innate immunity III Flashcards
what is immunological tolerance?
ability to discriminate self from nonself
tolerates self cells but not nonself cells
immune system is not activated by their own cells
what are MHCs?
major histocompatibility complex (MHC)
protein cell-surface molecule that allows the immune system to distinguish between self and nonself
inhibits killing activity of natural killer cells, a type of innate-like lymphoid cell (ILC)
how do NK cells determine what to kill
thru natural killer cell’s recognition of “missing self”
they are called NK, because they’re always “on” and always poised to kill unless told otherwise by self-nonself discrimination
they have inhibitory receptors that recognize MHC, which can send “self” signals to turn the NK off, telling it not to kill (inhibitory signals)
they also have activating receptors — they must balance both their inhibitory and activating signals to determine what of the 2 happens!
if inhibitory receptors don’t engage, but activating receptors are engaged, the NK remains on and is poised to kill
—- typically seen in viral infected cells as the infection causes the cell to downregulate the MHC molecule
if activating receptors have been upregulated – due to stress (seen in stressed and tumor cells), killing of altered self-cell is promoted
—- MHC is still present but more activating receptors are binding in comparison to the inhibitory receptor
where are NK cells found?
found in circulation (blood, lymphoid system, tissues) like other lymphocytes
describe the mechanism by which NK cells kill target cells
NK cells have granules which contain 3 major types of proteins
—— FasL = Fas Ligand
—— granzyme B
—— perforin
when NK is in close contact with a target cell, granule will undergo exocytosis, leaving the NK cell
FasL will engage with Fas on the target cell, inducing a death signal into the cell (tells cell to die)
—— Fas is present in all human cells
other contents of the granule (granzyme B and perforin) are released into the target cell via endocytosis
perforin molecules inserts itself into the endosomal lipid bilayer, making a ring which will allow granzyme B to leave the endosome and enter the cytoplasm of the cell
—— perforin can be considered a transmembrane protein!
the granzyme B induces apoptosis
REFER TO DIAGRAM
who discovered the complement system?
Paul Elrich
what is the complement system?
a complex network of approximately 50 proteins will roles in innate immunity, adaptive immunity, and inflammation
reason behind naming: soluble proteins in blood plasma that complement antibody action to kill target cells… they help antibodies kill cells
what are the different functions/pathways of the complement system
alternative pathway: directly kill cells
—– this pathway was found later, thus, named alternative
—– an innate immune pathway of self-nonself discrimination
classical pathway: interacts with antibodies to kill cells
—– this pathway was found first, thus, named classical
lectin pathway: interacts with lectins to kill cells
opsonize (marks) pathogens to flag them for phagocytosis
function as a chemoattract to recruit leukocytes and induce inflammation - they can function as cytokines
describe the alternative pathway of complement activation
REFER TO DIAGRAM!!!!!!
starts with the spontaneous cleavage of C3 to C3b protein in blood
complement activation happens outside of the cell in the plasma blood, although the proteins are made in the cell
C3 spontaneously associates with proteins called factor B
C3B then self catalyzes in the presence of factor D, cleaving the factor B component to a and Bb - we are now left with C3Bb
—— C3Bb is also called fluid-phase C3 convertase as it’s floating around in the blood plasma
fluid-phase convertase cleaves (a different) C3 to C3b and C3a
the C3B can then covalently bind to bacteria – this is enzymatic activity and is called membrane bound C3 convertase
the C3a functions like a cytokine, more specifically a chemoattractant and can attract neutrophils and NKs
the membrane bound C3 convertase can now recruit factor B and later, in the presence of factor D and properdin, factor B can be cleaved (to Bb and a) and will recruit another C3b molecule – forming C5 convertase (C3bBbC3b)
C5 convertase activity: in the presence of properdin, the complex can cleave (different) C5 proteins to C5a and C5b
—— this C5b can then covalently bind to bacteria…. the presence of C5b on pathogens or on our body cells (tumors) initiates a cascade of events (which leads to the membrane attack complex)
—— C5a is a powerful chemoattractant and can induce inflammation and attract neutrophils and lymphocytes
what is C5a?
a powerful chemoattractant and can induce inflammation and attract neutrophils and lymphocytes
what is C3a?
C3a functions like a cytokine, more specifically a chemoattractant and can attract neutrophils and NKs
what is the membrane attack complex?
the membrane attack complex / ring causes contents to leak out and allows thins like FasL to enter the cell
very important in fighting off invading organisms
describe the formation of the membrane attack complex
C5b recruits C6, C7, C8, and then a ring of C9 molecules – each molecule is one at a time in this sequence (each C9 is separately as well!)
C7, C8, and C9 are transmembrane (thus, the C9 ring is also transmembrane)
how does the alternative pathway of complement activation not kill us, even tho it is spontaneously happening in our body at all times? and how is it killing pathogens and altered-cells?
the reason it doesn’t kill us is thanks to decay-accelerating factors (DAF aka CD55) and complement receptor 1 (CR1 aka CD35)
DAF/CD55 and CR1/CD35 interact with and promote dissociation of C3 convertases on our own bodies cells – so they reverse the fluid phase C3 convertase on normal cells but not pathogens – prevents the pathway from going thru
note that tumor cells may be missing this activity because they could be downregulating CR1/CD35
most pathogens lack these proteins (DAF/CD55 and CR1/CD35) and are killed
describe the experiment of a mouse who was missing their DAF (decay accelerating factor) gene
in an experiment, gene that encodes the mouse version of DAF (Crry) is not there and the mouse is not born because it was spontaneously killed by the alternative pathway
