Innate Immunity (7-10) Flashcards
What are some barriers preventing pathogen entry?
Skin
- sebum (oil on skin) consists of lactic and fatty acids which maintain pH 3-5
- lysozyme in sweat cleaves bacterial cell wall proteoglycans
- normal microbiota can produce anti-microbial substances to compete for nutrients for nutrients and attachment to epithelium eg psoriasin selectively kills E. coli
Body temp
Mucous membranes
Toll-like receptors (TLRs) are a family of pattern recognition receptors. What does each one detect?
TLR1/TLR2 and TLR2/TLR6 Heterodimers:
Lipopeptides: Recognize bacterial lipopeptides, lipoproteins, and lipoteichoic acids from Gram-positive bacteria, such as Staphylococcus aureus and Mycobacterium tuberculosis.
TLR4:
Lipopolysaccharide (LPS): a component of the outer membrane of Gram-negative bacteria, including Escherichia coli and Salmonella..
TLR5:
Flagellin: certain strains of Escherichia coli and Salmonella.
TLR3:
dsRNA: Detects double-stranded RNA (dsRNA), a viral replication intermediate, and triggers immune responses against RNA viruses, such as influenza virus and hepatitis C virus.
TLR7 and TLR8:
ssRNA: Detect single-stranded RNA (ssRNA) from RNA viruses, including influenza virus, HIV, and other RNA viruses, and stimulate antiviral immune responses.
TLR9:
Unmethylated CpG DNA: motifs commonly found in bacterial DNA and certain viral genomes, such as those of bacteria like Streptococcus pneumoniae and viruses like herpes simplex virus (HSV)
What are mast cells?
- contain large quantities of histamine stored in intracellular granules
- upon activation by crosslinking of IgE on the cell surface, mast cells will degranulate
- play an important role in parasitic infections and are one of the key players in allergy
What are cytokines?
- small proteins that work in tandem w other signals to provide regulation for immune cells
- the majority are secreted but can be membrane bound eg TNF-alpha and IL-15
- can function at v low concentrations
- work locally, not systemically
- most have a short half like in bodily fluids (10-15)
What are chemokines?
- chemotactic cytokines, that control cell migration both during development and during an immune response
- two functional types
–> homeostatic
–> inflammatory - 4 structural groups defined by spacing of a conserved cystine motif
–> C
–> CC
–> CXC
–> CX3C
What are atypical chemokine receptors?
lack classical signalling capabilities typically associated with conventional chemokine receptors
the placenta has many so that the mothers cytokines do not affect development of the baby
What is meant by tissue post codes?
some chemokines can function as post codes to direct cells to specific tissues
eg CCL19 and CCL21 are expressed in lymphatic tissues and cells expressing CCR7 will be able to migrate towards sources of these chemokines
this is also true for in the liver, where CXCR6 expressing cells will migrate towards CXCL6 producers here
What are endogenous pyrogens?
molecules in the body that are capable of inducing fever
eg IL-1, TNF-alpha, C3a and C5a
What is the acute phase response?
the first mode of action in response so injury or pathogen detection
induced by cytokines made by macrophages
- endogenous pyrogens
IL-6 is also produced which regulates the synthesis of acute phase proteins in the liver
eg complement, mannose binding lectin, CRP
What are pentraxins?
family of conserved protein pentamers involved in the acute immune response
eg C reactive protein (CRP)
bind phosphocholine in certain bacterial & fungal cell walls
–> does not bind mammalian phosphocholine
Go into more detail about CRP.
C-reactive protein
acts as an opsonin
–> similar to antibodies but w more specificity
homodimer (native CRP (nCRP)):
- activates classical complement pathway
- induces phagocytosis
- increases IL-6 and TNF-alpha
- promotes apoptosis
monomeric CRP recruits circulating leucocytes to areas of inflammation
What is MBL?
Mannose-binding lectins
- liver-derived collagen-like serum protein
- binds mannose containing structures (lectins) on microorganisms and on dying host cells
- acts an an opsonin
- activates lectin complement pathway
REVISION: Complement Pathways
- The lectin pathway is initiated by mannose-binding lectin (MBL)that binds to particular carbohydrate structures on microbial surfaces. Specific proteases, called MBL-associated serine proteases (MASPs), that associate with these recognition proteins trigger the cleavage of complement proteins and activation of the pathway
- The classical pathway (found first) is initiated when complement component 1 (C1), which comprises a recognition protein (C1q) associated with proteases (C1r and C1s), either recognizes a microbial surface directly or binds to antibodies already bound to a pathogen
- the alternative pathway (found second) can be initiated by spontaneous hydrolysis and activation of complement component 3 (C3), which can then bind directly to microbial surfaces.
When any of the pathways interacts with a pathogen surface, the enzymatic activity of a C3 convertase is generated
various types of C3 convertase, depending on the complement pathway activated, but each is a multi-subunit protein with protease activity that cleaves C3
The C3 convertase is bound covalently to the pathogen surface, where it cleaves C3 to generate large amounts of C3b, the main effector molecule of the complement system, and C3a, a small peptide that binds to specific receptors and helps recruit phagocytic cells and induce inflammation
Completion of the complement cascade leads to formation of a membrane attack complex (C6-9) (MAC) which disrupts cell membrane and causes cell lysis
What is the coagulation cascade?
activates the zymogen (a protein w an inactive enzyme), prothrombin, to the serine protease, thrombin
thrombin converts fibrinogen into fibrin strands which polymerise to form a clot
fibrin is then cross linked by factor XIII to stabilise the clot
can also coat pathogen and prevent entry into the bloodstream = containment
What is the erythrocyte sedimentation rate?
the rate at which RBCs sediment in a period of one hour
- common haematology test, and is a non-specific measure
- pro-sedimentation factors (fibrinogen) vs anti-sedimentation factors
- the RBCs form stacks in the increased presence of fibrinogen and settle faster
higher rate of inflammation = higher ESR
measured in mm/hour
What is the difference between an autoimmune disease and an autoinflammatory disease?
autoimmune: adaptive immune system has mistakenly identified something specific in the body as harmful and attacks eg IBS
–> more common
autoinflammatory: the innate immune system reacts often without cause and without control eg periodic fever syndromes
–> rarer
What is the inflmmasome?
- multiprotein complexes that form in the cytosol in response to cytosolic PAMPs and DAMPs by NLRs
- formed of NLRPthree
- activates caspases leading to secretion of active forms of inflammatory cytokines IL-1beta and IL-18
- also leads to pyroptosis = programmed cell death of macrophages or DC
NLRP3 forms part of the inflammasome
–> gain of function mutation causes periodic fever syndromes
