The Immune System In Health & Disease Flashcards
(242 cards)
1
Q
What is the body’s largest immune organ?
A
The skin
2
Q
What mechanical, chemical & microbiological barriers does the skin provide to infection?
A
Mechanical:
- Epithelial cells joined by tight junctions
- Flow across the surface
- Movement of mucus by cilia
Chemical:
- Fatty acids & enzymes (lysozyme)
- Low pH
- Antibacterial peptides (Defensins)
Microbiological:
- Normal flora compete for nutrients & attachment
3
Q
What is Ebola virus, and what are some symptoms?
When do symptoms appear?
A
Ebola virus disease is a hemorrhagic fever whose symptoms include:
• Fever
• Aches and pains, such as severe headache, muscle and joint pain
• Weakness and fatigue
• Gastrointestinal symptoms including diarrhea and vomiting
• Abdominal pain
• Unexplained hemorrhaging, bleeding or bruising
Symptoms appear typically after 8-10 days.
4
Q
What is the average EVD case fatality rate?
What have case fatality rates varied from in previous outbreaks?
A
The average EVD case fatality rate is around 50%.
Case fatality rates have varied from 25% to 90% in past outbreaks.
5
Q
What is a current treatment for Ebola Virus Disease?
What type of therapy is this, and how is this treatment manufactured?
A
REGN-EB3 (Inmazeb) = treatment for EVD.
REGN-EB3 (Inmazeb) is an antibody therapy.
It is made up of a mixture of three human IgG1 monoclonal antibodies specific for soluble EBOV glycoprotein (Makona strain):
• Produced in VelocImmune mice
• Selected to have neutralizing activity and activate immune cells via FcyRIIIa
• High affinity – KD ranged from 3 to 8.4 at pH 7.2
• Recognize three individual epitopes
6
Q
Diagram of the lymphatic & CV systems
A
NOTION 1.1
7
Q
Where do white blood cells enter tissue via, and where does it return?
A
White blood cells enter tissue from blood and return via lymph.
8
Q
Where are immune responses generated?
A
Immune responses are generated in lymph nodes draining site of infection.
9
Q
Structure of a lymph node
A
NOTION 1.2
10
Q
Diagram of the variety of white blood cells
A
NOTION 1.3
11
Q
What are the 3 main polymorphonuclear phagocytic cells?
A
Polymorphonuclear phagocytic cells:
- Neutrophils
- Eosinophils
- Mast Cells (and Basophils)
12
Q
Abundance of neutrophils
Function of neutrophils
A
NEUTROPHILS make up more than half of our WBC and are our first line of defence. They enter tissue to phagocytose debris and pathogens and start inflammation.
13
Q
Function of Eosinophils
Abundance of Eosinophils
A
EOSINOPHILS migrate from the blood into other tissues and kill antibody coated parasites. They make up 1-3% of WBC
14
Q
Function of Mast Cells & Basophils
How abundant are they?
A
MAST CELLS (and basophils) migrate from the blood into other tissues and release histamine which stimulates inflammation and allergic responses. They make up <1% of WBC.
15
Q
Abundance of monocytes
Function of monocytes
A
MONOCYTES make up 1-6% of WBC, circulate in
the blood and migrate into other tissue where they
differentiate into… MACROPHAGES
16
Q
Where are macrophages located?
A
MACROPHAGES are phagocytic cells located throughout body (eg Kuppfer cells (liver), osteoclasts (bone) and microglia (brain)).
17
Q
What are lymphocytes?
A
LYMPHOCYTES recognise specific antigens from microbes (non-self antigens) or diseased cells (“altered self”) e.g., tumour cells
18
Q
Function of T Cells
A
T CELLS kill virus infected cells and regulate the activities of other white blood cells
19
Q
Function of B Cells
A
B CELLS differentiate to form plasma cells and secrete antibodies.
20
Q
Function of Dendritic Cells
A
DENDRITIC CELLS these are potent antigen presenting cells and are important for differentiating between invading pathogens (“non-self”) and normal cells (“self”).
21
Q
What are complement proteins?
What is their mode of action?
A
Complement proteins ~20 antimicrobial proteins
– Attach to microbes and help phagocytes recognise and engulf microbe
– Activate the inflammatory response
– Lyse (burst) invading cells such as bacteria
22
Q
What are interferons?
What is their mode of action?
A
Interferons
– Released by virus infected cells
– Increase resistance of other cells to infection~ bind to receptors on the surface of cells
23
Q
What are phagocytes?
A
Phagocytes
– Recognise and attack pathogens in infected tissue by secreting cytotoxic granules
– Ingest and dispose of “opsonised” microbial material
– Recognise “self” and “non-self” proteins and provide surveillance against invaders
24
Q
What is an example of a non-phagocytic cell?
A
Natural Killer Cells
25
What is the mode of action of NK Cells?
What do NK Cells respond to?
- NK cells kill host cells infected by intracellular microbes thus eliminating reservoirs of infection
- NK cells respond to IL-12 produced by macrophages and
secrete IFN-y which activates the macrophages to kill phagocytosed microbes
26
What is the effect of binding a molecule to a pathogen (in non specific innate cell signalling)?
Binding of a molecule from a pathogen to a receptor initiates a signal transduction cascade that results in the transcription of genes whose products are involved in defence against the pathogen.
27
Steps involved in inflammation
1. Damaged mast cells release histamine
2. Histamine diffuses into the capillaries
3. Histamine causes the capillaries to dilate and become leaky; complement proteins attract phagocytes
4. Plasma and phagocytes move into infected tissue from the capillary
5. Phagocytes engulf bacteria and dead cells
6. Histamine and complement signalling cease; phagocytes are no longer attracted; the tissue returns
28
Stages of an infection, and the responses to an infection
An infection, and the response to it can be divided into stages and involves soluble mediators and cells of the immune system:
1. Local infection, penetration of epithelium (Immediate)
- Wound healing induced
- Antimicrobial proteins and peptides
- Phagocytes & complement destroy microorganisms
2. Local infection of tissues (Hours later)
- Complement
- Phagocytes, cytokines, NK cells
- Activation of macrophages
- Dendritic cells migrate to lymph nodes= initiate adaptive
3. Adaptive immunity (Days)
- Infection cleaved by specific antibody
- T Cell dependent macrophage activation
- Cytotoxic T Cells
29
How long does it take for the adaptive immunity?
Antigen specific or ADAPTIVE immune responses take
up to 7 days to develop.
30
What are antigen presenting cells?
What is their function/ mode of action?
• Antigen presenting cells (APC) take up opsonised pathogens, infected necrotic or apoptotic cells and digest these down into peptide fragments.
• These are displayed on surface of cells by Major HistoCompatibility molecules (MHC) and recognised by receptors on T lymphocytes
31
MHC Class I vs II
• Cytotoxic T cells (CD8) recognise virus peptides on MHC
class I molecules of infected cells.
• Helper T cells (CD4) recognise microbial peptides
phagocytosed by APC and presented on MHC class II antigens
32
What are examples of APCs?
Dendritic cells, B cells and macrophages, are all ANTIGEN PRESENTING CELLS.
33
Stages involved in response by an APC
1. A macrophage takes up antigen by phagocytosis
2. The macrophage processes the antigen by breaking it into fragments
3. A class II MHC protein binds the processed antigen
4. The MHC presents the antigen to the Th cell
34
How many T cells are produced each day?
Billions of T cells are produced each day, each with a different antigen receptor.
35
Mode of action of T helper 1 cells
T helper 1 cells (Th1) activate macrophages and are involved in anti-viral and inflammatory responses.
36
Mode of action of T helper 2 cells
T helper 2 (Th2) cells are involved in humoral (antibody) responses and allergy.
NOTION 1.4
37
Basic Structure of human antibodies
NOTION 1.5
38
How was tetanus & diphtheria serum therapy discovered?
• Isolated and discovered that tetanus and diphtheria mediated their effects via a toxin
• Von Behring won the Nobel prize for Medicine in 1901
Process involved in discovery of serum therapy:
- Rabbit immunised with tetanus toxin
- Mice infused with immunised rabbit serum => Mice resistant to tetanus toxin
- Mice infused with normal rabbit serum => Mice susceptible to tetanus toxin
39
What serum was used to neutralise diphtheria toxin?
What type of immunity is this?
How many deaths, from diphtheria, were then prevented?
What problems occured?
Therefore what was this therapy replaced by?
- Horse antiserum containing specific antibody was used to neutralize the diphtheria toxin.
- Example of passive immunity
- Reduced diphtheria deaths by 50%
- Problems with serum sickness
- Replaced by the toxoid vaccines (active immunity)
40
What are epitopes?
Each antigen has many antigenic determinants (EPITOPES) that are recognised by specific antibodies. Each antibody recognises and binds to its particular epitope to initiate defensive measures against the antigen.
41
What is the humoral immune response made by?
The HUMORAL immune response is made by B cells:
each antibody matches an antigenic determinant
42
Interaction between T cells & B cells
T cells and B cells must communicate and cooperate to start antibody production
NOTION 1.6
43
Components of Blood and Lymph
- Cellular and non-cellular
- Erythrocytes (non-nucleated, >90% of blood cells)
- White Blood Cells – WBC / Leukocytes (<1% blood
cells)
- Thrombocytes (platelets) (~7%)
- Plasma = liquid containing cells, proteins (including clotting agents - fibrinogen), glucose, ions, CO2 …..
- Serum = plasma minus cells and clotting agent
44
What are the main stages in the fight against an infection?
1. Innate Immediate (0-4 hr)
2. Early Induced Response (4-96 hr)
3. Adaptive Response (> 96 hr)
45
What is involved in the innate immediate stage?
•Infection
•Recognition by pre-formed, nonspecific effectors
•Removal of infectious agent
46
What is involved in the Early Induced Response?
•Infection
•Recognition of microbial-associated molecular patterns
•Inflammation, recruitment & activation of effector cells
•Removal of infectious agent
47
What is involved in the Adaptive Response?
•Infection
•Transport of Ag to lymphoid organs
•Recognition by naïve T and B cells
•Clonal expansion & differentiation to effector cells
•Removal of infectious agent
48
Origin of the cells of the immune system
NOTION 2.1
49
Myeloid vs lymphoid precursors
- Myeloid precursors give rise to phagocytes: cells involved in innate immunity and antigen presentation.
- Lymphoid precursors generate T and B lymphocytes: cells responsible for antigen-specific immune responses.
50
What are the major cell types of the innate immunity?
- Phagocytes
- Granulocytes
51
What are phagocytes?
What happens when phagocytes destroy pathogens?
What substances do phagocytes use?
- Cells that can engulf, kill and digest most pathogens
- When phagocytes engulf and destroy pathogens it initiates complex host-mediated reactions, collectively known as inflammation
- Lysosomes – bactericidal substances (H2O2, lysozyme,
proteases, phosphatases, nucleases, lipases)
52
What are antigen presenting cells?
Antigen-presenting cells (APCs): monocytes, macrophages, dendritic cells
53
What are granulocytes? Give some examples
- Contain cytoplasmic inclusions / granules
- Granules contain toxins and enzymes used to kill pathogens
- Neutrophils (PMNs), Mast Cells, Basophils, Eosinophils
54
What pathogens does the innate immune system deal with?
Bacteria, viruses, parasites and fungi
55
What are pathogen associated molecular patterns (PAMPs)?
Pathogen-associated molecular patterns (PAMPs) are displayed by the pathogens.
They are microbial components that are essential for the fitness or survival of the microorganism. They include molecular signatures of particular groups of organisms or infectious agents i.e they are microbe specific
56
What are Pattern Recognition Receptors (PRRs)?
Pattern recognition receptors (PRRs) are membranebound phagocyte proteins that recognise PAMPs.
They are highly conserved among species (fruit flies to mammals).
They are germ-line encoded receptors which recognise PAMPs.
NOTION 2.2
57
Image of neutrophils, mast cells, basophils & eosinophils
NOTION 2.3
58
What are some examples of bacterial PAMPs?
- LPS
- Lipopeptides
- Lipoteichoic acid
- Peptidoglycan
- Porins
- Lipoarabinomannan
- Flagellin
- CpG-DNA
59
What are the 3 different types of bacterial cell wall?
NOTION 2.4
60
What are some examples of parasitic PAMPs?
- Glycoinositolphospholipids
- Hemozoin
- Profilin-like molecules
61
What are some examples of fungal PAMPs?
- Zymosan
- Phospholipomannan
- Mannan
- Glucuronoxylomannan
62
What are some examples of viral PAMPs?
- DNA
- dsRNA
- ssRNA
- Envelope proteins
63
What are some examples of PRRs?
Includes the TLRs
- TLR4 – LPS
- TLR7 – ssRNA
- TLR9 – CpG DNA
NOTION 2.5
64
What is involved in oxygen dependent phagocyte activation?
Some key molecules involved:
- Nitric Oxide
- Superoxide anions (O2-)
- Myeloperoxidase
- Hydroxyl radicals OH-
NOTION 2.6
65
What are some toxic oxygen species generated by activated phagocytes?
What is a respiratory burst?
- Toxic oxygen species such as hydrogen peroxide, hydroxyl radical, hypochlorous acid and superoxide anion are generated by activated phagocytes.
- Respiratory burst is the increase in oxygen uptake by activated phagocytes to produce toxic oxygen species.
66
What are also found in phagolysosome?
There are also enzymes in the phagolysosome to cleave all types of biomolecules (lipids, proteins, nucleic acids and carbohydrates).
67
Initiation of inflammation by innate immune cells
NOTION 2.7
68
What is inflammation characterised by?
Inflammation is characterised by: pain, swelling (edema), redness (erythema) and heat.
69
Is the inflammatory response good?
What can happen during uncontrolled inflammation?
The inflammatory response is a normal and generally desirable outcome of an immune response.
Uncontrolled systemic inflammation, called septic shock, can lead to serious illness and death.
70
What are some molecular mediators, and what is their role in inflammation?
Cytokines including IL-1, Tumour necrosis factor (TNF)-1 alpha and IL-6 initiate the Acute Phase Response. They:
- Increase the production of Mannose Binding Protein
- Increase release of C-reactive protein (CRP)
- Scavenge material released by tissue damage, improve phagocytosis of bacteria (CRP is an opsonin) and activation of complement
71
What stimulates the arrival of neutrophils to the injury site?
Neutrophils arrive first to the injury site in response to chemokine IL-8, produced by damaged host cells.
72
What is the average no of WBCs found in blood?
Avg = 40 x 10^9 WBCs in blood
73
Diagram displaying the different types of blood cells, and where they originate from
NOTION 3.1
74
Mode of action of mast cells
What granules do they release?
What cytokines do they release?
Degranulation after anti-IgE antibody treatment (e.g.
mimicking allergens)
- Granules = Histamine, Heparin
- Cytokines IL-4, IL-13
Mast cells have high affinity receptor for IgE
75
What proteins/ toxins can be found in eosinophils?
What pathogen can eosinophils specifically target?
What can eosinophils then induce?
- Major Basic Protein
- Eosinophil Cationic Protein
- Eosinophil-derived Neurotoxin
- Potent toxins for helminth worms (too large to phagocytose)
- Induce histamine release from mast cells and activate neutrophils.
- Relevance to allergy
76
What types of cells do Natural Killer Cells target?
How are these perfect targets for NK cells?
What antibody is involved?
- NK Cells target virus infected cells and tumour cells
- These cells contain lower levels of MHC molecules, making them perfect targets for NK-cells
- IgG antibody dependent cellular cytotoxicity
77
What is the complement system?
What is it made up of?
- Made up of plasma proteins that “complement” antibacterial activity of antibodies
- Contains around 30 plasma proteins, which trigger a biochemical cascade that catalyses bacterial cell destruction and opsonisation
78
How can the complement system be activated?
The complement system is activated in at least 3 different ways:
1. Classical Pathway
2. Lectin Pathway
3. Alternative Pathway
79
What is involved in the classical pathway?
Antibody binds to specific antigen on pathogen surface
80
What is involved in the lectin pathway?
Mannose-binding lectin binds to pathogen surface
81
What is involved in the alternative pathway?
Pathogen surface creates a local environment conducive to complement activation.
82
What are the 3 main functions of the complement system?
1. Recruitment of inflammatory cells
2. Opsonisation of pathogens, facilitating uptake and killing by phagocytes
3. Perforation of pathogen cell membrane
83
What complement proteins are involved in each of the 3 activation pathways?
What happens to these complement proteins?
Classical pathway: C1, C4, C2
MBL Pathway: MASP, C4, C2
Alternative Pathway: C3, CFB, CFD
These complement proteins then form a C3 convertase, which helps break down C3 into C3a and C3b.
84
What are the two different types of C3 convertase?
C3 Convertase:
C4bC2b: (CP & MBL)
C3bBb (AP)
85
What is the effect of C3b on C5?
C3b combines with the original C3 convertase complexes, to then convert C5 into C5a & C5b.
86
What are the 2 different types of C5 convertase?
C5 convertase:
C4bC2bC3b (CP & MBL)
C3bBbC3b (AP)
87
What other complement proteins can C5b be converted to?
C5b can be converted into C6, C7, C8 & C9
88
What complement protein is a potent opsoniser?
C3b = Opsoniser
89
What 2 complement proteins are involved in triggering inflammation?
What might this inflammation involve?
C3a & C5a trigger inflammation:
- Anaphylatoxis
- Chemotaxis
- Immune regulation
90
What complement proteins are involved in the lysis of a pathogen, followed by inflammation?
What cytokines are also involved here?
C5b - C9 = Lysis & Inflammation:
- Increase in IL-6, IL-8, CL2 & VEGF
91
Summary diagram of the complement proteins
NOTION 3.2
92
Diagram displaying initiation, early steps and late steps of complement activation
NOTION 3.3
93
Summary diagram of the classical pathway
NOTION 3.4
94
Summary diagram of the lectin pathway
NOTION 3.5
95
Summary diagram of the alternative pathway
NOTION 3.6
96
What pathway is part of the non specific defence, and why?
The alternative activation pathway is part of the non specific defence, as it does not need antibodies to initiate the pathway.
97
What pathway is the slowest?
The alternative pathway is slower than the classical pathway.
98
What do the C5b, C6, C7, C8 & C9 complement proteins form?
C5b, C6, C7, C8 and C9 together form the cylindrical membrane attack complex
99
Diagram of the membrane attack complex
NOTION 3.7
100
How can C3b be inactivated?
C3b can be inactivated by factor H and factor I, to give fragment iC3b.
NOTION 3.8
101
What can disrupt C3 convertase C3bBb?
DAF and MCP disrupt C3 convertase C3bBb on a human cell surface.
NOTION 3.9
102
Summary diagram of the complement system, along with the disposal system, innate immunity, and adaptive immunity
NOTION 3.10
103
What are 3 opsonins produced by the liver?
Liver produced opsonins = MBL, CRP and Complement
104
Structure of a MHC Class I molecule
NOTION 3.11
105
Where are MHC Class I molecules expressed?
MHC Class I molecules are expressed on all nucleated cells
106
MHC Class I antigen presentation pathway
NOTION 3.12
107
Structure of a MHC Class II molecule
NOTION 3.13
108
Where are MHC Class II molecules expressed?
MHC Class II mainly expressed by “professional” antigen presenting cells
109
MHC Class II Presentation Pathway
NOTION 3.14
110
What are the “professional” antigen presenting cells?
Macrophages and dendritic cells are the “professional” antigen presenting cells.
111
Levels of MHC Class II molecules in macrophages vs dendritic cells
Macrophages express low levels of MHC Class II molecules, and almost no co-stimulatory molecules without infection.
Dendritic cells constitutively express high levels of MHC Class II and co-stimulatory molecules.
112
What APCs are the most potent in activating naive T cells?
Dendritic cells are the most potent in activating naive T cells.
113
Where do APCs meet T cells?
- Peripheral lymphoid organs
- Lymph nodes
- Spleen
- Mucosal lymphoid tissues (gut, lung, and other mucosa)
114
Structure of lymphatic capillaries
NOTION 3.15
115
Lymphocyte trafficking
NOTION 3.16
116
What are hallmark features of the adaptive immunity?
Antigen specificity and “memory” are hallmark features
- Antigen receptors of T and B lymphocytes
- Generation of receptor diversity
- Deletion of self-reactive B and T cell receptors
- Clonal expansion of B and T lymphocytes
117
What are immunogens?
Immunogens = substances that generate immune response
118
What are antigens?
Antigens (Ag) = substances that bind to B and T cell receptors
119
What is a BCR?
BCR = B cell surface receptor (binds Ag)
120
What is a TCR?
TCR = T cell surface receptor (binds Ag in association with MHC)
121
What is a CD?
What are 2 examples?
CD = Cluster of differentiation (defines molecules on leukocytes)
- CD4 on Th cells
- CD8 on Tc cells
122
Diagram displaying the initiation of the adaptive immune response
NOTION 4.1
123
How do B and T cells detect antigens?
They use the “immunoglobulin (Ig) supergene family”
124
Conundrum: Given that there is a vast number of protein targets, how do B and T cells generate a receptor repertoire that is large enough to deal with every pathogen?
Who developed a theory for this conundrum, and what did it involve?
Nobel Prize in Medicine and Physiology 1987 - Susumu
Tonegawa "for his discovery of the genetic principle
for generation of antibody diversity”.
125
How many genes are there in the human genome?
An estimate of only 30,000 genes in the human genome.
126
Structure of an antibody
NOTION 4.2
127
What are the different isotypes of immunoglobulins?
- IgM
- IgA
- IgD
- IgE
- IgG_1-4
128
Usual form of the IgM isotype
When is this isotype produced?
Affinity and avidity of IgM
Additional function of IgM
- Usually pentamer (mononer on B cells).
- First class of Ig produced in response to bacterial infection.
- Low affinity but high avidity for antigen
- Strong complement activator
129
Usual form of IgA
Where is IgA present?
Where is IgA in monomer form?
- Dimers of IgA are present in body fluids (saliva, tears, breast milk colostrum etc.) and mucosal secretions (gastrointestinal, respiratory and genitourinary tracts).
- A monomer form in blood
130
Where is IgD present in low concentrations?
What is the function of IgD?
Where is IgD abundant?
- Present in serum in low concentrations
- No known function
- It is abundant on the surfaces of B cells (especially on memory B cells)
131
Where is IgE present in extremely small amounts?
What is IgE involved in?
- Extremely small amounts in serum
- Involved in allergic reactions and parasite immunity
132
What is IgG?
What are the different subclasses?
- Most common circulating antibody
- Four subclasses.
- IgG1 and IgG3 active complement
133
Structure of Ag binding site
CDR = Complementarity-determining region
NOTION 4.3
134
What determines Ag specificity?
Six hypervariable loops (3 from each chain) determine Ag specificity by forming a surface complementary to the Ag.
NOTION 4.4
135
What is “Combinatorial Diversity”?
Different combinations of variable H and L gene segments and pairing of H and L chains.
NOTION 4.5
136
How are BCR variable regions encoded?
BCR variable regions are encoded by gene segments (not one gene, one protein).
137
What is somatic recombination?
Complete genes are generated by somatic recombination (alteration of the DNA of a somatic cell).
138
All Ig diversity has been generated from recombination of existing genes.
The final light chain and heavy chain genes expressed by a given B cell result from chance re-assortment of these rearranged heavy chains and light chains.
How many possible antibodies can be expressed?
Humans:
40V X 5J = 200 possible κ light chains
30V X 4J= 120 possible λ light chains
40V X 25D X 6J = 6000 possible heavy chains
Assuming each heavy chain and light chain has an equal chance to be expressed in each cell:
6,000 X 200 = 1,2000,000 possible Igs with κ light chains
6,000 X 120 = 720,000 possible Igs with λ light chains
So at least 1,920,000 possible antibodies can be expressed.
139
What is somatic hypermutation?
Point mutations in the rearranged V-region genes of activated B cells in peripheral lymphoid organs.
Amino acid changes in CDRs of light and/or heavy chain alter antigen specificity (adapting to fit the antigen better).
Expansion of B cells with improved antigen binding.
140
Development of B cell precursors into plasma and memory cells
NOTION 4.6
141
Formation of T Cell Receptors
NOTION 4.7
142
How do T cell receptors detect antigens?
They have affinity for peptide presented by MHC molecules.
143
T Cell Receptor bound to MHC protein
NOTION 4.8
144
Hypothetical viral protein producing 16 different T cell epitopes, each 9 amino acids long
NOTION 4.9
145
C-regions of BCR vs TCR locus
C-regions (effector function) of BCR are more complex than TCR locus.
146
Where do TCR concentrate diversity in?
TCR concentrate diversity in CDR3 (which makes contact with peptide).
Less variable CDR1 and CDR2 loops make contact with MHC.
147
Does somatic hypermutation occur in TCR genes?
No, somatic hypermutation does not occur in TCR genes.
148
What are the different sets of gene segments, from which antigen receptors can be generated?
A vast number of different antigen receptors can be generated from a small set of V, D, J, C gene segments due to a complex process of somatic recombination (TCR and BCR) and hypermutation (BCR).
149
How can you prevent self reactivity?
- Deletion of cells expressing selfreactive receptors during B and T cell development
- Prevent the activation of self-reactive B and T cells
- Regulate activities of self-reactive B and T cells
150
What are 3 self tolerance mechanisms?
Central tolerance: during B and T cell development in the bone marrow and thymus
Peripheral tolerance: mature B and T cells in the periphery
Acquired tolerance: e.g. maternal tolerance to foetus and placenta
151
What are possible fates for self reactive immature B cells?
NOTION 5.1
152
What does clonal deletion involve?
Clonal deletion: removal through apoptosis of B cells (or T cells) expressing receptors for self. This prevent recognition and destruction of self host cells (negative selection or central tolerance)
153
What does receptor editing involve?
Receptor editing: antibody gene rearrangement in a lymphocyte that already has a functional antigen receptor.
The expression of a functional antigen receptor will normally terminate further rearrangement (allelic exclusion).
154
Some B cells are said to be anergic, what does this mean?
What is anergy?
B cells are said to be anergic when they fail to respond to their specific antigen.
Anergy is one of three processes that induce tolerance, modifying the immune system to prevent selfdestruction (the others being clonal deletion and immuno-regulation).
155
What is clonal ignorance?
Clonal Ignorance: A state where autoreactive cells are
neither, anergized, receptor edited, or deleted.
They co-exist with antigen in an unactivated state with low affinity for antigen.
156
What happens to a mature B cell?
Mature B cell: After B cells mature in the bone marrow, they migrate through the blood to secondary lymphoid organs (spleen and lymph nodes), which receive a constant supply of antigen through circulating lymph.
157
What is involved in T cell development in the thymus?
Positive selection: select for MHC-binding TCR
Negative selection: deletion of cells expressing TCR with high affinity for self peptide MHC
NOTION 5.2
158
What T cells die by apoptosis?
What % of T cells don’t make it out to the periphery?
Useless (non-MHC recognizing) or harmful (high affinity self-reactive) T cells die by apoptosis (programmed cell death) in the thymus (95-99% don’t make it out to the periphery!)
159
Frequency of T cells expressing a particular antigen
The frequency of T cells expressing a particular antigen specificity is low (1 in 10,000 or more)
Selection process is imperfect, self-reactive T cells are found in the periphery.
160
What 2 signals are required for activation of naive T cells?
Two signals are required:
1. Antigen recognition
2. Co-stimulation
161
What are some examples of cytotoxic effector molecules, released from activated T cells?
Perforin and granzymes
162
What enhances T cell binding to APCs?
CD4 and CD8 bind to the nonpolymorphic regions of MHC molecules (class II and class I respectively) and enhance T cell binding to antigen presenting cells.
Adhesion molecules prolong contact between T cells and antigen presenting cells.
163
What are the 3 classes of effector T cells?
What TCR does each class present?
What cells do each class of effector T cell interact with?
What is the effect of this interaction?
NOTION 5.3
164
What is a new subset of T helper cell that was discovered recently?
A new subset = TH_17 (for bacteria and fungi, implicated in
several autoimmune diseases).
165
What are T cell independent antigens?
Give an example
What do activated B cells generally produce?
T cell-independent antigens = cannot be presented by MHC molecules, but contain repeating epitopes to engage multiple BCR on a single B cell
e.g. DNA (repeating nucleic acid structures) and bacterial polysaccharides (repeating sugar structures)
Activated B cells generally produce low affinity IgM antibodies, and with a limited or no memory response.
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What are T cell dependent antigens?
What is involved in the response?
T cell-dependent antigens= cannot activate B cells without
antigen-presentation and T-helper cells i.e. protein antigens
High affinity antibodies and a memory response.
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What is most potent co-activating signal in B cells?
What does it drive?
In B cells, CD40 is the most potent co- activating signal.
Drives B cells into cell cycle.
Germinal centre development.
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What is involved in T-dependent B cell activation?
- B cell clonal expansion
- Somatic hypermutation
- Isotype switching in germinal centre
- Differentiation to plasma and memory cells
- Antibodies are produced
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What are some antibacterial roles of antibodies?
NOTION 5.4
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What are effector functions of different isotypes?
NOTION 5.5
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Memory B Cell Repsonse
NOTION 5.6
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What is the:
- Frequency of specific B cells
- Isotype of antibody produced
- Affinity of antibody
- Somatic hypermutation
In a primary vs secondary response
NOTION 5.7
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What is involved in defence against CMV?
Cytomegalovirus (CMV) - specific T cell responses eliminates CMV infection
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Do T cells have memory?
Yes, Memory T cells are more sensitive to restimulation by antigen than are naïve T cells.
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What happens to the following features:
- Peak response
- Antibody Isotype
- Antibody affinity
- Induced by
For primary vs secondary responses
NOTION 6.1
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What are the different types of vaccines?
1. Live attenuated (LAV)
- Tuberculosis (BCG)
- Oral Polio Vaccine (OPV)
- Measles
- Rotavirus
- Yellow Fever
2. Inactivated (killed antigen)
- Whole cell pertussis (wP)
- Inactivated Polio Virus (IPV)
3. Subunit (purified antigen)
- Acellular pertussis (aP)
- Haemophilus influenza type B (Hib)
- Pneumococcal (PCV-7, PCV-10, PCV-13)
- Hepatitis B (hepB)
4. Toxoid (inactivated toxins)
- Tetanus Toxoid (TT)
- Diphtheria toxoid
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With regard to some common vaccines:
- What type of vaccine are they?
- Is serum IgG activated?
- Is mucosal IgG activated?
- Is mucosal IgA activated
- Are T cells activated?
NOTION 6.2
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Examples of some common diseases, and the vaccines produced against them
NOTION 6.3
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What is the 2nd most common cause of cancer death in females?
Cervical cancer is the 2nd most common cause of cancer death in females.
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What virus is linked to cervical cancer?
HPV is linked to 100% of all cervical cancers.
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What protection does the HPV vaccine provide against cervical cancer?
How many vaccines are available?
Complete protection against >70% of cancer-causing HPV strains.
Currently 3 vaccines are now available.
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Why is it important to control the adaptive immune responses?
• Prevent over-vigorous response (bystander damage or disease)
• Switch off response once infection cleared (prevents waste of resources and allows immune system to still respond to diverse antigens)
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When would it be important to suppress immune response?
• Allergy and asthma
• Autoimmune disease
• Transplantation
• Sepsis
• (Pregnancy)
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Why would it be important to boost immune response?
•Cancer
•Parasitic disease
•Difficult to treat infections ➢ Influenza, HIV, Leprosy, TB
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What are 4 mechanisms of central tolerance?
1.Deletion – apoptosis of autoreactive clones
2.Deviation – reprogramming
3.Anergy – reduced sensitivity to antigenic stimuli
4.Editing – receptor editing to generate receptors that are not autoreactive
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What is the primary aim of central tolerance?
The primary aim of central tolerance: to ensure during development that any lymphocytes with high affinity receptors for self-antigens are eliminated or inactivated.
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What does central tolerance involve?
1.Required for adaptive immunity
• Alpha-beta T cells, B cells and gamma-delta T cells
2.Random selection of gene segments during TCR or BCR formation may give rise to autoreactive lymphocytes
3.Positive and negative selection
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Thymic selection during thymocyte development
NOTION 6.4
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What are 6 mechanisms of peripheral tolerance?
1.Deletion – apoptosis of autoreactive clones
2.Not able to recognise the antigen
3.Anergy – antigenic stimuli in the absence of costimulation
4.Exhaustion – Induction of anergy by inhibitory ligands
5. Active suppression – regulatory T and B cells, tolerogenic dendritic cells
6.Immune privilege
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Steps involved in costimulation and priming of naive T cells
• Signal 1: antigen recognition via antigen specific T cell receptor
• Signal 2: costimulation via CD28 to induce IL-2 production and increased expression of anti-apoptotic Bcl-2
• Signal 3 production of cytokines to drive activation and polarisation
NOTION 6.5
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Effect of regulatory T cells in active suppression
NOTION 6.6
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What is CTLA-4?
CTLA-4 is an inhibitory homologue of CD28. It is expressed on activated T cells and constitutively expressed on regulatory T cells. It is essential for immune homeostasis.
NOTION 6.7
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What happens to CTLA-4 knockout mice?
CTLA-4 knockout mice die of massive lymphoproliferative
infiltrates in organs and tissues.
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Incidence ratios of common autoimmune diseases
NOTION 6.8
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How are autoimmune diseases targeted/ treated?
• Blanket immunosuppression
• Side-effects including infection
• Targeted selective approach – target the aberrant immune activation while leaving the rest of the immune system intact
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Environmental vs genetic risk factors of autoimmune diseases
NOTION 6.9
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What are the 4 categories of hypersensitivity responses?
What do these involve?
• 4 categories: Type I, II, III, IV (V)
• Type I, II (V), and III, are antibody mediated while type IV is T cell mediated
• Autoimmune diseases usually fall into Type II, III, and IV categories depending on the type of damage associated with the disease
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With regard to the different types of hypersensitivity responses:
- What T cells/ antibodies are involved?
- What do they target?
- Examples of conditions
NOTION 6.10
199
Diagram of immunosuppression
NOTION 6.11
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How is tolerance induced by tumour cells?
NOTION 6.12
201
What targets can be used to induce immunological tolerance?
NOTION 6.13
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What are some examples of checkpoint inhibitors?
• Ipilimumab
• Tremelimumab
• Nivolumab
• Pembrolizumab
• Cemiplimab
• Durvalumab
• Atezolizumab
• Avelumab
NOTION 6.14
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Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer
NOTION 6.15
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What does CAR-T cell therapy involve?
CAR-T cell therapy involves collecting a patient's T cells, genetically modifying them in a lab to express a chimeric antigen receptor (CAR) that targets cancer cells, and then reinfusing the modified cells back into the patient.
NOTION 6.16
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What are 4 mechanisms by which extracellular bacteria evade the immune system?
Give examples of bacteria which use each mechanism
1. Resistance to phagocytosis e.g Pneumococcus, Neisseria meningitidis
2. Scavenging of reactive oxygen species e.g Catalase-positive bacteria
3. Inhibition of complement activation e.g Many bacteria
4. Evading antibodies e.g Neisseria gonorrhoeae, Escherichia coli, Salmonella Typhimurium
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What are 4 mechanisms which can allow extracellular bacteria to become resistant to phagocytosis?
- Entry of microbe into non-phagocytic cell: from camping to glamping
- Capsule: poor adherence plus the benefit of hiding PAMPS!
- Toxin: when being a friend is not an option, poison may be a solution
- Inhibitor: don’t even think about it!
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How can catalase-positive bacteria evade the immune system?
• Reactive oxygen species, such as H2O2, are toxic for bacteria and are therefore used by phagocytes as an efficient weapon to kill ingested microbes.
• Some bacteria have an enzyme called catalase which breaks down this H2O2
.
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What are 3 mechanisms by which extracellular bacteria can inhibit the activation of the complement system?
o Microbial proteases: speed up the degradation of complement components
o Distant binding site: keep it as far as possible from membrane
o Capsule:
- Sialic acid residues in capsules: non-stablilizing surface for alternative pathway convertase.
- Inhibition insertion MAC: Gram-positive thick peptidoglycan layers - no membrane, no pores!
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What are 3 mechanisms by which extracellular bacteria can evade antibodies?
o Antigenic variation: changing make up of surface antigens
o Shed antigens in membrane blebs: divert antibodies from themselves
o Proteases: chopping the antibody, end of the problem!
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What is an example of antigenic variation?
eg. Pili (adhesion molecules) - genes of some bacteria undergo extensive gene conversion, so that one organism can produce up to 10^6 antigenically distinct pilin (protein
that makes up pili) molecules.
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What are 3 mechanisms by which intracellular bacteria can evade the immune system?
1. Inhibition of phagolysosome formation e.g Mycobacterium tuberculosis, Legionella pneumophila
2. Inactivation of reactive oxygen (ROS) and nitrogen (RNS) species e.g Mycobacterium leprae, Salmonella enterica
3. Disruption of phagosome membrane, escape into cytoplasm e.g Listeria monocytogenes
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Mechanism by which mycobacteria evade phagolysosome formation
NOTION 7.1
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Inactivation of ROS and RNS intracellularly
NOTION 7.2
214
Mechanism by which listeria monocytogenes disrupts the phagosome membrane
NOTION 7.3
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What are 4 mechanisms by which viruses evade the immune system?
1. Interference with Type I interferons e.g HIV, Herpes simplex virus (HSV), polio
2. Evasion NK cells e.g Human Cytomegalovirus
3. Evasion Antibodies e.g Influenza A, rhinovirus, HIV
4. Evasion CD8+ T cells e.g Epstein-Barr Virus, Herpesvirus, Human Cytomegalovirus, Adenovirus
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How can viruses evade NK cells?
• Activating receptors recognize molecules on the surface of cells and engagement of the receptor generate activating signals that promote NK responses (killing activities).
• Inhibitory receptors recognize molecules in class I MHC molecules found in healthy cells and generate inhibitory signals that inhibit NK responses.
Viruses produce proteins that act as ligands for NK cell inhibitory receptors and thus inhibit NK cell activation or produce homologs of MHC-I which engage with inhibitory receptor and inhibit NK cell activation
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Antigenic variation in influenza virus
• The genome of the influenza virus is composed of eight separate RNA strands, which allows genetic recombination by re-assortment of the segments in various hosts that are simultaneously infected with two different strains.
• Genetic reassortments create new viruses that are antigenically distinct from their precursors and thus are able to evade immune detection in large numbers of newly infected hosts.
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How can viruses evade CD8+ T cells?
1. Inhibition of antigen processing
2. T cell exhaustion
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How can viruses inhibit antigen processing?
• Viruses make a variety of proteins that block different steps in antigen processing, transport, and presentation.
• Inhibition of antigen presentation blocks the assembly and expression of stable class I MHC molecules and the display of viral peptides.
• As a result, cells infected by such viruses cannot be recognized or killed by CD8+CTLs.
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How can viruses lead to T cell exhaustion?
In some chronic viral infections and cancers, CTL effector responses are generated, but they are then gradually extinguished, a phenomenon that is called exhaustion.
- Effector response starts but it is shut down.
- Repeated stimulation leads to functional defects in T cells (eg less proliferation and poor cytotoxic activity)
- Increased expression of inhibitory receptors: eg PD-1 and CTLA-4
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What do parasites include?
Parasites include single-celled protozoa and complex multicellular worms (helminths), therefore the immune responses to these will be different and varied.
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What is the main innate and adaptive immune responses to parasites?
The main innate immune response to protozoa is phagocytosis while it is eosinophils the main cell involved in the innate response to helminths. Adaptive immune responses are mediated by Th1 or Th2 cells and antibodies.
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Examples of parasites, with their diseases, and mechanisms of protective immunity
NOTION 7.4
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What are 4 mechanisms by which parasites evade the immune system?
1. Antigenic variation e.g Trypanosomes, Plasmodium
2. Acquired resistance to complement, cytotoxic T lymphocytes e.g Schistosomes
3. Inhibition of host immune responses e.g Filaria, Trypanosomes
4. Antigen shedding e.g Entamoeba
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How do Trypanosomes evade the immune system?
• Trypanosome continuously change major surface antigens while infecting a host and so they avoid being recognised by the immune system.
• This is due to changes in expression of the genes encoding the major surface antigen.
• Infected patients show waves of parasitaemia in the blood. Each of these is due to parasites expressing a different surface antigen, so new parasites for the immune system.
• By the time antibodies are produced against the parasite, a different organism is causing the infection.
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What are the main innate immune responses to fungi?
The main innate immune response to fungi are phagocytes
and the complement system.
• Phagocytes detect fungi via PRRs and produce cytokines that stimulate innate effector cells resident in tissues.
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What are the main adaptive immune responses to fungi?
Adaptive immunity to fungi is mediated by Th17 (extracellular fungal infections) and Th1 (intracellular fungal infections)
• Th17 recruit neutrophils that will phagocytose and destroy the fungi
• Th1 produce IFNγ which activates macrophages to efficiently kill intracellular fungi.
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What are 4 mechanisms by which fungi evade the immune system?
1- Avoidance of recognition e.g Aspergillus fumigatus, Cryptococcus neoformans, Candida albicans
2- Morphology variation e.g Candida albicans, Cryptococcus neoformans
3- Manipulation of phagocytes e.g Candida albicans, Candida, glabrata, Cryptococcus neoformans
4- Escape from immune cells e.g Aspergillus fumigatus, Candida albicans
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What are 2 mechanisms by which fungi can avoid recognition?
Avoiding opsonization:
- Binding of host molecules that inactivate complement
- Proteases that degrade host proteins
Avoiding recognition of PAMPS:
- PAMP masking or shielding using nonimmunogenic molecules
- PAMP variation
- Shaving immunogenic PAMPs
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What is the effect of morphology variation in fungi?
- Formation of hypha or titan cells impairs phagocytosis
- Capsule: cover immunogenic molecules
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What are 3 ways by which fungi can manipulate phagocytes?
3.1- Inhibition phagosome maturation
- Inhibition phagosomal acidification and fusion with
lysosomes
3.2- Metabolic remodelling
- Alternative carbon source metabolism
- Upregulate expression of ROS-detoxifying enzymes
3.3- Alteration of cytokine release
- Repression of pro-inflammatory cytokines
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What are 6 ways by which fungi can escape immune cells?
4.1. Massive proliferation
- Causes physical stress that leads to phagosome rupture and cell lysis
4.2. Filamentation
- Hyphal growth ends up with lysis of host cell
4.3. Secretion of toxins
- Cytolytic toxins (eg candidalysin) cause cell death
4.4. Glucose depletion of macrophages
4.5. Induction of pyroptosis, apoptosis and necrosis
4.6. Non-lytic escape
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Why does cancer occur?
Cancer happens when control systems in the cell become
corrupted. These control systems are:
- Systems that promote cell growth.
- Safeguard systems that protect against “irresponsible” cell growth
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Mutations & Cancer
Mutations make these system to malfunction and cells start proliferating out of control - This cell has now made the first step to become a cancer cell.
These mutations result in neoantigens or tumour antigens (antigens that are not present in normal tissue).
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What are neoantigens?
Neoantigens expressed in cancer cells stimulate adaptive immune responses that can potentially prevent or limit the growth of the tumour – Immune surveillance.
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What cells are mainly involved in protection against cancer?
Cells mainly involved in protecting against cancer are T cells both Cytotoxic T cells (CD8 T cells; CTLs) and Helper T cells (CD4 T cells).
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How do tumour cells become susceptible to NK cells?
When tumour cells downregulate the expression of MHC I molecules they become susceptible to be killed by Natural Killer cells.
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What are 3 mechanisms by which cancer evades the immune system?
1. Immuno-editing
2. Immunosuppression
3. T cell exhaustion
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What 3 steps makes up immunoediting?
Immunoediting is a process that comprises 3 steps: Elimination, Equilibrium and Escape.
240
Describe the 3 steps involved in immunoediting
• Cancer cells acquire mutations generating tumour antigens that differentiate them from normal cells.
• Those changes allow immune cells to recognise them as non-healthy cells – this eliminates transformed cells before they become a tumour.
• However, if the rate of elimination of these cells is the same as the rate of transformant cells growth they reach equilibrium.
• If the balance pushes towards proliferation, transformed cells escape immune surveillance.
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Immune responses lead to selective pressure, what is the effect of this?
Immune responses lead to selective pressure that results in tumour cells with low immunogenicity:
- Rise in tumour subclones that do not carry the mutations that encode immunogenic neoantigens (have lost strong tumour antigens).
- Tumour cells downregulate MHC-I expression
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What are 2 ways by which cancers cells suppress the immune response?
1. Production of immunosuppressive products (eg TGF-β) or expression of inhibitory cell surface proteins (immune checkpoint; eg PD1 ligand PD-L1; CTLA-4 ligand B7)
2- Creation of an immunosuppressive microenvironment
Cancer cells promote:
- Depletion of tryptophan (IDO) – CTL anergy
- Differentiation to regulatory CD4 T cells
- Accumulation of myeloid derived suppressor cells
