Key characteristics of the innate immune system [6]
Genome encoded
Some receptors are expressed by all cells of a cell type
- Like in macrophages.
Immediate response.
Not specific to antigens. - Recognizes broad class of antigens using PRRs.
Interacts with a range of molecular structures of a given type.
Able to discriminate between closely related molecular structures.
- As seen with MBL.
Mechanical anatomical barriers against pathogens [4]
Tight junctions in epithelial cells: skin, gut, eyes, nose, mouth, lungs.
Longitudinal flow of air/fluid: gut, skin.
Movement of mucus by cilia: lungs.
Tears and nasal cilia: eyes, nose, mouth.
Chemical anatomical barriers against pathogens [5]
All structures: antimicrobial peptides.
Skin: Fatty acids
Gut: Low pH, antimicrobial peptides.
Lungs: Pulmonary surfactant containing collectins.
Eyes, nose, mouth: Antimicrobial enzymes in tears and saliva.
Microbiological anatomical barriers against pathogens
Normal microbiota in all structures (skin, lungs, eyes, nose, gut, mouth)
Pentraxins
Soluble molecule- cyclic multimeric protein
Binds to pathogens, tags for phagocytosis.
Lysoszyme
Antimicrobial enzyme
- Found in tears, saliva
- Dirupts bacterial cells walls
Phospholipase A2
Secretory form acts as antimicrobial enzyme
- Found in the blood
- Disrupts bacterial cell wall
Antimicrobial peptides [4]
Amino acid chains secreted by neutrophils, paneth cells (small intestines)
- Cover epithelial surfaces, found in saliva.
- Disrupts bacterial membrane.
- Attacks fungi and viruses.
- Inhibits RNA and DNA synthesis.
Histatins
Antimicrobial peptide
- Produced in oral cavity
- Attacks fungi, like c. abicans
Defensins
Amphipathic, antimicrobial peptide that disrupt microbial cell membranes by forming a pore in plasma membrane
- Does not attack host cells
Structure
- 35-40 a.a
- Disulphide bonds to stabilise structure
Collectins
Pattern recognition receptor
- Lectin head binds to sugars on bacterial surface
- Collagen tail binds to phagocytes
Example: MBL, activates complement cascade
- Host cells are protected via sialic acid covering mannose
Ficolins
Trimer molecule that recognises acylated compounds on bacterial cell wall
- Collagen and fibrinogen domain
- Activates complement
- Carries out opsonisation
Action of ficolins, collectins and pentaxins.
Act as soluble PRR
Opsonisation of infected cells for phagocytosis
Activation of the classical/ lectin complement pathway.
Classical component pathway
- Activation
Activated by Ag-Ab complex binding to C1q on C1qC1rC1s.
- IgM is usually the antigen, and at least 2 Fc domain bound to C1q.
IgM can only bind in staple form, not planar
- Staple form occurs when bound to Ag.
Activated C1q cleaves C14.
Classical component pathway
- Amplification
Activated C1r cleaves C1s
- C1s cleaves C2 and C4
C2a and C4b form C3 convertase
- Cleaves C3 into C3a, C3b.
C3b, C2a, C4b combine to form C5 convertase
- Cleaves C5, forms membrane attack complex (MAC)
Lectin component pathway
- Activation
Activated by MBL or ficolin bound to pathogen
- MBL forms complex with MASP1, 2.
Lectin component pathway
- Amplification
MBL-MASP1/2 complex cleaves C2, C4
- Forms C3/5 convertase leaving to C3b and MAC production downstream
Alternative component pathway
- Activation
Pathogenic surface comes into contact with C3
- Spontaneous lysis into 3a, 3b.
Alternative component pathway
- Amplification
C3b binds to cell membrane/ factor B
- Cleaves Factor D into Bb.
C3bBb can cleave C3, making more C3b
C3bBb only has a half life of 5 mins
- Prolonged by the release of properdin from leucocytes during inflammation.
C3a, C5a function
Peptide mediator of inflammation
Recruits phagocytes
C3b function
Opsonisation
- Binds to complement receptor on phagocyte- facilitate phagocytosis to remove immune complexes
MAC
Membrane attack complex
- Formed from the activation form C6 by C5b—> cascade to from C5b6789
MAC forms pores in cell membrane
- Influx of water, ions, sugar= cell lysis
Host cells protected against MACs via soluble and cell surface proteins
Hereditary angioedema
Caused by C1 inhibitor deficiency
- Leads to easy activation of Classical complement cascade
Symptoms
- Swelling in hands, face, feet and airway
MBL deficiency
Inhibits Lectin complement pathway
- Leads to severe pyogenic infections in children and neonates
Eventually recovers with age due to compensation from adaptive immune system
C3 deficiency
Prevents the formation of C3b in all complement pathways
- Most severe due to the important role of C3b (cannot opsonise bacteria)
C8 deficiency
Associated with being prone to meningitis infection (Neissera)
SLE and complements
90% of those with C4 deficiency develop SLE
- Inability to make C3 convertase, hence C3b
C3b cannot bind to CR1 on rbc- not transported to phagocytes in liver/spleen- immune complexes not removed via phagocytosis
Roles of activated complements
- Creation of membrane attack complex (C5-9)= pores in microbial cell membrane
- Opsonisation (C3b)
- Chemoattractant for leucocytes