cytokines, acute phase reactions, defensins Flashcards
what stimulates inflammation
activation of innate immune cells by pathogens
responses go inflammation
swelling, redness, heat, pain, loss of function
what happens when inflammation fails to give a resolution
leads to fibrosis, septic shock and chronic inflam
t and b cell pathogen detection
individual t and b cells are highly selective for a specific pathogen species
immune memory for a faster secondary response
innate immune cell pathogen detection
less selective than t and b, recognise broad classes of pathogens and not specific species, no immune memory, 1st line of defence
detect pathogens via pathogen associates molecular patten
PAMP
pathogen associates molecular pattern
molecules or structures that are specific more microbes and viruses not visible to host cells
PRR
pattern recognition receptor
invariant germline encoded receptors
where are PRRs expressed
on innate immune cells and in some t, b and endothelial cells
classes of PRRs
toll like, nod like, c type lectin, dna and rna
what are cytokines
small proteins that mediate cell-cell communication during immune reactions
can have multiple targets
where are cytokines produced
cells in the immune system
main action of cytokines
on the immune system, some circumstances they target non immune cells
how do cytokines stimulate cells
via cytokine receptors
difff classes of cytokines
chemokines, interleukins and TNF
what to cytokines recruit
immune cellss
what do classical cytokines modulate
immune cell function
what effect do chemokines have
homeostatic or immune effects on leukocyte migration
chemokine types
4 groups divided based on the position of cysteine residues that mediate the formation of disulphide bridges in their 3d conformation
what do macrophages secrete
inflammatory cytokines, IL-1beta, TNFalpha, IL-6, CXCL8, IL-12 - all leads to inflammation at site of infection
IL-1beta and TNFalpha from macrophages
induce blood vessels to become more permeable, enabling effector cells and fluid containing soluble effector molecules to enter infected tissues
IL-6 from macrophages
induces fat and muscle cells to metabolise , make heat and raise temp in infected tissue
IL-12 from macrophages
recruits and activates NK cells that secrete cytokines that strengthen macrophages response to infections
host defence peptides (HDP)
peptides that can initiate prokaryotic cells or viruses, produced by both proks and euks
host defence peptides 3 main mechanisms of action
distribution of membrane integrity, bind precursors of cell wall formation to inhibit formation of bacterial cell wall and thus blocks bacterial replication, targets intracellular proteins to disrupt cell function
mammalian host defence peptides
cathelicidin and defensins
alpha defensins
restricted to certain mammalian species, mainly expressed in myeloid and paneth cells
beta defensin
found in vertebrates and invertebrates immune and epithelial cells
why are cytokines released
by macrophages in response to stimulation of pattern recognition receptors
what doers release of cytokines require
de-novo transcription and translation of cytokine genes and is regulated at transcription, mRNA stability and mRNA translation
what in cytokines allows their transport to the ER and subsequent secretion
their pro-sequence
(IL-1 and TNF are exceptions, IL-1b requires processing by inflammosome, TNF is transported to the cell surface where it is expressed as a plasma membrane protein and then cleaved by the protease TACE which releases mature TNF from the membrane)
TNF release..
attracts neutrophils and stimulates phagocytosis
IL-1b release…
causes t cell polarisation
IL-6 release..
promotes neutrophil and b cell survival and proliferation, t cell polarisation
IFNbeta release…
promotes IL-10 production by macrophages for antiviral responses
IL_10 release…
inhibits TNF, IL-6 and IL-12 production by macrophages
IL-12 release…
results in Th1 driven T cell responses and NK cell actviation
Acute phase reaction (APR)
involves changes in plasma conc of specific proteins in response to inflammation
driven by cyotkines produced during localised inflam responses
systemic not localised reponses
changes due to altered protein synthesis in the liver
some acute proteins are increased whilst others are decreased
acute phase proteins in preventing spread of infection
c reactive protein, SAP, complement proteins
acute phase proteins in wound healing
fibrinogen, von willebrant factor, coagulation
acute phase proteins in preventing systemic inflammation
c reactive protein, SAP, proteinase inhibitors, haptoglobin, manganese superoxide dismutase and serum amyloid A
c reactive protein
mayor acute phase protein in humans
pentraxin (5 identical subunits)
used as a marker of inflammation
respond to IL-6 and IL-1beta hepatic expression by increasing in no dramatically
T cell helper polarisation (2 steps)
- antigen presentation 0 antigens presented as MHC class 2 molecules on an antigen presenting cell recognised by t cell receptors of a naive CD4 t cell - this stimulates the t cell to proliferate
- polarisation - in response to cytokines secreted by the APC or other nearby immune cells, Th cell will polarise to take specific characteristics
naive CD4 t cell proliferation in response to IL-12
Th1, promotes killing by macrophages, response to intracellular pathogens
naive CD4 t cell proliferation in response to TGFbeta, IL-6, IL-1beta, IL-23
Th17, anti-fungal and anti-tumour immunity
naive CD4 t cell proliferation in response to IL-4
Th2, promotes antibody production by B cells, anti-worm immune responses
naive CD4 t cell proliferation in response to TGFbeta
Treg, immune suppressor
what is autoimmune disease caused by
excessive production of pro-inflammitory cytokines
autoinflammitory disorders
familial Mediterranean fever, noenatal onset multisystem inflam disease, TNF receptor-associated periodic syndrome, deficiency in IL/receptor antagonist, behcets disease
most result from genetic mutations that increase IL-1 production of signalling
cytokine directed therapy
anti-TNF therapy, binds to TNF and stops its ability to produce cells - approved for RA, psoriasis, prosatic arthritis, chrons disease, ulcerative colitis and ankylosing spondylitis
IL-1ra anti-inflammitory cytokine
binds to the IL-1 receptor but does not activate intracellular signalling - it is a competitive inhibitor of Il-1
