inflammation Flashcards
what is inflammation characterised by
inflammation characterised by increased blood flow and entry of leukocytes into the tissues, results in swelling, redness, elevated temperature and pain
what may stimulate infalmmation
before inflammation occurs recognition of an antigen/pathogen must occur, either via PAMP or DAMP
pattern recognition receptors:
on the surface; TLR, savanger receptors, lectins
within endosomal compartments (recognises viruses): TLR
soluble in cytoplasm: NOD like receptors (recognises peptidoglycans), NLRs
soluble in circulation: complement proteins, lipopolysaccharide-binding protein (LBP), ficoloins and collectins
what is complement
complement: a set of 20 or more different proteins which act in an enzymic amplification cascade system to generate a number of active complement components involved in several aspects of immune response. Key in inflammation, due to large amount of steps in enzyme cascade allows it to be very regulated
how might complement cascade be triggered
3 ways to activate complement: classical pathway, lectin pathway, alternative pathway
alternative pathway: starts with C3, activated by components of microbial cell surfaces which cause it to be cleaved into C3a and C3b
classical pathway: starts with C1, activated by an antibody
lectin pathway: starts with manose binding lectin (MBL), manose is usually a bacterial sugar
what is a key event in all complement pathways
key event in all pathways: C3 convertase cleaves C3 into C3a and C3b
how is C3 convertase made
C3 convertase is made by the classical and lectin pathways by generating C4b2a which is C3 convertase, a different one is made in the alternative pathway which is C3bBb
when are pathways active
classical and lectin must be triggered, alternative pathway is always a little bit active
describe a later reaction in complement cascade
C3 is then converted into an intermediate which is then converted to C5 via C5 convertase, which is then cleaved into C5a and C5b
what are actions of complement products
C5b-C9 causes cell lysis
C3b and C4b causes opsonisation
C3d causes B-cell activation
C3a C4a and C5a cause mast cell degranulation which also aids in chemotaxis of neutrophils
C3b causes clearance of immune complexes
end product of complement cascade is membrane attack complex (MAC)
describe the structure and function of MAC
MAC is a complex of C5b and C6-8 that bind to the outer surface of the plasma membrane as well as many copies of C9 that hook up to one another forming a ring in the membrane
ring strucutre formed by C9 is a pore in the membrane that allows free diffusion of molecules in and out of the cell, if enough pores form the cell is killed
C9 binds to complex and more copies of C9 are added to form pore
what are phases of acute inflammation
vascular phase: increased blood flow into infected tissues, localised increase in vascular permeability, endothelium becomes adhesive
cellular phase: leukocytes accumulate in local vasculature, leukocyte migration into infected tissue
vascular phase and cellular phase lead to removal of infectious agent
how might mast cells be activated, what does this lead to
mast cells: mast cells are activated by C3a and C5a, as well as PAMPs damage, can recognise tissue damage
degranulation of mast cells release granule contents; histamine, cytokines, chemotactic factors and vasoactive amines
mast cells also produce leukotrienes and prostaglandins (inflammatory mediators) through another pathway by releasing phospholipase A2
how might tissue macrophages be activated, what does this lead to
tissue macrophage: can be triggered via pattern recognition receptors
causes release of inflammatory mediators (prostaglandins and leukotrienes) cytokines; initiates cytokine cascade (TNF, IL-6, IL-1), releases chemokines which recruit more cells, they also antigen present to t cells
what are APPs
acute phase proteins
cytokines released by PRRs which act on liver to increase secretion of these by up to 1000 fold
APPs: C3, C-reactive protein (activates complement), fibrinogen; causes coagulation preventing blood leaving site of pathogen
how do neutrophils enter the tissue
selectins (P and E) expressed on endothelium, expression caused by cytokines
sugar on neutrophil surface binds to selectins ( CD15 on neutrophil binds to E selectin)
after neutrophils binds to selectins it causes neutrophils to start expressing integrins such as LFA-1, which allows it to binds to ICAM-1 on endothelium, causing firm binding/adhesion
ICAM-1 expression caused by TNF and other inflammatory mediators
after adhesion the neutrophil can squeeze through since vasculature is more permeable due to cytokines etc, process is called diapedesis
describe the process of leukocyte migration during inflammation
leukocytes move out of blood vessels (extravasation)
movement of cells from part of the body to another
highly ordered process
cell adhesion molecules (CAMs) promote transient adhesion of leukocytes to blood vessels
chemoattractants direct movement into tissues
acute inflammation is usually beneficial
what are cytokines
cytokines act as soluble messengers between cells they include;
interleukins (between leukocytes), interferons (very anti-viral), tumour necrosis factors, colony stimulating factors, growth factors, chemokines
colony stimulating factors and growth factors promote production of certain types of cell
cytokines can either work very locally or can have more of an endocrine effect
cytokines can cause; pleiotropism, redundancy, synergism and antagonism
cytokines produced by activated immune cells, epithelium and stromal cells
what are 2 phases of inflammation
Induction phase: (causes inflammation)
pro-inflammatory cytokines: TNF, IL-6 and IL-1
have local effects but also long range effects on the liver, production of APPs and fever
interferons (IFNalpha and IFNbeta) induced by viral infection;
they prevent viral replication, activate dendritic cells, macrophages, natural killer cells and induce chemokines
resolution phase:
(helps repair after inflammation)
macrophages then come into cell to phagocytose the apoptotic neutrophils, they also convert themselves from pro-inflammatory macrophages to pro-resolving macrophages. neutrophils undergo apoptosis
anti-inflammatory cytokines: TGF beta and IL-10 (cause repair)
what are chemokines
redundancies: several chemokines display similar activities, shared receptor usage
in naming:
C denotes a cysteine
L stands for the ligand and ordered by number
X means something between the cysteines
how do chemokines act in inflammation
inflammatory chemokines are only expressed during inflammatory episodes
main sources; activated macrophages and dendritic cells
cellular distribution of receptors dictates type of leukocytes recruited into tissues, together with cellular adhesion molecules (CAMs) influence selective recruitment
At start of inflammation oedema is caused due to entry of plasma/ neutrophils etc and kills pathogen
what are differences between acute and chronic inflammation
onset of acute is fast (hours or minutes), chronic is slow and takes days
the cellular infiltrate of acute inflammation is mainly neutrophils and in chronic is mainly monocytes/macrophages and lymphocytes
due to short duration acute inflammation does not lead to tissue injury however chronic inflammation may lead to severe and progressive tissue injury
local/systemic signs are much more prominent in acute inflammation/ chronic inflammation can be localised to just a joint
what may cause chronic inflammation
persistent injury or infection: tuberculosis, ulcers, chronic viral infections
prolonged exposure to a toxic agent; pulomary silicosis (silica in the lung)
autoimmune disease: self perpetuating immune reaction results in tissue damage and inflammation: rheumatoid arthritis, multiple sclerosis
