Innate Immunity + Complement Flashcards

1
Q

What do the components of the innate immune system aim to do?

A

= eliminate pathogens

= initiate an adaptive immune response

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2
Q

Innate vs adaptive immunity in defence against virusus?

A

Innate
= macrophages, DCs, NK cells, complement cytokines
= immediate response (hours)
= non-specific
= aims to eliminate infection and alert immune system

Adaptive
= T cell, B cells, antibodies
= delayed response (1-2 weeks)
= specific for pathogen
= memory
= aims to eliminate infection and prevent re-infection later

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3
Q

What are some barrier functions in innate immunity?

A

Physical
= e.g. skin, mucus, cilia, sneezing, coughin

Chemical
= low pH in stomach , urogenital tract
= anti-microbial peptides on skin, in saliva
(defensins and cathelicidin disrupt bacterial membranes)
= enzymes in secretions (saliva, tears)
(e.g. lysosyme cleaves peptidoglycans in bacterial cell wall)

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4
Q

What is phagocytosis?

A

= the uptake of particulate materials by a cell
(e.g. pathogens, dead cells)

Specialised phagocytes:
= e.g. Neutrophils = phagocytose pathogens, then die
= e.g. Macrophages + Dendritic Cells = phagocytose pathogens + present antigens

Phagocytes have multiple functions in innate and adaptive immunity:
= kill pathogens + take up cell debris
= detect pathogen-associated molecular patterns (PAMPs)
= secrete cytokines
= present pathogen-derived antigens on their surface (as APCs) to activate T and B cells

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5
Q

What are the stages of phagocytosis?

A
  1. Attachment
  2. Ingestion - phagosome
  3. Phagosome-lysosome fusion
  4. Killing / digesting

(adaptive)
5. Antigen presentation
6. Cytokines, chemokines

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6
Q

What are PRRs (Pattern Recognition Receptors) and PAMPs (pathogen-associated molecular patterns)?

A

PRRs = receptors on an in cells that recognise PAMPs (pathogen-associated molecular patterns)

PAMPs = molecular hallmarks of infection that are NOT usually present in / on health cells

4 main families of PRRs
= TLRs = toll-like receptors (macrophage surface / in endosomes)
= CLRs = C-type lectin receptors (in cytosome)
= Intracellular nucleic acid receptors (DNA / RNA receptors inside all cells - detect if virus is infected)
= NLRs = Nucleotide oligomerisation domain / leucine-rich repeat containing receptors (detect bacterial PAMPs)

Macrophages, dendritic cells and NK cells
= have PRRs on surface and in endosomes
(most cells in body have intracellular PRRs)

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7
Q

What are some examples of PAMPs and PRRs?

A
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8
Q

How does Toll-like receptor (TLR) signalling work?

A

External LRR (leucine rich repeat) domain recognises ligands

Ligand binding causes oligomerisation of receptor and clustering of TIR domains (Toll/IL-1 receptor homology)

Signalling cascades to activate the transcription factors: NF-kB, IRF3 and IRF7

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9
Q

What are intracellular RNA receptors?

A

= class of PRR

MDA5 = detects long double-stranded RNA (not in humans)

RIG-I = detects short dsRNA and RNA with a tri-phosphate at its 5’ end

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10
Q

What happens after PAMP detection?

A

PRR signalling activates transcription factors that then switch on many different genes , leads to secretion of:

= CYTOKINES = regulate immune response (e.g. IL-6, TNF-α)
= INTERFERONS = to warn neighbouring cells of viruses
= CHEMOKINES = to recruit immune cells to the site of infection
= ANTIMICROBIAL PEPTIDES = to kill pathogens directly
= ENZYMES = e.g. COX-2 to make prostaglandins

Different PRRs activate different signalling cascades
= different immune response for different pathogens

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11
Q

What is the role of cytokines in inflammation?

A

IL-6, TNF-α, IL-1:
Local Effects
= vasodilation, increased blood flow (redness)
= increased vascular permeability (swelling)
= activation of macrophages, B and T cells

Systemic Effects:
= bone marrow: haematopoiesis (neutrophils)
= hypothalamus: fever
= liver: acute phase response (complement)

IL-8 (CXCL8):
= recruitment of neutrophils and DCs

IL-10
= inhibition of macrophages and DCs, resolution of inflammation

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12
Q

What is the interferon response?

A

e.g. IFN-α, IFN-β

Increased antiviral state
= by inducing resistance to viral replication in all cells by inducing Mx protein, 2’-5’ linked adenosine oligomers, and the kinase PKR

Increased antigen presentation
= by increasing MHC class I expression and antigen presentation in all cells
= by activating dendritic cells and macrophages

Increased killing of infected cells
= by activating NK cells to kill virus-infected cells

Increased adaptive immune response
= by inducing chemokines to recruit lymphocytes

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13
Q

What are NK (natural killer) cells?

A

Activated NK cells release granules containing perforins and granzymes = kill target cell

NK cells have varierty of germline-encoded receptors:

Inhibitory receptors
= detect self molecules such as MHC I
= when MHC I is down-regulated by viruses, this is detected as ‘missing-self’ (tolerance)

Activating receptors
= e.g. NKG2D
= detects MIC-A and MIC-B expressed on epithelial cells that have detected a virus = ‘altered-self’

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14
Q

What is the complement system?

A

= group of serum proteins in the blood that performs a critical defence against pathogens (especially extracellular bacteria)

= has links to innate immunity (e.g. phagocytosis) and to adaptive immunity (e.g. antibodies)

= there are about 35 proteins in the complement system (including the processed forms)

= most complement proteins are made in the liver

= some produced in large quantities during the acute phase response stimulated by the pro-inflammatory cytokines (IL-6 and TNF-α)

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15
Q

What are the 7 functional categories of complement proteins?

A
  1. Initiators
    = bind pathogens components or antibodies
  2. Enzymes (convertases)
  3. Opsonins
    = promote phagocytosis
  4. Anaphylatoxins
    = cause inflammation
  5. Membrane attack proteins
    = lyse pathogens
  6. Complement receptors
    = on phagocytes or neutrophils
  7. Regulatory proteins
    = limit complement activation
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16
Q

What are the 3 pathways of complement activation?

A

Classical Pathway

Lectin Pathway

Alternative Pathway

17
Q

What is the classical pathway of complement activation?

A

= initiated by binding of antibodies (IgG and IgM) to the surface of a pathogen

= antigen binding causes conformational changes in antibody
(exposes binding sites in the constant Fc regions of the antibody)

= allows binding of the C1 complex as initiator
(made up of 18 polypeptide chains)

= conformational change in a C1r subunit = converts it to a protease = cleaves other C1r and C1s subunit

= starts the complement cascade

18
Q

What is the lectin pathway of complement activation?

A

= initiated by lectins that bind to carbohydrates on the surface of pathogens

= MBL (mannose binding lectin) binds mannose and other sugars on surface of bacteria (e.g. Salmonella, Listeria)

= MBL associated with MASP proteins (MBL-associated proteases)

= MASP2 = structurally related to C1s
(can cleave C2 and C4)

19
Q

What is the Alternative pathway in complement activation?

A

= does NOT require antibodies or lectins
(direct binding of C3b to microbial surfaces)

= uses many of components from other pathways (classical and lectin)

= initiation via the “tickover pathway”
(low level of spontaneous binding of a labile form of C3)

= in presence of suitable target = C3b generated by tickover is able to directly bind to microbial surface (otherwise degraded)

= alternative pathway C3 and C5 convertases are produced

= leads to C5-C9 + MAC formation

20
Q

What are the effector functions of the complement?

A
  1. Pathogen lysis using the MAC (membrane attack complex)
    = made of C5b, C6, C7, C8, C9
    = forms pore in pathogen membrane (water enters, cell bursts)
  2. Opsonins - C3b and C4b
    = bind to pathogen membranes
    = promote phagocytosis by macrophages and neutrophils which express complement receptor: CR1
    = helps eliminate pathogens
    = disposes of immune complexes to resolve inflammation
  3. Anaphylatoxins - C3a, C4a and C5a
    = promote inflammation by acting as chemoattractants for immune cells
    = and by binding to complement receptors
    = cause the secretion of IL-6 and TNF-α by macrophages and the degranulation of neutrophils
21
Q

What is the key bridge for interplay between innate and adaptive immune systems?

A

= Dendritic Cells

22
Q

What factors affect how quickly an infection is eliminated?

A

The type / amount of the infecting pathogen

The immune status of the host

There is:
= ubiquitous responses of innate immunity
= induced responses of innate immunity
= adaptive response

23
Q

Why do we need innate immunity?

A

Complement system
= provides fast response against bacteria
= patients with complement deficiencies develop recurrent bacterial infections

PRR-mediated innate immunity
= helps initiate adaptive response
= v. important during first encounter with pathogen (e.g. childhood infection , vaccines)
= children with PRR signalling factor deficiencies = have severe infections in childhood = BUT later cope due to adaptive memory response

Innate immunity is evolutionarily ancient
= many multicellular organisms have innate immune systems with PRRs
= only vertebrates also have adaptive immunity
= first protein Toll discovered in flies
= plants also have PRRs with leucine-ruch repeats