2. Innate immune defences & inflammation Flashcards Preview

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1

What is innate immunity?

1st line of defence against infection
Present at birth and passed down genetically
Occurs within minutes of pathogen recognition

2

Soluble innate immune molecules

Enzymes such as Lysozyme – disrupts bacterial cell walls; found in blood and tears

Antimicrobial peptides - disrupt microbial membranes

Collectins, ficolins and pentraxins –bind to pathogens targeting them for phagocytosis and activate complement

Complement components - lyse bacteria, opsonise bacteria, induce inflammation

3

Enzymes e.g. lysozyme

disrupts bacterial cell walls; found in blood and tears

4

Antimicrobial peptides

disrupt microbial membranes

5

Collectins, ficolins and pentraxins

bind to pathogens targeting them for phagocytosis and activate complement

6

Complement components

lyse bacteria, opsonise bacteria, induce inflammation

7

Lysozyme

Lysozyme disrupts peptidoglycan

Lysozyme is secreted by phagocytes and paneth cells from the small intestine

Cleaves the bond between the alternating sugars that make up peptidoglycan

Most effective against Gram-positive bacteria

8

Histatins

Produced in the oral cavity. Active against pathogenic fungi, e.g. Candida albicans

9

Cathelicidins

LL-37 broad-spectrum antimicrobial activity against both Gram-negative and Gram-positive bacteria

10

Antimicrobial peptides

histatins, defensins, cathethelicidins

Cover epithelial surfaces, found in saliva
Constitutively secreted by neutrophils, epithelial cells and paneth cells in the crypts of the small intestine
Kill bacteria in minutes, by disrupting the membrane
Also attack fungi, viruses (influenza and herpes virus)
Inhibit DNA and RNA synthesis

11

Defensins

Two classes – α, β defensins
35-40 aa amphipathic peptides which means they have both hydrophilic and hydrophobic regions on their cell surface.
Disulphide bonds stabilise the structure to have a positively charged region separated from a hydrophobic region
Disrupt microbial membranes but not that of the host

12

Collectins

Collectins have globular lectin like heads that bind bacterial cell surface sugars. Sialic acid hides mannose antigens on host cells

13

Ficolins

Ficolins recognise acylated compounds (COCH3) such as n-acetylglucosamine, a monosaccharide found in bacterial cell walls

14

Pentraxins

Pentraxins are cyclic multimeric proteins found in the plasma

C-reactive protein (CRP) is used as a clinical measure of inflammation

15

Actions of collectins, ficolins and pentraxins

Soluble pattern recognition receptors
Act as opsonins that bind to pathogens and infected cells targeting them for phagocytosis
Activate complement through the classical pathway/lectin pathway

16

Complement system

Series of over 30 proteins that constantly circulate in blood and fluids that bathe the body tissues
When they detect presence of foreign material, they initiate a cascade of reactions that amplify the signal
When activated, cooperate with other host defence systems to generate inflammation and rapidly remove the pathogen
Most made by the liver but also produced by monocytes, macrophages and epithelial cells of the intestine and urinary tract

17

Complement components

Circulate as a pro-form (inactive) in the blood
Numbered in the order they were discovered, not in the order they are activated
Some have proteolytic enzymatic activity
On activation they split into a small and large fragments triggering an amplification cascade
Normally ‘a’ is the small fragment - except c2a

18

Effects mediated by complement components

Lysis
opsonisation
activation of inflammatory response
Clearance of immune response
membrane attack complex
complement receptor activation

19

Classical pathway

Initiated by C1 activation

C1 is a complex of three proteins: C1q, C1r and C1s

The structure of C1 is dominated by C1q
a large molecule of 18 polypeptides that form six collagen like triple helix structures

20

Classical pathway: activation

Triggered when C1 binds to the Fc region of an antibody – antigen complex
C1 must bind at least 2 FC domains
IgM is the most efficient at activating complement as it has 5 Fc domains. IgG1 and IgG3, and to a lesser extent IgG2 can also activate complement when close together bound to antigen

21

How does IgM bind C1q?

Serum IgM cannot bind C1 as it has a planar conformation, the shape changes on binding antigen to reveal binding sites for C1q

22

Classical pathway: amplification

Binding C1q with the Fc domain causes a conformational change in C1r
C1s is cleaved and can activate C2 and C4 splitting into their large and small fragments
C3 convertase (C4b2a) can then activate over 200 C3 molecules producing a massive amplification of the signal
C4b, C2a and C3b fragments form the C5 convertase that activates C5 leading to the membrane attack complex

23

Lectin pathway

Antibody independent, activated by ficolins and mannose binding lectin (MBL)
MBL binds mannose residues on carbohydrates and glycoproteins on bacteria and some viruses
Similar downstream mechanism to the classical pathway
Upon binding MBL forms a complex with MASP-1 and MASP-2 (serine proteases)
Active complex cleaves C2 and C4

24

Alternative pathway

C3 spontaneous hydrolyses into C3a and C3b
C3b binds to a cell membrane and factor B, making it susceptible to cleavage by factor D to Bb
C3bBb has a half-life of 5 min, unless it binds the serum protein properdin, which extends it half-life to 30 min by protecting it from proteases
C3b,Bb can hydrolyse more C3 creating more C3b which can amplify the signal

25

Membrane attack complex

MAC forms a pore that inserts into the membrane allowing diffusion of ions and small molecules, water moves into the cell killing it
Human cells have soluble and cell surface associated proteins that prevent MAC formation

26

Hereditary angioedema: C1 inhibitor deficiency

Classical complement cascade easily activated but can be treated with an injection of C1 inhibitor

27

Complement deficiency

Patients deficient of components of the complement pathway experience recurrent infections
MBL deficiency causes serious pyogenic infections in neonates and children
C3 deficiency is the most severe leading to successive severe infections
Patients deficient of C8 are prone to infection with Neisseria meningitis

28

Complement deficiency in SLE

90% of people deficient for C4 develop the autoimmune disease systemic lupus erythematosus (SLE)
C4 deficiency means less C3b (C4b2a is C3 convertase)

C3b bound to immune complexes binds to CR1 on erythrocytes which transports them to phagocytes in the liver and spleen.

Phagocytes recognise the immune complexes via their Fc receptors and engulf them