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Immunology > L2. Innate Immunity: General Principles > Flashcards

L2. Innate Immunity: General Principles Flashcards

1
Q

What is the oldest form of immunity?

A

Innate Immunity

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2
Q

What is meant by innate immunity being “always available”?

A

Prior exposure not required.

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3
Q

At what stage of life is innate immunity most important?

A

In young children, period between loss of maternal antibodies/formation of their own

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4
Q

At what stage of infection is innate immunity most important?

A

Adaptive immunity takes ~ 4-6 days to develop. Innate immunity is critical in controlling infections before this.

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5
Q

What are the 3 elements of the innate immune system?

A
  1. Barriers
  2. Pre-formed mediators
  3. Innate immune cells
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6
Q

What is an overview of the function of barriers in the innate immune system?

A

Barriers prevent establishment of infection

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7
Q

What is an overview of the function of Pre-formed mediators in the innate immune system?

A

Pre-formed mediators are
proteins/peptides with broad specificity that damage pathogens, induce inflammation or help recruit and activate innate immune cells

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8
Q

What are 4 roles of innate immune cells in the innate immune system?

A

> Innate immune cells:

  1. Recognise and are activated by pathogen
  2. Eliminate pathogen
  3. Communicate with other cells
  4. Activate and “steer” adaptive immune response
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9
Q

Other than acting as a mechanical barrier how do barriers help prevent infection?

A

Secreted chemicals, anti-microbials and commensals make an unfavourable environment for pathogens

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10
Q

Describe 4 ways Keratinized skin helps prevent infection?

A
  1. Generally impermeable (only when comprised) asKeratinocytes (cells under skin) produce keratin
  2. Secretary cells (sebaceous glands) secrete sebum- contains fatty acids, defensins
  3. Shedding skin helps get rid of microbes.
  4. Commensals deters pathogens form colonizing.
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11
Q

What is the largest interface in the human body which has contact with the environment?

A

Mucous membranes (semi-permeable)

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12
Q

What are 3 examples of mucous membranes?

A

GI, UG, respiratory tract.

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13
Q

What are 4 ways mucous membranes help prevent against infections?

A
  1. Mucous traps pathogens, cilia beat away ASL containing pathogen (respiratory tract), secreted enzymes (e.g. lysozyme in tears and saliva) -issues in this by ineffcicient CFTR (extra reading)
  2. low pH (gut, vagina) deters division, peristalsis (gut cramps) expels pathogens.
  3. Shedding of epithelia to try get rid of infection.
  4. Commensals
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14
Q

What are 2 examples of mechanical barriers in the innate immune system?

A

1.Keratinized skin

  1. Mucous membranes
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15
Q

What are 3 examples of Pre-formed mediators in the innate immune system?

A
  1. Lysozymes
  2. Antimicrobial peptides (e.g. defensins)
  3. Complement
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16
Q

Where is Lysozymes present?

A

Lysozyme present in secretions (tears, saliva, mucous, etc.)

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17
Q

How do lysozymes defend against bacteria and which bacterial type are they more efficient against?

A

> Breaks a bond in peptidoglycan, destabilizing cell wall

> More active against +ve bacteria, where peptidoglycan is exposed.

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18
Q

What are defensins produced by?

A

produced by many epithelial cells and neutrophils

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19
Q

How do defensins (antimicrobial peptide) defend against pathogens?

A

> Cationic, insert to and disrupt lipid bilayers in bacteria, fungi and enveloped viruses (take part of host cell membrane)

> The peptidoglycan is porous enough to allow the passage of molecules with a certain size, and defensins, being relatively small peptides, can penetrate through these pores,so can still disrupt gram -ve bacteria.

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20
Q

What are the 2 subfamilies of defensins in humans, and their difference?

A
  1. Alpha are pre-formed in granules of innate immune cells (released and active quickly)
  2. Beta have to be formed de novo after infection.
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21
Q

What is complement and when is it active?

A

> 20+ soluble proteins found in blood and other body fluids

> Components normally inert, but “activated” by presence of pathogens or antibody bound to pathogen

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22
Q

Why are enzymes used in the complement pathways?

A

Pro-enzyme is inert, stimulus acts on this to activate it where it can activate further enzymes (complement cascade)- amplification

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23
Q

Why can complement be activated by non-antibody pathways?

A

As originally evolved as part of the innate immune response

24
Q

When are the MBL and alternative component pathway needed?

A

Provides protection early in infection in the absence of antibodies through other “older” activation pathways

25
Q

Which part of component is most abundant?

A

C3 is most abundant and is a most important.

26
Q

Where are complement proteins synthesised?

A

The Liver

27
Q

What is the central event of complement activation, conserved in all pathways?

A

C3 convertase cleaves C3 pro-enzyme exposing a reactive thioester bond in C3b, which can bind covalently to adjacent proteins/carbohydrates e.g. on the surface of a pathogen causing activation of the rest of the cascade.

28
Q

What enzymes are used in the complement pathways?

A

Proteases that cleave each other into 2 fragments (B is bigger fragment, A is smaller fragment).

29
Q

What happens to naturally occurring random C3b activation?

A

Activation of C3b occurs naturally in blood (without pathogen), if C3b doesn’t bind to a surface it is quickly inactivated doesn’t cause any damage

30
Q

What are the 3 pathways of complement activation?

A
  1. Classical pathway
  2. Mannose-binding lectin (MBL) pathway
  3. Alternative pathway
31
Q

How is the classical pathway activated?

A

Antibody bind to surface

32
Q

How is the Mannose-binding lectin (MBL) pathway activated?

A

Mannose binding lectin binding to mannose on bacterial surfaces

33
Q

What is lectin?

A

Lectin is a molecule that loves to bind to carbohydrates. MBL loves to bind to mannose residues which are often found on bacteria surface. (MBL= main lectin)

34
Q

How is the Alternative pathway activated (extra reading)?

A

> The alternative pathway can be initiated by the spontaneous hydrolysis of C3 in the blood to form C3(H2O). This hydrolysed form of C3 has a structural similarity to C3b.

> LPS can enhance the deposition of C3b on the bacterial surface, facilitating the formation of the C3 convertase and thus amplifying the complement activation.

35
Q

What is the order of activation for classical pathway of complement activation until the C3 convertase step in 4 steps?

A
  1. Initiation: The classical pathway is initiated when C1, a complex of proteins (C1q, C1r, C1s), binds to antibodies (IgM or IgG) that are attached to antigens on the surface of a pathogen. This binding activates C1.
  2. Activation of C4 and C2: The activated C1s enzyme in the C1 complex cleaves two other complement proteins: C4 and C2. C4 is split into C4a and C4b, while C2 is split into C2a and C2b.
  3. Formation of C3 Convertase: The fragments C4b and C2a combine to form the C3 convertase enzyme complex of the classical pathway, which is denoted as C4b2a. This complex has the ability to cleave C3 into C3a and C3b.
  4. Amplification and Further Steps: The C3b fragment can bind to the pathogen surface and participate in further steps of the complement cascade, including the formation of the C5 convertase and the eventual formation of the Membrane Attack Complex (MAC).
36
Q

What is the order of activation for Mannose-binding lectin (MBL) pathway of complement activation until the C3 convertase step in 5 steps?

A
  1. Lectin Binding to Bacterial Surface: The MBL pathway is initiated when Mannose-Binding Lectin (MBL) binds to mannose on a pathogen’s surface.
  2. Activation of MASP Proteins: This binding activates associated MASP (MBL-associated serine proteases) enzymes, particularly MASP-1 and MASP-2.
  3. Cleavage of C4 and C2: MASP-2, once activated, cleaves C4 into C4a and C4b. C4b then binds to the pathogen surface or to MBL itself. Subsequently, MASP-2 also cleaves C2 in the presence of C4b into C2a and C2b. This step is quite similar to the classical pathway.
  4. Formation of C3 Convertase: The fragments C4b and C2a combine to form the C3 convertase of the MBL pathway, which is the same as in the classical pathway, C4b2a. This complex cleaves C3 into C3a and C3b.
  5. Further Complement Activation: The C3b fragment then participates in the further steps of the complement cascade, leading to opsonization of pathogens, recruitment of immune cells, and the formation of the Membrane Attack Complex (MAC).(The C5 convertase is formed when another C3b molecule binds to the C3 convertase (C4b2a), resulting in the complex C4b2a3b. This complex can then cleave C5 into C5a and C5b, leading to the formation of the MAC.)
37
Q

What is the order of activation for Alternative pathway of complement activation until the C3 convertase step in 6 steps (extra knwoledge)?

A
  1. Spontaneous Hydrolysis of C3: The alternative pathway can be initiated by the spontaneous hydrolysis of C3 in the blood to form C3(H2O). This hydrolysed form of C3 has a structural similarity to C3b.
    >LPS can enhance the deposition of C3b on the bacterial surface, facilitating the formation of the C3 convertase and thus amplifying the complement activation.
  2. Binding of Factor B: C3(H2O) or surface-bound C3b can bind Factor B, which is then cleaved by Factor D into Ba and Bb fragments. The Bb fragment remains attached to C3(H2O) or C3b.
  3. Formation of Initial C3 Convertase: The complex of C3bBb (or C3(H2O)Bb) acts as the initial C3 convertase in the alternative pathway. This enzyme complex can cleave additional C3 molecules into C3a and C3b forming more C3 convertase to amplify the response
  4. Stabilization by Properdin (Factor P): Properdin (Factor P) binds to and stabilizes the C3bBb convertase on the pathogen surface, increasing its efficiency in cleaving C3.
  5. Amplification Loop: The newly formed C3b can bind to more Factor B, which is cleaved by Factor D, leading to the formation of more C3 convertase (C3bBb) and thus creating an amplification loop.
  6. Formation of C5 Convertase: The alternative pathway’s C3 convertase (C3bBb) can bind an additional C3b molecule to form a C5 convertase (C3bBbC3b), which then cleaves C5 into C5a and C5b, leading to the formation of the Membrane Attack Complex (MAC).
38
Q

What is the C3 convertase for the classical and MBL pathway made of?

A

C3 convertase = C4bC2a (from cleavage of C4 and C2 by C1 and MASP2, respectively)

39
Q

How is the C3 convertase different in the Alternative pathway and describe this process of its production?

A

> For Alternative pathway, C3 convertase = C3bBb.

  1. Some C3b is generated spontaneously in body fluids by a “tickover” mechanism, if an infection occurs some C3b binds to LPS on bacterial membrane
  2. Factor B (high conc in most body fluids) binds to C3b on bacterial surface.
  3. Factor D cleaves Factor B forming C3bBb acting as a C3 convertase (inactivated quickly at this stage)
  4. Factor P helps stabilise the enzyme so can work for longer on the bacterial surface (so a long lasting C3 convertase on a bacterial surface).
40
Q

How can complement activation of the classical and MBL pathways be further amplified and why?

A

> C3b generated by the Classical or MBL pathway can also bind factor B causing amplification of complement activation (important for early stages of infection)

> Important for easily stages of immune response, as causes amplification of component response it increases quicker

> When C3b generated from the classical or MBL pathway binds to a pathogen surface, it can interact with Factor B in the blood. Factor B, when bound to C3b, can be cleaved by Factor D to form the active enzyme complex C3bBb, which is the C3 convertase of the alternative pathway. It can cleave more C3 into C3a and C3b, with the newly generated C3b able to initiate more rounds of C3 convertase formation causing an amplification loop

41
Q

Describe the later stages of complement activation.

A
  1. C3 convertase cleaves C3 to C3b and small fragment (C3a)
  2. C3 convertase binds more C3b to form C5 convertase
  3. C5 convertase cleaves C5 to C5b and C5a
  4. This activates the remaining complement proteins forming membrane attack complex.

C3 convertase + C3b opsonin -> C5 convertase -> C5b -> C5b, C6, C7, C8, C9 (membrane attack complex).

42
Q

What are the 3 main roles of complement?

A
  1. Recruit phagocytes and induce inflammation
  2. Promote opsonization
  3. Membrane Attack Complex, leading to lysis.
43
Q

What are the roles of C5a and C3a

A
  1. Chemoattractants for phagocytes to site of infection.
  2. Anaphylatoxins to induce release of inflammatory mediators.
  3. Act on local blood vessels, increasing blood flow, permeability and phagocyte adhesion, all to enhance inflammation
44
Q

How do C5a and C3a act as Chemoattractants?

A

> Infection occurs in tissues causing generation of C3a and C5a at the site of infection in high concentrations.

> Phagocytes have C5a and C3a receptors and undergo chemotaxis in response to C5a/C3a peptide. Gets phagocyte out of blood stream and into tissues to deal with infection where concentration of C5a and c3a are highest (C5a is more potent than C3a).

45
Q

How do C5a and C3a act as anaphylatoxins?

A

C5a/C3a binding to C5a/C3a receptors on mast cells (under mucous surfaces) induces release of inflammatory mediators (like histamine)

46
Q

What is the role of C3b (other than activating complement pathways)?

A

C3b promotes opsonization

47
Q

How does C3b promotes opsonization?

A

Coats bacteria with C3b, phagocytes like neutrophils have C3b receptors on surface to recognise (makes pathogens more specific for phagocytes).

48
Q

How is the membrane attack complex (MAC) formed?

A

> Activation of C5b – C9 results in C9 polymerisation, forming a pore in the membrane, disrupting it and killing the pathogen.

> C9 polymers form the actual pore, polymerisation is triggered by C5b-8 binding

49
Q

What type of bacteria is the membrane attack complex (MAC) efficient against?

A

Important for killing of gram -ve bacteria (+ve have peptidoglycan layer blocking penetration)

50
Q

What are the 2 ways complement is regulated?

A
  1. components rapidly hydrolysed in fluid phase
  2. soluble and membrane bound regulatory proteins
51
Q

What are 4 examples of regulatory proteins of complement and what to they inhibit?

A

1.C1 inhibitor inactivates C1 in classical pathway

  1. Factor H inhibits alternative pathway by stopping Factor B(acting as competitive inhibitor by binding to C3b first and can accelerate dissociation of C3bBb complex)
  2. Carboxypeptidase N inactivates C3a and C5a (stopping inflammation from happening for too long)
  3. CD59 on our host cells binds C9, preventing MAC formation
52
Q

Why does complement need regulation?

A

It is a “Double-edged sword”, having good protection qualities but if attacking our own cells causes issues.

53
Q

Describe 2 examples of deficiencies in inhibitors of complement activation?

A
  1. Age-related macular degeneration (lack Factor H)
    >Blindness in old people caused by lack of factor H, overactive Factor B and therefore alternative pathway
  2. Paroxysmal nocturnal haemoglobinuria (lack CD59)
    >Form of anaemia caused by complement attacking red blood cells due to lacking CD59.
54
Q

Which pathways of activation of complement are important for early stages of infection?

A

MBL and alternative as don’t need antibodies to activate.

55
Q

What is complement especially important in defending against?

A

Complement is particularly important in extracellular bacterial and fungal infections, but may be active against some viruses (mainly enveloped)

56
Q

What does a defect in 1. C3 2. C5-C9 lead to?

A
  1. Defects in C3 – increased susceptibility to pyogenic (pus forming) infections e.g. S. Pneumonia
  2. Defects in C5- C9 – increased susceptibility to Neisseria infections
    -Ve bacteria (MAC important for dealing with these)
57
Q

How does complement play a role in autoimmune diseases and asthma?

A

When adaptive immune system is active against self, antigen which triggered autoimmune response is always present in body so complement is always active

Immunology (20 decks)

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