Innate Immunity Flashcards
What structures are recognised by the innate immune system?
PAMPs
What are 4 cells involves in both innate + adaptive immune responses?
- macrophages
- monocytes
- dendritic cells
- mast cells
What are 2 humoral factors involved in both innate and adaptive immune responses?
- complement
- cytokines
What are 5 things that phagocytic cells can ingest?
- whole microorganisms
- insoluble particles
- dead host cells
- cell debris
- activated clotting factors
What are 4 stages of phagocytosis?
- adherence of material to cell membrane
- pseudopodia (finger like projections) engulf the material, membrane-bound structure called phagosome formed
- this fuses with lysosome to form phagolysosome, mixing contents of lysosome with the engulfed material - digest + break down material
- waste products released from cell
What are 3 things contained in lysosomes of phagocytes that can digest + brek down engulfed material?
- hydrogen peroxide
- oxygen-free radicals
- hydrolytic enzymes
What are the 2 key types of phagocytic cells?
- neutrophils (PMN leukocyte)
- macrophages
What is the first cell to be recruited to a site of tissue damage/infection?
neutrophil
What is the lifespan of a neutrophil like?
short lived
Where do neutrophils circulate around the body?
circulate in the blood then migrate into tissues
How many neutrophils are produced per day in a health adult and how does this change in infection?
10^11, can increase 10x in infection
Where are macrophages found?
dispersed throughout the tissues
What is a key function of macrophages, in addition to phagocytosis?
signal infection by release of solbule mediators
What process directs neutrophils towards an area of infection?
Chemotaxis- directed migration along chemokine concentration gradient towards area of high concentration
What are the stages that lead neutrophils to migrate to a site of infection?
- Neutrophil rolls along normal endothelium
- At site of damage/when antigen is presented by macrophage, a change in the nature of the endothelium
occurs - Integrin activation by chemokines
- This leads to a change in adhesion molecules into high affinity state
- they flatten out and undergo migration through endothelium
How do neutrophils perform opsonisation?
coat pathogen with proteins to facilitate phagocytosis, opsonins are molecules that bind to antigens and phagocytes. antibody and complement function as opsonins
How is neutrophil binding to opsonins achieved?
bacterium-antibody complex -> complement activation -> Fc receptor on phagocyte binds to antibody -> CR receptor binds to complement -> oposonins bind to pathogen -> signal activation of phagocyte
How is neutrophil binding to opsonins achieved?
bacterium-antibody complex -> complement activation -> Fc receptor on phagocyte binds to antibody -> CR receptor binds to complement -> oposonins bind to pathogen -> signal activation of phagocyte
What may phagocytosis result in?
abscess formation
What process makes phagocytosis more effective?
opsonisation
What 2 groups can neutrophil pathogen killing mechanisms be split into?
- oxygen-independent - using enzymes or antimicrobial peptides (defensins)
- oxygen-dependent - respiratory burst (toxic metabolites) or reactive nitrogen intermediates
What are 3 examples of oxygen-independent neutrophil killing mechanisms?
- lysozyme (enzyme)
- hydrolytic enzymes
- antimicrobial peptides (defensins)
What are 2 types of oxygen-dependent neutrophil killing mechanisms?
- uses respiratory burst: toxic metabolites
- reactive nitrogen intermediates - nitric oxides
What are 4 toxic metabolites in the respiratory burst that is an oxygen-dependent neutrophil killing mechanism?
- superoxide anion
- hydrogen peroxide
- singlet oxygen
- hydroxyl radical
What is the result of phagocyte deficiency?
- infections due to extracellular bacteria + fungi
- bacteria: Staph aureus, Pseudomonas, E coli
- fungi: candida, aspergillus
- deep skin infections, impaired wound healing, poor response to abx
What are monocytes?
type of phagocyte - circulate in blood, smaller than tissue macropahges, precursor to tissue macrophages
What are 3 examples of pathogen recognition receptors that macrophages have?
- toll-like receptors TLR
- NOD-like receptors
- RIG-I viral genomes
What are 3 examples of pathogen recognition receptors that macrophages have?
- toll-like receptors TLR
- NOD-like receptors
- RIG-I viral genomes
What are 5 properties of cytokines?
- small secrete proteins
- cell-to-cell communication
- generally act locally
- powerful at low concentration
- short-lived
What are 5 types of cytokines?
- interluekins
- interferons
- chemokines
- growth factors
- cytotoxic
What is the function of interferons?
anti-viral effects
What is the function of growth factors in the immune system?
development of immune system
What is a key type of cytotoxic cytokine?
TNF
How do cytokines work?
transcription of gene for soluble protein in cytokine-producing cell – cytokine binds to receptor on target cell – Binding generates signal – changes in gene transcription and gene activation – biological effect
What are 3 types of method action which cytokines may have?
- Autocrine - same cell (e.g. IL2)
- Paracrine - nearby cells (e.g. IFN)
- Endocrine - circulate to distant cell (e.g. IL6)
What are 5 important cytokines and their functions?
- IL-1: alarm cytokine, fever
- TNF-alpha: alarm cytokine
- IL-6: acute phase proteins, fever
- IL-8: chemotactic for neutrophils
- IL-12: directs adaptive immunity, activates NK cells
How do bacteria cause septic shock?
systemic infection - Bacterial endotoxins cause massive release of the TNF-alpha and IL-1 by activated macrophages = increased vascular permeability, drop in BP
Where are dendritic cells located?
likely sites of infection - skin, near mucosal epithelia
What is meant by the triggered enzyme cascade system of complement?
initially inactive precursor enzymes - as a few are activated, they catalyse the cleaving of secondary components. rapid, highly amplified response
What 3 things produce components of complement?
- Liver (main site)
- Monocytes
- Macrophages
What are the 3 routes of activation of the complement cascade?
- classical pathway: antigen-antibody complexes
- alternative pathway: pathogen surfaces
- lectin pathway: antibody independent activation of classical pathway by lectins binding to carbohydrates on pathogens (MBL + CRP)
Where do the classical + alternative pathways converge?
C3 - leads to final common pathway resulting in formation of membrane attack complex (MAC) -
Hydrolysis of C3 by C3 convertase
What 4 types of immunoglobulin can activate the classical complement pathway?
- IgM
- IgG1
- IgG2
- IgG3
(not IgA/E/D)
Which immunoglobulin is most efficient at activating the complement cascade via the classical route?
IgM
How many plasma proteins circulate that contribute to the complement cascade and in what form is this?
9 - inactive form
What is a key property of the complement proteins?
heat labile
What are 5 constituents of bacterial cell wall constituents which can activate the alternative complement pathway?
- LPS
- techoic acid
- viruses
- dextran
- IgA (occasionally)
How does activation of the lectin complement pathway work?
initiated by binding of serum lectin to mannose-containing proteins or to CHO on the bacteria or viruses
What is the major amplification step of all 3 complement pathways?
Hydrolysis of C3 by C3 convertase
Which 2 organisms is the memrane attack complex particularly good at lysing?
- Enveloped viruses
- Gram-negative bacteria
lyses broad spectrum of organisms
Which organisms is the MAC bad at lysing and why?
gram positive bacteria - thick layer of peptidoglycan in their cell wall or due to capsular sialic acid
What is the classical infection people are affected by who have terminal complement deficiencies (C5-9)?
Neisseria spp
What is the principle opsonin of the complement cascade (common end pathway)?
C3b
What are 3 ways that control mechanisms of the complement pathway are achieved?
- lability of components - short half life
- dilution of components in biological fluids
- specific regulatory proteins - circulating/soluble + membrane bound
What are 4 examples of circulating/soluble specific regulatory proteins that control complement cascade?
- C1-inhibitor
- Factor I
- Factor H
- C4 binding protein
What are 2 examples of membrane bound specific regulatory proteins that control complement cascade?
- CD59 - interferes with MAC insertion
- DAF - competes for C4b
What are 7 key functions of the complement pathway?
- lysis
- opsonisation
- anaphylatoxins - C3b, C4b, C5a
- mediate degranulation of mast cells
- viral neutralisation
- promotes phagocytic clearance of immune complexes
- aiding in antigen presentation
How does the complement cascade aid in opsonisation?
Complement components (e.g., C3b, C5a and C4b) are recognised by specific receptors on phagocytes and enhance phagocytosis of the coated pathogen
Which complement components act as anaphylatoxins and how?
- C3a, C4a and C5a = induce smooth muscle contraction and increase vascular permeability
Which complement components mediate mast cell degranulation?
C3a + C5a
How can complement play a part in neutralising virus?
coating the virus and blocking their attachment to cellular receptors
How does complement promote humoral immunity?
by aiding in antigen presentation to B cells in germinal centres, and by binding to a receptor on B cells which acts as a co-stimulator
What are 2 sites of mast cells?
- mucosal - lung
- connective tissue - skin and peritoneal cavity, near blood vessels
Which complement products are degranulated by mast cells?
anaphylatoxins –> vasodilatation, vascular permeability
What are 3 key features of the local acute inflammatory response?
- invasion of pathogens
- complement activation
- endothelial damage
What are the consequences of the invasion of pathgens in the local acute inflammatory response?
- recognition by macrophages
- phagocytosis
- release of soluble cytokines + chemokines
- Diapedesis and Chemotaxis (slowing down of neutrophils in blood vessels and migration towards site of infection)
What are the consequences of complement activation in the local acute inflammatory respose?
- mast cell degranulates
- release of pro-inflammatory fragments + histamines
What are the consequences of endothelial damage in the local acte inflammatory response?
- change in nature of endothelium
- signals site of infectionto neutrophils
What are the consequences of endothelial damage in the local acte inflammatory response?
- change in nature of endothelium
- signals site of infectionto neutrophils
How long after the local inflammatory response may the systemic ‘acute phase’ response start?
1-2 days
What are 4 key acute phase proteins?
- CRP - activates complement
- Mannan binding lectin - opsonin for monocytes, activates complement
- Complement
- Fibrinogen - clotting
What are 3 things indicating the importance of cytokines?
- signal liver - produce acute phase proteins
- signal bone marrow - CSF by stromal cells and marophages, increase WBC production
- signal hypothalamus - prostaglandin production, fever, pituitary gland + adrenal cortex - corticosteroids
What type of cells are natural killer cells?
large granulated lymphocytes
What are the 2 key types of cytokines produced by NK cells?
- IFN-gamma
- TNF-alpha
Do NK cells have an antigen specific receptor?
no
What is a key role of the receptors on the surface of NK cells?
bind to antibody coated cells - ADCC - antibody dependent cell-mediated cytotoxicity
Which type of virus are NK cells particular important in defence against?
herpes
What processes prevent NK cells from killing non-infected self cells?
ligation of inhibitory NK receptors to inhibit target cell killing due to recognition of lack of MHC molecules
Which complement component is present in the highest concentration in serum?
C3
