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Cell Infection and Innate Response Flashcards

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1
Q

How does a cell die from necrosis?

A

Inflammatory, uncontrolled death (failure of cell degradative process):
- Cause often pH; temperature; xenobiotic…
- Mitochondrial damage forcing glycolysis (insufficient ATP)
- Leads to lactic acid; Na+ accumulation as Na+/K+ pump not active causing lysis and ribosomal detachment due to ER swelling; influx of Ca2+ increases activity of intracellular proteases/phospholipases/ATPases.
- Cell membrane damage (including lysosome rupture)

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2
Q

How does a Cell Die from Apoptosis? How is this distinct from other programmed cell deaths?

A

Programmed, non-inflammatory cell death:
- DNA damage (from UV; xenobiotic)
- BCL-2 gene inhibited meaning BCl-2 protein family becomes activated (e.g. Bax)
- Bax punches holes in mt membrane and Cyt C is released
- Cyt C binds to APAF-1 which activates initiator caspases and hence executioner caspases.
- Different from ferreoptosis and pyroptosis which are programmed but inflammatory.

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3
Q

Describe 4 types of adaptation a cell can make to stress (e.g. temperature increase)

A
  • Heat shock proteins: raised temperature increases dissociation of HSFs from complexes. These translocate to the nucleus and act as TFs for HSP production. HSPs chaperone partially denatured proteins (prevents damage).
  • +ve feedback provided by pre-conditioning to cope (incremental change better than sudden)
  • Unfolded Protein response: Increases chaperone synthesis; enhances proteasomal degradation and slows translation.
  • Cell-shut Down: reversible response to halt RNA/DNA synthesis and surplus reactions
  • Stress-kinase pathway: Modulates decisions for cells action when damaged (SAPK pathway; P38 pathway; JNK pathway)
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4
Q

What factors effect the immune response to a particular pathogen (broad)?

A
  • Pathogen type
  • Threat level (opportunistic/commensal)
  • Location of infection (interstitial/epithelial/intracellular/cytoplasmic/vesicular)
  • Stage of infection (primary/secondary response)
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5
Q

Using examples; describe the general characteristics of cytokines:

A

Short-lived autocrine/paracrine action, exhibiting:
- Redundancy (overlapping function)
- Pleiotropism (one cytokine; many effects such as histamine causing vasodilatation and bronchoconstriction and neurotransmitter)
- Antagonism (TNF-α and TGF-β)
- Synergism (scaled up effects when combined such as IFN- γ and IL-2 or TGF-β and IL-10 (anti-inflammatory))

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6
Q

What are Acute phase Proteins and what is their function?

A

Synthesised and released from the liver:
- E.g. Fibrinogen released following macrophage activation – can be changed to fibrin to entrap bacteria
- Defensins disrupt bacterial membranes
- Pentraxins bind pathogens and phagocyte receptors (opsonise for death)

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7
Q

Name 4 interleukins and detail their function:

A
  • IL-12 produced by T cells and actives macrophages and NK cells and can act as 3rd activation signal for CTL (induces perforin expression)
  • IL-4 helps eosinophils/basophils/mast cells in parasitic infections
  • IL-6: extracellular control of infections and activate B cells to produce specific IgMs
  • IL-10: anti-inflammatory secreted by Treg cells along with TGF-β
  • IL-17 recruits neutrophils for anti-microbial peptide production (particularly important for fungal infections)
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8
Q

Which cells arise from myeloid progenitors and how do they act?

A
  • Granulocytes (neutrophils, eosinophils, basophils) are mobilised using chemotaxis (C5a/fMLP). Release NETs; pus and free radicals.
  • Monocytes (macrophages): M1 secrete cytokines and ROS to activate inflammatory response; M2 involved in clean up and repair
  • Mast cells: induce inflammation on degranulation by releasing HA
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9
Q

Detail 3 types of antimicrobial substance produced by innate effector cells:

A
  • ROS: causes DNA damage, fatty acid oxidation (damages plasma membrane), protein misfolding. E.g. superoxide production by xanthine oxidase/NADPH oxidase system which kills pathogens. Removed by catalase and superoxide dismutase (SODs). Importance shown by NADPH oxidase system disorders allows infection by filamentous moulds.
  • Perforin: punches holes in cell membranes (particularly mt) releases intracellular cytotoxic substances (e.g. Cyt C)
  • Defensins disrupt membranes of gram +/- bacteria. E.g. Paneth cells in the gut produce α-defensin which induces ion channel formation in lipid bilayer, allowing K+ in and causing pathogen death.
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10
Q

How do NK cells detect and kill infected cells?

A

Detect using a balance of inhibitory and activator signals:
- Recruited by cytokines released from infected cells or macrophages (TNF-α and IFN- γ)
- Missing MHC I activates cell (suggests viral infection)
- Upregulated ligand presentation implies infection
- Can detect opsonised cells (Antibody dependent cell cytotoxicity (ADCC))
- Release perforin (creates holes in membrane = apoptosis induced)

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11
Q

Suggest criteria for an effective PAMP molecule and give examples:

A
  • Must be absent from host
  • Highly conserved between pathogens (increases chance of recognition)
  • Essential to pathogen survival (less likely to be altered by mutation and pathogen still survive)
  • Unmethylated CpG dinucleotide in DNA (5’-C phophate-G-3’) in bacteria
  • Gram +ve bacteria lipotechoic molecule
  • Gram -ve bacteria lipopolysaccharide molecule.
  • Flagella components
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12
Q

Name classes of pattern recognition receptors with examples:

A
  • Toll-like receptors (TLRs): recognise DAMPs and cause release of signalling molecules. Molecules released may depend on receptor position (TLR-4 on cell surface induces inflammatory response –mainly neutrophils as indicative of bacterial infection (binds to LPS on gram -ve bacteria) whereas binding in an endosome induces interferon response (suggests viral infection))
  • Noll-like receptors (NLRs): NOD1&2 recognise peptidoglycan fragments – mutation in NOD2 associated with Crohn’s disease.
  • Inflammasome is a structure of NLRP3 subunits activating caspases.
  • C-type (CLR): mainly for fungal infections
  • Rig-I-like receptors (RLR) for viral RNA
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13
Q

What is the acute Inflammatory Exudate and what is its purpose?

A
  • An increase vascular permeability and blood vessel dilatation.
  • Allows protein rich fluid to enter tissue and easier passage to leukocytes.
  • Stimulated by HA and neurogenic inflammation signals (substance P)
  • Induces recruitment of neutrophils and macrophages and mast cell activation.
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14
Q

Detail the process of leukocyte recruitment to infection site:

A
  1. Rolling: Weibel-Palade bodies release P-selectin in endothelial cells. P and E-selectin make weak interactions with effector cells.
  2. Tight adhesion: neutrophils bind integrin/Intracellular adhesion molecules (ICAMs) on endothelium
  3. Extravasation: leukocytes squeeze through endothelial gaps; neutrophils secrete degrading enzymes onto basement membrane – causes damage (and increased permeability)
  4. Migration: neutrophils follow CXCL8 gradient to infection site
  5. Monocytes recruited later
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15
Q

What is sepsis and how can it be fatal?

A
  • Widespread TNF-α production causing vasodilation, inflammation and collapse of blood pressure
  • Results in blood clotting
  • Septic shock due to lowered bp; intravascular clotting causes organ shut down and uses up clotting factors so bleeding potential.
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16
Q

Suggest some outcomes for infection and the cells involved:

A
  • Repair: granulation tissue with endothelial cells and fibroblasts (synthesise collagen to form scar tissue). Angiogenesis stimulated.
  • Clean-up: M2 macrophages recruited to degrade debris and produce ROS (NO) to kill remaining microbes; metalloproteinases to remodel matrix.
  • Cytokine signalling: macrophages switch from producing pro-inflammatory (leukotrienes/arachidonic acid) to anti-inflammatory (lipoxin)
  • Most white blood cells are short lived so die by apoptosis
  • Chronic inflammation: causative agent not removed completely – leaves granuloma or cycle of damage (e.g. peptic ulcer)
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16
Q

Describe the alternative pathway of complement activation

A
  • First to act due to spontaneous conformational change in C3
  • In aqueous cell environment C3H2O forms (= ‘tickover’) and joins factor B
  • Fluid phase convertase: complex cleaved to C3b and C3a. C3b binds to cell surface
  • This accelerates C3b production by +ve feedback
  • Known as the alternative pathway C3 convertase.
  • Weakest but fastest response
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16
Q

Suggest why an infection may not ever be cleared by host and give examples:

A
  • Agent may be endogenous (stomach acid in peptic ulcer)
  • Agent may evade host (granuloma in TB)
  • Host may attack self (autoimmune conditions)
  • Agent may not be degradable (silica or dust in lungs)
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17
Q

Describe the lectin pathway of complement activation

A
  • Activated by mannose binding lectin (MBL) associated serine protease (MASP)
  • Generally second response
  • MASP is a soluble PRR which bonds to mannose PAMPs
  • Causes cleavage of C2 and C4 to C4b starting the classical C3 convertase
  • C3 -> C3a + C3b
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18
Q

Describe the classical pathway of complement activation

A
  • PAMP recognised by antibody or C-reactive proteins
  • C4 recruited (through intermediates) forming C4b2a which acts as C3 convertase
  • Activates the C3 classical convertase
  • Third response unless secondary adaptive immune response
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19
Q

Name the activation molecules and effector functions of complement.

A

Activation:
- Spontaneous change to C3
- PRR activation (mannose binding lectin associated serine protease (MASP)
- Antibody or CRP binding
Effector:
- Opsonisation: C3b acts a a flag for phagocytosis (as long with co-stimulatory C5a signal)
- Inflammation: C3a is an anaphylatoxin (causes inflammation)
- Cell death (especially gram -ve bacteria): forms a membrane attack complex (MAC) as C3bBbC3b causes polymerisation of C9 forming a membrane pore

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20
Q

How is complement regulated?

A

Positive regulation = increase stability
- Properdin (released by neutrophils) increases stability of Cb3BbCb3 increasing MAC function
Negative regulation = accelerate decay
- Degrade Cb3 and 4
- Dissociation of Cb3Bb by membrane cofactor protein, factor H or decay acceleration factor (DAF)
- Protectin binds to MAC intermediate preventing its insertion

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21
Q

Explain the effects of losing specific complement components

A
  • C3 deficiency: infection by encapsulated bacteria (reduced MAC formation)
  • Properdin deficiency: susceptible to pyrogenic bacteria (more cell lysis so increased inflammation and endogenous pyrogens)
  • Protectin or DAF deficiency: non-specific autoimmune like conditions
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22
Q

Suggest some ways in which pathogens evade complement activation

A

Mechanisms:
- Interference of antibody complement interaction
- Destruction of complement by proteases
- mimicry of inhibitory regulators
- Recruitment of host inhibitors
Staphyococcus aureus:
- Has Staph. complement inhibitor (SCIN) preventing opsonin generation
- Secretes proteins to inactivate C3
- Protein A produced to block Fc region of antibodies (complement cannot bind)

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23
Q

Give 3 stimulatory signals for initial T cell activation:

A
  • Binding of TCR to MHC-peptide complex
  • Co-stimulatory B7 or CD40 on pAPC with CD28 or CD40L respectively
  • Cytokine detection (IFN- γ, IL-2, IL-4, IL-6…)
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24
Q

How do interleukins tailor the fate of CD4 cells?

A
  • Th0 cells become specialised following DC interaction depending on cytokine signal, often an IL
  • Th1 induced by IL-12 and IFN- γ for intracellular pathogens (stimulate macrophages)
  • Th2 induced by IL-4 for parasitic infections (stimulate eosinophils/mast cells)
  • Th17 induced by IL-6 or IL-23 for extracellular pathogens (stimulate eosinophils, neutrophils)
  • Tfh cells induced by IL-6 encourage B cells to switch from producing low to high affinity Igs
  • Treg cells induced by IL-2 and TGF-β
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25
Q

How do CD4 cells use +ve feedback to specialise response?

A
  • IFN-γ induces Th0 to become Th1. Th1 cells in turn secrete IFN-γ in surrounding area.
  • IL-4 induces Th2 formation which then secretes IL-4, IL-5, IL-13
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26
Q

Suggest some ways that the innate immune system responds to viral infection:

A
  • Phagocytosis
  • Apoptosis (prevents viral replication)
  • Cytokines (IFN-γ, IL-12, TNF, !L-18 to induce Th1 development
  • Chemokine secretion to recruit leukocytes
  • NK cells
  • Fever induced (endogenous pyrogens)
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27
Q

Describe the roles of innate lymphocytes and which infection type they tailor to

A
  • ILC1 (like Th1): intracellular pathogens (IFN-γ)
  • ILC2 (like Th2): parasitic/helminth infection (IL4/5/6 production). Forms mucus and stimulates muscle contraction
  • ILC3 (like Th17): extracellular pathogens (produce IL17/22). Recruits neutrophils and antimicrobial peptides.
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28
Q

Name 5 ways antibody binding site diversity is achieved

A
  • Somatic recombination (mixing of 40 V; 23 D and 6 J sequences)
  • Constant heavy and light chain combination (5 constant regions determining Ig subgroup – A, D, E, G, M) and two light chain options κ or λ.
  • Sequence diversity from variable addition/deletion of nucleotides at VDJ junctions (stop codons; elongation due to terminal deoxynucleotidyl (TdTs)
  • Somatic hypermutation: point mutations introduced at variable regions (e.g deamination of cytosine to uracil by activation induces deaminase (AID) enzymes
  • Allelic exclusion: B cell can only express one heavy chain – if a functional heavy chain is formed the other allele chromosome is inhibited.
29
Q

Explain what affinity and avidity mean and how antibodies change this.

A

Affinity: strength of interaction between single antibody binding site and monovalent epitope
Avidity: strength of interaction due to recognition of polyvalent epitopes
- Alternative splicing: Inclusion or not of transmembrane region produces membrane bound receptor or soluble antibody (poly A tail stops transcription signal to prevent TMR inclusion)
- Isotope switching changes constant region of Igs: IgM has high avidity but low affinity therefore produced first (can produce pentameric structure)
- IgG highest affinity

30
Q

What are some functions of antibodies?

A

Neutralisation: blocking of pathogenic molecule (e.g. antitoxin); released by eosinophils (IgE/A/G)
Opsonisation: binds to Fc receptor on effector cells. Can mediate ADCC with NK cells or Fcγ binds to IgG antibodies on macrophages stimulating being engulfed.
Complement activation: IgM activates complement efficiency (classical pathway) leading to MAP activation

31
Q

Name differences between TCRs and antibodies:

A
  • TCRs are membrane bound, antibodies are soluble BCRs
  • Antibodies can undergo somatic hypermutation but TCRs do not hence have lower diversity potential.
  • TCRs have no direct effector function but are used purely for recognition (associated with LCK tyrosine kinase). Whereas antibodies used to block toxins, for opsonisation.
32
Q

How does a TCR signal and accumulate given no intrinsic catalytic activity?

A
  • Lack intrinsic catalytic activity so non-covalently associated with LCK
    1. LCK is a tyrosine kinase which phosphorylates ζ and CD3 chains (associated with TCR)
    2. CD3 contains immunoreceptor tyrosine activation motifs (ITAMs) which opens up more docking sites for more TKs (clustering of TCRs on cell surface)
    3. Downstream ITAMs activate PLC-γ (increases Ca2+) and RAS (activates TFs e.g. AP-1)
    4. IL-2 production leading to perforin expression
33
Q

How is diversity in TCRs established?

A

All diversity established during development (no adjustments after):
- Recombination of β chain (catalysed by RAG1/2) – VDJ segments (have larger J diversity than BCR)
- Both CD4/CD8 receptors expressed (double +ve) then one selected for

34
Q

How are TCRs selected for to prevent self-reactivity?

A

Must have successful TCRβ rearrangement (can bind to MHC/peptide). Those that fail die by neglect.
Positive selection: choose useful cells.
- TCRαβ cells tested by cortical epithelial cells for MHC affinity
- Moderate affinity cells receive positive signal
- Cells can rearrange α chain to increase selection change
- Those that do not receive signal die by neglect

Negative selection:
- TCRαβ cells with high affinity for self-antigens are killed by apoptosis
- Can only be tested against self-antigens present in thymus

35
Q

How are high affinity BCRs formed in the lymph node pathway?

A
  1. pAPC (DC cells) enter, presenting antigens from periphery
  2. Naïve T cells survey MHC-antigen molecules and TFH cells with specific receptor activated
  3. Naïve B cells with receptors specific for antigen are internalised and presented to TFH cells
  4. T and B cells co-activate each other
  5. Some B cells differentiate into plasma cells to produce initial IgMs
  6. Affinity maturation occurs in germinal centres (B cells concentrate around follicular DCs) and compete with highest affinity BCR preferentially proliferating.
36
Q

Name some similarities and differences between MHC I and II structures

A
  • Both form a peptide binding groove
  • Class I formed from one long TM chain whereas class II has two symmetrical TM chains
  • Class II has open ended structure so longer peptides can fit (up to 25aas)
  • MHC I binds to CD8 while MHC II binds to CD4
37
Q

How is MHC diversity achieved?

A

An individual:
- Polygeny exhibited: 3 loci for each MHC class (HLA genes)
- Difference alleles (12 loci total) meaning more diversity as co-dominantly expressed
Population wide:
- Polymorphism: thousands of alleles throughout population (even if all genes inherited together from one parent)

38
Q

Why is MHC diversity necessary?

A

Balance between fastidious and promiscuous binding \t peptide binding domain (has anchor reisdues)
- Promiscuous binding maximises chance of MHC being able to present an internal peptide BUT reduces the likelihood of the same peptide being presented which is necessary for activation.
- Fastidious binding increases T-cell response BUT requires each cell to have many different MHCs to have chance of presenting pathogenic peptides (each pathogen has a short genome so few presentable peptides)
- Promiscuous binding does better in novel infections

39
Q

How are endogenous peptides presented on the cell surface?

A
  1. Proteosomes containing degraded protein translocate to the ER via the transporter associated with antigen processing (TAP).
  2. Suitable length peptides are loaded onto partially folded MHC Is using chaperones and the peptide loading complex (PLC
  3. Fully loaded MHC/peptides are released from chaperones and secreted to cell surface
  4. Defective ribosomal products (DRiPs) degraded
40
Q

How are exogenous peptides presented on the cell surface?

A
  1. Peptides are endocytosed and taken to ER
  2. Partially folded MHCs bound to invariant II chain which blocks the peptide binding groove and acts as chaperone – advances complex into endocytic pathway
  3. Invariant section removed to leave CLiP protein.
  4. CLiP removed by HLA-DM peptide editor and replaced with peptide
  5. MHC II presentation encouraged by IFN- γ
41
Q

What are the key principles behind tolerance?

A
  • Response to an antigen should not be damage to the host.
  • Tolerance is acquired not hard-wired (an intentional state of unresponsiveness)
  • Immune system adapted to respond to infectious non-self antigens
42
Q

How is central tolerance orchestrated? Include an example of failed central tolerance.

A
  • Developing T cells are exposed to a wide range of potential self-antigens.
  • Specialised cell antigens are expressed in the thymus due to the TF AIRE which induces peripheral genes, increasing the repertoire of antigens expressed.
  • Any TCRs with an affinity too high to any of these antigens are killed by apoptosis
  • Lack of the AIRE gene leads to autoimmune polyendocrinopathy candadisis (APECED) and damage to specialised cells. Results in diabetes, adrenal gland insufficiency, hypothyroidism…
  • Developing B cells which are highly reactive to common self-antigens are culled/undergo receptor editing (should need T cell activation so tight tolerance less important)
43
Q

Define peripheral tolerance and briefly list the forms of peripheral T cell tolerance

A

Peripheral tolerance: intentional state of unresponsiveness of lymphocytes after they leave their primary organ.
Types:
- Ignorance: potentially self-reactive cells are never activated (e.g. antigens hidden from the body in privileged sites such as the eye)
- Split tolerance: pathways in the immune system are interdependent so cannot function if not activated (e.g. autoreactive B cells not activated by strongly tolerised T cells)
- Anergy: state of non-responsiveness. Induced when TCR-MHC complex forms with no stimulatory signal on first activation.
- Treg suppression: reduces chance of activating effector cell (e.g suppresses proliferation of T cells)
- T cell exhaustion: failure to clear chronic infection where T cells become less responsive (no longer produce IL-2 and IFN- γ)

44
Q

Describe the roles of Treg suppression in peripheral tolerance:

A
  • Supresses T cell proliferation: binds to MHC II and secretes IL-10 and TGF-β
  • Reduce co-stimulatory signals on pAPCs: B7 presentation by pAPCs reduced and blocked by CTLA-4 receptors on Tregs. Soluble CTLA-4 used as immunosuppressant.
  • Particularly important for induced Tregs (iTregs) in gut associated lymphoid tissue (GALT) where many foreign but symbiotic organisms present.
  • Lack of Tregs leads to death by IPEX syndrome (in male mice)
45
Q

Suggest ways in which the body up or down regulates tolerance depending on infection status:

A
  • DC cells reduce anergy of naive T cells by upregulating B7 co-receptor presentation on pAPCs.
  • T cell exhaustion occurs after a prolonged/futile T cell response (exhausted T cells present PD1 rather than CD28 which is less responsive and stop producing IL-2 and IFN- γ
  • Body can produce immunosuppressive factors such as IDO and α-fetoprotein during pregnancy to reduce rejection chance.
46
Q

Suggest some factors which can affect tolerance of the immune system:

A
  • Timing (state of the body at that point e.g pregnancy)
  • Dose of antigen
  • Stimulation trigger: adjuvants are injected with antigens when an immune response is desired
  • Costimulation: cancer cells can lose MHC I expression effectively making immune system tolerant to them.
47
Q

What is complete Freund’s adjuvant (CFA) and why is it used?

A
  • Injected with antigens to stimulate an effective immune response
  • Made from ground up (heat killed) mycobacterium powder
48
Q

Describe Medawar’s experiments and how they show central tolerance:

A
  1. Mouse A injected with bone marrow from mouse B at birth
  2. Skin graft taken from mouse B six weeks later – put on mouse A and accepted
  3. Skin graft from control mouse C rejected
  4. Suggest mouse A had acquired specific tolerance to mouse B antigens
  5. If BM transplant done 1 week after birth, tolerance not acquired – suggests chimerism only possible in early life
  6. Occurs as some pAPCs which migrate to the thymus where they participate in -ve selection of thymocytes. Later donor cells are killed before they can migrate.
49
Q

Give reasons why pregnancy is a special case for tolerance.

A
  • Physical barrier to mother’s T cells due to placenta (no blood sharing)
  • Lack of MHC I expression on placental trophoblast cells (outer layer) to avoid CTL activity
  • Production of immunosuppressive factors (IDO and α-fetoprotein)
50
Q

Explain direct antibody mediated autoimmunity and give examples:

A

Hypersensitivity type II reaction (IgM/IgG):
- Citrullination: change of a peptide E.g. by deaminase causing foreign appearance of a peptide
- Graves disease (hyperthyroidism): antibody to TSH receptor, stimulating it continuously (no -ve feedback of thyroid hormone produced) – mainly Th2 type response with little inflammation.
- Hashimoto’s thyroiditis (hypothyroidism): antibodies against TSH receptors/thyroglobulin recruiting CD4/8 cells through Th1 response
- Myasthenia Gravis: antibodies to ACh receptors leading to decreased sensitivity at NMJ due to receptor degradation

51
Q

Explain immune complex mediated autoimmunity and give examples:

A
  • Normally immune complexes are cleared by complement binding (C1, C2, C4): binds to complement receptor 1 on RBCs which are cleared by spleen.
  • When this fails, autoimmunity can result.
  • Systemic lupus erythematosus (SLE): anti-nuclear auto-antibodies (against DNA) causing decreased complement action with impaired immune clearance. May be triggered by NETs and IFN-α which stimulates myeloid cells to produce BAFF (enhances survival of autoreactive cells)
52
Q

Explain T-cell mediated autoimmunity, giving examples:

A
  • Tissue destruction without requiring antibody production
  • Such as by cytotoxicity by CD8, direct destruction by TNF, recruitment of macrophages or apoptosis induction by Fas ligand
  • MS: damage to myelin sheath by T cells leading to impaired nerve transduction. Shown by mouse models of experimental autoimmune encephalitis (see notes for details)
  • Type-1 diabetes: T cells specific to β-cells in pancreas
  • Rheumatoid arthritis: leukocytes recruited and autoreactive CD4 cells activate macrophages = inflammation and production of MMP (attacks tissues)/RANK ligand (bone-destroying osteoclasts results in joint destruction) by fibroblasts.
53
Q

Suggest some risk factors for autoimmune disease:

A

Total risk = environmental + genetic + other factors
Genetic factors:
- HLA allotypes (GWAS)
- MHC association with different peptide binding (T1D: residue 57 of β-chain in MHC class II (HLA-DQ gene) is protective if charged but diabetogenic if hydrophobic)
Environmental factors:
- Infection with pathogen can initiate autoimmune problems (e.g. molecular mimicry with cross-reactive antibodies). Rheumatic fever and streptococcus.
- Twin concordance rate is 20-40%
Other factors:
- Sex (endocrine - oestrogen can be immunosuppressive; X-linked inactivation)
- Release of sequestered antigen (autoimmune sympathetic ophthalmia)
- Smoking (can induce protein modification
- Microbiota cross-reactivity (shown by germ-free mice)

54
Q

Name some mechanisms of treatment for autoimmune conditions:

A
  • Organ specific (e.g. thyroxine for hypothyroidism)
  • Immunosuppressive drugs (cyclosporin interferes with Ca2+ signalling in T-cells; rapamycin inhibits CD8 proliferation)
  • Antibodies (anti TNF-α for anti-inflammatory effect)
  • Preventing activation of T cells (CTLA4-Ig is a fusion protein complementary to CD80 and 86, preventing co-stimulation of T-cells by CD28)
55
Q

What is the key difference between autoimmunity and hypersensitivity?

A

Hypersensitivity is a failure of peripheral tolerance (to innocuous foreign antigens) rather than central tolerance
- Hypersensitivity can be IgE mediated (allergy); cell bound antigen recognised (IgM/G); soluble antigen recognition (IgG); T-cell mediated
- Autoimmunity can be direct antibody mediated; immune complex mediated or T cell mediated

56
Q

Discuss the mechanism of a type I hypersensitivity response. Include examples.

A

IgE mediated and fast response
1. Pre-existing IgE antibody from a previous Th2 mediated response
2. Cross linking of FcεRI (=bound IgE) to antigen
3. Primary response: rapid degranulation of mast cells (release of HA/SHT/prostaglandins)
4. Secondary response: inflammatory mediators are released
5. Predisposed (atopic) people have a serum IgE 10-100 times normal

57
Q

Discuss how an allergy induced asthma attack may occur

A

Chronic inflammation of airways characterised by increased Th2/lymphocytes/neutrophils
- Causes amplification of inflammation (sensitisation)
- DCs migrate to LN and activate allergen specific T-cells (induce clonal expansion)
Phase 1: degranulation of mast cells causes bronchiole constriction
Phase 2: leukotrienes facilitate eosinophils and Th2 recruitment
- Airways may become occluded by mucus plugs
- Can be exasperated by infection

58
Q

What is type II hypersensitivity? Include examples.

A

Cell bound antigen recognised (5-8hr response). For example:
- Penicillin binds to RBC (cross-reactivity) and becomes IgG/M target (new epitope formed)
- RBC then becomes target for clearance by macrophage or MAC formation
- Blood group cross-reactivity (ABP histocompatibility alloantigens)

59
Q

What is type III hypersensitivity? Include examples.

A

IgG mediated soluble antigens recognised:
- High concentration of soluble antigen
- Immune complexes form and trigger mast cells via low affinity FcγRIII receptor or complement activated (MAC)
- E.g. serum sickness

60
Q

What is type IV hypersensitivity? Include examples.

A

T cell mediated delayed hypersensitivity response (24-72hrs):
- Activated T cells secrete cytokines to recruit mononuclear cells
-Antigen concentration needs to be much higher than for antibody mediated
- Contact hypersensitivity – haptens form stable complexes with host proteins creating epitope (poison ivy or Ni contact dermatitis)
- Tested for using Mantoux test

61
Q

Why does blood cross-reactivity occur?

A

Blood Group Reactivity (problem for blood transfusions):
- ABO histocompatibility alloantigens (e.g. B adds a terminal galactose)
- AB people have antigens to neither A nor B (successful central tolerance)
- Rhesus marker another antigen (important for the second +ve child of a –ve mother as antibodies may have been stimulated by cross-contamination of blood in first birth)

62
Q

What is a Mantoux test and what does it prove?

A

Diagnosis of past mycobacterium tuberculosis infection (also reacts to vaccinated people)
- Inject small amount of tuberculin under skin and observe inflammation signs

63
Q

How can hypersensitivity reactions be reduced?

A

Inhibit mediator:
- Antihistamines or Leukotrienes receptor blocker
Chronic inflammation reduction:
- Corticosteroids
Reduce Th2 response:
- Desensitisation therapy by injection/ingestion of specific (non-lethal) antigens
Block immunoglobulin signalling:
- Anti-IgE antibodies (bind to Fc region) to prevent mast cell binding and hence degranulation

64
Q

Name the types of transplantation in order of rejection probability:

A
  • Autologous (self-self)
  • Syngeneic (identical twin - self)
  • Allogenic (same species) = most common
  • Xenotransplantation (different species)
65
Q

How can the chance of transplantation rejection be reduced?

A

Type of transplantation:
- Genetic matching
- Transplant type (vascularised organ, privileged site
Immunosuppression;
- Ablation of recipient immune system (chemotherapy/radiation)
- Steroids (mimic corticosteroids)
- Humanised anti-CD52 antibody, activates complement (ADCC) on leukocyte surface.
- Drugs targeting cell signalling pathways in lymphocytes (cyclosporin, rapamycin)
- Cytotoxic drugs against rapidly dividing T cells (azathioprine)
- CTLA-4Ig prevents CD28 co-stimulation (tolerance induced)
- Treg cell upregulated
Cross-matching:
- Similar HLA genotype (screen recipient to prevent hyperacute rejection)

66
Q

Discuss the types of haemopoietic stem cell transplant:

A

Autologous transplantation:
- Stem cells removed, remaining immune system ablated. Own cells re-infused after tumour removal (can be genetically engineered to express CARs specific for tumour targets: e.g. CD19 on cell lymphoma)
- No histo-incompatibility problem, but relapse chance higher
Adoptive T cell therapy:
- Isolation of tumour reactive cells, expanded in cell culture (in vitro)
- Transferred back to patient
Allogenic transplantation:
- HLA matched (as far as possible)
- GvH can occur
Haploidentical transplantation:
- Close relative (with HLA match) is donor
- Little GvH and some GvL
- Particularly effective for acute myeloid leukaemia (AML)

66
Q

Describe hyperacute rejection after transplantation:

A
  • Due to pre-existing antibody (e.g. ABO incompatible transplants)
  • Rapid rejection as HLA antigens are expressed on endothelial lining (damaged by complement/agglutination/microvasculature blocking)
  • Xenotransplantation particularly bad since discordant and complement does not function well cross-species (not disabled by DAF).
66
Q

Describe acute rejection after transplantation:

A

T-cell recognition of transplanted tissue due to difference in HLA genes. Either direct or indirect:
Direct recognition = detection of foreign MHC on donor pAPC
- Causes sensitisation by migration of DC cells to lymphoid tissue
Indirect recognition (slower):
- Reaction to foreign peptide presented (even if self MHC e.g. Y chromosome peptides presented on identical MHC)
- Stimulates CD4 alloreaction
- Donor DC cells killed off after migration to lymph node
- MHC sharing between donor/host increases reactivity since donor cells can bind TCRs directly.

67
Q

Describe the mechanisms of chronic rejection after transplantation:

A
  • Blood supply to organ compromised resulting in ischemia/functional loss
  • Type III hypersensitivity reaction: alloantibodies against foreign endothelium lining) where IgG antibodies against HLA class I form immune complexes which deposit in blood vessels
  • Can be induced by damage to endothelial lining allowing increased effector cell entry
68
Q

Explain the difference between graft-vs-host and graft-vs-leukaemia reactions following a bone marrow transplant.

A

GvH: type IV hypersensitivity reaction:
- Where donor cells recognise and attack host cells.
- Very bad since cells often already damaged by chemotherapy/irradiation
GvL: donor cells migrate and help kill leukaemia
- Useful since host immune system may not be fully functional.

69
Q

What is cross-matching during donor selection for transplantation and how is it achieved?

A

Get similar HLA genotype to reduce rejection chance:
- Screen recipient serum against microbead panel with specific HA antigens and tag using secondary antibody
- A +ve cross-matching test suggests recipient has pre-formed antibodies against donor alloantigens (likely to cause hyperacute rejection)

70
Q

Name immunosuppressive molecules and their mode of action:

A

Drugs:
- Cyclosporin: interrupts Ca2+ signalling in T cells by inhibiting calcineurin. Prevents IL-2 transcription, hence reducing inflammatory signals.
- Rapamycin: arrests T cell in G1 phase (inhibits proliferation)
- Azathioprine: cytotoxic drug against rapidly dividing cells (T cells) by inhibiting nucleotide synthesis
Antibodies:
- Humanised antibody to CD52 on leukocyte surface, causes complement activation (ADCC)
- CTLA-4Ig prevents CD28 co-stimulation (increases tolerance)
‘Living drugs’:
- Chimeric antigen receptors (CARs) on T cells: receptor directly linked to CD3ζ chain – upregulates T cell action, especially during B cell decrease
Steroids:
- Mimic corticosteroids giving similar generalised immunosuppression to endorphins

Biology of Disease (7 decks)

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