DEF Flashcards

Question

What are characteristics of NK cells?

Answer 1

Kill malignant tumour cells without prior activation. (CD8+ T cells need to be activated and differentiate into CTL (cytotoxic T lymphocytes) to kill target cells) - Contain perforin pores in target cells - Contain cytolytic enzymes (Granzymes A, B)

Answer 2

NK cells have Inhibitory and activating receptors. Inhibitory receptors: - KIRs (killer inhibitory receptors) - NKG2A (C type lectin receptors) - Lecocyte Ig-like receptors (LIRs) Inhbitory receptors recognise ligands on healthy cells. Activating receptors: - NKG2S - KIRs - CD16 - Adaptor proteins: DAP10, DAP12 Activating receptors recognise infected/injured cells. The outcome of NK cell interaction with other cells is determines by integration of signals form inhibitory and activating receptors. - All healthy autologous nucleated cells have MHC I Inhibitory receptors recognise MHC class I blockage of signals from activating receptors NK cells do not attack healthy autologous cells! - Virus infected cells: downregulate MHC I - Malignant (tumour) cels: downregulate MHC I Inhibitory receptors are not ligated by MHC class I signals from activating receptors are not blocked NK cells attack and kill virus infected/tumour cells * Activating receptors recognise ligands that are induced on unhealthy cells (stressed, infected by microbes, transformed cells) * Signals from activating receptors may overwhelm the signals from inhibitory receptors, especially if MHC I is also reduced or lost in unhealthy cells NK cells attack and kill virus infected/tumour cells

Answer 3

ITIM: immunoreceptor tyrosine-based inhibitory motif ITAM: immunoreceptor tyrosine-based activation motif * Cytoplasmic tails of inhibitory receptors contain ITIM motif * ITIMs engage molecules (phosphatases) that block the signalling pathways triggered by activating receptors * Activating receptors contain ITAM motif * ITAMs engages in signalling events that promote target cell killing and cytokine secretion by NK cells * ITAMs are often located not in activating receptors but in cytosolic portion of adaptor molecules (eg DAP 12)

Answer 4

Perforin: forms pores delivery of granzymes Granzymes: A,B, C: initiate apoptosis Delivered at the site of contact between NK cell: target prevents killing of neighbouring healthy cells In addition to killing target cells NK cels activate macrophages to destroy phagocytosed microbes via production of IFN-γ Granzymes activate caspases apoptosis Granzyme B: can trigger mitochondrial apoptotic pathway Killing of infected cells by NKs eliminates reservoirs of infection

Answer 5

Human NK cell deficiencies - As part of broader immune-deficiencies (eg Chediak-Highashi) - Complete absence of circulating NK cells - Functional NK cell deficiencies (normal numbers) Patients have fatal viral infections (herpes viruses)

Answer 6

Specialised cells: - Identify, ingest, destroy pathogens - Neutrophils, Macrophages, dendritic cells - Belong to the innate immune system

Answer 7

Cell ‘eating’ - Microorganisms - Other cells - Nutrients Mechanism of innate immune system

Answer 8

• Protection from pathogens • Disposal of damaged/dying (apoptotic) cells • Processing and presentation of antigens (Ag) - Activation of adaptive immune system - Links innate and adaptive immunity • Main phagocytes: PMG, macropahges, DCs

Answer 9

1. Phagocyte mobilisation (chemotaxis) 2. Recognition and attachment 3. Engulfment 4. Digestion: pathogen destruction

Answer 10

⎝ Quantitative (decreased number) ⎝ Qualitative (decreased function) Examples: - Chronic granulomatous disease - Chediak-higashi syndrome - defective phagosome-lysosome fusion - Leucocyte adhesion defects (LADs)

Answer 11

Defective phagosome-lysosome fusion Phagocytosed microbes can’t be killed recurrent infections * Rare genetic disease * Defective gene: LYSosomal Trafficking regulator (LYST) * Defect in lysosome fusion Neutrophils have defective phagocytosis. - Repetitive, severe infections

Answer 12

- Defect in beta-chain integrins | - Defective neutrophil chemotaxis

Answer 13

TLRs – recognise pathogens Present on: - Phagocytes - Mucosal epithelial cells - Endothelial cells Cellular location: - Cell surface (TLR1, TLR2, TLR4, TLR5) detect extracellular pathogens - Inside cells (TLR3, TLR7, TLR8, TLR9) detect microbial nucleic acids

Answer 14

Humans lacking TLRs have not been identified! Polymorphism in TLR genes predisposes to: - Bacterial infections - Asthma - Autoimmunity (lupus)

Answer 15

Tetrameric protein - 2 identical heavy chains - 2 identical light chains: either kappa or lambda Each chain has a variable region - amino acid sequence varies from one Ig molecule to another - binds antigen (Fab) And a constant region (Fc) - responsible for effector functions - eg activating complement, binding to phagocytes The complementary determining regions (CDRs) also known as the hypervariable regions, are the parts of the V region that bind the antigen. CDR3 is the most variable region.

Answer 16

* In the primary structure of the protein the CDRs are separated. * In the tertiary (3D structure) of the protein the CDRs lie adjacent to each other. * The rest of the V-region forms a framework, allowing the 3 CDRs to face the antigen.

Answer 17

During an infection a small number of B cells will, by chance, be making an Ig that binds to one of the foreign antigens. These B cells are activated and begin to multiply – ‘clonal selection’. Some of the replications become memory cells and others become plasma cells moving to the bone marrow, where they out out large amounts of Ig.

Answer 18

- Direct involvement of CD4+ T helper cells (Th1) | - Cytokines released by Th1 cells

Answer 19

- One constant region (C) segment - 35 variable region (V) segments - and 5 short joining (J) segments The J segments are quite close to the C segment, but the V segments are a long way away on the DNA. There is a binding site for an endonuclease enzyme after each V segment and in front of each J segment. The enzyme will cut randomly at 1V and one J. The free ends are then ligated together joining, in this case, V24 and J2.

Answer 20

1. One V segment and 1J segment are brought together via their recognition sequences 2. RAG recombinases cut and remove intervening DNA 3. End are processed before rejoining

Answer 21

An exonuclease will mess around with the free ends, before they are ligated together. An enzyme called terminal deoxynucleotidyl transferase (TdT) randomly adds a few nucleotides to the free ends, before they are ligated together.

Answer 22

After the hairpin is cut, or if its in the wrong place, some extra nucleotides are added in and TdT adds in some random ones as well. The V-J join and this further variation at the joins create the most variable region of the antibody – CDR3 CDR1 and CDR 2 are fairly variable, but CDR3 is by far the most.

Answer 23

1. For generating Ig and TCR gene diversity 2. As a leukaemia marker – disease of cells failing to differentiate, lymphoid blast cells make TdT 3. Useful enzyme in genetic engineering/ recombinant DNA work

Answer 24

Same process as the light chain, but one V can join with one D segment and one J segment, so giving even more combinations. Exonuclease and TdT can add further variation both to the V-D and D-J junctions.

Answer 25

- any B cell is diploid - it has two alleles of the Ig heavy chain gene - in theory it could make two different heavy chain proteins - this never happens – ‘allelic exclusion’

Answer 26

Mechanism: as soon as one allele successfully rearranges and starts making heavy chain protein, the gene rearrangement process for heavy chains is switched off. For light chains, a B-cell has two alleles of the κ chain gene and two alleles of the λ chain gene. In theory it could make four different light chain proteins. Again this never happens- “Allelic exclusion”

Answer 27

One clone of B-cells only makes κ or λ Polyclonal B cells will be a mixture of cells making either κ or λ light chain If B-cells in a patient are only making one kind of chain-------????

Answer 28

* Functional Ig expressed as membrane (cell surface) IgM * Membrane IgM acts as B cell receptor (together with IgD) * Ag recognition by membrane IgM activation of signalling pathways B cell activation

Answer 29

* Functional Ig is first expressed as IgM on the cell surface (sIgM) * This acts as a ‘B cell receptor’ in a similar way to a growth factor receptor. The IgM does not have intrinsic tyrosin kinase activity, but associates with SRC family tyrosin kinases, eg LYN and FYN * Binding of antigen to IgM activated the tyrosine kinases and their signal transduction pathways

Answer 30

1. Antigen binding to the B-cell receptor (sIgM), resulting in stimulation of signal transduction pathways 2. Co-stimulatory by T-cells 3. Co-stimulation by cytokines

Answer 31

Two forms: - Membrane-bound on B cell surface Ag receptor - Secreted (circulation, tissues, mucosa) Membrane-bound Igs Ag recognition B cell activation humoural IR

Answer 32

* The activated B-cell begins to secrete soluble IgM * Mechanism – differential splicing * Cμ is not coded for by a single exon (as implied in the simplified diagram in the previous lecture) * There are 4 exons, with two alternative versions of exon four * Differential splicing gives 2 different mRNAs, coding for 2 proteins which differ at the C terminal end * Note V region, coded by VDJ complex, is identical

Answer 33

- Circulate in blood - Access various sites to deal with pathogens - Effector function neutralisation of microbes, toxins opsonisation of microbes to enhance phagocytosis activation of complement (pathogen killing)

Answer 34

Different classes of Abs work best at certain sites (eg IgM, IgG – blood; IgA – mucosa) Different classes of Abs work best against certain pathogens: IgE – parasites Bind to extracellular microbes and toxins - Neutralise (block adherence/entry) - Eliminate Opsonisation = increased phagocytosis Complement activation = opsonisation, lysis

Answer 35

During an immune response B cells become capable to produce Abs of different classes without changing specificity (respond to the same Ag). IgM switch to IgG, IgA, IgE IgG switch to IgA, IgE - Ability to perform different effector functions - Can deal better with pathogens - Isotype switch needs signals from helper T cells Class switching does not alter specificity for Ag! Class switching does not alter the light chain! * B cells make many different classes of Ig * Different classes have different constant (Fc) regions to carry out different functions * But the first Ig made is always IgM * Cell needs mechanisms to keep antibody specificity (coded by rearranged VDJ) but add different C regions

Answer 36

``` Two mechanisms: Minor - IgD only - By differential splicing - Made at some time as IgM Major - All other classes - By DNA rearrangement ``` Cμ and Cδ are transcribed as part of a single precursor RNA. Differential splicing can remove the Cμ exons, so the Cδ exons are not used. Result is the same VDJ is now joined to Cδ making an IgD. * Endonuclease recognition site (switch region) before each CH segment. * Cut before Cμ and cut before alternative C segment * Original VDJ now transcribed along with new C region * Note no change in light chain!

Answer 37

Antibodies produced early during immune response have lower affinity for antigen. Later during immune response and in secondary immune responses production of high affinity antibodies. The process that leads to increased affinity of Abs = affinity maturation. Mechanism: somatic mutation of Ig genes followed by selection of B cells that produce Abs with highest affinity. Affinity maturation needs signals from helper T cells. * B cells with high affinity Ag receptors ae selected to survive * B cells with low affinity Ag receptors may fail to survive (competition for Ag recognition on follicular dendritic cells in the germinal centres) * Preferential selection of B cells with high affinity Ag receptors during immune responses Higher affinity gives stronger cell signalling. Faster cell replication. High affinity sub-clone outgrows the original clone.

Answer 38

Encounter soluble antigen, whole organism or peptides that are transported into a particular type of cell, processed and presented on the surface with an MHC molecules - then there will be proliferation.

Answer 39

* Viable APC with native ovalbumin will proliferate, but not if it’s a fixed APC * Native and fixed APC will proliferate if stimulated by digested ovalbumin

Answer 40

‘Professional’ Antigen-Presenting Cells (APCs): Immune cells that express high levels of surface MHC class II and can efficiently induce T-cell responses

Answer 41

* Rare in peripheral blood – enriched in mucosal tissues * Highly phagocytic cells – induce strong T-cell responses and inflammation. Important for protection against Mycobacterium tuberculosis * Macrophages better-equipped to kill pathogens (higher NO production); DCs better at migrating to lymph nodes (via CCR7) and presenting antigen to T-cells * Specialised but ultimately overlapping functions

Answer 42

* Highly abundant in blood and mucosal tissues * Receptor mediated internalisation of antigens, as opposed to phagocytosis * Primary function to make antibody (plasma cell) – but still very good at antigen presentation * Possibly main inducer of T-cell immune response to pathogens such as Neisseria meningitides

Answer 43

antigens/pathogens already present in cell

Answer 44

antigens synthesised in the cytoplasm undergo limited proteolytic degradation in the cytoplasm

Answer 45

loading of peptide antigens onto MHC class I molecules is different to the loading of MHC class II molecules

Answer 46

transport and expression of antigen-MHC completes on the surface of cells for recognition by T cells

Answer 47

Macrophages have well-developed lysosomal systems. They are specialised for motility, phagocytosis and the introduction of particles to the lysosomal system. Most cell types do not have lysosomal systems developed as well as macrophages BUT viruses can infect most cell types. A non-lysosomal mechanism to process antigens for presentation to T cells is required.

Answer 48

- Inactive virus raises a weak CTL response | - The processing of antigens from inactive viruses is sensitive to lysosomotrophic drugs

Answer 49

- Infectious virus raises a strong CTL response - The processing of antigens from infectious viruses is NOT sensitive to lysosomotrophic drugs - Most CTL recognise antigens generated via a non-lysosomal pathway - Protein synthesis is required for non-lysosomal antigen processing Antigens from infectious viruses are processed via the endogenous pathway.

Answer 50

Endocytosed antigens degraded within endosome/phagosome are broken into peptides. They are loaded onto the MHCII molecules generated in the golgi but transported by phagolysosomes. Following loading they travel to cell surface where they are expressed and ready to engage a CD4 type cell.

Answer 51

Unlike exogenous antigen processing, endogenous processing requires a viable cell producing proteins and they are then degraded, peptides formed, which need to travel to golgi, load MHC1 molecules and then travel to surface and present these endosomal peptides to CD8 cells.

Answer 52

Eliminated by: antibodies and phagocyte activation by T helped cells that use antigens generated by EXOGENOUS PROCESSING

Answer 53

eliminated by: killing of infected cells by CTL that use antigens generated by ENDOGENOUS PROCESSING

Answer 54

MHC I is expressed on all cells and tissues EXCEPT RBCs – not RBCs as they have no nucleus so no protein synthesis and no cytosolic proteins. MHC II only on a number of cell types – many cells don’t express them.

Answer 55

* Binds to peptide-MHC (pMHC) complexes – cannot recognise peptide alone * Huge diversity – potentially up to 1x1013 different TCRs * Exists in a TCR complex with accessory molecules such as CD3 * Needs to be in a complex with an MHC molecules – alone will not trigger activation

Answer 56

- Belongs to Ig superfamily - Like Fab fragment of antibody - Large diversity - Single specificity

Answer 57

- Lower affinity - Cannot be released - No Fc fragment, so no cellular functions - Single rather than two binding sites - B cell receptor/Ab: 5 classes - T cell receptor: 2 classes (alphabeta and gammadelta)

Answer 58

* Before antigen stimulation: somatic recombination of gemline gene * After antigen stimulation: somative hypermutation to generate further diversity

Answer 59

* Before antigen stimulation: somatic recombination generates all the diversity, no further – this explains why T cells have a much lower diversity than B-cells * After antigen stimulation: none Receptor gene rearrangement takes place during T-cell development in thymus.

Answer 60

1. Peptide-MHC (pMHC) 2. Co-stimulation 3. Cyotkines Signals 1 and 2 alone will activate a naïve T-cell, but signal 3 is also important for a strong response and also determining T-cell phenotype. • The main signal (signal one) is delivered from the APC by a peptide-MHC complex to the TCR • The co-stimulatory signal (signal two) is delivered from the APC by germline-encoded accessory receptors such as the ‘B7 family’ (CD80 and CD86) – although many of these receptors are not fully characterised or understood • Lastly, signal three is formed of cytokines secreted by the APC to determine the T-cell phenotype. - IL-12 promotes the TH1 cells - IL-4 promotes the TH2 cells - IL-23 promotes the TH17 cells

Answer 61

Complex interaction of many molecules – but simplistically Signals 1 and 2 are central, and surrounding integrins and accessory molecules help to stabilise the interaction.

Answer 62

* An overly-vigorous immune response is harmful to the host * Negative regulators of antigen presentation provide an ‘immune checkpoint’ to limit T-cell activation homeostasis * Two important molecules – CTLA4 (cytotoxic T-lymphocyte-associated protein 4) and PD-L1 (programmed death-ligand 1) are crucial for dampening the T-cell response

Answer 63

• T cells arise from the thymus, which is a ‘school’ for T-cells. T-cells are exposed to self-antigens and tested for reactivity. • T-cells that cant bind self antigen-MHC are deleted positive selection - These T-cells are useless because they wont protect against pathogens • T-cells that bind self antigen-MHC too strongly are also deleted negative selection - These T-cells are dangerous because they are too self-reactive

Answer 64

In some models (STOCHASTIC MODEL), a proportion of T-cells that are strongly reactive to self-antigen will express the transcription factor FOXP3, which is the ‘master controller’ of Regulatory T-cells (TREG)

Answer 65

Many organisms depend on human host for survival (‘obligate parasites’) – need to co-exist with the host immune system immune evasion

Answer 66

o Produce protein which binds to and inhibits TAP | o prevents viral peptide transfer to ER

Answer 67

``` o Produce protein which binds MHC class I molecule o Prevents MHC class I molecules from leaving ER ```

Answer 68

e.g. allergy to pollen On first exposure to pollen you get the sensitisation phase. B lymphocytes recognise the antigen and they internalise the antigen and present it to Th2 cells. Th2 cells secrete IL4 – this is important in inducing B cells to switch class and become IgE producing cells. The next stage is the effector phase. IgE that has been produced from previous contact with allergen diffuses throughout the body. IgE comes in contact with mast cells. IgE binds to mast cells by its tail end the Fc region. This is bcause mast cells have receptors for binding to the Fc part of IgE. On second exposure to pollen there are mast cells with antibodies attached to them. The pollen enters and binds to the antigen binding sites of the antibodies. Mast cells have granules of histamine inside. When pollen binds to the antibodies on the surface of the mast cell. Sometimes a pollen can link two antibodies together – cross linking. Histamine is released. This is not the only outcome. Late-phase reaction happens. Mast cells generate other cytokines. They encourage Thelper cells to produce cytokines as well. Allergic reaction is prolonged. Approximately 15% of the population suffer from IgE mediated allergic diseases. Asthma is another example. In asthma allergic inflammatory response to allergen sensitises the airways. Nonspecific agents can then cause allergic response.

Answer 69

- Myasthenia gravis - Rheuses isoimmunisation - Haemolytic disease of the new born - Grave’s disease - Myasthenia gravis and graves disease in some reports are classified as type V

Answer 70

In healthy individuals normal stimulation of muscle contraction- nerve impulses trigger release of acetylcholine from nerve endings. This binds to acetylcholine receptors on muscle cells triggering contraction. In Myasthenia gravis autoantibodies to acetylcholine receptors are produced. These block acetylcholine receptors at the postsynaptic neuromuscular junction. Muscle contraction diminished.

Answer 71

* RhD antigen is carried on red blood cells – mother RhD negative Father RhD positive * First pregnancy – mother sensitised – often sensitisation happens at birth of the first infant * Mother makes antibodies to RhD * Second pregnancy- Foetus Rh positive – small amounts of erythrocytes passing across placenta stimulate memory cells * More anti-RhD antibodies are produced and cross the placenta * Haemolytic disease of the new born

Answer 72

* This is an autoimmune thyroid disease * In healthy individuals pituitary makes thyroid-stimulating hormone TSH * TSH binds to TSH receptors on cells of the thyroid follicle * Triggers them to produce thyroid hormones * Thyroid hormones engage in an inhibitory feedback loop- they stop more TSH being produced Pituitary - TSH - bind to thyroid follicle - thyroid hormone produced - negative feedback stop TSH being made * Circulating autoantibodies to TSH receptor * These bind to TSH receptors and trigger the cells to release thyroid hormones * The antibodies stop the pituitary from making TSH * But autoantibodies are present and continue to trigger release of thyroid hormones – so the control system is not working any more.

Answer 73

soluble circulating antigen

Answer 74

* Aetiology unknown – familial pattern * Patients make autoantibody directed against several self molecules such as DNA and nuclear ribonucleoproteins * Immune complexes formed * The antibodies in these immune complexes can fix complement – tissue injury * Complexes trapped in kidney * Glomerulonephritis * B cell activation abnormal in patients with SLE * Higher number of B cells at all stages of activation in SLE patients. * Evidence that B cells in these patients more sensitive to stimulatory cytokines * Also an unusual problem – B cells can engage in polyclonal activation * Changes in cytokine levels * Changes in T cell function – Th1 response reduced * Problems with phagocytic cells – immune complexes not cleared by phagocytes

Answer 75

* Type IV- Delayed hypersensitivity * T cell mediated –but dendritic cells, macrophages and cytokines contribute to the disease process * Mantoux test is an example * Patient injected extract of mycobacterial antigen in skin * Macrophages present antigen * Th cells activated * Th cells in response release cytokines which activate macrophages to release cytokines * Firm red swelling of skin

Answer 76

* Another example of type IV hypersensitivity is Insulin dependant diabetes – type I diabetes * Beta cells in islets of Langerhans * Act as autoantigen * Presented by antigen presenting cells in the context of MHC class II * Stimulate CD4+ Th cells * Th1 cells release cytokines * Activate T cytotoxic cells * Damage Beta cells

Answer 77

Chron’s disease – any part of the GI tract may be involved. * Changes in relative proportion of T and B lymphocytes * High number of B cells producing antibodies on site * Deposition of complement components in the intestinal mucosa * Possible presentation of autoantigens on MHC II * Increased interleukin levels * Ulcerative colitis Th2 may be involved * Crohn’s Th1 may be involved

Answer 78

- Psoriasis - Chronic skin disease - 2% of Caucasians - onset usually puberty or menopause - red plaque covered by silvery skin scales - relapsing remitting - genetic + environmental factors may play a role - high number of CD4+ cells in the skin - immunosuppressive treatment is effective suggesting the cells are involved in pathogenesis - antigen specificity of the cells is not known

Answer 79

an acquired immune reactivity to self antigens. autoimmune disease occurs when autoimmune response leads to tissue damage.

Answer 80

* Multifactoral * Factors predisposing and/or contributing to disease development could be; * Age and gender * Autoantibodies more common in older individuals. * SLE and Grave’s disease more common in women 10:1 and 7:1 ratio * Drugs- Certain drugs can initiate autoimmune reaction. * Mechanism unknown. * Example Patients on treatment for ventricular arrhythmia (procainamide) develop SLE. Stopping treatment resolves the problem. * Immunodeficiency * Immunodeficiency may allow persistent infections or inflammation resulting in autoimmunity

Answer 81

* Severe combined immunodeficiency syndrome. * Lack of development of Stem cells into B cells and T cells * Hyper IgM syndrome * Increased IgM but little or no IgG * Common variable immunodeficiency * IgG/IgA deficiency * Mainly a consequence of B cells being unable to mature into plasma cells

Answer 82

- Lack of thymus is an example | - DiGeorge syndrome – incomplete development of the thymus

Answer 83

* HIV infection – acquired immunodeficiency syndrome * Malnutrition * Tumours – cancerous cells can release immunosuppressive factors * Therapy using cytotoxic drugs and irradiation

Answer 84

1. Challenge dose – proves protection from infection 2. Concept of attenuation 3. Concept that prior exposure to agent boosts protective response 4. Cross-species protection – antigenic similarity

Answer 85

How? - Vaccination programmes - Case finding (surveillance) - Movement control – peoples movement was restricted at this time, which was possibly most important.

Answer 86

Why possible? 1. no sub-clinical infections – always know that it is there 2. after recovery, the virus was eliminated – no carrier states, not going to be at risk of shedding and giving it to other people. 3. no animal reservoir for human small pox – not going to come back from the animal environment, there is not another source, so don’t need to keep vaccination high. 4. effective vaccine (live vaccinia virus) - of unknown origin, thought to have come from Blossom the cow, giving cross-species protection 5. slow spread, poor transmission – difficult to spread, needed close contact to get it.

Answer 87

Material from an organism that will actively enhance adaptive immunity. Produces an immunologically ‘primed’ state that allows for a rapid secondary immune response on exposure to antigen

Answer 88

* protection of the individual * protection of the population * eradication of the disease * decreased rate/severity

Answer 89

Herd immunity – memory boosted by - periodic outbreak of disease in community - vaccines Adults are naturally boosted as their children are infected. Older siblings will have been vaccinated. As disease rates decline – not natural boosting increases importance of vaccination take up rates

Answer 90

Active immunity - innate - adaptive (CMI; antibodies) * natural exposure (carriage) * infection * vaccination LONG EFFECT Passive immunity (antibody from another source: serum) Prophylaxis and/or treatment SHORT EFFECT

Answer 91

Primary exposure • 5-7 days antibody response • 2 weeks for a full response • IgM IgG switching memory B and T cells

Answer 92

* Prior exposure * 2 days for full protective response * post-exposure immunoprotection due to response vs specific antigens * eg surface proteins, polysaccharides, toxins, good targets for vaccine candidates

Answer 93

1. Induce correct TYPE of response - Antibodies polio virus - Cell mediated immunity tuberculosis 2. Induce response in RIGHT PLACE - Mucosal – sIgA flu; polio - Systemic yellow fever - Parenteral vaccines: poor mucosal immunity - Oral vaccines: produced by MALT good IgA 3. Duration of protection - Short-term (travel) antibody sufficient - Long-term memory essential - Boosters natural (seasonal epidemics; carriage), vaccines - Type of infection – long incubation; systemic measles, short incubation time – surface cholera

Answer 94

Maternal antibodies in neonate – sIgA in milk. Lasts 6 months. There is a problem for live attenuated viruses – eg MMR. Virus neutralised by maternal antibody no protection. Vaccinate > 9 months. But… many babies infected by then in endemic areas. Why and when we use vaccines – to protect people in risk categories. Adults have high immunity as have matured and encountered viruses for example.

Answer 95

* avoids needles (risk of HIV, HepB) * mimicry of natural route of infection * ensures exposure to ‘large immune surface’ * good sIgA response * humoural immunity via lymphocyte trafficking to other mucosal surfaces * BUT was it swallowed?

Answer 96

Monotypic Polytypic Decreasing antigen variation genetic diversity. Post exposure immunoprotection due to response vs specific antigens eg surface proteins, polysaccharised, toxins, good targets for vaccine candidates. Most antigens are immunogenic but NOT immunoprotective. Why? Cant predict… Serology can differentiate exposure from vaccination eg Hep B surface Ag.

Answer 97

1 - live, attenuated organism 2 - killed, whole organism 3 - sub-unit vaccines

Answer 98

Eg BCG, polio(Sabin), MMR, yellow fever, VZV - By serial passage - Low temperature adaptation - Recombinant genetics - Selection of natural attenuated strains • Polio (Sabin) type I has 57 mutations • Type 2 and 3 only a few • Possible to revert (wild-type in nappies!) - 3 separate doses to overcome strain antagonism and ensure adequate immune response against each type there is natural boosting

Answer 99

eg pertussis, flu (old type), polio (Salk type), cholera, HepA - reactogenicity - boosting required

Answer 100

(individual components) - proteins - toxoids (diphtheria; tetanus) - peptides (synthetic) - polysaccharide – poor antigens, conjugated to toxoid + outer membrane protein (eg MenC, Hib) - recombinant proteins - sub-cellular fractions - surface antigens (eg HepB, influenza haemagglutinins) - virulence determinant (eg aP-pertussis: adhesion + toxin + OMP) - DNA vaccines (encoding antigen): i/m expression MHC Ig + T-cells - Transgenic food

Answer 101

Conjugation links polysaccharide antigen to protein carrier (e.g. diphtheria or tetanus) that the infant’s immune system already recognises in order to provoke an immune response

Answer 102

* Enhance immune response to antigen * Promote uptake and antigen presentation * Stimulate correct cytokine profiles

Answer 103

Antibiotic therapy (ampicillin) immediately if diagnosis is suspected or G –ve pleomorphic rods seen in CSF. Vaccine effective: (99% cases are type b) Type b capsule polysaccharide linked to conjugate: - diphtheria/tetanus toxoids + outer membrane proteins.

Answer 104

Neisseria meningitides group B ¥ Capsular polysaccharide – poorly antigenic – sialic acid ¥ Non capsular vaccines Outer membrane vesicles of epidemic strains ¥ Efficacy in the age group at greatest risk ? ¥ Which antigen induces protective immunity? porA, adhesins and surface proteins ¥ Antigenic variation of many surface components It is as a result of the constant surveillance of infectious disease (only possible through notifications received from clinicians such as yourselves) and the ongoing development of new and improved vaccines that the vaccine programme in the UK is subject to ongoing review and changes.

Answer 105

Outer membrane vesicles (OMV) from the Neisseria meningitidis group B strain NZ98/254 - menZB In UK, Bexsero®. Contains MenZB PLUS Surface proteins (non-variant) of the bacteria – recombinant : • Factor H Binding Protein (fHbp) • Neisseria Heparin Binding Antigen (NHBA) • Neisserial Adhesin A (NadA) 88% efficacy and strain coverage Duration pof protection – 10 years 30% reduction in carriage rates

Answer 106

* meningitis * sinusitis (common_ * invasive pneumococcal disease (bacteramia) * soft tissue infection (rare) * arthritis (rare) * otitis media * pneumonia * peritonitis (rare)

Answer 107

1 - pneumococcal polysaccharide vaccine PPV23 2 - pneumococcal conjugate vaccine PCV-13V

Answer 108

- The 23-valent pneumococcal polysaccharide vaccine (PPV) for at risk adults and children over the age of 2 - Children under 2 can’t make a ling-lasting protective immune response to polysaccharide vaccines - These 23 types of bacteria cause about 96% of all pneumococcal disease cases in the UK

Answer 109

- Polysaccharides from 13 most common capsule types - Conjugated to T/D toxoids + OMP as for Hib and MenC Estimated that the capsular types in the vaccine cause: ~66% of all pneumococcal disease cases and 82% of pneumococcal disease in under 5 year olds

Answer 110

¥ Over 40 types ``` Genital Warts:- ¥ High risk types (16,18) – lead to cancer ¥ HPV16: 50% ¥ HPV18: 20% ¥ Low risk types (6,11) – warts ``` ¥ Cervical cancer kills 1100 women in UK each year (>200,000 cases p.a.) ¥ 2nd leading cause of cancer deaths in women

Answer 111

Two licensed vaccines: - gardasil: protects against HPV 6,11,16,18 - cervarix: protects against HPV 16,18 Clinical trials show high efficacy, well tolerated - 66% reduction I prevalence high grade pre-cancerous lesions - 76% reduction in cervical cancer deaths - will save 400 lives/year Schedule: September 2008 – all 12-13y and 17-18 year old girls (cervarix): 3 doses over 6 months – booster not currently thought necessary…? Recombinant capsid L2 protein in virus-like particles – subunit

Answer 112

¥ Sufficient organisms? : recombinant DNA technology ¥ Crude preparations (poor protection and toxicity) ¥ Correct Antigen? Can’t predict ¥ Type of immune response: to natural infection, to produce protection ¥ Live attenuated: reactivation (VZV), cancer (EBV) ¥ Many pathogens interfere with effective immune response e.g. gonorrhoea, HIV, Herpes ¥ Model to study: animal or cell lines, human challenge ¥ Latency ¥ Antigenic variation/diversity, serotypes

Answer 113

* The level of immunity in a population against a specific disease * Adequate herd immunity is necessary to prevent outbreaks of infectious diseases * A high level of herd immunity particularly protects vulnerable unprotected groups * When vaccination rates are low, herd immunity falls and epidemics can occur

Answer 114

- BCG introduced 1950s for secondary age. Around 50,000 cases TB annually UK - In 1960s selective immunisation of high risk neonates - TB causes fell from 50,000 to 5,800 late 1980s - Although total cases increased to approximately 7000 pa, epidemiology changed from disease of general population to one of predominantly high risk groups - Mainly large cities, 40% UK cases in London, 60% cases in people born abroad, rates high in their children, wherever born - Other risk groups, contacts of cases, homeless, HIV

Answer 115

- All infants living in areas where the incidence of TB is 40/100,000 or greater - Infants whose parents or grandparents were born in a country with a TB incidence of 40/100,000 or greater - Previously unvaccinated new immigrants from high prevalence countries for TB - Children who would otherwise have been offered BCG in the schools programme will now be screened for TB risk and vaccinated if appropriate ``` Nasal flu vaccine for children aged 2 and 3 years. Oral rotavirus (live vaccine) ```

Answer 116

* Case series in Lancet 1998 purporting to link MMR vaccine with autism. 12 cases with bowel abnormalities and serious developmental regression (9 had autism). In 8 cases parents reported regression starting shortly after MMR * Hypothesis that MMR leads to non-specific gut condition permitting the absorption of non-permeable peptides, leading to serious developmental disorders

Answer 117

- Temporal association with MMR likely to be due to chance - Serious selection bias - Findings not replicable - Post-marketing surveillance (based on >250 million doses) and licensing reviews confirm safety - Epidemiological evidence unsupportive - Serious conflict of interest and unethical behaviour (Wakefield struck off by GMC 2010) - Paper retracted by Lancet in 2010 - Data shown to be fraudulent Deer BMJ 2011

Answer 118

- travellers - occupational groups - patients with immundeficiency

Answer 119

• Make good deficiencies of primary courses of immunisation • No further immunisations usually required for Europe, N. America, Japan, Australia, N. Zealand • For other regions consider typhoid and hepatitis A if risk of faecal-oral infection • Consider HepB for high sero-prevalence areas • Yellow fever for S. America and Sub-Saharan Africa, certificate for entry • Other immunisations advised for special circumstances o Japanese encephalitis (SE Asia and far east endemic rural areas at end of monsoon season) o Rabies (pre-exposure immunisation if long journeys in remote enzootic areas) o Tick borne encephalitis (forested areas of Eastern Europe) o Meningitis ACWY for those on Hajj or Umra pilgrimage

Answer 120

* Health care and public safety workers need protection against hepatitis B * All health care workers should be immune to rubella, tuberculosis and chicken pox * Rabies prophylaxis for laboratory workers handling rabies virus and handlers of imported animals

Answer 121

* Health care and public safety workers need protection against hepatitis B * All health care workers should be immune to rubella, tuberculosis and chicken pox * Rabies prophylaxis for laboratory workers handling rabies virus and handlers of imported animals

Answer 122

• Primary • Secondary - Acquired through illness eg leukaemia, HIV - Acquired through treatment eg steroids, chemotherapy, radiotherapy • Particularly susceptible to many infections • May not be able to mount normal immune response to live vaccines • Could suffer severe manifestations eg disseminated infection with BCG or paralytic poliomyelitis form oral vaccine virus • If general live vaccines avoided, inactivated vaccines safe and indicated but may have reduced efficacy

Answer 123

* Children and adults with no spleen or with functional hyposplenism are at increased risk from bacterial infections, most commonly caused by encapsulated organisms * The following vaccines are particularly recommended: pneumococcal; Hib, influenza meningococcal A and C

Answer 124

* Acute illness – but minor infections without systemic upset NOT reasons to postpone * Live vaccines contraindicated in individuals with immunodeficiency and in pregnancy * Anaphylactic reaction to previous dose * Specific contraindications for individual vaccines eg hypersensitivity to egg contraindicates influenza vaccine

Answer 125

- There are very few individuals who cannot receive pertussis o Anaphylactic reaction to previous dose o Anaphylactic reaction to neomycin, streptomycin, polymyxin B (present in trace amounts)

Answer 126

• Children with family history or personal history of epilepsy of febrile convulsions - Give advice on prevention of pyrexia to minimise risk of febrile convulsions occurring • Children with stable neurological conditions such as cerebral palsy or spine bifida - Neurological complications more common after whooping cough infection than after pertussis vaccination

Answer 127

* Balance of public health needs against individuals rights to refuse vaccination * Importance of informed consent * Different approaches to increasing immunisation uptake – health education versus legal compulsion * General practitioner payments for immunisation targets * Ethical issues raised by MMR scare

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