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PVS > WEEK 4 - IMMUNOLOGY > Flashcards

WEEK 4 - IMMUNOLOGY Flashcards

1
Q

What are C3a, C4a & C5a and what do they cause?

A
  • They are anaphylatoxins & cause:
  • Contraction of smooth muscle
  • Increased vasodilation
  • Activation of mast cells or neutrophils
  • Increased fluid in the tissue and speeds up lymph flow
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2
Q

Describe the process of complement activation

A

30 plasma proteins
Circulate in blood as inactive precursors
Activated in response to infection – cascade reaction => rapid amplification of activated proteins

  • Inflammation - by stimulation of histamine release from mast cells (mast cell degranulation)
  • Chemotactic agents - recruitments of neutrophils & macrophages to site of infection
  • Cell lysis - through pore formation in cell membranes– including bacteria.
  • Opsonisation – coating of surface area leading to increased phagocytosis
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3
Q

What are the 2 innate pathways through which the complement system is activated and where do they converge?

A
  • Alternative & Lectin Pathway
  • antibody-dependent pathway – Classical Pathway
    All pathways converge on C3
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4
Q

What are the main differences between acute and chronic inflammation?

A
  • Acute inflammation is manifested by vascular changes, oedema and predominantly neutrophilic inflammation
  • Chronic inflammation is characterized by:
  • Tissue destruction (induced by the persistent offending agent or by the inflammatory cells)
  • Attempts of healing: Replacement of damaged tissue by connective tissue (fibrosis and angiogenesis) and tissue proliferation
  • Infiltration with mononuclear cells (macrophages, lymphocytes and plasma cells)
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5
Q

What is a granuloma?

A

. Granulomas are aggregates of chronically stimulated inflammatory cells, mm in size but they are a collection of macrophages which become modified to form epithelioid cells with a surrounding zone of T lymphocytes.

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6
Q

What is the function of a granuloma?

A

A granuloma is an attempt by the body to inhibit the spread of an infectious organisms e.g. bacteria and encapsulate it to prevent further spread.

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7
Q

What are the problems with granulomas?

A

The centre will become caseous and necrotic, eventually undergoing fibrosis and calcification. Granulomas can compromise the function of the organ due to their size.

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8
Q

What are Acute phase proteins?

A
  • Plasma proteins
  • Produced in the liver in response to cytokines secreted during inflammation – up to 1000 fold increase in plasma concentration
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9
Q

Give examples of acute phase proteins and which cytokine they are produced in response to.

A
  • C-reactive protein and Fibrinogen are produced in response to IL-6
  • Serum amyloid A protein is produced in response to In response to IL-1 and/or TNFa
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10
Q

How are acute phase proteins useful in a clinical setting?

A

MARKERS FOR SYSTEMIC INFLAMMATORY RESPONSE

  • Determine severity of disease
  • Monitor response to treatment
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11
Q

Give some examples of Lab diagnostic tests for immune mediated disease, viral infection (antibody)

A
  • ELISA
  • Coombs test
  • Radial immunodiffusion
  • Immunofluorescence
  • Anti-nuclear antibodies (ANA)
  • Paired serology testing for respiratory disease diagnosis
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12
Q

What is the function of tolerance to an antigen?

A
  • prevents damage to “self”

- regulates immune response to environmental antigens and fetus during pregnancy

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13
Q

Where does tolerance to an antigen develop?

A

develops outside the thymus or bone marrow in “peripheral” lymphoid organs / tissues

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14
Q

What are the 2 types of tolerance?

A
  • Central tolerance

- Peripheral tolerance

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15
Q

What is central tolerance?

A

education of T lymphocytes in thymus & B lymphocytes in bone marrow duration maturation

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16
Q

What is peripheral tolerance?

A

T and B cells in secondary (peripheral) lymphoid tissues require further education and regulation. Normally these responses are regulated by T regulatory cells but when these fail, disease develops – multiple examples

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17
Q

What happens if there is failure of tolerance? Give examples.

A

immune mediated disease
- Allergy (hypersensitivities) to food, fleas etc
environmental atopy
- autoimmune diseases (e.g. immune mediated haemolytic anaemia)
- immunodeficiency (SCID in dog & horse)
- uncontrolled inflammation

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18
Q

What is the definition of Hypersensitivity?

A

Sensitisation then repeated exposure of genetically susceptible individuals to the same antigen can lead to harmful, standard responses (which in non-sensitised animals are beneficial).

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19
Q

What are the two forms of immunodeficiency?

A

Primary – young animals

Secondary - adults

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20
Q

What are the consequences of immunodeficiency?

A
  • Immune system is damaged & unresponsive
  • Non specific (i.e. not restricted to one antigen)
  • Their presence may have an impact of vaccination effectiveness
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21
Q

Define hypersensitivity

A
  • Undesirable reaction produced by the normal immune system” e.g. allergens or autoimmunity
  • Immunological sensitisation to an inocuos environmental antigen (allergen) which leads to an excessive or inappropriate immune response or hypersensitivity on re-exposure to that antigen
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22
Q

Name the four types of hypersensitivity (I-IV)

A
  • Type I (Immediate, antibody IgE mediated) 15-20min
  • Type II (Antibody IgG mediated cytotoxic activity) days
  • Type III (Immune complex mediated) 24h
  • Type IV (T cell mediated, delayed type hypersensitivity DTH) 24-72h
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23
Q

Give some common immune mediated diseases of skin

A
  • Flea allergy dermatitis (FAD)

- Atopic dermatitis

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24
Q

Give some causes of Acute hypersensitivity

A
  • Contact with or infection by micro-organisms
  • Physical (e.g burns, UV light)
  • Chemical corrosives or irritants
  • Tissue necrosis
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25
Q

Give some causes of Chronic hypersensitivity

Including immune mediated diseases.

A
  • Persistent infection by micro-organisms

- Persistent presence of non-living material

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26
Q

How does healing of an inflammatory response normally occur?

A
  • Reduced presence of antigen (e.g bacteria) reduces
    cytokine/chemokine production
  • Anti-inflammatory cytokines and inhibitors produced
    which ‘switch off’ the production and inhibit the effect
    of pro-inflammatory cytokines
  • Acute inflammatory response is switched off
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27
Q

What are the 2 phases of the hypersensitivity immune response?

A
  • Sensitisation

- Re-exposure

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28
Q

What happens in the sensitisation phase of the hypersensitivity response?

A
  • Immune system exposed to antigen or allergen for 1st
    time
  • No clinical disease
  • Abnormal immune response generated (primary IR,
    sensitised)
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29
Q

What happens in the Re-exposure phase of the hypersensitivity response?

A
  • Immune system re-exposed to same antigen or
    allergen
  • Abnormal immune response is present & increases
    (secondary IR, primed)
  • Clinical disease apparent
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30
Q

What are some localised examples of Type I hypersensitivity?

A

pruritis (itch), bronchoconstriction

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31
Q

What are some systemic examples of Type I hypersensitivity?

A

anaphylactic shock

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32
Q

What are some allergic skin diseases of special significance that are Type I hypersensitivity reactions?

A
  • Atopic dermatitis (AD)

- Flea allergic dermatitis (FAD)

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33
Q

What is Atopy?

A

Genetic tendency to develop allergic disease

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34
Q

What is Environmental atopy?

A

Hypersensitivity in skin, respiratory tract

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35
Q

When does atopic dermatitis occur?

A

Atopic dermatitis occurs when atopic animals come into contact with allergen.

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36
Q

Describe the Immune response during FAD (an example of mixed hypersensitivities)

A
  • Type I hypersensitivity
    (Mast cells, and IgE in skin)- usually also causes migration of eosinophils into skin
    basophils also sensitive to allergens in flea saliva (remember fleas feed on blood therefore basophils would contact allergen)
  • Type IV hypersensitivity
    Many animals also show type IV hypersensitivity, therefore allergen exposure tests are measured after about 20 min (Type I) and also after 2-3 days (Type IV)
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37
Q

Give an example of Type I hypersensitivity used in a clinical setting.

A

Intradermal skin testing for environmental atopy allergens.

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38
Q

What are some examples of clinical disease caused by Type II hypersensitivity?

A
  • Incompatible blood transfusion (cats)
  • Autoimmune diseases: haemolytic anaemia,
    thrombocytopaenia, neutropaenia myasthenia gravis
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39
Q

How does Type II hypersensitivity occur?

A
  • Antibody mediated cytotoxic reactions involving cells
    too
  • Reaction to self antigen or small molecule e.g. drug
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40
Q

How is the host cell destroyed in hypersensitivity?

A
  • Opsonisation & complement
  • Antibody dependent cell mediated cytotoxicity (ADCC)
  • Macrophage phagocytosis
  • Natural killer cell granules
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41
Q

What is Pemphigus foliaceus and how does it work?

A
  • autoimmune disease
  • autoantibodies target desmosome between
    keratinocytes
  • vesicles & pustules form
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42
Q

How does Type III hypersensitivity work?

A
  • Immune complexes (Ag-Ab) form ie. antibody based
  • Deposit tiny antibody-antigen complexes in wall of
    small capillaries (renal glomerulus, uveal tract,
    synovium, cutaneous epidermal basement
    membrane)
  • Leads to vasculitis & ischaemic necrosis
  • Reaction within 24h
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43
Q

What are the 2 types of Type III hypersensitivity?

A
  • Antibody excess

- Antigen excess

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44
Q

What are the benefits of Type III hypersensitivity?

A

clearing infectious agents by phagocytosis / opsonisation

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45
Q

What are the benefits of Type II hypersensitivity?

A

clearance of virus infected cells

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46
Q

What are some examples of type III hypersensitivity clinical diseases?

A
  • Systemic Lupus Erythematosus (SLE)
  • Polyarthritis
  • Nephritis
  • Post-infection reactions e.g inflammatory joint disease
    following bacterial infection
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47
Q

What are the benefits of Type IV hypersensitivity?

A

Clearance of intracellular pathogens

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48
Q

How does Type IV hypersensitivity work?

A
  • Occurs within 24-72h
  • Involves dendritic cells and ‘primed’ T cells (e.g
    memory T cells)
  • T cells recruit and activate mononuclear cells (e.g
    monocytes and tissue macrophages)
  • Inflammation at the site of DC/T cell interaction occurs
    (rather than in the draining lymph node)
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49
Q

What are some examples of type IV hypersensitivity clinical diseases?

A
  • Granuloma formation in cattle
  • The tuberculin reaction in skin of cattle
  • Allergic contact (Atopic dermatitis)-Note this disease
    has both type I and type IV components
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50
Q

Whats is the process of Granuloma formation?

A
  • Granuloma occurs when pathogens survive in
    macrophages
  • A granuloma is cellular attempt to contain an
    offending agent that is difficult to eradicate
  • Chronically infected macrophage constantly produces
    TNF-α and this stimulates T lymphocytes to produce
    IFN-γ (These 2 cytokines are believed to maintain the
    granuloma in tissue)
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51
Q

What are some examples of Diseases involving granuloma formation?

A
  • Johne’s disease or paratuberculosis (Mycobacterium
    avium paratuberculosis, MAP) in the intestine -
  • Tuberculosis in lungs of cattle
  • Brucellosis – zoonotic infection with Brucella bacteria
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52
Q

How does Tuberculin testing work?

A
  • Bovine TB reactors tested by single intradermal comparative cervical tuberculin test (SICCT Test)
  • Animals which are positive for Mycobacterium bovis will react to intradermal injection of Mycobacterium bovis antigen within about 3 days (delayed reaction).
  • This occurs because T cells have already been primed by previous exposure to antigen and is a good example of Type IV hypersensitivity
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53
Q

What are some Potential treatment strategies for hypersensitivities?

A
  • Generally anti-inflammatory for both AD and FAD
  • Glucocorticoids (often with antibiotics)
  • Allergen removal
    In the case of FAD, removal of fleas from the animal
    and the home is important
  • Shampoos
  • Dietary modification
  • Contact desensitisation
    Increasing small doses of antigen lead to tolerance
    Variable success
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54
Q

What is Primary (central) lymphoid tissue? Give examples.

A

Where lymphocytes are generated/matured:

  • Bone marrow
  • Thymus gland
  • Bursa of Fabricius (in birds)
  • Ileal Peyers patch (in sheep,cattle, pigs, dogs and horses)
  • Appendix (caecal patch) (in rabbits)
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55
Q

What is Secondary lymphoid tissue? Give examples.

A

Where lymphocytes interact with Antigen Presenting Cells (APC) and immune responses are generated:
- Lymph nodes
- Mucosal-associated lymphoid tissue (MALT, e.g. BALT)
Spleen

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56
Q

How do lymphocytes look on cytology?

A
  • Large nucleus

- Thin rim of cytoplasm

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57
Q

What are the lymphocyte subset?

A
  • B cells or lymphocytes = plasma cells

- T cells or lymphocytes = CD4+ OR CD8+

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58
Q

What do lymphocytes express?

A

each cell expresses 1000s of identical receptors, unique for a single epitope/antigenic peptide

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59
Q

Where do B lymphocytes mature?

A

Bursa of Fabricius in birds or in the Bone marrow in mammals

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60
Q

Where do T lymphocytes mature?

A

Mature in the thymus

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61
Q

What is the function of T and B cell receptors?

A

T and B cell receptors recognise epitopes

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62
Q

What are the names of the T and B cell receptors?

A
  • T cell receptor (TCR or CD3)

- B cell receptor (BCR or membrane immunoglobulin)

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63
Q

What are the properties of CD3?

A
  • unique to T cells
  • recognises a small peptide of the antigen, presented by MHC molecules on another cell
  • the receptors on a single cell are identical and specific for a single epitope (~30,000)
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64
Q

What happens when an antigen binds to TCR?

A

Antigen binding to TCR results in a signalling cascade leading to lymphocyte activation & proliferation

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65
Q

What are the properties of B cell receptors?

A
  • unique to B cells
  • recognises a larger antigenic epitope, binds it directly
    antigen processing and presentation is not needed
    the receptors on a single cell are identical and specific
    for a single epitope (~30,000)
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66
Q

What happens when an antigen binds to BCR?

A

Antigen binding to BCR results in antigen presentation to T cells and a signalling cascade leading to lymphocyte activation & proliferation

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67
Q

How is diversity generated in lymphocytes and why is this needed?

A
  • There are not enough genes in an organism’s
    genome to encode these variants in full
  • To generate diversity, assembly occurs in a
    developing lymphocyte by somatic DNA
    recombination of different gene segments of the V region
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68
Q

What are the 2 main forms of antigen uptake?

A
  • Exogenous (MHC class II restricted)

- Endogenous MHC class I restricted

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69
Q

Give examples of Exogenous (MHC class II restricted) antigen uptake.

A
  • Infectious (bacteria, viruses, fungi, protozoa, helminths)
  • Environmental (pollen, dust mites, food)
  • Opsonised agents, BCR bound
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70
Q

How does Exogenous (MHC class II restricted) antigen uptake work?

A
  • Enter host cell endosomes via phagocytosis &
    pinocytosis
  • Can also enter by APC’s PRR recognition of PAMPs on
    micro-organisms and binding to BCR on B cells
  • Peptides derived from foreign object are presented
    by MHC class II on cell surface
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71
Q

Give examples of Endogenous MHC class I restricted antigen uptake.

A

Antigens from self, tumours, intracellular viruses, parasites etc (if infect cell)

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72
Q

How does Endogenous MHC class I restricted antigen uptake work?

A
  • Enters host cell’s cytoplasm
  • Peptides derived from foreign object are presented by MHC class I on cell surface
  • Cross presentation can occur
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73
Q

What does the Route of antigen uptake into the cell dictate and why is this important?

A
  • Route of antigen uptake into the cell will determine
    the bias of the immune response
  • The form in which antigens are presented to the
    immune system is therefore crucial
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74
Q

T cells must have peptide antigens presented to them in the groove of a specific class of MHC molecule. How are T cells MHC I restricted?

A
  • presents peptides to T cytotoxic cells
  • follows endogenous antigen processing e.g. viral
    infection of host cell
  • most host cells express MHC class I so can present antigen to Tc
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75
Q

T cells must have peptide antigens presented to them in the groove of a specific class of MHC molecule. How are T cells MHC II restricted?

A
  • presents peptides to T helper cells
  • follows processing of exogenous antigens e.g.
    phagocytosis, endocytosis
  • most host cells do not express MHC class II, unless
    “inflamed” so presentation is largely via APC
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76
Q

What are the properties of polyclonal antibodies?

A
  • serum
  • contains multiple clones of plasma cells
  • antibodies against multiple epitopes are secreted
  • can be used for passive transfer of immunoglobulin into new born mammals & in diagnostic tests etc
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77
Q

What are the properties of Monoclonal antibodies?

A
  • produced in vitro
  • contains a single clone of plasma cells
  • antibodies against a single epitope are secreted
  • starting to be used therapeutically as well as
    diagnostically
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78
Q

Describe clonal expansion - What happens once the antigen is presented?

A
  • Co-stimulation (multiple signals)
  • Lymphocyte activation then division
  • Multiple “clones” of identical antigen specific T or B
    lymphocytes
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79
Q

What happens in the absence / incomplete cascade of co-stimulation signals?

A

In the absence / incomplete cascade of co-stimulation signals, you get tolerance to the antigen.

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80
Q

What is the 1st signal in T Cells?

A

Engagement of TCR with MHC and antigen. TCR can only recognise cognate peptide antigen in conjunction with MHC presented by APC

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81
Q

What is the 2nd signal in T Cells?

A

Co-stimulation to stabilise contact between the APC & T cell e.g. CD4-MHC II or CD8-MHC I

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82
Q

What is the 3rd signal in T Cells?

A

APC cytokines bind to T cell receptors

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83
Q

What is the outcome of co-stimulation in T Cells?

A

This induces intracellular signalling which drives the T cell to activation.

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84
Q

What is the process of Co-stimulation in B cells?

A
  • Signal 1: antigen binds to BCR (surface immunoglobulin) on B cells. The B cell processes the antigen and presents it on the surface with MHC class II
  • Signal 2: The peptide-MHC complex is recognised by circulating, antigen specific T helper cells. These then co-stimulation the B lymphocyte via secretion of cytokines
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85
Q

What happens if co-stimulation fails?

A
  • Tolerance to an antigen
  • occurs if even one of these co-stimulatory signals is absent
    antigen specific
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86
Q

Where does tolerance normally occur?

A

Tolerance normally develops outside the primary lymphoid tissues, in “periphery” e.g. gut

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87
Q

Why is tolerance important?

A
  • very important regulation of immune response:

- tolerance to food, fleas etc develops, allows survival of the fetus & placenta

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88
Q

What happens if there is failure of tolerance?

A
  • failure of tolerance leads to auto-immune disease (multiple conditions in small animals), allergy to food, fleas etc
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89
Q

What Changes within the cell occur during clonal expansion?

A
  • Cell enlarges (lymphoblast)
  • Lymphoblasts which are specific for a single antigen divide - clonal expansion
  • After 5 day period there could now be up to 1000 identical effector cells
  • Interleukin-2 (IL-2) secreted by T cells promotes proliferation
  • Effector (& memory) cells produced
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90
Q

What are B cells?

A

B cells are the precursors of plasma cells.

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91
Q

What is the difference between B cells and Plasma cells?

A

The key difference is that B cells only have immunoglobulin on their surface (gM and IgD). In contrast plasma cells secrete IgG immunoglobulin, which can then be found in blood, lymph and within interstitium.

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92
Q

How many signals are required for naive B cell activation?

A
  • binding of antigen to their surface immunoglobulin (B
    cell receptor) & internalisation
  • molecular interaction with Th2 cells in T cell areas of
    lymphoid tissue. CD40-CD40L binding
  • co-stimulation by cytokines from the Th2 cell
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93
Q

What happens to B cells on activation?

A

On activation, B cells undergo:

  • class switch
  • clonal proliferation
  • transformation into lymphoblasts then plasma cells
  • formation of memory cells
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94
Q

Describe the Antibody synthesised by plasma cells.

A
  • Same antigen specificity as parent B cells
  • Same immunoglobulin class as parent B cells
  • Promoted by cytokines (IL-6, IL-11)
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95
Q

Where are B cells/plasma cells located?

A
  • During an immune response, antigen drains to the local lymph nodes, where naïve B cells are activated and multiplying plasma cells are found in the germinal centres of the lymph node.
  • Plasma cells tend to remain in lymphoid tissues, rarely found in blood but sometimes in tissues.
  • Final stages of B cell maturation occurs in ileal Peyer’s patch (ruminants & dogs) or in avians, Bursa of Fabricius
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96
Q

How are Memory B lymphocytes similar to normal B lymphocytes?

A

Still require signals & help from Th2 cells to become activated

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97
Q

How are Memory B lymphocytes different to normal B lymphocytes?

A
  • much more rapid Ab synthesis
  • increased affinity for Ag
  • increased expression of MHC class II & co-stimulatory
    molecules
  • interact with armed T cells at lower Ag dose
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98
Q

What is the Fab region of immunoglobulins?

A

antigen binding site

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99
Q

What is the Fc constant region of immunoglobulins?

A

Determines biological activity, actively transport immunoglobulin to location & binds to FcR on phagocytes - antigen destruction!

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100
Q

What are the main functions of antibodies?

A
  • Soluble Ab binds pathogen / toxin
  • Ag-Ab complexes form
  • Antibody binds to antigens on cells
  • Antibody on surface of B cells binds antigen
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101
Q

What is the Effect & impact of Soluble Ab binds pathogen / toxin?

A

Pathogen is neutralised - further infection blocked

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102
Q

What are the Effects & impacts of Ag-Ab complexes forming?

A
  • Opsonisation by complement - phagocytosis
  • Binding to FcR on phagocytes - phagocytosis
  • Persistence can damage organs (Type III hypersensitivity)
  • Crosslinking of IgE receptors - degranulation of mast cells
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103
Q

What is the Effect & impact of Antibody binding to antigens on cells?

A

Recognised by specialised lymphocytes - cytotoxicity

104
Q

What is the Effect & impact of Antibody on surface of B cells binding antigen?

A

Exogenous antigen presentation to Th2 cells, promotes plasma cell formation

105
Q

What determines the class of antibody?

A
  • Fc structure

- Carbohydrate groups

106
Q

What are the 5 classes of antibody?

A
  • IgG (IgY in chickens)
  • IgA
  • IgM
  • IgE
  • IgD
107
Q

What is the functional relevance of IgG?

A
  • Secondary Insulin Receptor
  • dominant in serum
  • transudates into tissues
  • fixes C’
  • binds to FcR
  • opsonisation
  • neutralise toxins / pathogens, diagnostics
108
Q

What is the functional relevance of IgA?

A
  • Serum
  • mucosal surfaces, & secretions,
  • prevents colonisation
  • can neutralise
  • weak opsonin
109
Q

What is the functional relevance of IgM?

A
  • Primary immune response
  • serum
  • large pentamer multiple binding sites so can’t transudate easily
  • predominates in serum
  • fixes C’
  • effective agglutination,
  • Diagnostics – because of primary IR
110
Q

What is the functional relevance of IgE?

A
  • Serum & tissues
  • anti-endoparasitic response
  • binds via Fc Component to receptors on mast cells & basophils
  • involved in Type I hypersensitivity - allergy, parasites
111
Q

What is the functional relevance of IgD?

A

Rare, expressed only of surface of naïve B cells

112
Q

What is class switching?

A

Class switching means the alteration in the class of immunoglobulin which the B cell expresses on its surface membrane

113
Q

When does class switching occur in B cells?

A

Immunoglobulin class switching occurs as the naïve B cell becomes activated and forms a lymphoblast.

114
Q

What is the process of class switching?

A
  • Class switching means the alteration in the class of immunoglobulin which the B cell expresses on its surface membrane.
  • Naïve B cells express IgM and IgD on their surface. During the class switch, each B cell will express a single type of immunoglobulin on its surface.
  • So after class switching, a B cell will have only IgG, or IgA or IgE on its surface
115
Q

What are the features of a primary antibody response?

A
  • short lived
  • low magnitude
  • isotype is IgM (low affinity), but multiple binding sites mean it’s good at agglutinating pathogens
  • initiated in local lymph nodes (Ag presented to naïve lymphocytes)
  • memory cells established
116
Q

What are the features of a secondary antibody response?

A
  • more rapid (recall of memory cells)
  • longer duration
  • higher magnitude
  • initiated in local lymphoid tissues (activation of primed
    lymphocytes)
  • isotype switches to predominance of IgG & IgA
  • higher affinity for antigen
117
Q

What is the presence and amount of antibody during an outbreak of infectious disease used to monitor?

A

The outbreak / infected animals / resolution

118
Q

How is passive immunity obtained in newborn animals?

A
  • colostrum is ingested within a closely defined period
    immediately after birth (12-36h)
  • maternal antibodies in colostrum either remain in gut (IgA) or are simply transferred (IgG; passive transudation or active transport) from the gut lumen, across the gut epithelium into the local blood vessels and extracellular spaces, then spreads systemically
119
Q

What does passive immunity provide to newborn animals?

A
  • Provides immunological protection against pathogens to which the mother has been exposed for several months.
120
Q

What happens to a newborn’s immune system after birth?

A
  • After birth, the youngster’s own immune system is activated
121
Q

What are the contents of colostrum - write this down if needed?

A
  • IgG – transported across the gut epithelium to provide protection in blood and interstitial spaces. Major component
  • IgA – protects gut epithelium against bacteria invasion until newborn’s own IgA production starts
  • IgM & IgE
  • Cytokines (e.g. bovine IFN, TNF, IL-6, IL-6)
  • Trypsin inhibitors
  • Lymphocytes, majority T cells, some migrate into maternal blood stream, uncertain transfer of CMI?
122
Q

What is the Mechanism of IgG transport across gut epithelium?

A
  • IgG transport protein: Fc receptor neonatal (FcRn) expressed on gut epithelium
  • Two molecules of FcRn bind one molecule of IgG
  • Binding is via Fc portion of IgG
  • Endocytosis to reach local capillaries
123
Q

Give at least 3 factors that Factors which influence the success of passive immunity.

A
  • Type of placenta
  • Infection & vaccination history of mother e.g. efficacy
    & duration of immunity
  • Maternal immune response to vaccines
  • Concentration of antibodies in mother’s serum &
    hence colostrum
  • Colostrum lost pre-parturition (mother “runs milk”)
  • Number of young
  • Teat conformation
  • Vigour of offspring e.g. time to standing & suck reflex
  • Patency of gut epithelium to antibodies (closes by 12-36h post partum)
124
Q

What are the effects of Placental types & Ig transfer?

A

Minimal transfer (5-10% IgG):
- Endotheliochorial placenta (puppy & kitten): IgG 5-10%
No transfer (competely reliant on colostrum ingestion)
- Syndesmochorial (calf, lamb, ruminants)
- Epitheliochorial (foal & piglet): no placental transfer

125
Q

Which tests can be used to Measure of successful Ig transfer?

A
  • Turbidity test using precipitation of immunoglobulins
  • Single radial immunodiffusion
  • Latex agglutination
126
Q

How does the Turbidity test using precipitation of immunoglobulins work?

A
  • chemical + serum
  • quantify using spectrophotometer & standard curve
  • e.g. zinc sulphate, glutaraldehyde, sodium sulphite
127
Q

How does the Single radial immunodiffusion test work?

A
  • more accurate & specific
  • Agar gel, antiserum to IgG + serum
  • 18-24h result
128
Q

How does the Latex agglutination test work?

A
  • reliable, rapid
  • latex particles coated with anti-IgG + serum = agglutination
  • 10mins
129
Q

What is the process of Infection by pathogens?

A
  • Entry into the host (via epithelium or blood).
  • Invasion and colonisation of tissues /cells.
  • Evasion of host immunity.
  • Tissue injury /functional impairment.
  • Disease is caused by host cell destruction /toxin
    production.
  • The host response to pathogen can cause tissue
    damage and disease.
130
Q

What are some examples of Extracellular bacteria?

A

E.coli, Streptococcus spp, Salmonella spp

131
Q

What are some examples of Intracellular bacteria?

A

Mycobacteria spp; Listeria spp, within phagocytes

132
Q

What is the process of immunity to intracellular bacteria?

A
  • Innate: Macrophages and NK cells (IFN-γ activates macrophages to become phagocytic) can be protective. Bacteria usually succeed in infection though.
  • T cell-mediated adaptive immunity. CD4 Th1 cells and CD8 CTLs. Delayed-type hypersensitivity (DTH) reaction (e.g. tuberculin test) and granuloma formation (contains bacteria).
  • Tissue damage is mainly due to host DTH response.
133
Q

What is Delayed Hypersensitivity reaction?

A

Recognition of infected cells.

134
Q

How do extracellular bacteria evade the immune system?

A
  • Inhibition of complement (sialic acid-rich sAgs inhibit alternative pathway – many bacteria).
  • Resistance to phagocytosis (polysaccharide rich capsules – many bacteria e.g. pneumococcus spp).
  • Antigenic variation in surface antigens (e.g. Haemophilus sp LPS variants; E.coli pili)
135
Q

How do intracellular bacteria evade the immune system?

A
  • Inhibition phago-lysosome fusion (e.g. mycobacteria spp.

- Escape to cytosol (e.g Listeria spp).

136
Q

How does the innate immune system respond to viruses?

A
  • Infected tissue production of type I IFNs.Induced by TLR recognition of viral DNA and RNA.
  • NK cells (important in herpesvirus infections). Active where there is virus inhibition of MHC class I CTL responses or where CTLs not induced.
  • Apoptosis. Mediated by the host PKR kinase that inhibits protein synthesis within cells.
  • (Complement, removal of lipid envelope viruses?)
137
Q

How does the adaptive immune system respond to viruses?

A
  • Neutralising antibody. Prevents virus entry (e.g. IgA) and removes free virus.
  • Cytotoxic T cells (CTL). MHC-I restricted killing of virus-infected cells.
  • Antibody and complement-mediated opsonisation for phagocyte clearance.
138
Q

How do viruses evade the immune system?

A
  • Inhibition of antigen presentation: inhibition of MHC-I synthesis; decoy MHC molecules; inhibition of proteosomal activity. (Herpesviruses).
  • Antigenic variation: E.g. flu virus haemagglutinin.
  • Inhibition of interferons (decoy receptor or inhibition of IFN signalling pathways).
  • Inhibition of apoptosis (anti-apoptopic homologues).
  • Latency (herpesviruses); provirus (retroviruses)
139
Q

How does the innate immune system work against protozoa (parasites)?

A

Phagocytosis (but often overcome for establishment of infection).

140
Q

How does the innate immune system work against Helminths (parasites)?

A

Thick teguments. Generally resistant to phagocytes and complement.

141
Q

How does the adaptive immune system work against protozoa (parasites)?

A
  • Those in macrophages (e.g. Leishmania spp) - Th1 CMI and macrophage activation (by IFN-γ).
  • CTL killing of infected cells; Neutralising antibody.
142
Q

How do protozoa evade the immune system?

A
  • Antigenic variation; different life cycle forms (e.g. plasmodium malaria; trypanosomiasis).
  • Stimulation of Tregs (Leishmania spp)- immunosuppression.
143
Q

How do Helminths evade the immune system?

A
  • Large size, different life cycle stages, thick cuticle.
  • Resident in gut or lung.
  • Immunosuppressive factors?
144
Q

Why vaccinate?

A
  • Individual animal health & welfare
  • Disease control
  • Disease eradication
  • Altruism
145
Q

What are some animal factors to consider prior to vaccination of animals?

A
  • Pathogen and protective immune response required ( if known!)
  • Age of animal / colostral Ab decline / immunosenescence
  • Health e.g. immunodeficiency
  • Management: individual pet / competition or herd / flock / shoal food animal
  • Timing of vaccination (e.g. in relation to competition / food chain)
  • Previous disease / vaccination history
  • Pregnancy status
146
Q

What are some vaccine factors to consider prior to vaccination of animals?

A
  • Content of vaccine (recent strains / adjuvants?)
  • Types of vaccine available
  • Route of vaccination (impact on performance / carcass
    quality)
  • Course of vaccination i.e. timing of primary then
    intervals between secondary and booster
    vaccinations
  • Vaccine efficacy
  • Registration license – can vaccines be combined?
  • Adverse effects / risks (e.g. safety in pregnancy)
147
Q

What are some other factors to consider prior to vaccination of animals?

A
  • Compulsory or not?
  • Compliance if farmer administered
  • Requirements of governing body (e.g. OIE)
  • Risk of infection
  • Disease status of country
  • Differentiating Infected from Vaccinated Animals (DIVA)
  • How to assess efficacy of vaccination – routine
    monitoring?
148
Q

What is Passive immunisation?

A
  • Pre-formed antibodies
  • Rapid protection but short-term (days)
  • Banks often available
149
Q

Give examples of passive immunisation methods used to induce immune responses.

A

Colostrum (common)

  • Protection against local pathogens
  • Administered orally to foals with low IgG within 24-36h of birth

Serum or purified Ig

  • Donor animals hyper-immunised against specific pathogen
  • Serum collected or Ig purified
  • Administered to deficient animal e.g. im or iv (more rare)
  • Horse & sheep commonly used
  • e.g. anti-tetanus toxoid, Rhodococcus equi antiserum in foals raised in horses, anti-venoms in sheep
150
Q

What are the Dangers of administering antibody-rich serum?

A
  • “Serum sickness”
  • Immune complex disease (Type III hypersensitivity)
  • Immune responses against donor’s Igs – hypersensitivity reactions
  • Inadvertent disease transfer
151
Q

What is Active immunisation?

A
  • (Repeated) immunisation with vaccine antigen (usually
    against an infectious pathogen)
  • Commonly with adjuvants
  • Induces long-term (protective) immunity
  • Memory cells formed
  • Multiple routes of administration
152
Q

What are the Routes of administration of active immunisation?

A 
Systemic (common)
- Intramuscular (to avoid adverse effects of adjuvants)
- Subcutaneous (small animals)
- Intradermal
Mucosal (common)
- Aerosol
- Intranasal
Water (drinking or immersion i.e. fish)
In ovo
Combinations
153
Q

What are the Mucosal vaccination routes?

A
  • Oral
  • Intranasal
  • Aerosol (chickens)
  • Immersion (fish; oral)
154
Q

What are some Mucosal vaccination examples?

A
  • Oral best (e.g. Salmonella)
  • Intranasal
    Bovine IBR
    canine Bordetella & parainfluenza virus
    feline calicivirus & herpesvirus
  • Aerosol
    Newcastle disease vaccines for chickens
    Vaccination of broiler chickens with dispersed dry powder vaccines as an alternative for liquid spray and aerosol vaccination (Corbanie et al 2008; Vaccine 26, 4469)
  • Immersion (gills & oral uptake)
    Fish vaccines (e.g. Intervet vaccine for bacterial disease)
155
Q

What are adjuvants?

A

Non-specific enhancers (Th2) of immune responses to non-living (inactivated) vaccines

156
Q

How do adjuvants function?

A
  • enabling slow-release of vaccine antigens into the body to enhance immune recognition and response
  • stimulating the immune system non-specifically
157
Q

Name and compare the potential of some typical adjuvants used to enhance immune responses to vaccine antigens.

A
  • Aluminium and calcium salts (very safe; alum)
  • Microbial products (bacterial cell wall extracts/fragments; “Freunds”)
  • Synthetic agents (Carbopol, Immune stimulating
    complexes ISCOMs)
  • Exogenous cytokines (e.g. IL-2 in tetanus vaccines)
158
Q

What are the preferred Immunological outcomes of vaccination?

A
  • Generate a protective immune response (if known)
  • Long term immunity
  • Stimulation of long-lived memory
  • Rapid secondary response (anamnestic)
159
Q

Describe Effective immune responses: antibody v Cell Mediated Immunity?

A
  • Extracellular virus or bacteria are bound by neutralising antibody, preventing further infection and removal by effector mechanisms
  • Effector mechanisms include opsonisation, phagocytosis, ADCC
  • Intracellular virus or bacteria which infect host cells are lysed by cytotoxic T lymphocytes (CTLs)
  • CTLs do not kill extracellular virus
  • VN Ab is less effective against intracellular pathogens
160
Q

What are the different types of vaccines?

A
  • Live (attenuated)
  • Marker / gene deletion mutants
  • Inactivated / killed
  • Subunit (selected proteins or peptides of pathogen)
  • Multivalent – multiple pathogens in one administration
  • Recombinant protein (desired gene is expressed in - vitro & protein purified)
  • Naked DNA (transfect in vivo host cells stimulating IR)
161
Q

What are live vaccines?

A
  • Whole pathogen but attenuated
  • Mutants selected in vitro to reduce virulence but retain antigenicity (viruses and bacteria)
  • Mutants identified and selected from natural (field) strains
162
Q

What is the advantage of live vaccines?

A

Cell Mediated Immunity & Ab responses

163
Q

What is the disadvantage of live vaccines?

A

Potential reversion to virulence

164
Q

What are the Outcomes of live / vectored vaccination - CMI (CTL)? (write this down if needed)

A
  • Vaccines infect host cells to a limited degree
  • Endogenous processing of antigens & presentation by APC in vivo via MHC class I
  • Infection of target cells and presentation by MHC Class I in vivo follows
  • Results in CTL recognition of virus & memory cells established
  • (Th1 helper responses to enhance CTL activity & memory cells established)
  • Humoral immunity is also generated but less efficiently
  • Re-exposure of the vaccinated host to the pathogen results in anamnestic response
165
Q

Give at least one example of a live attenuated vaccine?

A

Rhinomune (EHV-1/4 in horses)
- field strain, passaged 256x in hamster cells, some
genes lost.
- only available in USA

Infectious bovine rhinotracheitis (BHV-1) gE-gM-

  • Gene deletion mutant
  • DIVA
166
Q

What are examples of Live vectored vaccines?

A
  • Pox viruses (Adenovirus, Vaccinia virus, Canarypox)
    are used as a backbone
  • Selected gene which encodes a protein associated
    with protective immunity is inserted.
  • E.g. Canopox + haemagglutinin gene of equine
    influenza virus – ProteqFlu, Merial)
167
Q

What are Inactivated vaccines?

A
  • Killed whole or part organisms (inactivated virus or bacteria)
  • Unable to replicate so no clinical disease
  • Retain a degree of antigenicity
168
Q

What is the benefit of inactivated vaccines?

A

No danger of reversion to virulence

169
Q

What are the disadvantages of inactivated vaccines?

A
  • only structural proteins are presented

- need an adjuvant

170
Q

What is the Immune response stimulated by killed vaccines?

A
  • Ag presentation to Th1 and Th2 cells results in promotion of B cells (Ab)
  • Likely to stimulate Ab but less CTL
171
Q

What are the Outcomes of inactivated vaccination? (write this down if needed?)

A
  • Inactivated organisms (whole virus/bacteria) are taken up by APC and the proteins / polypeptides processed exogenously
  • Exogenous antigen processing & presentation by MHC Class II follows.
    Results in:
  • Th2 helper responses & cytokines to enhance differentiation of B cells into plasma cells (specific Ab secreted)
  • Memory cells established
  • Cell mediated immunity (CTL) is also generated but less efficiently
  • Re-exposure of the vaccinated host to the pathogen results in anamnestic response
  • Potential for combined im / in (mucosal) vaccination
172
Q

What are the different examples of Inactivated vaccines?

A
  • Whole pathogen
  • Inactivated toxins
  • Subunit vaccines (contain fragments of native or recombinant antigens – e.g. influenza virus haemagglutinin)
  • Subcellular fragments (e.g. cell wall extracts)
  • Specific recombinant gene products
  • Naked DNA (rare- plasmid encoding gene is injected)
173
Q

Give at least 2 specific examples of Inactivated vaccines?

A
  • Subunit – FeLV gp70, equine flu HA
  • Recombinant protein FeLV p45
  • Inactivated toxins – tetanus toxoid
  • Subcellular fragments (e.g. cell wall extracts)
  • Naked DNA (West Nile virus in horses)
174
Q

What are some Modern trends in vaccines?

A
  • Naked DNA & recombinant organisms
    • Stimulate both Ab & CMI responses
    • Effective even in the presence of maternal Ab
  • FeLV
    • Needle free technology, high pressure, transdermal
  • Differentiating infected from vaccinated animals (DIVA) potential
175
Q

What is antigenic variation?

A

Pathogen exists as multiple strains e.g. 84 serotypes of S. pneumoniae

176
Q

What is antigenic drift?

A

Point mutations in the DNA which lead to a coding change in the amino acid which in turn results in a small change in the structure of the protein e.g. haemagglutinin & neuraminidase of influenza virus

177
Q

What is antigenic shift?

A

Reassortment of segments in the genome between different strains of the same pathogen, leading to dramatic changes in the expressed protein. The change is so radical that the protein(s) is no longer recognised by the immune response, causing serious disease outbreaks e.g. haemagglutinin of influenza virus.

178
Q

How does antigenic drift effect the immune response?

A
  • Subtle variation in some proteins
  • Some antibodies bind to protein antigens which are
    unchanged, giving partial protection
  • No antibodies recognise drifted epitope
  • Therefore immune response is partially but not fully
    protective
179
Q

How does antigenic shift effect the immune response?

A
  • Two virus strains circulating in the same host
  • Major variation in protein
  • No antibodies recognise shifted protein
  • Therefore immune response is not protective
180
Q

What are the General consequences of variation, drift and shift?

A
  • Clinical disease is more severe:
  • Alters the antigens, therefore specific immune
    response no longer recognises them
  • Particularly important for extracellular pathogens and
    their surface antigens, against which antibodies are
    the primary defence
  • Vaccines efficacy may be compromised to a variable
    degree (slightly to severely)
181
Q

What are the Consequences of variation in relation to vaccination?

A
  • leads to multiple (consecutive) infections with the
    same pathogen
  • vaccine must contain all strains…. feasibility,
    geographical variation?
182
Q

What are the Consequences of drift in relation to vaccination?

A
  • mild epidemic occurs as degree of immunological
    cross protection still exists
  • Mild clinical disease & pathogen shed, even in
    vaccinated animals
183
Q

What are the Consequences of shift in relation to vaccination?

A
  • pandemic occurs as population has no immunity
  • Vaccines are no longer protective – severe clinical
    signs, shedding
184
Q

What are the Strategies to overcome variation, drift and shift?

A
  • Continuous surveillance of circulating strains

- Repeated updating of strains in vaccines

185
Q

What are the requirements for commercial vaccine?

A
  • Licensed:
  • Target species
  • Safe
  • Efficacious – stimulate effective immune response
  • Route of immunisation stated
  • Pregnancy status may also be included
186
Q

What are the Requirements for safety and efficacy in vaccines (can write down if needed)?

A

Currently, both safety and efficacy must be shown before approval of a vaccine by the regulatory authorities (Vet Medicines Directorate in UK)
Safety demonstrated by absence of adverse effects after a selection of conditions that may include:
- Experimental & field trials
- Multiple immunisations in target species
- 5 to 10 times antigenic payload
- Responses in pregnant animals
- Should include possibility of reversion to virulence
of live-attenuated vaccines
- Shedding of vaccine virus to cohorts (why is this
considered?)

187
Q

What are the Causes of ineffective vaccination in neonatal animals?

A
  • immunologically naïve (lack Ag exposure)
  • immature immune systems (e.g. inefficient T cell
    production of IFNg)
  • colostral antibody interferes with vaccine response
    until it has waned
188
Q

What are the Causes of ineffective vaccination in aged animals?

A
  • often show immune senescence or compromised immunity.
  • e.g. old horses (>15y) respond poorly to EIV vaccination. Experimentally, use of exogenous IL-2 enhances Ab responses to tetanus vaccines in old animals and people
189
Q

What is an adverse vaccine reaction?

A
  • Inflammation at site of (usually) injection
    good as recruits macrophages etc to present antigen
    bad if excessive - owner concern
    warm, oedematous / firm
    appear 1dpv - ~7d
    rare (<1 per 10,000 doses in dogs & cats)
  • FISS Feline injection site sarcoma(adjuvanted FeLV & rabies vaccine) - distal limb
  • Hypersensitivity responses
  • Lack of efficacy may result
190
Q

What is the process and purpose of Reporting adverse vaccine reactions?

A
  • Reporting of adverse reactions is required and data
    recorded/analysed by VMD
  • This provides the objective, population based
    evidence for alerting manufacturers and reviewing
    licensing
  • Monitors /defines any problems
  • Important to recognise adverse reactions as real vs
    supposed effects
191
Q

What is the Definition of immune tolerance?

A

Tolerance is the failure of the adaptive immune system to respond to an antigen

192
Q

What is CENTRAL TOLERANCE?

A

Selection of T and B cells which only react with “non-self” antigens in the thymus and bone marrow respectively.

193
Q

What is PERIPHERAL TOLERANCE?

A

T and B cells in the secondary lymphoid tissues (peripheral lymphoid tissues) require further education and regulation

194
Q

What is self tolerance (central)?

A
  • Immune system has been educated to ignore “self” antigens
  • Negative selection of T cells in thymus… but it’s not perfect
  • Some auto-reactive T cells escape – need to be controlled in peripheral tissues
  • If control fails, autoimmune conditions develop
195
Q

What is Neonatal (central) tolerance?

A
  • Occurs in fetus or neonate
  • If fetal thymus is exposed to non-self antigens before
    it’s mature / immunocompetant, then the animal
    becomes tolerant to those antigens
  • Examples are dizygotic, allogeneic twin cattle which
    share a placenta
  • Fetal calf infection with BVDV results in a persistently
    (silently) infected animal, which then infects other
    cattle
196
Q

What is Adult (peripheral) tolerance?

A
  • Lymphocytes are regulated
  • Failure results in hypersensitivity / allergic responses
  • Can be induced….repeated administration of low dose
    antigen can induce tolerance (Tregs)
  • Pregnant mammal is tolerant to her fetus and placenta
    – can’t fail!
197
Q

What is Oral (peripheral) tolerance?

A
  • Huge significance
  • Prevents response to dietary proteins / gut microflora
    (while preserving protective immune responses to GI
    pathogens!)
  • Failure results in hypersensitivity disease (food allergy, IBD)
198
Q

How does central tolerance develop and where does it occur?

A
  • Central tolerance develops when T and B
    lymphocytes become “educated” within central
    lymphoid tissues as part of their maturation
  • Thymus and bone marrow are central (primary)
    lymphoid tissues
  • Occurs in fetus in utero and continues until puberty
    when thymus regresses
199
Q

Describe central tolerance in bone marrow (B cells).

A
  • Induced in bone marrow where stromal cells support
    B cell development and B cell receptor (BCR)
    immunoglobulin (Ig) is acquired
  • BCR+ cells that interact with self antigens on stromal
    cells are deleted by apoptosis).
  • Mature “educated” B lymphocytes move to populate
    secondary lymphoid organs (adaptive immune
    response repertoire)
  • Most antigens are T dependent, and induction of T
    cell tolerance will lead to B cell tolerance
200
Q

Why is peripheral tolerance needed?

A
  1. Many antigens may not be presented to T cells in the thymus
  2. Some T cells which react to “self” peptide may escape thymus by accident, enter peripheral lymphoid tissues where they may, if not controlled, generate an unwanted immune response against “self” peptides (autoimmune response)
201
Q

Give examples of antigens that may not be presented to T cells in the thymus (don’t need to know all of them).

A 
For example, allergens:
Certain proteins in food 
Dust mite faeces
Flea saliva 
Household cleaners etc
Pollens
202
Q

Where does Peripheral tolerance occur and what does it prevent?

A
  • Occurs in peripheral lymphoid tissues (lymph nodes,
    spleen, MALT)
  • Prevents over-reaction of autoreactive T and B cells to
    allergens and /or “self” antigens in the tissues
203
Q

What are the mechanisms by which T cells become tolerant / unresponsive (in periphery)? - write this down if you need.

A
  • Anergy
    • T cells fail to receive appropriate co-stimulatory
      signals for activation
    • Failure of T cell activation leads to cytokine
      deficiency, so B cells also become anergic
  • Immunological ignorance
    • Immune privileged sites (testis, brain, eye, kidney
      etc)
  • Antigen presenting cell failure
    • Processes “self” antigen but fails to present
  • T regulatory cells (Tregs)
    • 3 types
204
Q

What is the function of Regulatory T cells (Treg)?

A

Inhibit Th1 and Th2 cell function via production of inhibitory cytokines (TGF-β and or IL-10) or direct cell / cell contact

205
Q

What are the three types of Regulatory T cells that are known?

A
  • Natural Tregs cells (nTreg)
  • T regulatory cells, subset 1 (Treg1)
  • T helper 3 cells (Th3)
206
Q

How do nTreg cells inhibit immune responses?

A
  1. Cytokine production

2. Cell to cell contact between APC and nTreg

207
Q

How do nTreg cells inhibit immune responses by cytokine production?

A

Activation of nTregs causes large amounts of IL-10 to be produced which has immunosuppressant properties on the activity of both Th1 and Th2 cells. Inhibition of Th2 cells then inhibits B cell activity and antibody production

208
Q

How do nTreg cells inhibit immune responses by Cell to cell contact between APC and nTreg?

A
  • upregulating CTLA-4 which ligates B7 but does not
    cause activation (inhibitory receptor)
    1. This interaction blocks the activation of immunogenic T cells with APC
    2. nTreg contact with naïve or memory T cells inhibits production of IL-2, these immunocompetent T cells cannot expand their population and are effectively prevented from taking part in a response
    3. nTreg populations are expanded by TGF-β which may be produced by the APC
209
Q

What happens if If immune tolerance fails?

A
  • Allergic (abnormal) immune responses to environmental antigens
    • e.g. food, pollen, moulds, insect bite saliva,
      ectoparasites’ faeces / saliva, house dust mites etc
  • Autoimmunity develops
    • the animal’s immune system attacks “self” cells &
      tissues e.g. rheumatoid arthritis
210
Q

Describe the process of hyposensitisation / immunotherapy. How to assess tolerance in practice.

A
  • Administration of selected allergens at a low dose (with alum adjuvant)
  • Intradermal injection
  • Sublingual administration
  • Tailored to animal – multiple allergens
211
Q

Outline reasons why a developing conceptus / foetus is not destroyed by the maternal immune response.

A
  • Physical barrier
  • Fails to express paternal (MHC) antigens
  • Local immunosuppression - Evidence for Tregs and split immunological tolerance (local immune tolerance / suppression vs peripheral activity) exist in people, horses…..?
212
Q

Give examples of Natural immunosuppressives?

A
  • Regulatory T cells (Tregs)
  • Antibodies (neutralisation / removal of antigen)
  • Specific cytokines (e.g. IL-10)
  • Hypothalamus-pituitary-adrenal (HPA) axis important
213
Q

Give examples of Natural broad ranging immunosuppressive substances?

A
  • Hypothalamus-pituitary-adrenal (HPA) axis important
  • Production of glucocorticoids such as cortisol has a
    very broad effect on the immune response as a
    whole
214
Q

Describe Broad ranging versus specific immunosuppressive control.

A
  • Broad
    • General effects: many aspects of inflammation and /
      or the immune response e.g. glucocorticoids and
      NSAIDs
  • Specific
    • Targeted e.g. cytokine inhibitors (e.g. Interleukin 1
      receptor antagonist (IL-1Ra)
215
Q

How do specific inhibitors work?

A
  • Binds to the immune protein preventing it from interacting with its receptor.
  • Binds to the receptor without activating it, preventing interaction of the immune protein with its receptor (Steric hindrance)
  • Inhibiting inflammatory cytokines such as IL-1 and TNF-α are good examples.
216
Q

Common immune mediated diseases

A
  • Haemolymphatic
    • Immune mediated haemolytic anaemia (common)
  • Cutaneous
    • Atopy (VERY COMMON)
  • GI
    • Inflammatory bowel disease (common)
  • MSK
    • Chronic osteoarthritis
217
Q

What are Corticosteroids?

A
  • Synthetic form of corticosteroids (produced by adrenal cortex)
  • Glucocorticosteroids are a type of corticosteroid
218
Q

What is the Mechanism of glucocorticoid action?

A
  • Absorbed through cell membrane
  • Bind to intracytoplasmic receptors, forming complex
  • Results in:
    • reduction of pro-inflammatory proteins and
    • increase of anti-inflammatory proteins
219
Q

What are the Additional effects of glucocorticoids?

A
  • Stablise cell membrane of macrophages, neutrophils
    & mast cells
    • This inhibits inflammatory mediators and pro-
      inflammatory cytokines release (IL-1, IL-6, TNFa)
  • Inhibit T cell function, and thus B cells indirectly, but
    direct effects on B cells are less
  • Inhibit complement function
  • Down regulate FcRs on phagocytic cells  Igs less
    effective
220
Q

What are the variables of Glucocorticoids?

A
  • Administration: systemic or local
  • Formulation
  • Potency
  • Duration of action (<12h - >48h)
  • Dose rate
  • Dose influences the outcome:
    • Anti-inflammatory - allergy
    • Immunosuppressive –autoimmune / idiopathic
      inflammation ie more severe??
221
Q

What are the Side effects of Glucocorticoids to consider?

A
  • Blanket immunosuppression - susceptibility to secondary infections
  • Mimic endogenous glucocorticoids - chronic use may lead to iatrogenic hyperadrenocorticism
  • Abrupt withdrawal - adrenal insufficiency, (hypoadrenocorticism)
222
Q

Describe the Treatment of immune mediated haemolytic anaemia.

A
  • Corticosteroids
    • Reduce egress of inflammatory cells into tissues
    • Reduction in inflammatory mediators
    • Suppression of macrophage & neutrophil function
    • Lymphocytotoxic
    • Reduced macrophage Fc receptor expression
    • Inhibition of complement
223
Q

What is Atopic dermatitis?

A

Type I hypersensitivity to environmental allergens

224
Q

Describe the Treatment of atopic dermatitis.

A
  • Finances important
  • No money - no sensitivity testing - prednisolone
  • Sensitivity test - hypoimmunisation
  • Shampoo
  • Anti-histamines
225
Q

Describe the Therapeutic treatment of atopic dermatitis. Write this down if needed.

A
  • Systemic / topical corticosteroids
    • Inflammatory cytokine reduction
  • Cyclosporine (Atopica)
    • inhibits T Lo function
  • Oclocitanib maleate (Apoquel)
    • Selective molecule which inhibits Janus kinase 1
      (JAK1) signalling (part of itch / inflammation pathway
  • Monoclonal anti-canine IL-31 antibody
226
Q

What are the immunological effect of NSAIDs?

A

Most common NSAIDs work by inhibiting cyclo-oxygenase 1 (COX1) and cyclo-oxygenase 2 (COX2).

227
Q

What is COX1?

A

COX1 (constitutively produced) protects intestinal tissues by stimulating mucous production, therefore NSAIDS such as aspirin can cause gastric bleeding and ulceration.

228
Q

What is COX2?

A

COX2 is induced during immune responses and is an essential component of the pathway which produces prostaglandins and thromboxanes (Eicosanoids).

229
Q

What is IL-1β and where is it produced?

A
  • IL-1β is a pleiotropic cytokine affecting many different biological functions: E.g. inflammation.
  • It is one of the first cytokines produced during inflammation (fever, inappetance)
  • Innate immune cells produce IL-1β and are activated by IL-1β (including maturation of APCs and the production of inflammatory cytokines)
230
Q

What are the contra-indications of IL-1β?

A
  • IL-1β is contra-indicated in a number of severe inflammatory diseases including Rheumatoid arthritis, sepsis and periodontal disease in animals
  • Once produced, it is therefore critical that it can be controlled
231
Q

What is IL-1 receptor antagonist?

A

A competitive inhibitor of IL-1β

232
Q

What is Autologous conditioned serum: equine and what is its function?

A
  • Interleukin-1 receptor antagonist protein (IRAP) is an
    example
  • “Inhibits inflammatory cascade incited by IL-1”
  • Osteoarthritis (chronic)
  • Administered intra-articularly
  • “Enhances healing”
233
Q

Give examples of Food supplements with possible anti-inflammatory effects.

A
  • Devils Claw

- Green lipped mussel

234
Q

Give examples of Food supplements with possible supplementary effects.

A
  • Glucosamine

- Chondroitin sulphate

235
Q

What is the general procedure for an Enzyme- linked immunosorbent assay (ELISA)?

A

(1) Antigen is immobilized on a solid support either non-specifically (via adsorption to the surface – indirect ELISA) or specifically (via capture by another antibody specific to the same antigen – sandwich ELSIA) (sorbent)
(2) Antigen is recognised by specific antibody (‘immuno’).
(3) This antibody is recognised by second antibody (‘immuno’) which has enzyme attached (‘enzyme-linked’).
(4) Substrate reacts with enzyme to produce product, usually coloured.

236
Q

What are the Uses of ELISA in Veterinary Medicine?

A
  • Disease detection e.g. Canine Distemper virus, Canine & feline heartworms, feline leukemia virus, BSE
  • Detection of illegal drugs in horses, ie Alfentanil, an narcotic analgesic often administered to race horses, or Salbutamol, a bronchodilator.
  • Detection of hormones, e.g. pregnancy testing kits.
237
Q

What is the function of an Indirect ELISA?

A

To measure antibody concentrations in whole blood or plasma or serum.

238
Q

Write down the procedure for an Indirect ELISA.

A
  1. Antigen is bound to plastic well
  2. Test sample is added (e. g. serum) and any antibodies that react against antigen will bind
  3. 2ndary antibody conjugated to enzyme such as horse radish peroxidase (HRP) is added. This antibody is raised against antibodies from test species, ie dog and will bind to all dog antibodies
  4. Substrate is added and converted by the enzyme
  5. View/quantify the result using a spectrophotometer
239
Q

What is the function of the Sandwich ELISA?

A
  • To measure antigen concentrations in various different type of samples, eg cytokines, hormones (ie pregnancy or ovulation testing)
240
Q

What is the concept of the Sandwich ELISA?

A
  • Plate is coated with specific antibody to capture the antigen.
  • Another specific antibody is used for detection.
  • antigen being sandwiched between the capture and the detection antibody
241
Q

What is C-Reactive Protein (CRP) a marker of?

A

Inflammation

242
Q

What is a Competitive ELISA?

A

ELISA technique used to detect small antigens with only 1 epitope and hence not possible to do a sandwich ELISA

243
Q

What is the concept behind a Competitive ELISA?

A

A known amount of labeled antigen will compete with the unknown amount of antigen in the sample for binding the capture antibody.

244
Q

What is the Limit of detection in interpretation of ELISA data?

A

Minimal concentration that will be detected positive by the ELISA test

245
Q

What is sensitivity?

A

The test’s ability to identify positive results

246
Q

What is sensitivity?

A
  • The test’s ability to identify positive results
  • the proportion of animals that are known to have the disease who will test positive for it
  • probability of a positive test, given that the patient is ill.
247
Q

What is specificity?

A
  • The test’s ability to identify negative results
  • the proportion of animals that are known not to have the disease who will test negative for it.
  • probability of a negative test given the patient is uninfected/healthy.
248
Q

What is Seroconversion?

A

Development of detectable specific antibodies to microorganisms in the blood serum as a results of exposure, infection or immunization.

249
Q

What type of samples can be be used to assess seroconversion?

A

Paired serum samples (samples that are taken from the dame animal), taken at least 10-14 days apart (for some diseases longer time intervals are specified) .

250
Q

What is the Direct Antiglobulin test (Coombs Test) used for?

A

To identify the presence of non-agglutinating antibodies on the surface of particles such as bacteria or erythrocytes.

251
Q

Which diseases are the Direct Antiglobulin test (Coombs Test) used to test for?

A
  1. Neonatal Isoerythrolysis in Horse and Mule Foals
    - blood type of the mare is different than that of the stallion and the foal inherits the sensitizing RBC type from the stallion.
    - The mare produces antibodies against the foal’s red blood cells and transfers those antibodies to the foal through colostrum during the early stages of lactation and nursing.
    – Coombs test will confirm antibodies attached to foal’s RBC
  2. Immune mediated Haemolytic Anaemia (dogs & cats)
252
Q

What is the procedure for the Direct Antiglobulin test (Coombs Test)?

A
  1. RBCs covered in antibodies

2. Antiglobulin is added & agglutination occurs

253
Q

What is Immunodiffusion?

A

Method to demonstrate precipitation of antigen by antibody

254
Q

What is the procedure for Radial immunodiffusion?

A
  1. Antigen solution diffuses into agar with specific antiserum
  2. Ring of precipitation forms around antigen well
  3. Area of ring is proportional to amount of antigen in the well - Standard curve
255
Q

What is an example for a use for Radial Immunodiffusion?

A
  1. Colostrum containing antigen IgA* diffuses into agar with specific anti-IgA antibodies
  2. Ring of precipitation forms around antigen well
  3. Area of ring is proportional to amount of antigen in the well - Standard curve

PVS (2 decks)

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