1. The immune response to infections / primary immune deficiencies - part 1 Flashcards
1
Q
What is the route of entry, mode of transmission and pathogen for Athlete’s foot?
A
External eptihelia: external surface, physical contact, Trichophyton
2
Q
What is the route of entry, mode of transmission and pathogen for cutaneous anthrax?
A
External epithelia: wounds and abrasions, minor skin abrasions, Bacillus anthracis
3
Q
What is the route of entry, mode of transmission and pathogen for tetanus?
A
External epithelia: wounds and abrasions, puncture wounds, Clostridium tetani
4
Q
What is the route of entry, mode of transmission and pathogen for tularemia?
A
External epithelia: wounds and abrasions, handling infected animals, Francisella tularensis
5
Q
What is the route of entry, mode of transmission and pathogen for yellow fever?
A
External epithelia: insect bites, mostquito bites (Aedes aegypti), Flavivirus
6
Q
What is the route of entry, mode of transmission and pathogen for Lyme disease?
A
External epithelia: insect bites, deer tick bites, Borrelia burgdorferi
7
Q
What is the route of entry, mode of transmission and pathogen for Malaria?
A
External epithelia: insect bites, mosquito bites (Anopheles), Plasmodium spp.
8
Q
What is the route of entry, mode of transmission and pathogen for Influenza?
A
Mucosal surfaces: airway, inhaled droplet, Influenza virus
9
Q
What is the route of entry, mode of transmission and pathogen for meningococcal meningitis?
A
Mucosal surfaces: airway, spores, neisseria meningitides
10
Q
What is the route of entry, mode of transmission and pathogen for inhalation anthrax?
A
Mucosal surfaces: airway, spores, Bacillus anthracis
11
Q
What is the route of entry, mode of transmission and pathogen for typhoid fever?
A
Mucosal surfaces: gastrointestinal tract, contaminated water or food, Salmonella typhi
12
Q
What is the route of entry, mode of transmission and pathogen for diarrhoea?
A
Mucosal surfaces: gastrointestinal tract, contaminated water or food, rotavirus
13
Q
What is the route of entry, mode of transmission and pathogen for syphilis?
A
Mucosal surfaces: reproductive tract, physical contact, Treponema pallidum
14
Q
What is the route of entry, mode of transmission and pathogen for AIDS?
A
Mucosal surfaces: reproductive tract, physical contact, HIV
15
Q
What are the specific, constitutive barriers to infection of the skin?
A
- Consists of tightly packed keratinised cells. This physically limits colonisation by microorganisms.
- There are physiological factors such as a low pH and low oxygen tension
- Sebaceous glands produce hydrophobic oils that repel water and microorganisms. They produce lysozyme which destroys the structural integrity of bacterial cell walls. They produce ammonia and defensins that have anti-bacterial properties.
16
Q
What are the specific, constitutive barriers to infection of mucosal surfaces?
A
- Physical barrier
- Contains secretory IgA which binds to pathogens and prevents bacteria and viruses from attaching to and penetrating epithelial cells.
- Lysozyme and antimicrobial peptides directly kill invading pathogens.
- Lactoferrin starves invading bacteria of iron
- Cilia trap pathogens and contribute to removal of mucous, which is assisted by physical manoeuvres such as sneezing and coughing
17
Q
What are the specific, constitutive barriers do commensal bacteria have to infection?
A
- 100 trillion bacteria normally reside at the surfaces
- Compete with pathogenic bacteria for scarce resources
- they produce fatty acids and bactericidins that inhibit the growth of many pathogens
18
Q
What cells make up the innate immune system?
A
Polymorphonuclear cells (neutrophils, eosinophils, basophils), monocytes and macrophages, NK cells and dendritic cells
19
Q
What soluble components make up the innate immune system?
A
Complement, acute phase proteins, cytokines and chemokines
20
Q
What are key features of cells of the innate immune system?
A
- Essentially identical responses in ALL individuals.
- Cells express receptors that allow them to detect and home to sites of infection.
- Cells express genetically encoded receptors (PRRs) that allow them to detect pathogens at the site of infection.
- Cell has phagocytic capacity that allows them to engulf pathogens.
- Cells secrete cytokines and chemokines that regulate the immune response.
21
Q
How are polymorphonuclear cells involved in the innate immune system?
A
- They are produced in bone marrow.
- They migrate rapidly to site of injury.
- Express receptors for cytokines/chemokines - to detect inflammation.
- Express pattern recognition receptors - to detect pathogens
- Express Fc receptors for Ig - to detect immune complexes
- Capable of phagocytosis / oxidative & non-oxidative killing - particularly neutrophils
- Release enzymes, histamine, lipid mediators of inflammation fromm granules.
- secrete cytokines and chemokines to regulate inflammation.
22
Q
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the liver?
A
Kupffer cell
23
Q
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the kidney?
A
Mesangial cell
24
Q
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the bone?
A
Osteoclast
25
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the spleen?
Sinusoidal lining cell
26
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the lung?
Alveolar macrophage
27
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the neural tissue?
Microglia
28
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the connective tissue?
Histiocyte
29
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the skin?
Langerhans cells
30
What is the name of the specialised cell that derived from the monocytes/macrophages lineage that is found in the joints?
Macrophage like synoviocytes
31
Briefly, how do monocytes become macrophages?
Monocytes are produced in the bone marrow, circulate in the blood and migrate to tissues where they differentiate into macrophages
32
What do macrophages do as part of the innate immune system?
1. Present within tissue
2. Express receptors for cytokines and chemokines - to detect inflammation
3. Express patter recognition receptors - to detect pathogens.
4. Express Fc receptors for Ig - to detect immune complexes.
5. Capable of phagocytosis / oxidative and non-oxidative killing
6. Secrete cytokines and chemokines to regulate inflammation
7. Capable of presenting processed antigen to T cells
33
How are macrophages different to polymorphonuclear cells?
Can process antigens and present it to T cells
34
How does phagocyte recruitment work?
1. Cellular damage and bacterial products trigger the local production of inflammatory mediators (cytokines and chemokines)
2. Cytokines will activate the vascular endothelium enhancing permeability
3. Chemokines attract phagocytes (NOTE: macrophages are already present at peripheral sites)
35
How are microoganisms recognised?
1. Pattern recognition receptors (PRRs)
| 2. Fc receptors on microorganism
36
How do PRRs allow recognition of microorganisms?
Pattern recognition receptors (PRRs) like Toll-like receptors and mannose receptors recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA and RNA
37
How do Fc receptors allow recognition of microorganisms?
Fc receptors on these cells allows them to bind to the Fc portion of immunoglobulins thereby allowing the phagocytes to recognise immune complexes
38
How is endocytosis facilitated by opsonisation?
Opsonins act as a bridge between the pathogen and the phagocyte receptors. Covering the pathogen with attractive substances to make them appear more attractive to macrophages e.g.:
• Antibodies binding to Fc receptors
• Complement components binding to complement receptors (CR1)
• Acute phase proteins e.g. c-reactive protein (CRP)
39
How is a phagolysosome produced and how does this kill the pathogen?
1. The pathogen is taken up into a phagosome.
2. The phagosome will fuse with a lysosome to form a phagolysosome
3. This is protected compartment in which killing of the organism occurs
4. The killing of the pathogen can occur by oxidative mechanisms or non-oxidative mechanisms
40
How does oxidative killing occur in a phagolysosome?
1. NADPH oxidase converts oxygen into reactive oxygen species (superoxide and hydrogen peroxide)
2. Myeloperoxidase catalyses the production of hydrochlorous acid from hydrogen peroxide and chloride
3. Hydrochlorous acid is a highly effective oxidant and anti-microbial
41
How does non-oxidative killing occur in a phagolysosome?
1. Killing by the release of bacteriocidal enzymes such as lactoferrin and lysozyme into the phagolysosome
2. Enzymes are present in granules
3. Each has a unique antimicrobial spectrum
4. This results in a broad range of cover against bacteria and fungi
42
How does the death of a phagocyte occur?
1. The process of phagocytosis depletes glycogen reserves within the neutrophil, which is then followed by neutrophil death.
2. As the cells die, residual enzymes are released which causes liquefaction of the adjacent tissue
3. Accumulation of dead and dying neutrophils within the infected tissue results in the formation of pus
4. An accumulation of pus forms an abscess
43
What does oxidative killing describe?
Describes killing mediated by reactive oxygen species generated by action of the NADPH oxidase complex.
44
What is pathogen recognition mediated by and what does it recognise?
Mediated by Toll-like receptors which recognise pathogen associated molecular patterns
45
What is opsonisation mediated by and what does it facilitate?
May be mediated by antibodies, complement components or acute phase proteins and facilitaties phagocytosis
46
What is non-oxidative killing mediated by?
Bacteriocidal enzymes such as lysozyme
47
What type of cells are natural killer cells and where are they present?
They are a type of lymphocyte. They are present within the blood and may migrate to inflamed tissue
48
What do NK cells do?
1. Express inhibitory receptors for self HLA which prevents inappropriate activation by normal self cells
2. Express a range of activatory receptors including natural cytotoxicity receptors that recognise heparan sulphate proteoglycans
3. Integrate signals from inhibitory and activatory receptors (usually the inhibitory signals will dominate)
4. They are cytotoxic - kill 'altered self' cells (i.e. malignancy or virus-infected cells)
5. Secrete cytokines to regulate inflammation and promote dendritic cell function
49
Where are dendritic cells found?
Reside in peripheral tissues
50
What do dendritic cells do?
1. Express receptors for cytokines and chemokines (to detect inflammation)
2. Express pathogen recognition receptors (to detect pathogens)
3. Express Fc receptors for immunoglobulin (to detect immune complexes)
4. Capable of phagocytosis
5. Following phagocytosis, dendritic cells will:
upregulate expression of HLA molecules; express co-stimulatory molecules and; migrate via lymphatics to lymph nodes (mediated by CCR7)
6. Present processed antigen to T cells in lymph nodes to prime the adaptive immune system
7. Express cytokines to regulate the immune response
51
Summarise neutrophils:
polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms.
52
Summarise NK cells:
Lymphocytes that express inhibitory receptors capable of recognising HLA class I molecules and have cytotoxic capacity
53
Summarise dendritic cells:
Immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells
54
Summarise macrophages:
Derived from monocytes and resident in peripheral tissues
55
What components make up the adaptive immune system?
1. Humoral Immunity (B lymphocytes and antibody)
2. Cellular Immunity
(T lymphocytes (CD4+ and CD8+))
3. Soluble Components (cytokines and chemokines)
56
What are primary lymphoid organs?
These organs involved in lymphocyte (B cell and T cell) development, which are the bone marrow and thymus.
57
How is bone marrow a primary lymphoid organ?
Both T and B lymphocytes are derived from haematopoietic stem cells in the bone marrow. It is the site of B cell maturation.
58
How is the thymus a primary lymphoid organ?
Site of T cell maturation, and deletion of T cells with inappropriately high or low affinity for HLA molecules and of maturation of T cells into CD4+ or CD8+ cells. Most active in the foetal and neonatal period, involutes after puberty.
59
What is the definition of secondary lymphoid organ?
Anatomical sites of interaction between naïve lymphocytes and microorganisms
60
What are examples of secondary lymphoid organs
Spleen, lymph nodes, MALT
61
Summarise the role of the thoracic duct
Carries lymphocytes from lymph nodes back to the blood circulation.
62
What is the germinal centre?
An area within secondary lymphoid tissue where B cells proliferate and undergo affinity maturation and isotope switching
63
What are key features of cells of the adaptive immune responses?
1. Wide repetoire of antigen receptors
2. Exquisite specificity
3. Clonal expansion
4. Immunological memory
64
How is there a wide repertoire of antigen receptors?
1. Receptor repertoire is not entirely genetically encoded. Genes for segments of receptors are rearranged and nucleic acids are deleted/added at the sites of rearrangement almost randomly. This means there's a potential to create in order of 10^11 to 10^12 receptors.
65
How may the wide repertoire of antigen receptors be a problem?
Autoreactive cells are likely to be generated. Mechanisms must exist to delete or tolerise these autoreactive cells.
66
Why is exquisite specificity a key feature of adaptive immune response?
Able to discriminate between very small difference in molecular structure
67
Why is clonal expansion a key feature of adaptive immune response?
Cells with appropriate specificity will proliferate during infection
68
Why is immunological memory a key feature of adaptive immune response?
Following infection, residual pool of specific cells with enhanced capacity to respond if re-infection occurs
69
Why is the receptor repertoire not genetically encoded?
Because VDJ recombination means that a vast array of specificities can be generated.
70
What is VDJ recombination?
The process by which T cells and B cells randomly assemble different gene segments – known as variable (V), diversity (D) and joining (J) genes – in order to generate unique receptors (known as antigen receptors) that can collectively recognize many different types of molecule.
71
Briefly, how does T lymphocyte maturation occur?
1. Arise from haematopoietic stem cells. 2. Exported as immature cells to the thymus where undergo selection. 3. Mature T lymphocytes enter the circulation and reside in secondary lymphoid organs.
(They undergo positive and negative selection before being exported to the periphery)
72
What do CD4+ and CD8+ recognise?
Peptides pressented by HLA Class II and Class I respectively
73
What happens to T cells with low, intermediate and high affinity for HLA?
Cells with intermediate affinity will undergo positive selection, this is ~10% of original cells. They will go on to differentiate into either CD4 or CD8 lymphocytes based on which class of HLA they have intermediate affinity to (class I or class II). Whereas cells that have too low affinity or too high affinity, will be removed.
74
CD4+ T cells (Helper T cells) recognise peptides derived ...?... These peptides are usually presented on HLA Class II molecules.
Extracellular proteins
75
What are the peptides presented on HLA Class II molecules which CD4+ T cells recognise?
HLA-DR, HLA-DP, HLA-DQ
76
What are the important immunoregulatory functions via cell: cell interations and the expression of cytokines of CD4+ T cells?
They provide help for the development of a full B cell response and they provide help for the development of some CD8+ T cell responses.
77
What are the effector subsets of CD4?
Th1, Th17, Treg, TFh, Th2
78
What are the polarising factors of Th1?
IL-12, IFN gamma
79
What is the effector profile of Th1 and what does it do?
IL-2, IFN gamma, TNF alpha, IL-10. Help CD8 T cells and macrophages.
80
What are the polarising factors of Th17?
IL-6, TGF beta
81
What is the effector profile of Th17 and what does it do?
IL-17, 1L-21, IL-22. Helps neutrophil recruitment and enhances generation autoantibodies
82
What are the polarising factors of Treg?
TGF beta
83
What is the effector profile of Treg and what does it do?
IL-10, Foxp3, CD25. IL-10/TGF beta expressing CD25+ Foxp3+
84
What are the polarising factors of Tfh?
IL-6, IL-1 beta, TNF alpha
85
What is the effector profile for Tfh and what does it do?
IL-2, IL-10, 1L-21. Follicular helper T cells.
86
What are the polarising factors of Th2?
IL-4, IL-6
87
What is the effector profile for Th2 and what does it do?
IL-4, IL-5, IL-13, IL-10. Helper T cells.
88
CD8+ Cytotoxic T Cells are specialised cytotoxic cells that recognise peptides derived from ...?... presented on HLA Class I
intracellular proteins
89
What are the peptides presented on HLA Class I which are recognised by CD8 cytotoxic T cells?
HLA-A, HLA-B, HLA-C
90
How do cytotoxic T cells kill cells directly?
Perforin (pore-forming) and granzymes; and expression of Fas ligand
91
What do CD8+ cytotoxic T cells do?
Kill cells directly, secrete cytokines, and are particularly important in defence against viral infections and tumours.
92
How does T cell memory occur?
1. Responsive to successive exposures of antigen is qualitatively and quantitatively different from that of first exposure.
2. There is a pool of memory T cells that are ready to respond to antigen.
3. These cells are more easily activated than naive cells.
93
Summarise Th1 cells
A subset of cells that express CD4 and secrete IFN gamma and IL-2
94
Summarise CD8 T cells
Express receptors that recognise peptides usually derived from intracellular peptides usually derived from intracellular proteins and expressed on HLA class I molecules
95
Summarise T follicular helper (Tfh) cells
Play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells.
96
Summarise T regulatory cells
Subset of lymphocytes that express Foxp3 and CD25.
97
How does B cell maturation occur?
They initially exist in the periphery as IgM B cells, but then they can undergo a germinal centre reaction to differentiate into plasma cells expressing IgG, IgE and IgA
98
What is central tolerance?
o If the receptors on the B cells recognise self in bone marrow, then they will be deleted. If not, they survive.
99
What happens in an antigen encounter by B cells?
An early IgM response and a germinal centre reaction.
100
What is an early IgM response, which occurs when antigens are encountered by B cells?
If the B cell in the periphery engages an antigen you can get an early IgM response where the cell differentiates into an IgM secreting plasma cell.
101
What is a germinal centre reaction, which occurs when antigens are encountered by B cells?
1. This is dependent on T helper cells. Firstly, dendritic cells will prime the CD4+ T helper cells
2. The CD4+ cells then provide help for B cell differentiation
3. This interaction is mediated by CD40L: CD40
4. With the help of CD4+ cells, the B cells will proliferate
5. They then undergo somatic hypermutation and isotype switching (from IgM to IgG/A/E)
6. They will then become plasma cells which produce antibodies
102
Immunoglobulins are soluble proteins made up of ...?
Two heavy chains and two light chains
103
What determines the antibody class of an immunoglobulin?
Heavy chain
104
What part of the immunoglobulin recognises the antigen?
Antigen binding region (Fab) which is made up of both heavy and light chains
105
What part of the immunoglobulin determines the effector function?
The constant region (Fc) of the heavy chain
106
What is the function of antibodies?
1. Identification of pathogens and toxins (Fab-mediated), 2. Interact with other components of immune responses to remove pathogens (Fc-mediated), 3. Particularly important in defence against BACTERIA of all kinds
107
How does B cell memory develop?
1. Response to successive exposures to an antigen is qualitatively and quantitatively different from that of first exposure
2. Lag time between antigen exposure and antibody production is decreased (to 2-3 days)
3. Titres of antibody produced is increased
4. Response is dominated by IgG antibodies of high affinity. As opposed to primary response in which you will get an early IgM response
5. The response may be independent of help from CD4+ cells
108
Summarise pre-B cells
Exists within the bone marrow and develop from haematopoietic stem cells
109
What is IgA?
Divalent antibody present within mucous which helps provide a constitutive barrier to infection
110
What are IgG secreting plasma cells?
Cell dependent on the presence of CD4 T cell help for generation
111
What are IgM secreting plasma cells?
They are generated rapidly following antigen recognition and are not dependent on CD4 T cell help.
112
What is complement, where is it produced and where is it found?
Complement includes 20+ tightly regulated, linked proteins. Produced by the liver. Present in the circulation as inactive molecules.
113
What happens when the complement system is triggered?
They will enzymatically activate other proteins in a biological cascade. This results in a rapid, highly amplified response.
114
What are the three pathways of complement activation?
Classical, mannose-binding lectin, alternative. They all join the final common pathway.
115
How is the classical pathway activated?
Activated by immune complexes. Involves C1, C2, C4.
1. The formation of antibody-antigen immune complexes results in a conformational change in antibody shape which exposes the binding site for C1
2. Binding of C1 to the antibody results in activation of the cascade
3. As it involves antibodies, it does depend on the activation of the adaptive immune response (i.e. it will NOT occur very early in the immune response).
116
How is the mannose binding lectin pathway activated?
1. Activated by the direct binding of MBL to microbial cell surface carbohydrates
2. This directly stimulates the classical pathway involving C4 and C2 (but NOT C1)
3. This is NOT dependent on the adaptive immune response
117
How is the alternative pathway activated?
1. This is directly triggered by binding of C3 to bacterial cell wall components (E.g. lipopolysaccharide of Gram-negative bacteria, teichoic acid of Gram-positive bacteria)
2. This is NOT dependent on the acquired immune response. Involves factors: B, I, P.
118
How is the final common pathway activated?
1. Activation of C3 convertase is the major amplification step.
2. This triggers the formation of the membrane attack complex via C5-9
3. The membrane attack complex makes holes in membranes
4. Complement fragments that are released during complement activation play other roles in the immune response
119
Complement fragments that are released during complement activation play other roles in the immune response. What are the other roles?
1. Increase vascular permeability and cell trafficking to sites of inflammation
2. Opsonisation of immune complexes keeps them soluble
3. Opsonisation of pathogens to promote phagocytosis
4. Activation of phagocytes
5. Promotes mast cells/basophil degranulation
6. Punches holes in bacterial membranes
120
Summarise C3
Cleavage of this protein may be triggered via the classical, MBL or alternative pathways
121
Summarise C1
Binding of immune complexes to this protein triggers the classical pathway of complement activation
122
Summarise C9
Part of the final common pathway resulting in the generation of the membrane complex attack
123
Summarise MBL
Binds to microbial surface carbohydrates to activate the complement cascade in an immune complex independent manner.
124
Describe cytokines:
Small protein messengers, immunomodulatory function, autocrine and paracrine dependent action.
125
Describe chemokines:
Subset of cytokines. Their role is: direct recruitment/homing of leukocytes in an inflammatory response.
- CCL19 and CCL21 are ligands for CCR7 and important in directing dendritic cell trafficking to lymph nodes.
- Other examples: IL8, RANTES, MIP-1 alpha and beta
