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HIS > HIS15 Cell Mediated Immune Reactions > Flashcards

HIS15 Cell Mediated Immune Reactions Flashcards

1
Q

Cell-mediated immune reactions

A
  • ***Localised reaction (as opposed to Ab-mediated systemic (Humoral) reaction)
  • Immune reactions mediated primarily by immune cells (esp. T cells)
  • Ab and other humoral factors: Subordinate roles
  • AKA Cell-mediated Immunity (CMI)
  • ***Innate + Adaptive immune responses
  • Basic elements and Effectors mechanisms:
  1. T cells (induction and maintenance of CMI) —> Specificity by TCR for immune recognition reactions
    - Helper T cell (Th) —> Cytokines
    - Cytotoxic T cell (CTL) —> Target cell killing
  2. Phagocytes
    - Macrophages, Neutrophils etc.
    —> Kill / inactivate pathogens / infected cells directly
    —> Play roles in bridging innate and adaptive immunity —> present Ag on MHC to TCR of T cell
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2
Q

Classification of CMI

A

According to:

  1. T cell dependency
    - T-dependent (specific) —> CTL, Th
    - T-independent (early phase / non-specific) —> NK, MQ
  2. Main effector mechanisms
    - Cell-mediated cytotoxicity (by CTL, NK)
    —> CTL-mediated Killing
    —> ADCC
    —> NK cell-mediated Killing
  • Phagocytosis (by MQ, Neutrophil)
    —> T-dependent Macrophage activation
    —> T-independent Macrophage activation
  • Cytokine-mediated direct target cell killing (by Th1)
    —> Released from Cytotoxic cell (e.g. MQ, CTL, NK)
    1. IFNγ
    2. TNFα/β
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3
Q

***Cell-mediated cytotoxicity

A

3 types:

  1. Cytotoxic T Lymphocyte (CTL)-mediated Killing
  2. Antibody-dependent Cell-mediated Cytotoxicity (ADCC)
  3. Natural Killer (NK) cell-mediated Killing (***INNATE)
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4
Q

Cytotoxic T lymphocytes (CTL)

A
  • Mainly CD8+ T cells
  • MHC class I restricted (i.e. recognise intracellular / endogenous Ag) (~90% CD8+ T cells are MHC class I restricted)
  • Activation of CTL requires 2 signals
    1. TCR (interact with MHC-I) —> include CD8 co-receptor
    2. ***CD28 (interact with CD80/CD86 on APC)
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5
Q
  1. CTL-mediated killing
A

***Via TCR

T cell mediate cytolysis of Target cells which present Ag (but not nearby normal cells)

  1. Virus infected cells —> e.g. viral protein
  2. Tumour cells —> e.g. mutated tumour Ag
  3. APC with Intracellular bacteria / parasites —> e.g. peptide antigen
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6
Q

5 stages of mechanism of Target cell killing by CTL

A
  1. CTL bind to Target cell (MHC class I for CD8+ T cell lysis)
  2. TCR-MHC interactions and CTL activation
  3. CTL introduce “lethal hit” via activation of target cell’s apoptosis / through a “toxic hit” of chemicals
    —> Cytotoxic factors release (***Perforin, Granzymes, Lymphotoxin)
    —> Perforin: introduce transmembrane pores on Target cell —> Osmotic lysis
    —> Granzyme: enter through pores and kill Target cell by activating apoptosis
    —> Lymphotoxin: programmed cell death
  4. Target cell death once CTL detached
  5. Recycling of CTL for additional attacks

Other mechanisms
1. CTL can also receive Cytokines (***IL-2) from Th cells
—> further stimulated
—> Clonal expansion with specificity to Ag presented by APC

  1. Activated CTL also release ***IFNγ for activation of macrophages
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7
Q

Perforins and Granzymes

A

Both primarily used for lysis of cells infected with ***intracellular pathogens

Perforins:

  • released from cytoplasmic granules of CTLs
  • form pores in target cell membrane
  • ***allow granzymes to enter
  • also cause ***osmotic lysis

Granzymes:

  • Protein molecules that ***activate apoptosis
  • some are also ***toxic to intracellular pathogen itself (e.g. Granulysin)

Others: Fas - Fas ligand binding also induce apoptosis (via Caspase and Endonuclease reactivation)

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8
Q

CTL recognition blocked by Ab binding

A

Ab binding:
1. Directly to microorganism surface
2. MHC / peptide complex
—> block access of CTL to MHC / peptide complex
—> CTL cannot be activated
—> Antibody-dependent Cell-mediated Cytotoxicity (ADCC) become useful

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9
Q
  1. Antibody-dependent Cell-mediated Cytotoxicity (ADCC)
A
  • Mediated by ***Large Granular Lymphocytes (LGL) (e.g. NK cells)
  • Cytotoxic cells possess ***Fc receptors
    —> Ab as a bridge between effector cell (LGL) and target antigen
    —> Antigen specificity by Ab
    —> Ab Fc receptor (FcR) on LGL recognises Ab on abnormal cell
    —> Activated LGL
    —> Release cytotoxic factors (Perforin, Granzymes) to kill cell

Target cells:

  1. Virus infected cells
  2. Tumour cells
  3. APC
  4. Microorganism itself (no need APC, Ab directly bind to Ag on microorganisms)
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10
Q
  1. Natural Killer (NK) cell-mediated Killing
A

***NO Ag specificity —> Innate response

NK cells:

  • 2 receptors: KAR (killer activatory receptor) + ***KIR (killer inhibitory receptor)
  • KAR (Lectin): recognise Carbohydrate on cell surface —> Killing signal
  • **KIR (Ly49): recognise **Self MHC-I (normal MHC) —> Inhibit Killing signal

Normal cell:
NK cell both KAR + KIR activated —> NK cell not activated —> No killing

Abnormal cell:
**Change in MHC/peptide complex (e.g. **MHC not expressed) —> KIR not activated —> no KIR signal, NK cell only KAR activated —> NK cell activated —> Killing by cytotoxic factors (Perforin, Granzymes)

Target cells:

  1. Tumour cells (no MHC-I)
  2. Grafts (non-self MHC-I)
  3. Virus-infected cells (foreign Ag)
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11
Q

***Summary of CTL-mediated killing, ADCC, NK cell-mediated killing

A

CTL-mediated killing:

  • CTL
  • ***TCR recognising MHC/peptide complex

ADCC:

  • LGL
  • ***Fc receptor recognising Ab (bound on MHC/peptide complex OR Ag of microorganism)

NK cell-mediated killing:

  • NK cell
  • KAR recognising Carbohydrates / ***KIR recognising MHC-I
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12
Q

Phagocytes

A
  • ***Innate immunity
  • Recognition + Elimination of invading pathogens
    1. Neutrophils
    2. Monocytes
    3. Macrophages
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13
Q

***T cell-independent Phagocytosis / Macrophage activation

A

T-independent Macrophage activation: ***靠Complement + Ab + Bacteria component + IFNγ from NK cell

  1. Chemotaxis
    - Chemotactic components from **Complement (Ab-Ag complex) / **Ab / ***Bacteria itself
    —> create concentration gradient
    —> concentration gradient attract phagocytes to migrate towards bacteria
  2. Adherence, **Membrane activation, Phagocytosis
    - **    change in surface of phagocytes (e.g. Complement receptor, Fc receptor, Adhesion molecules)
    —> able to attach to microorganism
    —> initiation of Phagocytosis
    —> Phagosome
  3. Destruction
    - Lysosome fuse with Phagosome
    —> ***Lysosome release toxic substances
    —> killing and digestion of microorganism
  4. Release of degradation products
    —> degraded Ag bind to MHC-II molecules
    —> present on surface of Phagocyte as MHC-II/Ag complex (i.e. APC)
    —> bridge between Innate and Adaptive immunity
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14
Q

Chemotaxis

A
  1. Bacterial components (e.g. Formyl-Methionyl-Leucyl-Phenylalanine (f-Met-Leu-Phe / fMLP))
  2. Complement products (e.g. ***C5a, triggered by Ab-Ag complex)
  3. Chemokines and Cytokines (locally released from other immune / tissue cells)
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15
Q

Mechanisms of recognition in Phagocytosis

A
  1. **Fc receptor-mediated
    - recognise **    Ab on pathogens bind to Fc receptor on phagocytes
  2. **Complement receptor-mediated
    - e.g. C3b, C3bi / C1q receptors on macrophages
    - recognise **    Complement deposited on pathogens (via alternative / classical / lectin-induced pathway) bind to Complement receptor
  3. **Mannose receptor-mediated
    - recognise mannose and fucose-containing **    oligosaccharides on pathogen surface (e.g. cell wall)
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16
Q

***T-independent Macrophage activation: Cytokine release from Macrophage and NK cell

A

NK cell
1. ***IFNγ —> attract Macrophage —> adhere to and squeeze through endothelium to infection site

Macrophage
1. ***IL-12 —> activate NK cell + Th
2. ***TNFα
—> activate NK cell
—> attract Granulocyte —> adhere to and squeeze through endothelium to infection site
17
Q

***T-dependent Macrophage activation

A

Late phase of phagocytosis

T-dependent Macrophage activation: ***靠IFNγ from Th

Macrophage (Primed with inactivated pathogens) (本身食左野):
—> Ag presented on MHC-II + Co-stimulatory signal (CD40)
—> Activate Th1 (with CD40L)
—> Th1 produce IL-2 (—> IL-2 activate Th1 itself (自己stimulate自己) —> Clonal expansion of Th1)
—> Th1 release IFNγ
—> activate Macrophage
—> further enhance Antimicrobial function (再增強自己食野能力)

  • **Effects:
    1. MHC expression ↑
    2. Lysosomes formation ↑
    3. Phago-lysosomal fusion ↑
    4. Inducible NO synthase (iNOS) —> ROS ↑ for pathogen killing
    5. IL-12 production ↑ —> further stimulate Th (+ve feedback)
18
Q

Effector mechanisms for Macrophage-mediated killing of microorganisms

A
  1. Reactive Oxygen Intermediate (ROIs) (majority)
    - by Myeloperoxidase in Lysosome / Catalase from Peroxisomes
    - Superoxide anion
  2. Reactive Nitrogen Intermediate (RNIs)
    - Nitric oxide (by nitric oxide synthase)
  3. Other mediators
    - Defensins, Lysozyme, Complements, Cytokines, Chemokines (e.g. IL-1, TNF, IFNγ)

End result:

  • Bacterial killing
  • Recruit + Activate additional immune cells
19
Q

Cytokines classification

A

Small pharmacological active products (peptides / glycoproteins) of cells (mainly by Th cells)

  1. Lymphokines
    - cytokines by lymphocytes
  2. ***Interleukins
    - IL1-39
    - Interferons (IFN)
    - TNF
    - etc.
  3. Monokines
    - cytokines by ***monocytes/phagocytes
  4. Chemokines
    - cytokines with ***chemotactic function
    - CXC (IL-8)
    - CC (MDC)
    - CX3C (Fractalkine)
20
Q

***Cytokines principles of action

A

Function:

  1. Activate MQ, lymphocytes
  2. Direct killing of infected / tumour cells

Features:

  1. Local / Systemic effects
    - Autocrine action (e.g. IL-2: 自己stimulate自己)
    - Paracrine action (local, short distance)
    - Endocrine action (travel in circulation)
  2. ***Unique receptor for each cytokine
  3. **Pleiotropic (different actions by 1 cytokine) + **Redundant (multiple, overlapping cell regulatory actions)
  4. ***Synergistic (cooperative effect)
    - dual activation
    - induction of receptors for other cytokines
  5. Complex network
    - a single cell can secrete / susceptible to >=1 cytokine
  6. Bind to cytokine receptor
    —> signal transduction
    —> trigger ***gene activation (e.g. adhesion molecules, NO synthase, cytokine receptors, MHC molecules)
    —> biological effects (e.g. adhesion, phagocytosis, activation, proliferation, differentiation, growth inhibition)
21
Q

Cytokine-mediated Direct Target cell Killing

A

Released from Cytotoxic cell (e.g. MQ, CTL, NK)

  1. TNFα/β
  2. IFNγ
22
Q

***Th cell subsets and their reciprocal control

A

Th0 (Naive T cell)

簡單而言:

  • Intracellular pathogen —> Th1 —> IFNγ (inhibit Th2) —> CMI
  • Extracellular pathogen —> Th2 —> IL-4 (inhibit Th1) —> Ab production
  1. Intracellular pathogens (e.g. virus, mycobacteria, protozoa)
    (—> IL-12, IL-18, IFNγ)
    —> Th1
    —> **IFNγ, IL-2, TNFα (Th type 1 cytokine) —> **Inhibit Th2
    —> Cell-mediated immunity
  2. Extracellular pathogens (e.g. bacteria, parasitic worms)
    (—> IL-4, IL-6, IL-10)
    —> Th2
    —> **IL-4, IL-5, IL-10 (Th type 2 cytokine) —> **Inhibit Th1
    —> Antibody production

Type of immune effector mechanism induced (i.e. Th1 / Th2) may determine outcome of infection
E.g. Leishmania infection (intracellular pathogen)
—> Th1 cytokine profile
—> CMI
—> macrophage activation
—> disease resolved

If condition changed and favour Th2
—> Th2 cytokine profile
—> progressive disease due to CMI suppression

23
Q

***Th1 cells

A

Orchestrate CMI through

  1. Cytokines secretion (e.g. IFNγ, TNFα, IL-2)
  2. Enhances activity of Macrophages, Neutrophils, CTLs
  3. Causing B cells to produce Ab subtypes (e.g. IgG) capable of mediating ***ADCC
24
Q

CMI in Delayed Type Hypersensitivity reactions (DTH)

A

DTH: immune reactions that show peak responses at 24-72 hours after antigen administration

  • e.g. TB infection, Contact dermatitis
  • Important for resistance to intracellular pathogens
  • Specific ***T cell responses to Ag (e.g. TB)

Mediator: Th1
Effector: MQ

  1. Induction phase
    - antigen-sensitised T cells release IFNγ following a secondary contact with same antigen
  2. Inflammatory phase
    - IFNγ induce inflammatory reactions (e.g. Contact dermatitis)
    —> activate and attract MQ
    —> MQ release IL-12 to attract more Th1
  3. Effector phase
    - activated MQ kill intracellular pathogens
  4. Chronic DTH reaction
    - persistent sources of Ag (e.g. Mtb)
    —> large mass of MQ and Th1
    —> granuloma formation (Th1 + Epitheloid cell + Multi-nucleated giant cell + Mtb)
    —> Th1 contain tuberculoid infection
25
Q

CMI and clinical relevance

A
  1. Immunity against tumours (CTL, NK)
  2. Transplantation graft rejection (CTL, NK)
    - Delayed type hypersensitivity reaction
    - Cell-mediated cytotoxicity

HIS (30 decks)

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