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MII2 > 2. Pathogen detection by the immune system > Flashcards

2. Pathogen detection by the immune system Flashcards

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1
Q

What are the innate immunity and adaptive immunity cells?

A

Innate imm cells/molecules:
- Macrophages
- Dendritic cells
- Mast cells
- NK cells
- Complement proteins
- Granulocytes: basophils, eosinophils, neutrophils

Adaptive imm cells:
- T cells
- B cells

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2
Q

How is pathogen detection different in innate and adaptive immunity?

A

Innate: recognises generic ‘danger’ signals (PAMPs / DAMPs) -> limited receptor diversity

Adaptive: recognises very specific microbial / non-microbial molecules - antigens -> very large receptor diversity

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3
Q

What is the Complement System in pathogen recognition? What are the pathways of working?

A

The Complement System - biochemical cascade that functions to recognise pathogens and destroy them - early warning system

Has 3 pathways of working:
- Alternative (innate immunity)
- Lectin (innate immunity)
- Classical (adaptive immunity)

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4
Q

What functions can be performed using the Complement System to destroy pathogens?

A

The Complement system does to destroy pathogens:
- Recruit immune cells
- Label microorganisms for phagocytosis by other cells
- Lyse pathogens

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5
Q

How each Complement system pathway is activated?

A
  • Direct pathogen recognition => alternative + lectin pathway
  • Via adpative immunity + antibodies => classical pathway
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6
Q

Explain the alternative pathway of the Complement System

A

Alternative pathway acts as innate immunity sensor:
- C3 protein - (C3 convertase) -> C3a + C3b
- C3b attacks amino + hydroxy groups on pathogen surface
- Complement system cascade ativated to neutralise the pathogen

Problem: host cells also have amino + hydroxy groups on the surface - must de-activate C3b

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7
Q

Explain lectin pathway of the Complement System

A

Lectin pathway acts as innate immunity sensor:
- lectin receptors bind to mannose on pathogen surface
- binding activates C3 convertase -> C3b produced -> bind to pathogen amino and hydroxy groups
- Complement System cascade ativated to neutralise the pathogen

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8
Q

What does the innate immunity use to recognise pathogens?

A

Innate immunity uses evolutionary conserved molecules in many classes of microbes that are not present in host cells - PAMPs

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9
Q

What are PAMPs?

A

Pathogen Associated Molecular Patterns (PAMPs) - evolutionary conserved molecules shared by various classes of microbes, ex: mannose

PAMPs - on pathogens
PRRs - on imm cells

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10
Q

What are the receptors used to detect PAMPs?

A

Pattern Recognition receptors (PRRs) - proteins / receptors on the surface of innate immunity cells used to recognise PAMPs, ex.: mannose binding lectin

PAMPs - on pathogens
PRRs - on imm cells

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11
Q

Explain the mechanism of phagocytosis

A
  1. Chemotaxis: attract phagocytes to the site
  2. Attachment: phagocyte attaches to surface of foreign particle
  3. Engulfment: ingested
  4. Phagosome maturation: fusion with lysosomes with digestive enzymes -> phagolysosome
  5. Degradation: in phagolysosome particle digested
  6. Exocytosis: waste eliminated form phagocyte

Chebra Atvaro i Edinburga Pilt, Dirbt, Edukuotis

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12
Q

What are sentinel cells?

A

Sentinel cells - general term for any immune cell at the first line of defence - always alert, ex.: macrophages, dendritic cells

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13
Q

What are the roles of sentinel cells to sense infection and induce response?

A
  • Use phagocytosis to sample environment
  • If detected APC - communicate to T cells
  • Activate T cells
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14
Q

What are APCs?

A

Antigen Presenting Cells (ACPs) - immune cell that detects, engulfs, and informs the adaptive immune response about an infection

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15
Q

Compare macrophages and dendritic cells (DC) as sentinel cells

A
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16
Q

Explain macrophages as sentinels

A

Macrophages as sentinels - found** in all barrier tissues** - skin, intestine, lungs

Resting state - help regulate metabolism:
- clear apoptotic cells
- remove debris
- sample env for antigens via PRRs-PAMPs

Activated state:
- detected DAMPs (1st danger signal) - warning but not necessarily infection - activate Complement System pathway - ready for phagocystosis
- detected PAMPs (2nd danger signal) by PRRs - infection alert - increase in size, increase phagocytosis, release toxic molecules + cytokines
- in the end - macrophages revert to resting state / apoptose

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17
Q

What are DAMPs?

A

Damage-Associated Molecular Patterns (DAMPs) - molecules released from damaged / necrotic cells

  • potential break in barrier
  • pathogen is causing damage while invading
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18
Q

Do innate immunity cells express only one PRR? Where are they found?

A

No, innate immunity cells can express multiple PRRs - can recognise and respond to wide range of pathogens with different PAMPs

PRRs are both on the surface and inside the cell - intracellular / extracellular

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19
Q

What are the examples of PAMPs?

A

Possible PAMP molecules:
- mannose
- lipopolysaccharides (LPS) - Gram-
- lipoteichoic acid (LPA) - Gram+
- teichoic acid (TA) - Gram+
- peptidoglycan
- flagellin
- dsRNA
- ssRNA
- unmethylated CpG DNA

Recognised by PRRs - majority by Toll-like receptors (TLRs)

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20
Q

How can pathogens try to avoid recognition by the immune system?

A

Pathogen adaptations:
- Modification of PAMPs
- Inhibition of PRRs signalling pathways

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21
Q

Summary of macrophage activation as a sentinel cell

A
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22
Q

Explain how inflammation is induced

A
  • By both innate / adaptive immunity
  • Release of pro-inflammatory cytokines (ex: interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α))
  • Recruit immune cells to infection site
  • Activate immune cells and stimulate to produce more cytokines
  • Production of APPs
    => tissue redness, swelling, fever
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23
Q

What are APPs? What are the types?

A

Acute Phase Proteins (APPs) - group of plasma proteins - the conc varies - produced in response to inflamm / infection - function is to regulate imm response

  • Positive APPs: increase in conc upon inflamm / infection, ex: CRP - binds to pathogens and enhances recognition + activates Complement system (practical 1: diagnostic for severity of inflamm), fibrinogen
  • Negative APPs: decrease in conc upon inflamm / infection, ex: albumin
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24
Q

What are the functions performed by neutrophils?

A

Neutrophils:
- recruited from blood to the infection site
- phagocytosis of pathogens
- release of destructive chemicals (cytokines, chemokines, ROS, enzymes, defensins)
- short-lived - apoptose

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25
What are the immune cells involved in killing pathogens during inflammation?
Killers in inflammation: - Neutrophils - NK cells - Macrophages
26
What are the functions performed by NK cells?
Natural killer (NK) cells: - **recruited from blood** to infection site in response to cytokines / chemokines - produce cytokines / chemokines - **kill pathogens / infected + abnormal cells** without activation - detect downregulation of MHCI - kills by releasing **cytotoxic granules** with perforin + granzyme -> **induces apoptosis** - apoptose / revert to resting state
27
What are the main immune cells involved in inflammation?
- **Macrophages**: phagocytic, produce cytokines/chemokines - **Neutrophils**: phagocytic, produce cytokines/chemokines - **NK cells**: recognise + kill infected / cancerous cells, release cytotoxic granules, produce cytokines
28
Can PAMPs be toxins?
Yes, ex.: PAMP - **LPS toxin** - induce **too strong cytokine production** => **sepsis**: - inhibits **heart contractions** - **fluid leaks** into tissues - increased **blood clotting** - **cachexia** (muscle wasting) => reduced blood presure => septic shock
29
What is sepsis?
**Sepsis** - body's **extreme response to an infection** - life-threatening medical emergency - happens when an infection you already have triggers a chain reaction throughout your body
30
What are the advantages of **innate** immunity sensing?
**Adv**: - PAMPs allow **distinguish foreign microbes** + **indicate what kind of microbe** - **PAMPs** evolutionary conserved - **well detected** - small number of PRRs needed - **PRRs germline encoded** - don't need modifications - can be used for quick response - **multiple cell type**s can express **same PRRs** - many cells can respond to same infection - **one cell** can express **many PRRs** - can detect many PAMPs - many different microbes
31
What are the disadvantages of **innate** immunity sensing?
**Disadv**: - **not very specific** - rough idea of microbe type - **not adaptable** (only through evolution) - doesn't develop into **immune memory**
32
What are the advantages of **adaptive** immunity sensing?
Adv: - very **adaptable** - somatic rearrangement of gene segments allows creation of receptors for any antigen - very **specific** for the antigen - having a receptor gives **immune memory** - can identify particular microbes for the rest of organism's life
33
What are the disadvantages of **adaptive** sensing?
- **slow** - takes time for clonal expansion - highly specific - easy for **microbe to evade** by slightly changing antigens - **receptors can't tell what they are recognising** - can't distinguish pathogen from self / innocuous molecules (ex.: pollen)
34
What are innocuous molecules?
**Innocuous molecules** - **harmless** molecules, ex.: pollen, other allergens
35
Define what is an antigen
**Antigen** - a molecule recognised by adaptive immune cells as non-self Bound by B or T cell receptors: - T cells only bind Ag on APC presented on MHC - B cells recognise Ag on their own
36
Define what is an epitope
**Epitope** - the precise **part of the antigen** **recognised** by **antibody** / **T cell receptor** An antigen can have multiple epitopes
37
Define what is a paratope
**Paratope** - the **part of** the **antibody** / **T cell receptor** that **binds the epitope**
38
Where do antibodies come from?
Antibodies - **secreted B cell receptors**
39
What are the adaptive immunity cells?
- B lymphocytes - Helper T cells (Th) - Regulatory T lymphocyte (Treg) - Cytotoxic T lymphocytes (CTL)
40
What is the difference how B and T cells recognise antigens?
B and T cells have **different receptors**: - B cells: **recognise Ag on their own** - membrane bound receptors - B cell receptors (**BCR**) **=** surface immunoglobulins (**sIg**) same thing - when secreted **Ab** **=** immunoglobulins **Ig** same thing - secreted form has effector function - T cells: **recognise Ag** **presented by APC** (ex: macrophages / DC) - T cell receptors only membrane bound - T cell receptors (TCR)
41
How do the antigens recognised by B and T cells differ?
**B cell recognised Ag**: - pretty much **any organic molecule** - bind on their own without APC - conformational - **structure important** in binding - epitope can cross loops - **discontinuous** - native molecule - also recognises **native molecules + unprocessed native molecules** **T cell recognised Ag**: - recognises **only proteins** - **Linear** - **8-25 am a long** - must be **presented by APC** - protein has to be broken down into peptides
42
How do B and T cell receptors differ?
- **T cell** receptors have **one Ag binding site** - **B cell** receptors have **two Ag binding sites**
43
What are the types of antibody epitopes?
Antibody - antigen binding: - **Linear** - **Discontinuous**
44
What is the structure of an antibody?
Antibody (Ab) = immunoglobulin (Ig) - secreted B cell receptor structure: - **Light chain** - **Heavy chain** - **Fc region** - **Fab region**
45
What is the in depth structure of a T cell receptor?
- α and β chains - sulphide bonds - transmembrane region
46
How is almost an infinite range of antigen receptors created?
- **Some** are **encoded in germline** - not enough - **Somatic recombination** - antibodies are **modular** - different **VDJ combinations** can be created - **Junctional diversity** (part of somatic recombination) - addition / deletion of bases - new DNA sequences at borders between VDJ modules
47
Explain what is somatic recombination
**Somatic recombination** - genetic info in non-reproductive cells rearranged for new gene combinations - occurs **during B / T cell development** - **V(D)J** gene recombination - antigen **binding domains are modular** - segments can be **re-arranged** using **recombinases** - higher diversity of BCRs and TCRs for Ag recognition - somatic recombination can also generate **self-reactive BCRs and TCRs** - autoimmune disorders
48
What is an antigen binding domain characteristic which allows somatic recombination?
**Antigen binding domains** are **modular** - **VDJ domains** can be miss-matched for specific antigen complementarity - **highly variable sites** created - VDJ recombinase used
49
Explain what is junctional diversity
**Junctional diversity** - **variability** that arises **at junctions between VDJ segments** during somatic V(D)J recombination - addition of a base - deletion of a base => **changes amino sequence** -> more unique Ag
50
What kind of rearrangements can be produced by somatic recombination (+junctional diversity)?
New rearrangements can be: - **Productive**: results in **functional receptor** - those B cell survive - **Non-productive**: results in **non-functional receptor** - B cell that produces non-productive arrangement for a receptor (-> Ab) die - apoptosis - MAJORITY of rearrangements non-productive - **not sustainable mechanism**
51
Where are VDJ genes located for VDJ modules of antigen receptors?
**VDJ genes** are located on both **chromosomes 14** (from each parent) - **two chances** to make **productive VDJ** **arrangements for each cell** because: - **each B cell** is **specific for one Ag** - only **one Ab** (BCR) is allowed **per one B cell** => successfully rearranged chain will block gene rearrangement on the other chromosome - already has a functional receptor in the B cell
52
What is clonal expansion?
Clonal expansion: - T/B cell **sees Ag** - becomes **activated** - T/B cells **divide** -> all **daughters** have **identical Ag** specificity - **time required** to **activate + proliferate** to an effective number makes **adaptive immunity slow** - 5-7 days
53
What is the timeline of an adaptive immune response to a specific pathogen?
54
How can pathogens evade adaptive immune recognition?
Pathogens can **mutate their Ags** - immunity **can't recognise** them - adaptive immunity especially - even single change can cause the **receptor** to be **non-complement** for Ag - because highly specific
55
What is the central tolerance?
**Central tolerance** - a **mechanism** by which **T and B cells** that are capable of **recognising self Ag** are **deleted before they are released to fight self** - Self-reactive **B** cells removed in **bone marrow** - Self-reactive **T** cells removed in **thymus** [However, doesn't remove T cells which have receptors to recognise innocuous antigens (food) - ?? B cells can also recognise]
56
What is the main problem with B and T cell antigen detection?
B and T cells **can't distinguish what they recognise** - pathogen / toxin / innocous antigen / self
57
How does innate immune system communicate with T cells?
Correct **T cells are activated** by **professional APCs** which are innate immunity cells - mostly dendritic cells (DC)
58
What is a naive T cell?
T cell - circulating in the body - **haven't been exposed to an Ag** - professional APCs introduce to Ag -> activation / differentiation => activated functional T cell
59
What is MHC?
**Major Histocompatibility Complex** (MHC) - **class I** + **class II** proteins - **present Ag on APC surface for T cell recognition** - can bind several peptides - **not highly specific as receptors**
60
What is the structure of MHC I and II?
**MHC I**: **α** chain transmembrane - **intra-cellular Ag** **MHC II**: **α + β** chains trnsmembrane - **extra-cellular Ag** S-S - disulphide bonds
61
What is the difference between MHC I and II?
**MHC I**: - binding peptide **7-11 am. a.** - **α** chain embedded in membrane - binds intra-cellular Ag - **endogenous pathway** - present on **all nucleated cells** - binds **CD8+ CTL cells** -> infected cells killed **MHC II**: - binding peptide **12-15 am. a.** - **α + β** chains embedded in membrane - binds extra-cellular Ag - **exogenous pathway** - present only on professional APCs - binds **CD4+ Th cells** -> cytokines produced to regulate imm response
62
What is MHC haplotype?
**MHC haplotype** - s**et of MHC alleles** present **on each chromosome** - MHC genes are **codominantely expressed** - alleles **from both parents expressed equally** Each organism expresses a **diverse set of MHC molecules** - encoded by MHC class I /II genes (HLA-X)
63
What is the difference between intracellular and extracellular Ag?
**Intracellular Ag**: processed within the cytoplasm - tumor / bacterial / viral proteins / cellular proteins - **processed within the cytosolic pathway** (MHC I) **Extracellular Ag**: internalised by phagocytosis / endocytosis - **processed within the endocytic pathway** (MHC II)
64
What are CD4 and CD8?
CD4 / CD8 - **proteins** which form a bridge between TCR and: - MHC II - CD4+ Th cells - MHC I - CD8+ CTL cells => **CD4 and CD8** termed **co-receptors** and considered an integral part of this multimolecular complex
65
Why is MHC haplotype important in organ transplant?
**MHC haplotypes of donor - recipient** must be **matched** - **tissue typing** - foreign MHC molecules on graft activate T cells - **kill the graft as an infection** => hard to find donor matches - everyone has different mixes of MHC - **MHC genes mots polymorphic genes in mammals**
66
How are pheromones involved in MHC haplotype?
**T shirt experiment**: the opposite sex smells best when the MHC alleles match the least - **ensures that children have varied MHC alleles** - best for Ag recognition if different MHC present
67
What is the sequence of events in endogenous and exogenous pathways?
68
Extra reading for MHC I, MHC II, Ag processing and presentation
https://microbenotes.com/mhc-antigen-processing-presentation/
69
What is the role of DC cells in immune response?
**Dendritic cells** (DC) - innate immunity cells: - present in all barrier tissues - scan for infection via PRRs by **sampling environmental Ag** - when Ag found - **take to lymph nodes** (LN) - talk with T cells - **present** **self-Ag**, **harmless Ag** and **pathogenic Ag** to T cells - **don't kill** like macrophages
70
What are the three phases of DC cells?
1. **Sampler**: samples the env for Ag - expressed **PRRs to detect DAMPS and PAMPs** - bad at presenting Ag 2. **Traveller with cargo**: has **taken in env Ag** - both dangerous and innocolous Ag - **carries to LN** to present for T cells 3. **Presenter**: **presents Ag to T cells in LN** - upregulates MHC II + molecules for pathogen signalling (B7 or CD80/CD86) to T cells
71
How does DC communicate danger to T cells in LN?
**DC** need to **release signals to activate T cells**: 1. **Communicate** **Ag specificity**: MHC-Ag interacts with TCR 2. **Co-stimulation**: danger signals - PAMPs - upregulate B7 (CD80/CD86) on APC - signals to T cell via CD28 => **T cell activates -> clonal expansion + effector functions**
72
What is the difference between B7 and CD80/CD86?
**B7** - type of **integral membrane protein** - **on activated APCs** - when paired with **CD28 / CD152 surface protein** **on T cell** -> **costimulatory / coinhibitory** signal to **enhance / decrease** activity of a **MHC-TCR signal** between the APC and the T cell No difference, same thing: B7 I = CD80, B7 II = CD86
73
What does it mean if no signal 2 is released by APC for T cell?
If **no signal 2** - **B7-CD28 binding** - no danger - self / food Ag => **T cell not activated**
74
Why do B and T cells don't have more than one receptor?
**If B and T cells** had **several receptors** - **chance** that the **same cell** could have **receptors for pathogen + self** - if **activated** for pathogen - **would also act on self** => self destruction - autoimmune disease
75
What are cytotoxic T lymphocytes and what is their function?
**Cytotoxic cells** (CTL) - type of T cell: - CD8+ - recognises Ag presented by **MHC I** on APCs - intracellular Ag - identifies - **kill infected cells**
76
What is the role of macrophage as APC?
**Macrophages** act as **APCs** by i**nitiating iflammatory cascades**: - **senses DAMPs, LAMPs** - **signals to Th cells** -> go kill / the infection has been cleared - no more adaptive imm needed
77
What is the role of B cells as APC?
B cells require permision from T cells to have fulll effector functions to fight the infection ?? read more
78
Explain the process from DC cells acting as APCs to activating Th cells to Th cell communication with macrophages
79
What is the difference between macrohpages and neutrophils in inflammation?
Macrophages vs neutrophils in inflammation: - **timing**: neutrophils first -> then macrophages - **phagocytosis**: macrophages more effective - **cytokines**: macrophages produce more - **tissue damage/repair**: macrophages play critical role in repair - produce growth factors + ECM proteins; neutrophils damage - produce enzymes + ROS
80
Explain humoral vs cell-mediated immunity
**Humoral** immunity: mediated by **B lymphocytes** **Cell-mediated** immunity: mediated by **T lymphocytes**

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