W11 Innate immunity Flashcards
Sites of Microbe Entry
Conjunctiva Arthropod Capillary Scratch, injury Skin Anus Urinogenital tract Alimentary tract Respiratory Tract
The Inflammatory Response
A generic defence mechanism whose purpose is to localize and eliminate injurious agents and to remove damaged tissue components
Enhanced permeability and extravasation
Neutrophil recruitment
Enhanced cell adhesion
Enhance clotting
Triggered by the release of pro-inflammatory cytokines and chemokines at the site of infection
Cytokines
Act to modify the behaviour of cells in the immune response
Most of these are called interleukins (eg. IL-1)
Chemokines
Act as chemotactic factors – i.e. they create concentration gradients which attract (or occasionally repel) specific cell types to a site of production/infection
IL-1
Main producer = Macrophages + keratinocytes
Acts upon = lymphocytes + liver
Effect = Enhances response
Induces acute-phase protein secretion
IL-6
Main producer = Macrophages + dendritic cells
Acts upon = lymphocytes + liver
Effect = Enhances response
Induces acute-phase protein secretion
CXCL8 (IL-8)
Main producer:
Macrophages + dendritic cells
Acts upon:
Phagocytes
Effect:
Chemoattractant for neutrophils
IL-12
Main producer:
Macrophages + dendritic cells
Acts upon:
Naive T cells
Effect:
Diverts immune response to type 1, proinflammatory, cytokine secretion
TNF - alpha
Main producer:
Macrophages + dendritic cells
Acts upon:
Vascular endothelium
Effect:
Induces changes in vascular endothelium (expression of cell-adhesion molecules (E- + P- selectin), changes in cell-cell junctions w/increased fluid loss
How do macrophages “see” microbes?
Passive sampling
Scavenger receptors
Engulfing apoptotic cells
Pattern recognition is through Pathogen-associated Molecular Patterns (PAMPs)
Pattern recognition is through Pathogen-associated Molecular Patterns (PAMPs)
Examples of Pathogen-associated Molecular Patterns (PAMPs)
Gram-negative bacteria; lipopolysaccharides (LPSs) found in outer membrane
Gram-positive bacteria; teichoic acid, lipoteichoic acid, peptidoglycan found in outer membrane
Other PAMPs include
Bacterial flagellin
Abnormal protein glycosylation
Abnormal nucleic acids - viruses
Pattern recognition receptors (PRRs)
Host factors that specifically recognise a particular type of PAMP
They are germ-line encoded
There are several classes of PRR, but functionally they are either
Extracellular – they recognise PAMPs outside of a cell and trigger a co-ordinated response to the pathogen
Intracellular (cytoplasmic) – they recognise PAMPs inside a cell and act to co-ordinate a response to the pathogen
Secreted – they act to tag circulating pathogens for elimination
Lectin receptors
Ligand:
terminal mannose and fucose
Outcome:
phagocytosis
Scavenger receptors
Ligand:
bacterial cell walls
modified low-density lipoproteins
Outcome:
phagocytosis
Toll-like receptors (TLRs) (surface and endosomal)
Ligand: LPS (together with CD14) lipoproteins unmethylated CpG flagellin ds RNA; ss RNA (in endosomes)
Outcome:
inflammation: cytokine release (TNF, IL-1, IL-12)
enhanced killing: reactive oxygen species, NO)
NOD-like receptors (NLRs) (cytoplasm)
Ligand:
peptidoglycan from Gram positive and negative bacteria
some viral DNA and RNA (indirect?)
Outcome:
inflammation: cytokine release (IL-1, IL-8)
RIG-like receptors (RIG-1 and MDA5) (cytoplasmic)
Ligand:
dsRNA and 5’-triphospho RNA
Outcome:
type I interferon production
Complement
A system of secreted proteins made in the liver that recognise PAMPs on the surface of microbes and “decorate” or “tag” them. The microbes are then cleared by phagocytosis, “opsonised” or they have holes punched in them
Three ways of activating complement:
i) . Recognition of LPS and other PAMPs by the C1q component of “classical” pathway
(ii) . Non-host glycosylation is recognised by MBP and other lectins to activate the “lectin” pathway
(iii) . Membranes that are recognised as “non-self” activate the “alternative” pathway
Complement activation involves a proteolytic cascade
Natural Killer (NK) cells (Large granular lymphocytes)
4% white blood cells
Lymphocyte-like but larger with granular cytoplasm
Kill certain tumour & virally infected cells
Target cell destruction is caused by cytotoxic molecules called granzymes & perforins
Natural Killer (NK) cells are activated by loss-of-self
NK cells possess the ability to recognise and lyse virally infected cells and certain tumour cells.
Selectivity is conferred by LOSS of “self” MHC molecules on target cell surfaces, AND up-regulation of activating ligands
Cell death
(i). Perforin +
cytotoxic granules
(ii). Engagement of
death receptors
CMV has four gene products which
which reduce the expression of Class 1 MHC molecules and two class I MHC homologues (UL18 & M144), that give a negative signal to NK cells
NK cells bind
cells bind HLA-E which carries in its groove a peptide from the leader sequence of classical class I MHC molecules
Leader sequence found on
This same peptide sequence is found on the leader sequence of human hCMV. Thus, whilst MHC class I molecules are down regulated in hCMV infected cells, HLA-E is up regulated
There are many inherited defects associated with Innate Immunity
Complement – core defects (e.g. C3) linked to development of autoimmune diseases such as lupus
Complement – non-core defects linked to suspectibility to specific types of pathogens such as Neisseria
Macrophage deficiencies - Chronic granulomatous disease (CGD); No oxidative burst for bacterial killing
Macrophage deficiencies – IRF8 mutations linked to susceptibility to TB
Aicardi–Goutières syndrome associated with constitutive production of inflammatory cytokines
Lack of interferon-responsiveness – sensitivity to viral infection (e.g. measles)
