T1 L2 Innate immune defences and inflammation 1 Flashcards
How long does the immediate innate immune response take?
0-4 hours
How long does the induced innate immune response take?
4h to 4 days
Describe the steps of the immediate innate immune response
1) Pathogen invades tissue and proliferates
2) Pathogen is recognised by preformed soluble effector molecules and resident effector cells in infected tissue
3) Pathogen is eliminated, infection ends and minor tissue damage is repaired
OR
Pathogen is not eliminated so proceed with induced innate immune response
Describe the steps of the induced innate immune response
1) Pathogen invades tissues and proliferates
2) Activation of cells resident in infected tissue. Recruitment of effector cells to infected tissue.
Inflammation, fever, acute phase response
3) Soluble effector molecules and effector cells recruited to infected tissue recognise and attack pathogen
4) Pathogen is eliminated
OR
Pathogen is not eliminated so proceed with adaptive immune response
What type of immunity has its specificity inherited in genome?
Innate
What are the differences between innate and adaptive immunity?
Innate triggers immediate response
Innate recognises broad classes of pathogens
Innate interacts with range of molecular structures of given type
Adaptive is encoded in multiple gene segments
Adaptive requires gene rearrangement
Adaptive has clonal distribution
Both are able to discriminate between closely-related molecular structures
What are the 3 types of innate barriers to infection?
Physical
Soluble
Induced
What are some mechanical barriers to infection?
Epithelial cells joined by tight junctions in the skin, gut, lungs, eyes / nose / oral cavity
Longitudinal flow of air or fluid in skin and gut
Movement of mucus by cilia in lungs
Tears and nasal cilia
What are some chemical barriers to infection
Antimicrobial peptides in skin, gut, lungs, eyes / nose / oral cavity Fatty acids in skin Low pH and antimicrobial enzymes in gut Pulmonary surfactant Antimicrobial enzyme in tears and saliva
Describe what happens when tissue is damaged
1) Damage to tissue leads to release of vasoactive and chemotactic factors
2) Triggers local increase in blood flow and capillary permeability
3) Permeable capillaries allow influx of fluid (exudate) and cells
4) Phagocytes migrate to site of inflammation (chemotaxis)
5) Phagocytes and antibacterial exudate destroy bacteria
What are some soluble innate immune molecules?
Enzymes e.g. lysozyme
Antimicrobial peptides
Collectins, ficolins and pentraxins
Complement components
Where are lysozyme secreted?
By phagocytes and paneth cells from small intestine
What do lysozyme do?
Cleave bond between alternating sugars that make up peptidoglycan to disrupt peptidoglycan
Most effective against gram positive bacterial
What are antimicrobial peptides secreted by?
Neutrophils
Epithelial cells
Paneth cells in crypts of small intestine
Where are histatins produced?
Oral cavity
What are histatins active against?
Pathogenic fungi e.g. Candida albicans
Describe the structure of defensins
2 classes (alpha and beta)
35-40 aa amphipathic peptides
Disulfide bonds that stabilise structure have a positively charged region separated from hydrophobic region
Disrupt microbial membranes
Describe collectins
Globular lectin-like heads that bind bacterial cell surface sugars
Sialic acid hides mannose antigens on the host cells
Describe ficolins
Recognise acylated componds
Describe pentraxins
Cyclic multimeric proteins found in plasma
What are the actions of collectins, ficolins and pentraxins?
Act as opsonins which bind to pathogens and infected cells to target them for phagocytosis
Activate complement through classical / lectin pathway
What are complements?
Series of more than 30 proteins that constantly circulate in blood and fluids that bathe the body tissue
What are complements made by?
Liver
Monocytes
Macrophages
Epithelial cells of intestine and urinary tract
What happens when complements are activated?
Split into small and large fragments which triggers an amplification cascade
What are the effects mediated by complement components?
Lysis (membrane attack complex)
Opsonisation
Activation of inflammatory response
Clearance of immune complexes
How is the classical pathway initiated?
C1 activation
What is C1?
A large molecule of 18 polypeptides that form 6 collagen-like triple helix structures.
What 3 proteins make up C1?
C1q
C1r
C1s
What protein dominates C1?
C1q
Describe the steps of the classical pathway
1) C1 binds to Fc region of antibody antigen complex which activates it
2) Binding C1q with Fc domain leads to conformational change in C1r
3) C1s is cleaved which activates C2 and C4 which split into their large and small fragments
4) C3 converts (C4b2a) activates over 200 C3 molecules causing amplification of the signal
5) C4b, C2a, C3b fragments form C5 converts which activates C5 forming membrane attack complex
What activates the lectin pathway?
Ficolins and mannose binding lectin
Describe the steps of the lectin pathway
1) Upon binding, MBL forms complex with MASP-1 and MASP-2
2) Active complex cleaves C2 and C4 which split into large and small fragments
3) C3 convertase (C4b2a) activates over 200 C3 molecules causing amplification of signal
4) C4b, C2a, C3b fragments form C5 convertase which activates C5 leading to membrane attack complex.
Describe the steps of the alternative pathway
1) C3 spontaneously hydrolyses into C3a and C3b
2) C3b binds to cell membrane and factor B making it susceptible to cleavage by factor D to Bb
3) C3bBb can hydrolyse more C3 leading to more C3b
What does the membrane attack complex do?
Forms a pore that inserts into the membrane to allow diffusion of ions and small molecules so water moves into the cell and the cell dies.
What is a C1 inhibitor?
Soluble protein that prevents C1 activating C4 and C2.
What is hereditary angioedema?
C1 inhibitor deficiency
Means that the classical complement cascade is easily activated
How is hereditary angioedema treated?
Injection of C1 inhibitor
What is the consequence of have complement deficiencies?
Experience recurrent infections
What is the most severe complement deficiency?
C3 deficiency
What does MBL deficiency cause?
Serious pyogenic infections in neonates and children
What does a C8 deficiency increase the likelihood of?
Infection with Nisseria meningitis
Describe systemic lupus erythematous
Autoimmune disease
Occurs in 90% of those deficient for C4
A C4 deficiency means less C3b
What happens to C3b that is bound to immune complexes?
Binds CR1 on erythrocytes which transports them to phagocytes in liver and spleen. The phagocytes recognise immune complexes via their Fc receptors and engulf them.
