the complement immune system?
* Plays a major role in complementing the activity of a specific antibody
* Major role in innate and antibody-mediated immunity
48
What are the three major pathways involved in complement activation?
* **The Classical Pathway** - initiated by antigen-antibody complexes
* **The Alternative Pathway** - direct activation by pathogen surfaces
* **The Lectin Pathway -** antibody-independent activation of Classical Pathway by lectins which bind to carbohydrates only found on pathogens
49
What are the main functions of the complement system?
* Lysis
* Opsonisation
* Active inflammatory response
* Clearance of immune complexes
50
What is inflammation?
A localised, acute inflammatory response
51
Outline the systemic acute phase of inflammation
(eg: fever)
* Fever, increased production of white blood cells (leukocytosis), production of “acute-phase” proteins in the liver
* Induced by cytokines
* Inolves the acute phase proteins
* C-reactive protein (CRP)
* Mannan binding lectin (MBL)
* Complement
* Fibrinogen (clotting)
52
How do T and B cell receptors develop?
T and B cell receptors (TCR and BCR) are generated by somatic (VDJ) recombination (joining) of gene segments to encode the complete receptor.
53
Outline the process of somatic (VDJ) recombination to produce TCRs
* The genes for the alpha segment are found of the V (variable) and J (joining) segments.
* The genes for the beta segment are found on the V, J and D (diversity) segments.
* During development, there is rearrangement of the gene segments – this results in diversity of the TCRs (this is the same process in the BCRs)
* TCRs are made from one alpha and one beta chain
* Various recombinations occur to provide diversity
* Initially, a diversity (D) segment joins to a joining (J) segment – this makes a unit to express the heavy chain (D and J --\> D/J and V --\> V and J)
* This same process repeats until the V(D)J recombination has taken place to generate enough diversity
* There are insertions and deletions of DNA to create diversity
54
How is auto-immunity avoided?
* Receptors are made in a near-random formation therefore they will include self-reactivity – in-built in the system are mechanisms to avoid this
* Multiple levels of tolerance induction to eliminate self-reactivity from repertoires.
* Auto-immunity can happen although this is rare.
55
What is immunological memory?
* Once the adaptive immune system has eliminated a pathogen, pools of antigen specific T/B cells persist – this creates immunological memory
* Re-encounter of antigen results in a faster and more potent memory immune response.
56
Describe the general structure of BCR/TCRs
BCR and alpha-beta TCR are structurally similar heterodimers
57
What are Complementary Determining Regions?
* Each recombined chain of the TCR has 3 complementarity determining regions (CDR) – these are variable regions and form the antigen-biding site
* CDR1 and 2 are germline encoded (more conserved)
* CDR3 produced by VDJ recombination (therefore is the most variable, it is the segment that mostly sees the peptide – from the pathogen)
58
How do T cells recognise antigens?
T cells will only respond to peptide antigens loaded onto MHC class I/II
The function of the T cell is to “look inside” the cell – i.e. it is able to detect whether or not a cell is infected by recognising non-self antigens
59
How do T cells recognsie MHC-loaded antigens?
MHC molecules are membrane-bound; recognition by T cells requires cell-cell contact.
* A peptide must associate with a given MHC of that individual, otherwise no immune response can occur. That is one level of control.
* Mature T cells must have a T cell receptor that recognises the peptide associated with MHC. This is the second level of control.
60
What role do cytokines have in T cell recognition?
Cytokines (especially interferon-γ) increase level of expression of MHC.
61
What is the difference between MHC Class I and Class II molecules?
* **MHC Class I** – binds peptides derived from the internal contents of the cell and meets them in the ER - major purpose is to target cells for killing
* **MHC Class II** – binds peptides derived from external sources and meets them in the endosomes - major purpose is to monitor the environment
62
Outline the role of MHC Class I molecules
* Binds to extracellular antigens (eg: the bacterial cell) because they are on antigen presenting cells
* The extracellular antigen is endocytosed and are broken down by peptidases into small peptides
* Peptides bind to the mature MHC Class II molecule in the endosomes. They are sorted at this stage (in the Golgi) before they join the exocytotic pathway and are presented on the cell surface (only when a peptide is bound)
63
Outline the role of MHC Class II molecules
* Already an intracellular antigen (because the cell has taken up the pathogen free in the cytoplasm)
* Intracellular antigen is degraded by the proteasome into small peptides
* Peptides move to the ER where the bind to the pre-formed MHC Class I molecule
* As the MHC Class I molecule matures (in the Golgi) through the normal exocytosis pathway, the Class I-Peptide complex moves towards the cell surface
64
Describe the structure of MHC Class I molecule
* Two polypeptide chains – long alpha chain (heavy) and a short beta chain
* Upper surface forms a peptide-binding groove into which small 8-10 amino acid peptides sit
* Four regions make up MHC Class I molecules:
* Cytoplasmic Region – contains sites for phosphorylation and binding to cytoskeletal elements
* Transmembrane Region – composed of a heterodimer
* Conserved Region – alpha3 domain: binds CD8 (associated T cell receptor – involved in cell-cell interactions)
* Polymorphic Peptide Binding Region – alpha1 and alpha2 domains: form peptide binding region
65
Describe the structure of MHC Class II molecule
* Two chains (alpha and beta) both membrane-bound
* Upper surface forms peptide-binding region into which longer peptides sit (around 18 aa)
* Four regions make up MHC II molecules:
* Cytoplasmic Region – contains sites for phosphorylation and binding to cytoskeletal elements
* Transmembrane Region – contains hydrophobic amino acids
* Conserved Region – highly conserved alpha2 and beta2 domains: bind CD4
* Polymorphic Peptide Binding Region – highly polymorphic alpha1 and beta1 domains (which form the peptide binding region)
66
What are the differenes in peptide cargo between MHC Class I and II molecules?
* Class I – presentation of endogenously synthesised proteins: portions of viral proteins are loaded when the cell is infected enabling recognition of infection (this presentation process is highly conserved from yeast)
* Class II – presentation of endocytosed, exogenous material: portions of pathogenic proteins which have been engulfed are presented signalling phagocytosis
67
Where is the polymorphism in MHC molecules located?
Polymorphism is driven by evolution and is located in the binding groove
68
Where are T cells produced?
Thymus
69
Outline the T cell maturation process
1. Bone Marrow – stem cell --\>T-cell progenitor
2. Thymus - Double-negative cell (CD4-/CD8-) located in sub-capsular zone
3. Commitment to alpha/beta or gamma/delta (if receptor)
4. Double-positive cell (CD4+/CD8+) located in the cortex
5. Selection of double positive cells by MHC Class I or Class II molecules (in the cortex)
Selection of single positive cells (depending on which cells reacted with which MHC molecule – DP cells become SP cells once they react with just one type of MHC molecule)
6. Periphery – release of single positive cells (either CD4+ or CD8+) into periphery
70
What is thymic selection?
* There must be the correct binding affinity – too low or too high and they will be destroyed
* Thymic selection removes most auto-reactive T cells
71
What is negative selection?
Tolerance to self is a fundamental requirement of the adaptive immune system – to avoid auto-immunity there must be elimination of self-reactive cells, this happens in a process known as negative selection
*(reminder - normal T cell maturation = positive selection)*
72
Outline the basic structure of an antibody
* Immunoglobulins (antibodies) are symmetrical molecules
* There are two heavy chains and two lights chains held together by inter-chain disulphide bonds
* V – variable region (i.e. determines whether it is IgG or IgE etc.)
* C – constant region
* Antigen binding – site of antigen binding
* Biological activity – confers function (part of the constant region)
73
Where does B cell development occur?
Bone Marrow
(it is antigen independent)
74
Outline the process of B cell development
1. **Stem cell --\> Progenitor cell:** Interaction between stromal cell and precursor B cells (VCAM-1/VLA-4 and CAMs). B cells need IL-7 to develop.
2. **Early Pro B cell:** up-regulation of Kit (CD117) and binding to SCF (stem-cell factor) – this is the earliest committed B-lineage cell (recognised by the appearance of surface markers).
3. **Late Pro B Cell:** pro-B cells proliferate.
4. **Pre B Cell:** Expression of pre-B cell receptor - at this stage the receptor complex is formed.
5. **Immature B Cell**: B-lineage cells move towards the central axis of the marrow cavity – early maturation occurs in the bone marrow. Late maturation is completed as the cells migrate towards the periphery – at this stage they become mature B cells
75
What must occur for a B cell to mature?
Rearrangement of receptor genes is required for B cell maturation.
B cells that have rearranged their immunoglobulin genes but not encountered non-self antigens are referred to as naïve B cells
76
How are antibodies generated?
To generate antibodies, there is an antigen-dependent phase which occurs in secondary lymphoid tissues – most antibody responses require T cell co-operation
77
What is Class Switching?
Affinity Maturation – Class Switching: mechanism that changes a B cell's production of immunoglobulin from one class to another, such as from the isotype IgM to the isotype IgG.
## Footnote
78
Outline the process invovled in Class Switching
* During this process, the constant-region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same
* Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules
* In the germinal centres of the lymph nodes there are follicular dendritic cells enable the selection of antibodies with higher affinity for the pathogen (i.e. class switching – releasing antibodies from a class that has a higher affinity for the detected antigen)
79
Describe the structure of a BCR
* Transmembrane protein complex composed of mIg and Heterodimers of Iga linked to Igb
* Iga/Igb heterodimers contain immunoglobulin-fold structure
* The cytoplasmic tail of mIg is too short to signal
* The cytoplasmic tails of Iga/Igb contain ITAM (immunereceptor tyrosine-based activation motifs) motifs for signalling
80
What are the various antibody classes?
* IgG (has subclasses)
* IgG1-4
* IgA (has subclasses)
* IgA1-2
* IgM
* IgD
* IgE
81
Give a summary of the major roles of each antibody
82
Describe IgG (structure and function)
* g heavy chain
* Most abundant immunoglobulin
* Occurs as a monomer, but 4 subclasses
* variability mainly located in hinge region and effector function domains
* Actively transported across the placenta
Blood and extracellular fluids
* Major activator of classical complement pathway (mainly IgG1 and IgG3)
83
Describe IgA (structure and function)
* a heavy chain
* Second most abundant immunoglobulin after IgG
* Occurs as a monomer (blood) and as a dimer (secretions)
* Major secretory immunoglobulin
* Protects mucosal surfaces from bacteria, viruses and protozoa
* The secretory component comes from polyIg
84
Describe IgM (structure and function)
* m heavy chain
* large pentameric molecule
* 5 monomers joined by J chain (10 x Fab)
* mainly confined to blood (80%)
* first Ig synthesised after exposure to antigen
* primary antibody response
* multiple binding sites compensate for low affinity
* efficient at agglutination
* activates complement
85
Describe IgD (structure and function)
* d heavy chain
* extremely low serum concentrations
* surface IgD expressed in B cell development
* involved in B cell development and activation
86
Describe IgE (structure and function)
* e heavy chain
* present at extremely low levels
* produced in response to parasitic infections and in allergic diseases
* binds to high affinity Fc receptors of mast cells and basophils
* cross-linking by antigen triggers mast cell activation and histamine release
87
What do Naïve B cells need to activate a response?
Naïve antigen-specific lymphocytes (B or T) cannot be activated by antigen alone. Naïve B cells require _accessory signal_
* Directly from microbial constituents
* from a T helper cell
88
What are the two mechanisms of antibody production?
* Directly activate B cells without the help of T cells
Can induce antibodies in people with no thymus and no T cells (Di-George syndrome)
* The second signal required is either provided by the microbial constituent or by an accessory cell
89
Outline the antibody recognition process
1. The membrane bound BCR recognises antigen
2. The receptor-bound antigen is internalised and delivered to intracellular sites
3. The internalised antigen is degraded into peptides
4. Peptides associate with “self” molecules (MHC class II)
5. The antigen/self-complex is expressed at the cell surface
90
List some of the factors that may affect immune responses
* General health and nutrition status
* Previous exposure (immune memory)
* Immune-deficiencies (eg: SCID, HIV, immune suppression due to transplantation etc.)
* Polymorphism in innate immune genes
* Polymorphism in adaptive immune genes, particularly HLA (=‘human leucocyte antigens’)
91
What is the role of commensal microbiota?
Commensal microbiota are essential for tissue integrity and immune function - the symbiotic relationship is based on a molecular exchange involving bacterial signals that are recognized by host receptors to mediate beneficial outcomes for both microbes and humans.
92
List some of the host barriers to infection
* Structural barriers: skin, mucous membranes, respiratory cilia
* Competition with commensal microbiota for niches
* Chemical – eg low pH of stomach
* Anti-microbials - lysozyme in mucous sectretions, a-defensins (intestine), b-defensins (respiratory and skin)
* Collectins - Lung surfactant proteins A and D, mannose binding lectin (MBL)
* a and b interferons
* Complement activation
* Neutrophils
* Monocytes
* Natural killer cells
* NKT cells
93
What is the function of dendritic cells?
Dendritic cells are the bridge between the adaptive and innate immune responses - they are essential in the activation of the correct immune response
94
What is an anticipatory receptor?
There are millions of “anticipatory” receptors in the adaptive response which will not necessarily be used but are present to cover potential peptides
95
Briefly outline how dendritic cells (via TLRs) activate the correct immune responses
The dendritic cell however, has a limited number of receptors which recognises the pathogen and activates the correct downstream adaptive response (key concept is how a limited number of dendritic TLRs can stimulate a huge variety of immune responses appropriate for the infection type)
96
Define hypersensitivity
Hypersensitivity reactions are inappropriate (unwanted) immune responses against harmless antigens:
97
Briefly outline the 4 types of hypersensitivity reacion
* **Type I**: immediate hypersensitivity, IgE mediated
* **Type II**: antibody binds to cell or matrix associated antigen, IgG mediated
* **Type III**: antibody binds to soluble antigen, IgG mediated
* **Type IV**: delayed hypersensitivity, T cell mediated
98
Define autoimmunity
Autoimmunity = adaptive immune responses with specificity for self antigens (autoantigens)
99
Briefly outline the general mechansisms of autoimmune diseases
Autoimmune diseases involve breaking T-cell tolerance - because self-tissue is always present, autoimmune diseases are chronic conditions.
Effector mechanisms resemble those of hypersensitivity reactions, types II, III, and IV
100
Define tolerance - what are the "3 As"?
Tolerance is defined as the acquired inability to respond to an antigenic stimulus
* **Acquired** -involves cells of the acquired immune system and is ‘learned’
* **Antigen** specific
* **Active** process in neonates, the effects of which are maintained throughout life
101
What are the two general mechanisms of tolerence?
Central (T cell maturation) and Peripheral (anergy, immune privelege/ignorence and regulation)
102
How does central tolerance work?
* Central tolerance refers to the what develops in the primary lymphatic organs (i.e. T and B cells)
* It is the selection of thymocytes (T cells) that gives tolerance is it prevents autoreactivity
* The same happens for B cells in the bone marrow
103
Why is peripheral tolerance also required?
Some antigens may not be expressed in the thymus or bone marrow, and may be expressed only after the immune system has matured.
Mechanisms are required to prevent mature lymphocytes becoming auto-reactive and causing disease
104
Outline the principle of Anergy
* Naïve T-cells require costimulation for full activation:
* Without costimulation then cell proliferation and/or factor production does not proceed.
* Subsequent stimulation, even in the presence of costimulatory molecules leads to a refractory state termed ‘ANERGY’
105
What is antigen priveledge or ignorence?
* Occurs when antigen concentration is too low in the periphery
* Occurs when relevant antigen presenting molecule is absent: most cells in the periphery are MHC class II negative
* Occurs at immunologically privileged sites where immune cells cannot normally penetrate: for example in the eye, central and peripheral nervous system and testes. In this case, cells have never been tolerised against the auto-antigens
106
Explain the role of regulatory T cells
Autoreactive T-cells may be present but do not respond to autoantigen due to suppression by regulatory T cells
107
What is APECED?
* APECED results from a failure to delete T-cells in the thymus - it is a failure of central tolerance
* Caused by mutations in the transcription factor AIRE (autoimmune regulator) gene
* AIRE is important for the expression of “tissue-specific” genes in the thymus
* Involved in the negative selection of self reactive T-cells in the thymus
108
What is IPEX?
* IPEX = failure in the regulation of peripheral tolerance
* Fatal recessive disorder presenting early in childhood
* Caused by mutation in the FOXP3 gene which encodes a transcription factor critical for the development of regulatory T-cells
* It is an accumulation of autoreactive T cells
109
What type of hypersensitivity reaction is allergy?
Type I Hypersensitivity
110
List some of the environmental and genetic risk factors for allergy
Genetic
* Family history (80% of atopy has FH)
Environmental
* Age
* Gender
* Infections
* Animals
111
Name some of the major immediate Type I hypersensitivity reactions
* Anaphylaxis
* Asthma
* Seasonal rhinitis
* Food allergy
112
Which antibody is most commonly associated with allergic reactions?
IgE
113
Outline the pathogenesis of Type I hypersensitivity (allergic reaction)
The key to allergic reactions is that there is primary and secondary antigen exposure - there is no allergic reaction in the primary exposure
1. Primary exposure = formation of antibodies to the normally harmless antigen (IgE + mast cell formation)
2. Secondary exposure = activation of the antibody (IgE) and mast cell degranulation (release of various pro-inflammatory substances)
114
What type of allergic (hypersensitive) reaction is rejection?
Type IV delayed hypersensitivity
115
Define alloantigen
Antigens from the same species
116
Describe the following types of transplant:
Autograft
Isograft
Allograft
Xenograft
Prosthetic graft
* Autografts – within the same individual (eg: vein/skin etc.)
* Isografts – between genetically identical individuals (eg: twins, saviour siblings)
* Allografts – between individuals of the same species (eg: organ transplants – living or deceased donor)
* Xenografts – between individuals of different species (eg: porcine valve)
* Prosthetic graft – plastic or metal (eg: metal valves)
117
What are the two major immunogenic considerations of transplants?
ABO Blood Group
HLA (human leukocyte antigens)
118
Describe what would happen if a person who is type B (donor) donates an organ to a person who is type A (recipient)
1. The donor organ will present type B antigens in its endothelial lining
2. The recipient will have group A antigens and anti-B antibodies circulating it the blood (all pre-formed)
3. The circulating anti-B antibodies bind to the exposed B antigens of the donor organ and begin a hyperacute reaction
4. Hyperacute reactions involve the activation of the complement system, recruitment of immune cells (phagocytes) and disruption of the endothelium (of the organ)
5. This causes the organ to be rejected (i.e. organ is destroyed)
119
How are mismatched ABO organs able to be transplanted?
You can now transplant ABO incompatible organs when using immunosuppressant therapy
120
What are HLAs? Describe their important in transplantartion
* HLAs were descovered following rejected organ transplants - they are cell surface proteins important in infection defence.
* Mismatched HLAs will cause rejection as the organ is recognised as foreign
121
Name the 5 immunological reactions involved in rejection
* Hyperacute rejection
* Acute rejection
* Chronic rejection
* T-cell mediated rejection
* Anti-body mediated rejection
122
Describe T-cell mediated rejection
* This is a Type IV hypersensitivity response
* Recognition of donor HLA antigens by CD4+ T cells
* Activation of CD4+ cells
* Production of cytokines
* Help for CD8+ cells
* Help for B cells
* Recruitment and activation of macrophages and neutrophils
123
Describe antibody mediated rejection
* Antibody against graft HLA and AB antigen
* Antibodies arise
* Pre-transplantation (“sensitised”)
* Post-transplantation (“de novo”)
124
How is rejection (a) prevented and (b) treated?
The key points of prevention are:
* Maximising HLA compatibility
* Life-long immunosuppressive drugs
* Target T cell activation and proliferation
* Target B cell activation and proliferation and antibody production
If rejection does occur, treatment is to increase immunosuppression
