Innate immune response Flashcards
Innate immune system
- Innate since all animals have the system
- Evolutionary the oldest natural defence against infection
- First line of attack to deal with pathogens before the adaptive immune system kicks in
- Produces the local redness and swelling associated with infections
Effectors of the complement system
1- MAC: membrane attack complex that “stabs” invading pathogens
2- Anaphylatoxins- important for permeability and attacking neutrophils
3- Opsonisation- Priming of pathogens for phagocytosis
4- Neutrophils are attracted to infection site
3 complement activation pathways
1) Classical
2) Lectin or mannose- binding
3- Alternative
All pathways centre around activation of complement factors C3 & C5
What is the classical pathway?
- Activated by antigen- antibody complexes (activation of adaptive immune system)
- Many of the complement factors are serine proteases
- Similar to blood coagulation, complement activation involves limited proteolysis to activate the next factor
- Produces anaphylatoxins, opsonins & MAC
Steps in the classical pathway
C1 activated by antigen- antibody complex
Step 1) C1 cleaves complement factor C2 into C2a & C2b through limited proteolysis
Step 2) C1 cleaves C4 into C4a & C4b
Step 3) C2a + C4b= complex cleaves C3 into C3a & C3b
Step 4) C3b joins the C2a/C4b complex forming C2a/C4b/C3b complex that cleaves C5 into C5a & C5b
Step 5) C5b finally forms a complex with C6, C7, C8 & C9 producing MAC
What is MAC?
Membrane attack complex
perforates the cell membrane of pathogens and infected host cells
What are C3a, C4a & C5a & C3b roles?
C3a, C4a & C5a= anaphylatoxins
C3b= role in opsonisation
What is the Lectin or mannose- binding pathway?
- Mannose- binding lectin (MBL) binds mannose found on the surface of pathogens
- MBL binds MBL associated serine protease (MASP) 1& 2 which cleaves C2 & C4
- Rest of pathway (C3-9) identical to the classical pathway
Pathogens activating lectin pathway
- Yeast
- Viruses
- Bacteria
- Parasites
What is the alternative pathway?
- Spontaneous low- rate auto- activation (upon direct contact with pathogens) of C3
- Auto- activated C3b binds factor B and properdin on pathogen surface which activates more C3 & C5
- Rest of pathway the same as classical (C6-9)
What are anaphylatoxins?
- C3a, C4a & C5a
- Trigger degranulation of endothelial cells, mast cells (histamine) and phagocytes
- Enhance vascular permeability
- C3a & C5a are chemoattractants for neutrophils
What is opsonisation by C3b?
- C3b binds to pathogens
- C3b is cleaved to iC3b
- Macrophages express receptors for iC3b, facilitating phagocytosis
What are professional phagocytes?
Cells with phagocytosis as their main function
- Macrophages
- Dendritic cells
- Neutrophils
NK Cells function differently
7 Steps in Phagocytosis and what cell it takes place in
Macrophages
1- Chemotaxis and adherence of microbe to phagocyte
2- Ingestion of microbe by phagocyte
3- Formation of phagosome
4- Fusion of the phagosome with a lysosome to form a phagolysosome
5- Digestion of ingested microbe by enzymes
6- Formation of residual body containing ingestible material
7- Discharge of waste materials
Macrophages
- Located in the skin, lungs and intestines
- First defence against pathogens
- Three activation states: Resting, primed and hyper- active
What is a resting macrophage?
- Collects tissue debris
- Eliminates apoptic cells
- Low major histocompatibility complex (MHC) class II expression
What is a primed macrophage?
- Primed by interferon gamma (IFN- y) produced by NK cells and helper T cells
- Increased expression on MHC II
- Increasingly phagocytotic
What is a hyperactive macrophage?
- Stimulated with IFN- y and lipopolysaccharide (LPS) produced by gram- neg bacteria
- Stop proliferating, become larger and very phagocytotic
- Produce cytokines: tumour necrosis factor (TNF) and interleukin- 1(IL-1)
What are neutrophils?
- Reside in the blood
- Activated and attracted to site of infection
- Short lived (5 days)
How do neutrophils “sniff out” infections?
- Double- key mechanism to infiltrate inflamed tissue from the blood
1. Selectin ligand- selectin
2. ICAM- integrin - Selectin and integrin are expressed and activated in response to IL-1, TNF, LPS and C5a
How do neutrophils sniff out infection in inflamed tissue?
- IL-1 and TNF is secreted by hyperactive macrophages
- Endothelial cells express Selectin which binds SLG on the Neutrophil
- Neutrophils start to “roll” and slow down
-C5a and LPS from inflamed tissue induce neutrophil integrin activation - INT (integrin) binds ICAM (intercellular adhesion molecule) on endothelial cells
- Neutrophil stops rolling
- C5a and F-Met peptides stimulate neutrophil infiltration of infected tissue (vascular permeability)
What are natural killer cells?
-Lymphoid
- Blood, liver spleen
- Roll, stop, exit mechanism to infiltrate infected tissue
Apoptosis of infected cells
- Fas binds Fas ligand on target cell
- Saves healthy host cells by recognising MHC- I
- Perforin and granzyme B (“Suicide enzyme”)- induce apoptosis
- IFN- y & IL-2 production
Innate immune system and virus infection
- Complement opsonises viruses with C3b
- Complement produces MAC on enveloped viruses
- Virus infected host cells
- NK cells induce apoptosis
- TNF & IFN reduce viral reproduction
What is TNF?
Tumour necrosis factor
What is IL-1?
Interleukin- 1
What is LPS?
Lipolysaccharide
what is IFN- y?
Interferon gamma
What is MHC?
Major histocompatibility complex
