:) Immunology Flashcards
1
Q
Innate immune system
A
Innate immune system: A common set of responses turned on by most microbial agents. non-specific, fixed – “innate.”
2
Q
Adaptive immune system
A
Adaptive immune system: Individual response to specific antigen exposure. Capable of change during response – “adaptation”
3
Q
4 Components of the Innate Immune system
A
- Physical barriers – epithelial surfaces
- Cellular components – phagocytes & NK cells
- Complement system & mediators of inflammation
- Cytokines
4
Q
4 Physical barriers & examples
A
- Epithelial surfaces – skin, GI tract, respiratory tract, urinary tract
- Secrete anti-microbial substances – defensins (broad spectrum antibiotic)
- Secretion increased by cytokines (IL-1 and TNFa)
- Epithelia also contain lymphocytes & mast cells
E.g. Peritoneal lymphocytes secrete antibodies against LPS
5
Q
Innate immune system - 4 components
A
- Physical barriers – epithelial surfaces
- Cellular components – phagocytes & NK cells
- Complement system & mediators of inflammation
- Cytokines
6
Q
Physical barriers - list 4
A
- Epithelial surfaces – skin, GI tract, respiratory tract, urinary tract
- Secrete anti-microbial substances – defensins
- Secretion increased by cytokines (IL-1 & TNFa)
- Epithelia also contain lymphocytes & mast cells
E.g. Peritoneal lymphocytes secrete antibodies against LPS
7
Q
Base Neutrophils, Macrophages, Dendritic cells & NK cells purpose
A
- Neutrophils last 6 hours, produced by bone marrow. If bone marrow damaged, patients may have low level of neutrophils.
- Neutrophils & Macrophages both perform Phagocytosis.
- Dendritic cells bridge innate & adaptive system
- NK cells lyse virally infected cells, & allow the fragments to be phagocytosed
8
Q
Immune system recognition - 6
A
- Immune system recognises microbes using pattern recognition receptors
- Mannose is not on human cells, but is present on bacteria, mannose receptors identify the foreign.
- Opsonin coats bacteria/virus, enhances ability of macrophages to consume
- toll-like receptors recognise sequences on surface of pathogens e.g. LPS
- 7TM a helical receptors recognise peptide sequences of microbes
- Each recognise difference between foreign & self
9
Q
Results of binding to receptors on innate cells - 3
A
Pathogen binding to receptors on innate cells results in
1. phagocytosis of pathogen by macrophages or neutrophils
2. killing of infected cell by NK cells
3. presentation to T cells by APCs (dendritic cells)
10
Q
Toll-like receptors (TLR) - 4
A
- Bind to microbial markers e.g. LPS
- Activation results in Cytokine secretion e.g. (TNF, IL-1)
- TLR agonists could stimulate the IS to fight infection/ cancer
- TLR antagonists could dampen IS for the treatment of chronic inflammation.
11
Q
LPS (Lipopolysaccharide)/Endotoxin - 5
A
- Product of G-ve bacteria cell wall
- Stimulates innate immune system (TLR4)
- Pathogenic- induces local & systemic inflammation
- Potent activator of macrophages inducing cytokine release & Reactive Oxygen (superoxides) bursts, meaning the body will respond better to G-ve bacteria.
- If overwhelmed may cause Systemic Inflammatory Response Syndrome (SIRS) – fever, neutrophilia, septic shock
12
Q
Phagocytosis depth - 4
A
- Mediated by neutrophils & macrophages
- Microbe binds to cell surface receptors & is endocytosed
- Phagosome fuses with lysosomes containing degrading enzymes – e.g. lysozyme
- Relies on Reactive oxygen species – superoxide, hydrogen peroxide. Important they are contained as may result in tissue damage, only replaced by inefficient scar tissue.
13
Q
Phagocytosis basic steps - 5
A
- Bacterium attaches to membrane evaginations called pseudopodia
- Bacterium is ingested forming phagosome
- Phagosome fuses with lysosome
- Lysosomal enzymes digest captured material
- Digestion products are released from cell
14
Q
NK (Natural Killer cells) -5
A
- Recognise microbial markers on surface of infected cells
- Perforins make holes in membrane allowing entry of granzyme
- Infected cell dies by apoptosis
- NK cells activated by IL-12 from mac, secretes IFNg which activates macrophages & cleans up fragments.
- Action inhibited by MHC class I binding inhibitory on NK cell, prevents self consuming. When virally infected MHC class I downregulated so NK cells detect cell marked for destruction.
15
Q
Complement system - 5
A
- Cascade of plasma proteins activated by microbes resulting in their destruction
- Zymogens circulate in plasma & gain enzymatic activity when cleaved.
- 3 pathways of activation. (mannose receptors, antibodies binding to microbes, some bind to microbes)
- All result in cleavage of C3 to C3a & C3b leading to opsonisation & phagocytosis.
- Then cleaves into C5a (Draws neutrophils from the blood into the tissue)
16
Q
Complement system depth - 6
A
- C3a involved in inflammation, attracts WBCs to infection
- C3b attracts white blood cells, acting as opsonin & coating pathogen
- Leads to C5 cleaved into C5a & C5b
- C5a draws neutrophils into infected area
- C5b can form pore in membrane of microbe, destroying membrane integrity, lysing the microbe or enhancing phagocytosis
- Too much activation leads to too much inflammation
17
Q
Cytokines: TNF/ IL-1 - 3
A
TNF/ IL-1
1. Majority produced by LPS challenged macrophages
2. Pro-inflammatory cytokines
3. Stimulate neutrophil migration to site of infection
18
Q
Cytokines: IL-12 - 4
A
IL-12
1. Produced by macrophage & dendritic cells
2. Promotes NK cytolysis
3. Stimulates IFNy production in T & NK cells
4. IFNy stimulates macrophages to kill microbe
19
Q
Cytokine targeted therapies - 3
A
Dysregulation of cytokine expression can lead to disease
Targeting cytokines & receptors can minimise chronic inflammation.
Main approaches are to:
1. Mop up excess cytokines with abs/ soluble receptors e.g. infliximab
2. Stimulate or block cytokine receptors
3. Try to restore the homeostatic balance of pro vs anti-inflammatory cytokines
20
Q
Limitations of the innate system - 4
A
- Nonspecific (weak recognition of epitopes, bacteria surface sequences)
- Limited recognition of pathogen surface molecules
- No memory
- Localised
21
Q
Adaptive immune system - 4 characteristics
A
Four characteristics
1. Antigen specificity – can determine between pathogens
2. Diversity – lots of receptors
3. Immunological memory – better & faster responses
4. Self/nonself recognition – tolerates self
22
Q
Phagocytosis - 5
A
- Immunoglobulin within plasma membrane, with antigen binding arms facing outward
- Crosslinking of antibodies on surface activates B cell
- B cell binds to pathogen, endocytoses pathogen, breaks into fragments
- Some fragments expressed on B cell surface in conjunction with class II MHC
- This fragment will be presented to a T cell, which sends signals back to fully activate the T cell.
23
Q
B cells action - 8
A
- B cells produced in bone marrow, from haemopoietic stem cells
- Express immunoglobulin on surface
- B cells circulate in lymph nodes around the body
- Lymph nodes sample tissue fluid using antibodies to detect pathogens
- When triggered, results in B cell endocytosing, then present a fragment to T helper cells.
- T cell provides 2ndry signal (Costimulatory), helps stimulate antibody production
- B cells express Cd40, T cells express Cd40 ligand. T cell binds, & produces cytokine (IL-4), which binds IL-4 receptor on B cell.
- Antibody production begins, (antibodies identical to B cell’s original receptor)
24
Q
Class Switching & Somatic hypermutation - 3
A
Class Switching & Somatic hypermutation
1. Originally antibodies of Igm class but will swap to 2ndry class which has improved antibody affinity, producing stronger responses.
2. Couples with Somatic mutation (mutation of antibody binding site), changes how well they bind to antigen. Overall improves response.
3. Some remain after antigen elimination as memory cells.
25
B cell activation - 4
1. B cell receptor recognising through antibody arms & epitope on the pathogen
2. Opsonin sticks to pathogen & helps B cell recognise, because B cells have complement receptors (microbe is covered due to innate system)
3. Causes stronger binding
4. B cells will become tolerant, so T cells send Co stimulatory signal using Ccd40 ligand interaction
26
B cells - 4
1. Pathogen is presenting fragment to T cell, which binds
2. B cell expressing cd40, T cell upregulates cd40 ligand when activated
3. T cell secretes IL-4, which results in binding to IL-4 receptors
4. When B cell gets signal from T cells, it begins to make copies which recognise pathogen’s antigen
27
Downregulation of B cell activation - 3
1. B cells use their surface antibody to engage the microbe
2. The pathogen has soluble antibody bound to it (a copy)
3. The FC region combines to FC receptor on B cell surface, which deactivates the B cell
28
Antibodies base info - 2
1. Great specificity – recognise one epitope of one antigen
2. Typically, microbe activates several B cells which recognise different B cells, each recognising different epitopes using different Immunoglobulin antibodies.
29
Antibodies action - 2
1. Circulating antibodies bind to microbe or toxin & carry it towards phagocyte. (act as opsonin to enhance phagocytosis).
2. Phagocytes has FC receptors which combines with FR region of antibody & is then also phagocytosed.
30
Antibodies activated vs passive - 2
1. Antibodies (activated) e.g. we give pathogen to give immunological memory
2. Antibodies (passive) e.g. inject antibodies which last temporarily
31
Antibody structure - 7
1. FAB (fragment antigen binding) & FC bind to antigen.
2. Low affinity, weakly bind
3. Many binding sites provide high avidity
4. Results in quickly mopping up antigen in area, but weak binding
5. Better response requires stronger binding
6. As B cell is activated, switches from IGM to IGA, G or E.
7. Switch as some more effective based on region or pathogen
32
Antibody typing: IgM purpose
Antibody typing: IgM – good at complement activation
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Antibody typing: IgD purpose
Antibody typing: IgD – B cell receptor
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Antibody typing: IgA purpose
Antibody typing: IgA – found in respiratory tracts
35
Antibody typing: IgE purpose
Antibody typing: IgE – for parasites & allergies
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Antibody typing: IgG purpose
Antibody typing: IgG – gut antibody
37
Somatic hypermutation - 4
Somatic hypermutation
1. Occurs in hypervariable regions of antibodies
2. Binding affinity changes due to mutations
3. Better binding = better B cell activation
4. Weak binding = B cell not activated, the antibody dies
38
Antibody production - 5
1. When maturing B cells undergo genetic recombination to produce antibody of restricted specify
2, Membrane bound IgM from, then IgD
3. Antibody generally binds antigen with weak affinity
4. Activation of B cell leads to Ig class switching (G,A,E) & somatic hypermutation producing better binding
5. Activated B cells become plasma cells, some become memory cells
39
Fc mediated effects - 6
1. Fc region mediates many effector functions of antibodies
2. Variability in Ig class affects function
3. IgG binds FcR on neutrophils & mac to promote phagocytosis
4. IgE binding causes eosinophil activation & mast cell degranulation, histamine release & allergies
5. IgG & IgM can trigger complement activation by binding C1q
6. All require bound ag to initiate cross linking of abs
40
Antibodies as tools - 3
1. Usable in lab to detect proteins (e.g. immunoblotting, blood groups)
2. Detection of antibodies in patients can be diagnostic (e.g. autoimmune disease)
3. Prevention/treatment of disease – vaccines, antibody therapies (e.g. Herceptin)
41
Monoclonal antibodies - 6
1. Inject mouse with human protein we want antibodies to be made against
2. Harvest those B cells & fuse the myeloma cells (live long)
3. Replace antibodies sequence with human, except for fab fragment (bind to antigen)
4. These are Chimeric antibodies (still part mouse)
5. Replace everything except antigen receptor to produce humanised antibodies
6. The more human, the less the immune response
42
Blocking antibodies - 5
1. When an antibody is put in the body, it binds to the receptor & blocks the ligand binding (anti TNF, anti VEGF, Herceptin)
2. Ligand can’t stimulate receptor
3. So antibody is injected, antibody binds to ligand, preventing binding to receptor
4. This will flag & recruit immune cells (antibody dependent cellular cytotoxicity)
5. T cells & NK cell bind to the antibody, destroying it
43
Antibodies as form of immunotherapy - 4
Antibodies as form of immunotherapy:
1. Quick development
2. Expensive
3. Immune system modulation can have dramatic effects e.g. Anaphylactic shock
4. Treatments decrease in effectiveness over time due to common resistance
44
T cells - 5
1. Mature in Thymus, made in the bone marrow.
2. T cells mediate cell immunity, secreting cytokines, express antibodies, & help other cells.
3. Help in phagocytosis, & cytotoxic T cells will kill infected cells.
4. Respond to antigenic fragments presented by MHC molecules
5. Required for B cell activation & antibody production
45
T Cell Repertoire - 5
1. T cells divided into subsets based on different surface expression & different cytokine production.
2. Helper T cells = CD4, Cytotoxic T cells = CD8
3. Proteins CD4 & CD8 can be used as markers, in investigations.
4. Helper T cells recognise antigen on class II presented to them.
5. Cells with Class II MHC macrophages, neutrophils, B cells, & dendritic cells
46
Th1 & TH2 responses - 3
Th1 & TH2 responses
1. Th1 recognises fragment of antigen from phagocytosis & sends out more macrophages. Also stimulate cytotoxic T cells (e.g. IFNy).
2. Th2 – Stimulates B cells (IL-4, IL-5), increasing antibody production.
3. Activation is based upon the pathogen itself.
e.g. inflammation is mainly Th1 response, Th2 arthritis due to antibodies targeting self
47
TCR - 5
1. Whole receptor complex is referred to as CD3.
2. Similar structure & assembly as antibodies
3. Associated with CD3 signalling chains & CD4/8
4. Undergo thymic selection for self-tolerance
5. No somatic hypermutation – ag affinity remains low
48
Major histocompatibility complex - 4
1. MHC (Major histocompatibility complex) class I on every cell type in the body, bar RBCs.
2. MHC Class II used to present antigens to show T cell
3. The 12 genes represent self, unlikely to be shared by another person.
4. Better antigen is presented, better your immune response will be.
49
MHC genes - 3
1. MHC Class I (HLA A,B,C) – recog by CD8+ T cells
2. MHC Class II (HLA,DP,DQ,DR) – recog by CD4+ T cells
3. The mixture of these genes represent self
50
Antigen recognition - 5
1. T cells only recognise small fragment of antigen
2. Requires endocytosis, processing & presentation by APC in conjunction with MHC molecule
3. Peptide fragments bind in groove of MHC
4. TCR binds across both peptide & MHC residues
5. CD4/8 bind MHC to prevent T cells killing APCs
51
Thymic Selection - 5
1. In Thymus developing T cells encounter self antigen presented on self MHC found on thymic epithelial cells
2. If T cell doesn’t recognise & binds MHC – signalled to die by apoptosis – positive selection
3. If T cell binds strongly & is activated – signalled to die by apoptosis – negative selection
4. Surviving T cells kept alive in peripheral lymphoid organs by continual interaction with self peptide/MHC
5. Become activated only when encountering foreign antigen presented on self MHC
52
Co-stimulation - 4
1. T cells don’t activate in response to antigen alone [TcR-peptide/MHC derived signal 1 is not enough]
2. Normal T cell activation requires 2nd signal, generated by co-stimulatory molecules
3. TcR engagement (signal 1), without signal 2 causes T cell to be unresponsive (anergic) & undergo apoptosis
4. Basis of peripheral tolerance (T cells which only recognise foreign peptides & not self)
53
Co-stimulation Depth -4
1. CD28 expressed on resting T cells, B7-2 expressed on resting APCs
2. Antigenic engagement of TCR results in activation of CD28 by binding B7-2 (positive signal)
3. T cell upregulates of CTLA-4 & B cell upregulates B7-1
4. CTLA-4 & B7 interaction switches off T cell because it has higher affinity to bind
54
Co-stimulation manipulation - 2
Manipulation
1. Blocking CTLA-4 keeps T cells active for longer to fight infections
2. Blocking B7 will down regulate T cells to combat allergic rxn
55
Short range effects of TH1 cells - 6
TH1 cells:
1. Migrate to infection site
2. Release IFNy to activate macrophages
3. Stimulate production of monocytes in BMw
4. Increase expression of adhesion molecules on endothelium
5. Induce leucocyte migration via chemokine release
6. Components of acute inflammation
56
Short range effects of TH2 cells - 1
TH2: provides signal 2 to B cells
57
Kill cells infects by virus:
A Perforin-dependent killing - 3
Kill cells infects by virus:
A Perforin-dependent killing
1. Cytotoxic T cell recognises virus fragment presented by MHC
2.Supported by Interferon gamma, secreting perforating molecules
3. Membrane damaged, digestive enzymes injected, trigger apoptosis
58
Kill cells infects by virus: B Fas-dependent killing - 3
B Fas-dependent killing
1. Cytotoxic T cells expresses Fas ligand
2. Host expresses receptor
3. Engagement results in apoptosis
59
T Cell summary - 6
1. T cells develop in Thymus, & undergo selection
2. Mature in 2ndry lymphoid tissues on antigen encounter
3. Cytokines from class II +APCs induce TH cells to differentiate
4. TH1 cells migrate to tissues & activate macrophages
5. TH2 activate B cells to produce antibodies
6. Cytotoxic T cells kill infected cells expressing class I MHC
60
Hypersensitivity rxns - 4 types
I - Immediate hypersensitivity (allergies)
II – autoantibodies production, generally localized to a specific tissue
III – more system wide, deposition of immune complexes
IV - (T) cell mediated tissue injury
61
Type I - Immediate Hypersensitivity - 5
1. Inactive FCR bound IgE bind to mast cells through FC receptors, when allergen is crosslinked
2. Mast cell degranulated & histamine is released, causing redness, vasodilation, & local inflammation.
3. Immune system retains allergen memory, making subsequent responses stronger.
4. Treatment is antihistamines, can make you drowsy.
5. Allergy, rapid after exposure to antigen
62
Allergens - 5
1. No Th1 or macrophage activation due to not being pathogens,& having no epitopes, immediately moving to adaptive response.
2. B cells activates TH2 cells, stimulating IGE class switching
3. Require repeated exposure before immune response
4. IL-4 promotes TH2 development & antibody class switching to IgE
5. Allergens typically small glycosylated molecules with high solubility in body fluids
63
Type II - autoantibodies
1. Production of self-reactive autoantibodies because peripheral tolerance goes wrong
2. Autoantibodies can activate complement & stimulate phagocytosis (haemolytic anaemia)
3. Autoantibodies Recruit neutrophils causing tissue damage (glomerular nephritis)
4. Autoantibodies bind to receptor & stimulate or inhibit function e.g. Graves disease (antibodies target thyroids stimulating hormone as an agonist, stimulating receptor)
64
Type III - Immune complexes - 9
Lupus:
1. Can occur after multiple injections of ag (immunisation)
2. Usually occurs in small vas, beds, joints & renal glomeruli
3. Leads to complement activation & FcR mediated response
4. Predisposed may develop over time
5. Start making antibodies because the antibodies binding to something throughout the body.
6. Get lots of cross-linking between the antibody & the antigen, different epitopes of the antigen.
7. Causes big immune complexes which are deposited in capillaries
8. Attract neutrophils which cause tissue damage, or blood cell blockage
9. May cause organ failure, likely kidney failure
65
Type IV - Cell mediated tissue injury - 5
1. Delayed type hypersensitivity & cytotoxicity
2. Mediated by TH1 & CD8 cells
3. Release IFNy to activate macrophages & TNF to induce inflammation
4. Tissue damage caused by hydrolytic enzymes, ROIs & cytokines
5. Prototype disease – Type I diabetes
66
Type IV causing Type I diabetes - 4
1. Surface proteins on pancreatic beta cells not recognised, body mounts immune response
2. T cells activate, secret interferon gamma, CD8 cells pass through MHC Class I
3. Get boosted by T cells & use perforations to lysis cell
4. Leads to Type One Diabetes due to loss of Insulin secreting cells
67
Autoimmunity - 6
1. Type II, III, and IV are each autoimmune.
2, Results form failure in mechanisms for maintaining self tolerance
3. Main factors: Genetic susceptibility & environmental triggers
4. Systemic or organ specific
5. Various effector mechanisms responsible for tissue injury in autoimmune diseases
6. Once initiated can result in epitope spreading, resulting in chronic disease
68
Autoimmune diseases - 4
1. RA – inflammation & destruction of joints, abs possibly involved
2. IBD – mainly mediated by cytokines
3. Can occur during chronic infection – TB
4. Mainly treated with anti-inflammatories (naproxen/steroids) & disease modifying agents e.g. methotrexate
69
Genetic susceptibility - 4
1. Most diseases polygenic
2. Inheritance of some alleles increases risk
3. Often associated with HLA (HLA-DR4 possible increase in RA)
4. HLA-B27 associated with increase risk of ankylosing spondylitis
70
Transplantation - 6
1. Immune response of recipient to donor tissue
2. Recognition of donor MHC as foreign
3. Donor tissue killed by CTL(Tc), TH cells & abs
4. Requires blood & tissue typing (ABO, HLA systems)
5. Check for preformed antibodies
6. Graft versus host disease
71
Blood typing - 6
Antigens on surface of RBCs:
1. Everyone has base glycolipid antigen (O)
2. Some people have attached carbohydrate groups (A or B)
3. Produce antibodies against antigens we don’t have
4. Group A has anti B antibodies
5. Group has anti A & B antibodies
6. Recipient must not have antibodies against donor antigen
72
Tumour immunology - 5
1. Most tumours weakly immunogenic
2. Rapidly grow & overwhelm immune system
3. Few tumour specific antigens (oncoproteins) or self antigens usually hidden
4. Mainly targeted by CTL & NK cells
5. Therapy – antibodies, vaccines, co-stimulation
73
Immunodeficiency - 2
1. Congenital
e.g. Severe combined immunodeficiency
2. Acquired e.g. HIV, result of infection, drug treatment
74
HIV - 5
1. Infects dendritic cells & carried to lymph nodes
2. Activation of CTLs & antibody production results in partial control of infection
3. Infects T cells via CD4 & chemokine receptors
4. Gradually causes lymphopenia
5. Patient dies of opportunistic infections
