Immunity Flashcards
(153 cards)
1
Q
What is a significant reason the elderly eventually die?
A
Immune system declines with age, and no. of immune cells reduce, so many elderly people eventually succumb to respiratory infections because their ability to fight them off is significantly reduced
2
Q
What is immunity?
A
Immunity is defined as the ability of an organism to defend itself against:
Infectious agents
Foreign cells and proteins
Catastrophic cell dysfunction (e.g. cancer).
The human body is subject to invasion by a variety of PATHOGENIC (damage- or disease-causing) organisms – mostly microorganisms. It is therefore essential that there are mechanisms in place to fight off infection. The ability of an organism to defend itself against infectious agents, foreign cells and proteins and catastrophic cell dysfunction (e.g. cancer) is known as IMMUNITY.
3
Q
What is immunodeficiency? How is it acquired?
A
Immunodeficiency results when immunity fails; it can be the result of:
Genetic inheritance (e.g. severe combined immune deficiency [SCID]) (bubble children) Acquired during life (e.g. acquired immune deficiency syndrome [AIDS])
4
Q
What are allergy and hypersensitivity?
A
Allergy and hypersensitivity result when the immune system responds inappropriately to antigens.
5
Q
What is infection?
A
INFECTION is defined as the invasion of host tissues by foreign organisms which may or may not cause disease. Infection in humans is caused by:
Bacteria e.g. Tuberculosis, plague
Viruses e.g. Common cold, influenza
Fungi e.g. Thrush, athlete’s foot
Protozoa e.g. Sleeping sickness, malaria
Multicellular parasites e.g. tapeworm, flea
6
Q
WHAT HAPPENS IF THE IMMUNE SYSTEM CEASES TO FUNCTION CORRECTLY?
over (3 examples) or under reactive? (2 examples)
A
An OVERACTIVE immune system may result in:
ALLERGIES – activation of mast cells by ALLERGENS (antigens) results in the production of histamines, causing redness, swelling, mucus secretion and bronchial contractions (asthma). In extreme cases, the sufferer may die of ANAPHYLACTIC SHOCK.
GRAFT REJECTION – if a non-self organ is transplanted into a recipient wit a fully functional immune system.
AUTOIMMUNITY – when T cell control mechanisms fail, and B and T cells mount an attack against self tissues.
An UNDERACTIVE immune system results in IMMUNODEFICIENCY, and the patient will die from opportunistic infections (e.g. Acquired Immune Deficiency Syndrome [AIDS] and genetically inherited immune deficiencies).
7
Q
What is Immune tolerance?
A
Tolerance is defined as a state of immunological non-reactivity to an antigen.
The immune system has powerful weapons at its disposal to attack and destroy pathogens and infected tissues, and it is vital that any attack is initiated because it is essential to survival.
Many potential antigens are not harmful:
Our own cells and tissues (‘self’ antigens)
Harmless environmental antigens (food sources, pollen)
Commensal organisms (e.g. skin and gut flora)
8
Q
What is autoimmune disease?
A
An immune response to self tissue – a breakdown of tolerance – results in autoimmune disease.
9
Q
What is SCIDs
A
severe combined immune deficiency [SCID]) (bubble children)
10
Q
What is AIDs
A
Acquired Immune Deficiency Syndrome [AIDS]
11
Q
Full immunodeficiency is…
A
…life threatening
12
Q
partial immunodeficiency can…
A
…make you more susceptible to certain types of infections or cellular dysfunctions (e.g. cancer)
13
Q
What is innate immunity?
A
Innate immunity responds rapidly to infection, but the lack of ability to adapt may sometimes result in failure.
14
Q
What is adaptive immunity?
A
Adaptive immunity takes time to develop, but the ability to recognize a vast variety of antigens makes it potent.
In addition, adaptive immunity exhibits a memory function that kicks in quickly if a pathogen is encountered again later in life.
15
Q
What are the lymph tissues (4 key components)
A
LYMPH NODES
RED BONE MARROW
SPLEEN
THYMUS
16
Q
Overview of lymph node function role
A
LYMPH NODES
1-25mm egg-shaped (ovoid) or round structures found in lymphatic vessels. (all over body, filter lymph (chyle etc.) and also in gut etc.
Contain resident lymphocytes and macrophages, cells which neutralise pathogens and clear debris.
Nodes become enlarged as a result of infection.
17
Q
Overview of red bone marrow function role
A
RED BONE MARROW
Site of production of all blood cells (including B and T lymphocytes).
18
Q
Overview of Spleen role
A
SPLEEN
Acts as an “emergency” blood store. Blood is cleansed of
pathogens and debris.
19
Q
Overview of Thymus role
A
THYMUS
Site of maturation of T-lymphocytes.
20
Q
What is a leucocyte
A
Leucocyte is an alternative name for the group known as white blood cells.
21
Q
How does the body clear viruses?
A
Immune system can kill own cells
22
Q
What is an “immune privileged” area?”
A
Areas that are not immunologically screened,
Immune-privileged sites include the central nervous system and brain, the eyes and the testes.
They are able to tolerate the introduction of antigens without eliciting an inflammatory …
23
Q
What is a haematopoietic stem cell?
A
The haematopoietic stem cell is non-differentiated and capable of division, thus producing multiple copies of itself without committing to a particular lineage.
Can become a myeloid or lymphoid progenitor cell
these differentiate into all the types of immune cells
24
Q
What is immunological memory?
A
Cells/antibodies can remember encountering components of a particular virus/bacteria and mount a specific and significant response to the re-infection.
25
What can a haematopoietic stem cell become?
Under appropriate conditions – and triggered by specific sets of molecular messengers (e.g. cytokines and chemokines) that bind to receptors, the stem cell can differentiate into either a myeloid progenitor cell, or a lymphoid progenitor cell.
26
What can a myeloid progenitor become?
basophils,
eosinophils,
neutrophils,
monocytes
macrophages
The myeloid progenitor can then continue along the pathway of specialization, eventually leading to the production of the full repertoire of leucocytes of myeloid lineage (basophils, eosinophils, neutrophils, monocytes and macrophages) as well as dendritic cells, platelets and erythrocytes.
27
What can a lymphoid progenitor become?
Cytotoxic T cells (CD8+)
helper T cells (CD4+)
B cells
Dendritic cells
natural killer cells (NK)
The lymphoid progenitor differentiates further to produce the full repertoire of leucocytes of lymphoid lineage (CD8+ cytotoxic T cells, CD4+ helper T cells, B cells, dendritic cells and natural killer [NK] cells).
28
Cytotoxic T cells
Which CD\_\_ are these positive for?
Cytotoxic T cells (CD8+)
29
helper T cells
Which CD\_\_ are these positive for?
helper T cells (CD4+)
30
What does a T-cell progenitor become?
lymphoid progenitor\> T cell progenitor\> Th helper cell or
Tc cytotoxic cell
31
What does a B-cell progenitor become
lymphoid progenitor\> B cell progenitor\>B cell
32
What is a dendritic cell precursor?
They come straight from lymphoid progenitor
33
What is a natural killer cell precursor?
They come straight from lymphoid progenitor
34
What is a neutrophil precursor?
Granulocyte/monocyte progenitor
Myeloid progenitor\>Granulocyte/monocyte progenitor\> Neutrophil OR
Monocyte\>macrophage
35
What is a macrophage precursor?
Monocyte from
Granulocyte/monocyte progenitor
Myeloid progenitor\>Granulocyte/monocyte progenitor\> Neutrophil OR
Monocyte\>macrophage
36
What is an eosinophil precursor?
Eosinophil progenitor
from myeloid progenitor
37
What is an basophil precursor?
basophil progenitor
from myeloid progenitor
38
what is a platelet precursor
Megakaryocyte
from myeloid progenitor
39
what does megakaryocyte become
platelets
from myeloid progenitor\>Megakaryocyte\>platelets
40
What is the erythrocyte precursor
erythroid progenitor
from myeloid progenitor\>erythroid progenitor\>erythrocyte (RBC)
41
What does a macrophage do?
Phagocytic; highly migratory; professional antigen presentation.
42
Neutrophil
Highly abundant and migratory; coordinate inflammatory response.
43
Eosinophil
Involved in host defence against nematodes and other parasites
44
Basophil
Involved in host defences against multicellular parasites.
(fx not fully understood)?
45
Dendritic cell
The most adept of the family of antigen presenting cells.
46
B cell
Adaptive; produce antibodies that bind to antigens on pathogens; exhibit immunological memory.
47
T cell
Adaptive; involved in killing virus infected cell; involved in coordinating immune responses – orchestrators of activation/termination.
48
How do B and T cells find their targets in the body?
B cells and T cells continually circulate around the blood and lymphatic systems in constant surveillance for invading pathogens.
Because B cells are able to access all areas, the same is true for the antibodies they produce. Antibodies are NOT restricted to the blood stream.
49
What is a HEV?
High Endothelial Venules (HEVs) are the sites in lymph nodes where lymphocytes cross from blood to the lymphatic system.
Because B cells are able to access all areas, the same is true for the antibodies they produce. Antibodies are NOT restricted to the blood stream.
50
Are antibodies restricted to the blood stream
No
Because B cells are able to access all areas, the same is true for the antibodies they produce. Antibodies are NOT restricted to the blood stream.
51
How do cytokines work/specify cells?
Only bind the cpefici receptors, so cells must have correct receptor if they are to respond to cytokines
52
Purpose of lymphocyte recirculation
The process of continual lymphocyte recirculation allows maximum numbers of antigenically committed lymphocytes to encounter and interact with antigen.
53
How many times might an individual lymphocyte circuit the body in a day?
An individual lymphocyte may make a complete circuit around the system 1 to 2 times a day.
54
How many lymphocytes will bind to a particular antigen?
Approximately 1 in 100,000 lymphocytes will bind to a particular antigen, so it is essential that each lymphocyte travels widely in the body to stand a chance of detecting the presence of antigen.
55
Before a lymphocyte can enter inflamed tissue or peripheral lymphoid organs, it must do what?
Before a lymphocyte can enter inflamed tissue or peripheral lymphoid organs, it must adhere to and penetrate the layer of endothelial cells lining the walls of blood vessels.
56
How do leucocytes communicate?
All members of the leucocyte family communicate using small soluble messaging proteins known as cytokines and chemokines.
57
How do cytokines and chemokines trigger signalling?
They bind to receptors on the target cell to trigger signalling transduction cascades that ultimately lead to changes in gene expression – and therefore cell function.
58
What are Cytokines and chemokines?
Cytokines and chemokines are typically low molecular weight proteins that serve as molecular messengers in the immune system to allow cells to communicate with each other. They are synthesized and secreted by a wide variety of white blood cells (leucocytes), including lymphocytes, macrophages, neutrophils, basophils and eosinophils (amongst others). Whilst the majority of signalling takes place between cells that are physically close together (paracrine action), in some circumstances this is not the case. Autocrine signalling occurs when a secreted cytokine/chemokine binds to receptors on the secreting cell and induces changes in gene expression and function as a result. Such autocrine action may stimulate or inhibit cellular activity as required in the ongoing immune response. Less commonly, signalling takes place between cells that are spatially distant (endocrine signalling), although this is much less common than would be the case for hormonal signalling (e.g. via insulin).
59
How can signalling molecules play a role in anaphylaxis?
Inappropriate and excessive endocrine activity as a result of over-secretion of immune signalling molecules can be catastrophic – in the case of anaphylaxis, for example.
60
what is a "lock and key" concept in ab:ag binding?
Immune cells communicate by binding of a molecular messenger (the ligand) to a receptor on the target cell. This “lock and key” interaction is specific and is typically of a moderate to high affinity (= strength of binding). The receptor may be located on the surface of the target cell, or occasionally intracellularly in the case of ligands that are capable of passing through the cell membrane. In some cases (1), the ligand is itself anchored on the surface of a cell so that ligand binding to receptor requires a close physical proximity between the cell sending the signal and the one receiving it. Ligand binding to the receptor typically induces a signal transduction cascade that eventually results in changes to the pattern of gene expression (and therefore function) in the target cell.
61
What are the key steps of the inflammatory response?
heat (calor),
pain (dolor),
redness (rubor), and
swelling (tumor)
Damaged tissues rupture and release BRADYKININ, which results in the sensation of pain, and stimulates MAST cells to release HISTAMINE.
Capillaries dilate and become permeable. Local temperature rises.
NEUTROPHILS migrate to the damaged area. They engulf and destroy invading bacteria.
MONOCYTES escape from the permeable capillaries, and mature into MACROPHAGES.
MACROPHAGES engulf invaders, and also secrete protein factors, which in turn recruit more neutrophils.
62
How many different antibodies can a B cell produce?
1 type because they are antigenically committed
63
What is an antibody
Antibodies are glycoproteins (proteins with carbohydrates attached at specific glycosylation sites) with a minimum molecular weight of around 150,000 Daltons (=150 kiloDaltons or 150 kDa)
Each antibody will bind to a single specific antigen
64
Where on the antigen does the antibody bind?
The part of an antigen to which the antibody binds is known as the epitope.
65
What is a naive B cell distinguished by (receptor)
In a naïve (non-activated) B cell, the antibody includes an additional transmembrane domain that anchors it on the surface of the B cell. In this format it is known as a B cell receptor (BCR).
66
What happens when BCR is activated?
Once the BCR is activated by antigen cross-linking and additional cytokine-mediated stimulation by TH cells, the mature B cell undergoes BCR gene rearrangements that allow the secretion of a soluble antibody form of the BCR.
The structure of the antigen binding site remains identical throughout.
67
What is the BCR
B cell receptor - is on naive B cell
68
What does an antibody molecule consist of?
An antibody molecule consists of four polypeptide chains – two Heavy (H) chains, and two Light (L) chains. The chains are covalently linked together by inter-chain disulphide bonds. Each H chain has a molecular weight of around 50 kiloDaltons (kDa), and each light chain is around 25 kDa, giving a total of -150 kDa. The polypeptide chains may be post-translationally modified by the addition of sugars (glycosylation) which takes place in the endoplasmic reticulum and/or Golgi complex. Such modifications rarely play a role in antigen binding via the antigen binding (Fv) domain. In a given antibody molecule, the two heavy chains are identical to each other, as are the two light chains. Each single B cell makes many identical copies of the same antibody that binds to the same antigen.
69
which cells can produce antibodies
Only cells of B lymphocyte lineage produce antibodies
70
How is the B cell activated to remove the BCR and produce soluble ab?
the BCR is activated by
antigen cross-linking
and
cytokine-mediated stimulation by TH cells,
the mature B cell undergoes BCR gene rearrangements that allow the secretion of a soluble antibody form of the BCR.
71
What does CD stand for
CD stands for cluster of differentiation – a historical term.
Early on, immunologists recognized that specific cell surface molecules can be used to distinguish between the leucocyte sub-types.
72
what are CD markers used to do (nomenclature/classification)
Common CD markers used to distinguish functional lymphocyte populations
A cell that is CD4+ expresses CD4, and is therefore likely to be a T helper cell.
A cell that is CD8+ expresses CD8, and is therefore likely to be a cytotoxic T cell.
73
what triggers clonal expansion/proliferation of B or T cells?
Once the antibody has bound to an antigen, they are a "useful" B cell, and lots of identical copies are produced ..
Each T cell and B cell expresses its own antigen receptor.
Activation of a particular cell leads to the production of clones with the same antigen binding capability.
74
What does B or T cell need as well as ag binding to ab in order to trigger clonal proliferation?
Activation requires not only binding of antigen to the receptor, but also stimulation by growth factors such as interleukin-2 (IL-2).
Either of these binding events alone can result in an inability to subsequently be activated (anergy), or even in cell death by apoptosis.
75
When a B (or T?) cell is clonal proliferated/expansed, what two main cell types can occur?
Memory cells
Very long lasting, permit subsequent secondary immune response
Effector cells e.g.
-B cell antibody synthesis cell
-T-cell help
-T-cell regulation
-T-cell cytotoxicity
cytokine release
76
What is IgG
Fixates complement?
Crosses placenta?
fix to homologous mast cells/basophils?
binding to macrophages and polymorphs?
Most abundant internal Ig
YES Fixates complement
YES Crosses placenta
NO fix to homologous mast cells/basophils
YES binding to macrophages and polymorphs
77
What is IgA
Fixates complement?
Crosses placenta?
fix to homologous mast cells/basophils?
binding to macrophages and polymorphs?
Protects against external surfaces
NO Fixates complement
NO Crosses placenta
NO fix to homologous mast cells/basophils
YES a little bit\> binding to macrophages and polymorphs
78
What is IgM
Fixates complement?
Crosses placenta?
fix to homologous mast cells/basophils?
binding to macrophages and polymorphs?
Very efficient against bacteria
a Pentamer - 5 Ab molecules stuck together, 10 ag binding sites (lots of velcro hooks, sticks and remains stuck)
YES STRONGLY Fixates complement
NO Crosses placenta
NO fix to homologous mast cells/basophils
NO binding to macrophages and polymorphs
79
What is IgD
Fixates complement?
Crosses placenta?
fix to homologous mast cells/basophils?
binding to macrophages and polymorphs?
Mostly lymphocyte receptor
YES a bit\> Fixates complement
NO Crosses placenta
NO fix to homologous mast cells/basophils
NO binding to macrophages and polymorphs
80
What is IgE
Fixates complement?
Crosses placenta?
fix to homologous mast cells/basophils?
binding to macrophages and polymorphs?
Initiates inflammation raised in parasitic infections, cause symptoms of allergy
NO Fixates complement
NO Crosses placenta
YES \> fix to homologous mast cells/basophils
YES a little bit \> binding to macrophages and polymorphs
81
What distinguishes the different immunoglobulins?
The variation in function of the five antibody isotypes is largely a result of differences in the three dimensional structure of the heavy chain constant region. (The "stalk")
These differences affect function by influencing which immune system partner the antibody molecule works with (e.g. antibody receptor on macrophages, complement protein), but NOT the antigen to which the antibody binds.
82
How many Ig types are there
which can activate complement?
5 which are:
IgG \>complement activation
IgA
IgM \> strong complement activation
IgD \>lower level complement activation
IgE
83
What is antibody valency?
A valency of one refers to a single four chain molecule (2 x heavy, 2 x light chain), each with two antigen binding sites.
Differences in the structures of isotype constant domains can be caused not only by changes to the amino acid sequence, but also by the introduction of post-translational modifications like covalently associated sugar molecules (glycosylation).
84
IgG molecules possess heavy chains known as ?chains;
IgMs have ?chains
IgAs have ?chains;
IgEs have ?chains; and
IgDs have ?chains.
IgG molecules possess heavy chains known as γ-chains; IgMs have μ-chains; IgAs have α-chains; IgEs have ε-chains; and IgDs have δ-chains.
85
What is affinity ab
strength of binding to Ag epitope
Affinity measures the strength of interaction between an epitope and an antibody's antigen binding site
86
What is avidity
Avidity describes the measure of overall or accumulated strength of a protein-protein complex,
87
IgM structure - overview
IgM exists in a pentameric form where five individual antibody molecules are linked together by the J chain. This gives the molecule 10 antigen binding sites, so even if the affinity for antigen is not yet fully developed, the avidity effect compensates for this.
88
Secretory IgA overview
```
Secretory IgA (sIgA) exists as a dimer\* where two individual antibody molecules are linked together by a J chain and a so-called secretory piece that protects from proteolysis and facilitates secretion across mucus membranes. The four antigen binding arms contribute to increased avidity for binding to extracellular pathogens.
\* A dimer is two identical molecules joined.
```
89
Outline barrier systems in immunity (innate)
5 significant examples
Skin -Antimicrobial properties, fatty acids in Sebum
Mouth, Epithelial lining of alimentary canal - Enzymes, antimicrobial peptides, sweeping of surface by directional flow of fluid towards stomach
Stomach - Low pH, digestive enzymes, antimicrobial peptides, fluid flow to large intestine
Small intestine
Large intestine - Normal intestinal flora compete with invading microbes, fluid and faeces explelled from rectum
Airway, Lung, Epithelial lining of airway and lung - cilia sweep mucuous outwards, coughing, sneezing, expel mucuous, macrophages monitoring in alveoli
90
are barrier systems in immunity innate or adaptive
innate
91
What is a PRR
Pattern Recognition Receptors (PRR) in innate immunity detect antigens non-specifically using receptors for Pathogen Associated Molecular Patterns (PAMPs).
Examples of PRR include a large family known as the Toll-like receptors.
92
What is a PAMP
Pathogen Associated Molecular Patterns (PAMPs).
PAMPS are molecular structures that occur in lower organisms, but not in humans.
Examples of PAMPs include Lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria and peptidoglycan found abundantly on the Gram-positive cell wall.
93
What is a TLR
Pattern Recognition Receptors (PRR) in innate immunity detect antigens non-specifically using receptors for Pathogen Associated Molecular Patterns (PAMPs).
Examples of PRR include a large family known as the Toll-like receptors.
94
What is LPS
PAMPS are molecular structures that occur in lower organisms, but not in humans.
Examples of PAMPs include Lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria and peptidoglycan found abundantly on the Gram-positive cell wall.
95
what is Complement
Soluble factor that plays a role in innate immunity
A family of plasma proteins that activate each other - the “complement cascade”.
Capable of destabilising the membranes of invading bacteria.
Coats invading bacteria, marking them for destruction by antibodies.
Attracts phagocytes to the site of infection.
96
whats Lysozyme
Soluble factor that plays a role in innate immunity
A hydrolytic enzyme present in saliva, tears.
Destroys the bacterial cell wall.
97
what are Cytokines
Soluble factors that play a role in innate immunity
(including chemokines that attract cells to the site of infection)
e.g. interferon, a glycoprotein that interferes with viral replication.
cell communication
up regulation of immune response
cofactors in cell activities
98
What is somatic recombination?
Somatic recombination contributes to antibody diversity
The chains of the antibody molecule are put together by splicing variable (V), diversity (D), joining (J) and constant (C) gene segments together.
The heavy (H) chain is formed from V, D, J and C whilst the light (L) chain lacks D.
99
What is the splicing variable
The chains of the antibody molecule are put together by splicing variable (V), diversity (D), joining (J) and constant (C) gene segments together.
The heavy (H) chain is formed from V, D, J and C whilst the light (L) chain lacks D.
100
What is the heavy chain of ab formed from
The chains of the antibody molecule are put together by splicing variable (V), diversity (D), joining (J) and constant (C) gene segments together.
The heavy (H) chain is formed from V, D, J and C whilst the light (L) chain lacks D.
101
What do V, D, J, C mean?
Which are in the heavy chain, which are in the light chain?
The chains of the antibody molecule are put together by splicing variable (V), diversity (D), joining (J) and constant (C) gene segments together.
The heavy (H) chain is formed from V, D, J and C whilst the light (L) chain lacks D.
102
What is RAG-1/2
The chains of the antibody molecule are put together by splicing variable (V), diversity (D), joining (J) and constant (C) gene segments together.
The reaction requires recombination signal sequences, recombination activation enzymes (including RAG-1/2) and epigenetic\* changes to the DNA structure that include changes to methylation and acetylation.
This generates a huge repertoire of available antibodies allowing the immune system to tackle the many pathogenic threats we face in a lifetime.
103
Somatic recombination contributes to antibody diversity 2
PICTURE
104
what do B cells mostly do?
Adapted to secrete antibodies into interstitial fluid - extra cellular effects
105
Antigenic commitment in B cells via affinity maturation?
Pluripotent stem cells in the bone marrow undergo gene rearrangements that result in each single B cell expressing a slightly different version of the B cell receptor on the cell surface. This random process in independent of the presence of antigen, and bearing in mind there are many millions of different B cells, in theory there is the capacity to recognize similarly large numbers of target antigens. Once the gene rearrangement is complete, there is no going back, and the B cell is now antigenically committed – however further “tweaks” in the structure of the antibody may occur if it encounters an antigen to which it is capable of binding; this process of “affinity maturation” results in further improved affinity for the antigen, with an associated higher chance of clearing the infection. Importantly, the cell that is capable of binding to antigen (in this case cell number 2) not only divides to produce identical daughter clones know as plasma cells that are essentially short-lived factories for producing soluble antibody, but also differentiates into memory cells that have a very long life span. Memory cells can reside in the tissues for decades, and if they ever encounter antigen again (from a subsequent reinfection), they respond very quickly indeed, negating the need for the immune system to go through another protracted primary response. One of the goals of vaccination is to induce memory B cells; even if levels of soluble antibody decline over weeks and months once the infection is cleared, the memory cell remains on surveillance duty.
106
What are the primary and secondary responses
After the first exposure to a novel antigen, there is a lag of 1-2 days before the first response is seen – the production of IgD and then IgM that is specific for the antigen. At this point, the affinity of the antibody binding site for the target epitope may be less than optimal, but this is compensated for by the pentameric structure of IgM that leads to a relatively high functional affinity (avidity). A good analogy here is the concept of Velcro, where each individual eye and hook contributes little to the strength of binding, but numerous small binding events can add up to a strong (avid) interaction overall (functional affinity). In time, and after class switching (changes to the structure of the antibody constant region) and affinity maturation (genetic changes that result in tighter binding to the antigen), IgG is produced. The levels of IgM and subsequently IgG may deplete over time once the antigen has been successfully neutralized. On a second exposure to the same antigen the speed of the response is much faster, and whilst IgM is produced, the bulk of the antibody generated will be of the IgG type. The response is faster because memory B cells are produced after the first exposure, and on second exposure, these can rapidly produce plasma cells – B cells that are essentially factories for producing large amounts of IgG. In time, once the antigen has been dealt with the amount of antigen-specific IgG in circulation may or may not decrease, but the memory B cells remain for long periods – potentially for an entire lifetime. This means that re-exposure to the antigen at any point in the future can immediately initiate a response equivalent in speed and magnitude to the initial secondary response. Declining levels of antigen-specific IgG are therefore not too much of a concern post-vaccination, and the implications for this are clear as we push forward with vaccines for SARS-CoV-2. It is always important to focus on measuring the right things to gauge the success of a given vaccine, and this may mean that antigen specific IgG levels over time is a ”red herring”.
107
which antibody types feature most in primary and secondary response
picture
At the start of the Primary phase, the first isotypes to be produced by a B cell are IgD and IgM, and then class switching results in the generation of IgG, which is the main mature antibody form. A switch back from IgG to IgM is not then possible.
The switching affects the constant domain, and therefore the antibody retains affinity for the same antigen but can interact with different effector molecules.
108
How is phagocytosis triggered?
Phagocytosis is triggered by receptor cross-linking
Like poking a cat in the tummy - claws come round the outside (cytoskeleton activated by g-protein mediated gene transcription up regulation)
The intracellular domains of receptors on the surface of the phagocytic cell are associated with protein enzymes that can phosphorylate others of their kind (but not themselves). Normally, membrane structure keeps these signalling domains spatially apart, but antigen-mediated cross linking drags the receptor complexes closer together and phosphorylation occurs. This triggers a signal transduction pathway that leads to phagocytosis.
109
Comparison of primary and secondary antibody responses
PRIMART
Responding B cell
lag period following antigen administration
Magnitude of peak antibody response
PICTURE
110
Comparison of primary and secondary antibody responses
PRIMARY
Responding B cell
lag period following antigen administration
Magnitude of peak antibody response
Isotype produced
Antigens
Antibody affinity
PICTURE
111
Comparison of primary and secondary antibody responses
SECONDARY
Responding B cell
lag period following antigen administration
Magnitude of peak antibody response
Isotype produced
Antigens
Antibody affinity
PICTURE
112
Overview of the innate v adaptive system
The physical barriers and soluble mediators that make up the innate immune system play a vital role in immunity. Whilst elements of the innate immune system do not adapt to tackle pathogens, they are capable of recognising and responding to specific molecular patterns found on pathogens via pattern recognition receptors. B cells produce antibodies that bind specifically to antigens. The antigen binding domain is not germline encoded, but rather is generated by the genetic rearrangement processes of somatic recombination and affinity maturation. As the primary immune response matures into the secondary (more robust) response, antibodies to the invading pathogen maintain their specificity, but are able to adapt their effector functions by swapping the Fc domain (isotype switching).
113
What are the 4 main classes of T cells
Cytotoxic (killer)
Helper
Suppressor
Memory
114
Classes of T cell
and roles explained: Cytotoxic (killer) T cell
```
Cytotoxic (killer)
Search for and destroy target cells that bear non-self antigens presented in MHC class I context.
```
115
Classes of T cell
and roles explained: Helper T cell
Helper CD4+
Secrete hormones known as cytokines (also known as lymphokines) that bind to receptors on B cells and T cells to stimulate their activity.
These are the ones infected by HIV so get killed by cytotoxic T cells with the help of other T helper cells - this negative spiral will decrease the numbers of CD4+ T helper cells means killer T cells cannot be activated and you are extremely vulnerable to viral infections
116
Classes of T cell
and roles explained: Suppressor T cell
Suppressor
Secrete hormones that bind to receptors on other immune cells to terminate their activity, thus suppressing immune responses that are no longer needed.
117
Classes of T cell
and roles explained: Memory T cell
Memory
Persist for life in a semi-dormant state, but rapidly re-activated on a second exposure to the antigen (pathogen) they are specific for. Bypass the need for the primary immune response on second infection.
118
How do T cells ensure they don't destroy self tissues by accident?
Require 3 signals at once to begin cytotoxic activity
- Cytotoxic T cell checks if there is a foreign antigen presented
- T helper cells secrete molecular messengers - Interleukins, if they encounter an appropriate antigen- PROXIMITY to cytotoxic T cell is nessecary
If insufficient number of signals, the T helper cell with stop and possibly even apoptose.
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What do dendritic cells do?
Collect debris and carry to the lymph node, then show to the T helper cells for inspection
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What does MHC stand for
Major histocompatibility complex
Class I and II
Intracellular infections
Haplotype varies dependant on the genes for MHC inherited from parents
Certain haplotypes will have different protective qualities against different pathogens (e.g. European selection pressure from yrsinia pestis, and different responses now to covid.)
Only on intracellular things
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How do Cytotoxic T cells respond to antigens presented in MHC class I context
PICTURE Once peptide is loaded into the MHC class I complex and presented on the surface of an infected cell, it engages with the T cell receptor on a passing cytotoxic CD8+ T cell (CTL).
The CD8 molecule on the surface of the CTL simultaneously “double checks” that the peptide is presented correctly by recognizing that the MHC class I molecule is from a matched allele.
The CTL will only kill the target cell once these engagements are complete.
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How do Helper T cells respond to antigen presented in MHC class II context
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PICTURE
Once peptide is loaded into the MHC class II complex and presented on the surface of a professional antigen presenting cell (APC), it engages with the T cell receptor on a passing CD4+ helper T cell. The helper T cell “double checks” the identity of the presenting cell before it becomes activated to secrete molecular messengers (cytokines) that further promote immune responses.
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The CD4+ T helper cell plays a slightly different role depending on the type of cell that is presenting antigen to it
give two examples
The CD4+ T helper cell plays a slightly different role depending on the type of cell that is presenting antigen to it.
If the presenting cell is a professional antigen presenting cell (APC), the helper cell becomes “alert” to the fact that it possesses a T cell receptor shape that may be needed to play a role in an immune response, and signal transduction events lead to changes in transcription and translation that induce behavioral changes in the helper cell.
If the helper cell recognizes antigen presented by a B cell, signal transduction events also lead to changes in the helper cell that result in the secretion of soluble factors that stimulate the B cell to divide and secrete soluble antibody. Without this double-checking process, B cells will never become fully activated and the B cell/antibody arm of the immune response will not take place.
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MHC I v MHC II
Where are they found?
What do they present ag to?
What/where do they present ag from?
Where are ag fragments loaded onto MHC I v MHC II
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CHANGE FOR PICTURE?
MHC class I
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Found on all nucleated cells
Presents antigen directly to CD8+ cytotoxic T cells
Presents peptide fragments derived from intracellular antigen
Peptide fragment is loaded on to MHC class I in the rough ER
MHC class II
Found only on antigen-presenting cells (e.g. B cell, macrophage, dendritic cell)
Presents antigen to CD4+ helper T cells
Presents peptide fragments derived from extracellular antigen
Peptide fragment is loaded on to MHC class II in endosomal vesicles
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What is Endogenous antigen presentation
The endogenous pathway evolved to deal with intracellular infections (largely viruses). The vast majority of vertebrate nucleated body cells are capable of expressing class I MHC, and cytosolic peptides are presented constitutively (= all of the time), not just during infection. This means that the vast majority of peptides presented in class I context are self-derived and will not trigger an immune response.
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What is Exogenous antigen presentation
The exogenous pathway evolved to deal with extracellular infections (non-viral pathogens). Only a select group of immune cells are capable of class II MHC presentation, including dendritic cells, macrophages and B cells.
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What is the crossover pathway
The crossover pathway in professional antigen presenting cells (APCs) allows antigens to be taken into the cell through the exogenous route, with the peptide fragments produced then transferring to the endogenous route for MHC class I presentation. Why is this mechanism needed? Firstly, it allows the APCs to take in and process viruses without themselves risking becoming infected and subsequently destroyed because viral antigens are presented in MHC class I context. The crossover pathway is an important component of a number of cancer immunotherapy and vaccination strategies.
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Endogenous v endogenous antigen presentation
In the endogenous pathway, intracellular proteins are continuously sampled regardless of whether there is an infection or not. Cytosolic proteins are degraded by the proteasome complex, and the peptides produced associate with the transporter associated with antigen processing (TAP) prior to translocation into the Rough ER. There, the peptide encounters and ultimately binds to the class I MHC molecule. Prior to this binding however, the MHC protein is quite unstable, and needs to chaperoned by other molecules (e.g. calnexin, tapasin, beta2-microglobulin). Once peptide is bound, the class I MHC-peptide complex is transported via the Golgi complex to the cell surface where the peptide is presented to CD8+ cytotoxic T cells. Recognition of a foreign peptide will trigger an attack on the presenting cell.
In the exogenous pathway, extracellular antigens are phagocytosed by professional antigen presenting cells, and degraded in intracellular endosomes to produce peptide fragments. These endosomes then fuse with vesicles that have budded off from the Golgi complex taking with them class II MHC molecules with the binding site protected by CLIP (Class II-associated invariant chain peptide). CLIP is then proteolytically degraded and peptides derived from the extracellular antigen are loaded onto the class II MHC molecule that continues on its journey to the cell surface where the peptide is presented to the T cell receptor found on CD4+ helper T cells. Recognition of the antigen as foreign will trigger signal transduction pathways in the helper T cell which then secretes chemical messengers that promote and maintain immune responses in other cells (e.g. cytotoxic T cells and B cells).
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Endogenous and Exogenous antigen presentation 2
which MHC class is each?
PICTURE
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What is T cell receptor rearrangement
The number of potential antigen shapes that need to be recognized by T cell receptors is huge, and it would not be possible for all of this to be encoded in the germline (genome).
T cell receptors include alpha and beta subunits, each of which is made by randomly combining V/J/C (alpha) or V/D/J/C (beta) regions; the largest diversity is in the V regions, and all three mRNA “frames” can be used during translation.
Unlike B cells, there is no affinity maturation in T cells, nor is there substitution of C domains during the immune response.
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What does the CHD8 molecule do during cytotoxic T cell assessment of MHC class I printed peptide?
The CD8 molecule on the surface of the CTL simultaneously “double checks” that the peptide is presented correctly by recognizing that the MHC class I molecule is from a matched allele.
The CTL will only kill the target cell once these engagements are complete.
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What is T cell positive selection?
T cells that express T cell receptors that are incapable of binding peptides would be effectively useless, and these are deleted by apoptosis in the thymus by a process known as positive selection. In the process of negative selection, any T cell whose TCR binds too strongly to self-MHC molecules is also deleted, as it would pose a risk of causing autoimmunity. The potential repertoire of different TCR shapes exceeds that available to B cells.
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What do T cell receptors include as subunits
T cell receptors include alpha and beta subunits, each of which is made by randomly combining V/J/C (alpha) or V/D/J/C (beta) regions; the largest diversity is in the V regions, and all three mRNA “frames” can be used during translation.
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Do B cells and T cells both undergo affinity maturation
Unlike B cells, there is no affinity maturation in T cells, nor is there substitution of C domains during the immune response.
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How does the thymus stop T cells killing own cells
Screens T cells for self reactivity to anything in the thymus and T cells die if they self react
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What type of cell does MHC class I present from
Nucleated cells - endogenous peptides, particularly viruses
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Where are MHC class II presented
By professional antigen presenting cells (APCs)
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Which cells can provide all three stimulus for T cells
Only professional APCs provide all three signals (antigen presentation via MHC molecules, expression of costimulatory molecules, and cytokine/chemokine secretion) needed to train and activate T cells to recognize, destroy, or tolerate cells that carry these antigens, and thereby to control viral infections or cancer cell growth
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What's the difference between "professional" and non prof. APCS?
The main difference between professional and nonprofessional APCs is the absence of MHC class II and costimulatory molecules on nonprofessional APCs
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What are the three main professional APCs?
dendritic cells [DCs], B cells, and macrophages MHCII
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What is the point of APCs and MHC II
exogenous peptide presentation - pick up and phagocytose and present exogenous antigens
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What is the point of MHC class I
monitoring intracellular environment and if necessary activation of T cells
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Can MHC present caborhydrate, protein, DNA/RNA
Only presents proteins, (peptides) in the binding cleft
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T cell receptor rearrangement
PICTURE
T cells that express T cell receptors that are incapable of binding peptides would be effectively useless, and these are deleted by apoptosis in the thymus by a process known as positive selection. In the process of negative selection, any T cell whose TCR binds too strongly to self-MHC molecules is also deleted, as it would pose a risk of causing autoimmunity. The potential repertoire of different TCR shapes exceeds that available to B cells.
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CD8+ T cells
How to recognise antigen
After activation...
T cell receptor response to...
Requires stimulation by...
CD8+ T cells
Recognise antigen presented in MHC class I context on infected body cells
On activation, engage with and attack target cells by triggering apoptosis and damaging the cell membrane
T cell receptor responds to antigens derived from the endogenous pathway
Requires stimulation by an infected target cell AND a CD4+ helper T cell before full activation occurs
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CD4+ T cells
How to recognise antigen
After activation...
T cell receptor response to...
Requires stimulation by...
CD4+ T cells
Recognise antigen presented in MHC class II context by professional APCs
On activation, secrete a variety of chemical messengers that stimulate immune responses
T cell receptor typically responds to antigens derived from the exogenous pathway
Requires stimulation by an APC before full activation occurs
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T cells
Originate in...
Recognise...
Receptor is on...
Subsets?
Do they affinity mature?
T cells
Originate in the bone marrow but develop further in the thymus
Recognise peptides derived from processed antigen and presented to them by another cell
Receptor is on the cell surface only
Major subset differentiation (CD4+ vs CD8+)
No affinity maturation takes place
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B cells
Originate in...
Recognise...
Receptor is on...
Subsets?
Do they affinity mature?
Develop and partially mature in the bone marrow
Recognise intact protein antigen –soluble or pathogen-associated
Receptor (antibody) is both on the cell surface and secreted (soluble)
Subsets are reported, but no major differences (other than Ag specificity)
Mutate their receptor during affinity maturation
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Mode of Pfizer vaccine action
picture
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The high efficacy is based on inducing presentation of spike protein antigens in both MHC class I and class II context – just like in a “real” infection.
More conventional antigen-based vaccines generate class II presentation and can elicit robust B cell responses, but CD8+ T cell involvement is lacking (little or no class I presentation).
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Can B cells or T cells recognise secondary structure
The epitope recognized by an antibody located on the surface of a B cell can be continuous or discontinuous. A continuous epitope is a string of amino acids that are immediately next to one another on the target antigen (part of the primary structure of the protein – essentially the order of amino acids encoded in the gene). However, proteins fold in three-dimensional space so that peptide regions that are far apart in the primary amino acid sequence can be close together in the folded protein (this is known as secondary structure). B cells are capable of recognizing such regions of secondary structure, whereas T cells are not because T cell receptors recognise only small linear peptides that are presented to them by MHC class I (for CD8+ T cells) or MHC class II (for CD4+ helper T cells).
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Pfizer mRNA vaccine
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The mRNA vaccine encoding the viral spike protein is packaged in a lipid-based nanoparticle. The nanoparticle fuses with the target cell, and the mRNA is delivered to the cell cytosol. The mRNA is then translated by cytosolic ribosomes to form the spike protein. In a normal process that takes place continuously in cells, some of the spike protein is broken into smaller pieces by the proteasome, whilst other intact proteins are transported via the Golgi apparatus and secreted outside of the cell. The smaller pieces remaining in the cell are then assembled as a complex with MHC class I and transported to the cell surface for presentation to CD8+ cytotoxic T cells (CTL). As the spike peptide fragment is of viral origin (or “non-self”), CTL with appropriately shaped T cell receptors will bind to the antigen/MHC I complex leading to destruction of the target cell. Spike proteins that have been exported from the target cell will be taken up (phagocytosed) by professional antigen presenting cells (APC) for presentation on the cell surface as a complex with MHC class II protein. CD4+ helper T cells possessing T cell receptors that are the right shape to bind the antigen/MHC II complex will be activated and produce chemical messages (cytokines) that in turn stimulate antigen-specific B cells to secrete antibodies that have specificity for the spike protein.
Food for Thought: The Pfizer vaccine for SARS-CoV-2 is based on the delivery of messenger RNA (mRNA) to target cells. Unlike DNA, mRNA is an unstable molecule with a short half life, and so the vaccine needs to be stored at very low temperatures. To ensure both class I and class II presentation of spike protein antigens, mRNA must be delivered to target cells that are capable of both pathways (e.g. professional antigen presenting cells). Whilst the vaccine is currently non-targeted, future iterations may incorporate targeting features into the lipid coat. In humans there is significant variation in the genes that allow MHC presentation – some people will be able to present a particular peptide antigen whilst others will not. This means that immune responses to the vaccine – and the level of protection that it offers – are highly likely to vary to some degree between those vaccinated.
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Innate v adaptive immunity
do they communicate?
The innate and adaptive systems do communicate with each other.
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Examples:
Antibody Fc domains can activate the complement cascade.
Phagocytes can process and present antigens in MHC class II context
Natural killer (NK) cells possess receptors that bind to the Fc domain of antibodies, thus arming themselves to attack a specific antigen target.
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Innate v adaptive immunity
Major elements
Response to microbial infection
PICTURE
