Immune Response to Infection (1) Flashcards

1
Q

What routes to pathogens use to infect the body?

A
  • External epithelia
    • External surfaces
    • Wounds and abrasions
    • Insect bites
  • Mucosal surfaces
    • Airway
    • GI tract
    • Reproductive tract
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2
Q

What are the constitutive barriers to infection in the skin?

A
  • Tightly packed keratinised cells
  • Physiological factors
    • Low pH
    • Low O2 tension
  • Sebaceous glands
    • Hydrophobic oils repel water/microorganisms
    • Lysozyme destroys cell walls
    • Ammonia/defensins have anti-bacterial properties
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3
Q

What are the constitutive barriers to infection in the mucosal surfaces?

A
  • Secreted mucous
    • Physical barrier traps invading pathogens
    • Secretory IgA (prevent entry/attachment into epithelia)
    • Lysozyme and antimicrobial peptides directly kill invading pathogens
    • Lactoferrin starves bacteria of iron
  • Cilia – trap and remove pathogens, assisted by physical manoeuvres such as sneezing and coughing
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4
Q

What are the constitutive barriers to infection by commensal bacteria?

A
  • 100tn bacteria
    • Compete for resources (scarce) with pathogenic microorganisms
    • Produce fatty acids & bactericidins to inhibit growth
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5
Q

Name the cells and soluble components of the innate immune system.

A
  • Cells
    • Polymorphonuclear cells (neutrophils, eosinophils, basophils)
    • Monocytes and macrophages
    • Natural killer cells
    • Dendritic cells
  • Soluble components
    • Complement
    • Acute phase proteins
    • Cytokines and chemokines
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6
Q

What are the features of cells of the innate immune system?

A
  • Identical in all individuals
  • Cells express receptors that allow them to detect and home to sites of infection
  • Cells express genetically encoded receptors (pattern recognition receptors) that allow them to detect pathogens at site of infection
  • Cells have phagocytic capacity that allows them to engulf the pathogens
  • Cells secrete cytokines and chemokines to regulate immune response
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7
Q

What are the features of polymorphonuclear cells?

A
  • Polymorphonuclear cells (neutrophils, eosinophils, basophils/mast cells)
  • Produced in bone marrow
  • Migrate rapidly to site of injury
  • Express receptors for cytokines/chemokines (to detect inflammation)
  • Express pattern recognition receptors – to detect pathogens
  • Express Fc receptors for Ig (to detect immune complexes)
  • Capable of phagocytosis / oxidative & non-oxidative killing – particularly neutrophils
  • Release enzymes, histamine, lipid mediators of inflammation from granules
  • Secrete cytokines and chemokines to regulate inflammation
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8
Q

Name the monocytes and macrophages of these organs.

A
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9
Q

What are the features of the mononuclear cells?

A
  • Mononuclear cells (monocytes, macrophages, lymphocytes) – monocytes produced in bone marrow and circulate in blood to migrate to tissues to differentiate into macrophages
  • Present within tissue
  • Express receptors for cytokines and chemokines (to detect inflammation)
  • Express pattern recognition receptors –to detect pathogens
  • Express Fc receptors for Ig (to detect immune complexes)
  • Capable of phagocytosis / oxidative and non-oxidative killing
  • Secrete cytokines and chemokines to regulate inflammation
  • Capable of presenting processed antigen to T cells
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10
Q

Describe phagocyte recruitment.

A
  • Cellular damage and bacterial products –> local production of cytokines and chemokines
  • Cytokines –> activate vascular endothelium –> enhanced vascular permeability
  • Chemokines attract phagocytes (not macrophages as they are already present)
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11
Q

Describe the recognition of micro-organisms.

A
  • Recognition of micro-organisms
  • Pattern-recognition receptors (PRR) – e.g. Toll-like Receptors (TLRs), Mannose Receptors
    • Recognise generic motifs (Pathogen-Associated Molecular Patterns – PAMPs)
    • PAMPs = bacterial sugars, DNA, RNA
  • Fc receptors bind to the Fc portion of Ig to allow for recognition
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12
Q

Describe opsonisation and endocytosis.

A
  • Opsonisation & endocytosis (phagolysosome = phagosome & lysosome fusion)
  • Endocytosis is facilitated by opsonisation
  • Opsonins act as a bridge between the pathogen. And the phagocyte receptors
  • E.G. Antibodies –> Fc receptors; complement –> complement receptors; Acute Phase Proteins (i.e. CRP)
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13
Q

Describe the formation of phagolysosomes

A
  • Phagosome and lysosome fuse to form phagolysosome
  • Protected compartment in which killing of the organism occurs
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14
Q

What are the types of microbial killing?

A
  • Oxidative
  • Non-oxidative
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15
Q

Descrive oxidative killing.

A

Oxidative killing (HOCl acts as an oxidant and anti-microbial)

(1) NADPH oxidase converts O2 –> O·
(2) Superoxide dismutase converts O· –> H2O2
(3) Myeloperoxidase converts H2O2 (+ Cl-) –> hydrochlorus acid (HOCl)

Requires H2O2 and chlorine

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16
Q

Describe non-oxidative killing

A
  • Release of lysozyme and lactoferrin into phagolysosome
  • Enzymes present in distinct specific granules which can provide coverage against many bacteria and fungi
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17
Q

What happens after a neutrophil has completeled phagocytosis?

A
  • The phagocytosis depletes neutrophil’s glycogen reserves and is followed by neutrophil death
  • As the cell dies, residual enzymes release and liquify local tissues
  • Accumulation of dead/dying neutrophils in tissues –> pus formation
  • Extensive pus formation causes abscess formation
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18
Q

What do macrophages do after phagocytosis?

A

Become antigen presenting cells and communicate with the adaptive immune response

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19
Q
A
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20
Q

Name features of natural killer cells.

A
  • Present within blood and migrate to inflamed tissues (kills ‘altered self’ or virus-infected)
  • Express inhibitory receptors for self-HLA molecules to prevent mal-activation by normal-self
  • Express a range of activator receptors (i.e. natural cytotoxicity receptors to recognise heparan sulphate proteoglycans)
  • Integrate signals from inhibitory and activator receptors
  • Secrete cytokines to regulate inflammation (promote dendritic cell function)
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21
Q

Name features of dendritic cells.

A
  • Dendritic cells (reside in peripheral tissues) – represent the INNATE-ADAPTIVE transition
  • Express;
    • Cytokine-Rs and chemokine-R–>detect inflammation
    • PRRs–>detect pathogens
    • Fc receptors for Ig–>detect immune complexes
  • Capable of phagocytosis (and following this, the dendritic cells mature)
    • Upregulate expression of HLA molecules
    • Express costimulatory molecules
    • Migrate via lymphatics to lymph nodes (mediated by CCR7)
  • Present processed antigen to T cells in lymph nodes to prime the adaptive immune response
  • Express cytokines to regulate the immune response
22
Q

How do lymphocytes travel in the body?

A
  • Naive lymphocytes enter lymph nodes from blood
  • Antigens from sites of infection reach lymph nodes via lymphatics
  • Lymphocytes and lymph returns to blood via the thoracic duct
23
Q
A
24
Q

Name the components of the adaptive immune system.

A

Components

  • ‘Humoral’ immunity – B lymphocytes, antibodies
  • ‘Cellular’ immunity – T lymphocytes (CD4 T-cells, CD8 T-cells)
  • Soluble components – cytokines, chemokines
25
Q

Name the characteristics of the adaptive immune system.

A
  • Wide repertoire of antigen receptors
    • Receptor repertoire is not entirely genetically encoded
    • Genes for segments of receptors are rearranged and nucleic acids deleted/added at the sites of rearrangement almost randomly
    • (potential to create 1011 to 1012 receptors
    • Autoreactive cells are likely to be generated
    • (mechanisms delete/tolerate these)
  • Exquisite specificity – detects small differences in molecular structure
  • Clonal expansion – cells with appropriate specificity will proliferate during infection
  • Immunological memory – following infection, residual pool of memory cells with enhanced capacity to respond if re-infection occurs
26
Q

Name the primary lymphoid organs and what they produce/mature.

A
  • Primary lymphoid organs – organs involved in lymphocyte development
    • Bone marrow – T and B cells derived, B cells mature
    • Thymus – T cells mature, most active in foetal/neonatal –> involutes after puberty
27
Q

Name the secondary lymphoid organs.

A

Secondary lymphoid organs – sites of interaction between naïve cells and microorganisms

  • Spleen
  • Lymph nodes
  • Mucosal Associated Lymphoid Tissue (MALT)
28
Q

Describe T lymphocyte maturation

A
29
Q

What do T cell receptors recognise?

A
30
Q

Describe the selection and central tolerance of T cells.

A

CD3 is found on all T-cells

The +ve and -ve selection of T-cells in thymus

  • Intermediate affinity for HLA class I –> Differentiate as CD8+ T cell
  • Intermediate affinity for HLA class II –> Differentiate as CD4+ T cell
31
Q

What are the different types of T lymphocytes?

A
  • CD4+ (helper) T lymphocytes
  • CD8+ cytotoxic T cells
  • Memory T cells
32
Q

How do Helper T cells work?

A
  • Recognise peptides (from extracellular proteins)
    • Presented on HLA Class II molecules (HLA-DR, HLA-DP, HLA-DQ)
  • Immunoregulatory functions via cell-cell interactions and expression of cytokines
    • Provide help for developing full B-cell response
    • Provide help for developing some CD8+ T-cell responses
33
Q

Name the CD4+ T cell subsets

A
34
Q

How do CD8+ cytotoxic T cells work?

A
  • Specialised cytotoxic cells that kill cells directly
    • Perforin (pore-forming) and granzymes
    • Expression of Fas ligand
  • Recognise peptides derived from intracellular proteins in association with HLA class I
    • HLA-A, HLA-B, HLA-C
  • Secrete cytokines (e.g. IFN-gamma, TNF-alpha)
  • Particularly important in defence against viral infections and tumours
35
Q

How is a primary exposure different to a secondary exposure with regards to T cell response?

A

The response to successive exposures to antigen is qualitatively and quantitatively different from that of the first exposure

  • Pool of memory T cells ready to respond to antigen
  • the memory T-cells active quicker and more easily
36
Q
A
37
Q

Describe B lymphocyte maturation.

A

If the cells interact with the antigen –> become plasma cell

38
Q

Describe the central tolerance for B cells

A
39
Q

Describe what happens when a B cell encounters an antigen.

A

Activation

  • B cell receptor (surface expressed Ig) binds to antigen
  • Some B cells mature to plasma cells secreting IgM
  • If provided with appropriate signals from CD4+ T cells in secondary lymphoid tissue, stimulated B cells rapidly proliferate (undergo highly complex genetic rearrangements)
    • (1) Isotype switching to IgG, IgA or IgE (TFh cells) – needs CD40: CD40L (not present in Hyper-IgM)
    • (2) Somatic hypermutation to generate high affinity receptors (occurs over a long time)
  • Further differentiation
    • Plasma cells which produce IgG, IgA or IgE antibody
    • Long-lived memory cells
40
Q

What are immunoglobulins and describe their structure. What are their functions?

A
  • Immunoglobulins – soluble proteins made up of 2 heavy and 2 light chains
    • Heavy chain determines the antibody class (IgM, IgG, IgA, IgE, IgD)
      • Subclasses of IgG and IgA also occur
    • Antigen is recognised by the antigen binding regions (Fab) of both heavy and light chains
    • Effector function is determined by the constant region of the heavy chain (Fc)
  • Antibody functions:
    • Identify pathogens/toxins (Fab-mediated) – esp. bacteria of all kinds
    • Interact with other components of immune response (Fc-mediated)
      • Complement
      • Phagocytes
      • NK cells
41
Q

How does B cell memory develop?

A
  • Response to succesive exposures to antigen is qualitatively and quantitatively different from that of first exposure
    • the Lag time between antigen exposure to production of antibody is decreased (to 2-3 days)
    • the Titre of antibodies produced is greatly increased
    • the Response is dominated by IgG antibodies of high affinity
    • the Response may be independent of help from CD4+ T lymphocytes
42
Q

Describe the antigen encountering of B cells.

A
  • Dendritic cells takes up antigen and presents to CD4
  • Prime CD4 –> provide help for CD8
  • CD8 becomes activated – recognise intracellular peptides and kill infected cells
  • B cells recognise pathogen and produce IgM
  • In a late response dendritic cell presents to CD4+ which helps B cells
  • B cells differentiate into plasma cells which produce IgG, IgA, IgE
43
Q
A
44
Q
A
45
Q

What is complement? Where is it produced? How is it present in the circulation?

A

>20 types of proteins, produced in the liver and present as inactive molecules in circulation

When triggered, enzymatically activate each other in a biological cascade

46
Q

Describe the 3 pathways of complement activation.

A
  • 3 pathways of activation:
    • Classical pathway (Antibody + C1 –> C2, C4 –> C3)
      • Formation of antibody-antigen immune complex
      • Changed antibody site exposes C1 binding site
      • C1 binding to antibody activates cascade
      • Dependent upon activation of acquired immune response
      • Antibody-antigen immune complexes
    • Mannose Binding Lectin (MBL –> C2, C4 –> C3)
      • Activated by the direct binding of MBL to microbial cell surface CHO
      • Direct stimulation of classical pathway (only C4, C2)
      • Not dependant on acquired immune response
    • Alternative pathway (PAMP (LPS, teichoic acid)  C3)
      • C3 binding to bacterial cell wall components
        • E.G. Lipolysaccharide of (gram -ve) or teichoic acid (gram +ve)
      • Involves factors B, I, P
      • Not dependant on acquired immune response
47
Q

Describe the activation of C3 convertase

A
  • C3 activation is the major amplification step in the complement cascade
    • Increase vascular permeability and cell movement
    • Opsonisation of immune complexes so soluble
    • Opsonisation of pathogens to promote phagocytosis
    • Active phagocytes
    • Promote mast cell and basophil degranulation
    • Form MAC (via C5-C9) to punch holes in membranes

Membrane attack complex - punches holes in bacterial membranes

48
Q
A
49
Q

What are cytokines?

A
  • Small protein messengers
  • Immunomodulatory function
  • Autocrine or paracrine dependent action
  • Examples include IL-2, IL-6, IL-10, IL-12, TNF-alpha, TGF-beta
50
Q

What are chemokines?

A
  • Chemokines (chemoattractant cytokines)
    • Direct recruitment / homing of leukocytes in an inflammatory response
    • CCL19 and CCL21 are ligands for CCR7 and important in directing dendritic cells to lymph nodes
    • Other examples of chemokines include IL-8, RANTES, MIP-1 alpha and beta