inflammation and blood proteins

what is the sequence of globulin banding via electrophoresis from anode to cathode?
albumin, alpha1, alpha2, beta and gamma
what makes up the gamma globulin band?
the Igs
what globulins should we know for the alpha1, alpha2, beta and gamma bands?
alpha1: alpha1 antitrypsin. alpha1/alpha2: ceruloplasmin. alpha2: haptoglobin and alpha2-macroglobulin. beta1: transferrin. beta 2: fibrinogen. gamma: Igs
what band do you see an increase in for hepatic cirrhosis?
gamma globulins, (Igs in response to damaged tissue)
what band do you see an increase in for multiple myeloma, (monoclonal gammopathy)?
massive amounts of Ig, (gamma globulin)
what band do you see an increase in for in early response pattern/acute inflammation?
small decrease in albumin, increase in alpha 2
what band do you see an increase in for in delayed response pattern, (primary viral/microbial infection)?
slight alpha2 increase, massive gamma globulin/Ig
what band do you see an in nephrotic syndrome?
(in nephrotic syndrome, kidneys lose ability to fractionate a lot of the components in the plasma, some of the larger fragments are going to be retained, some of the smaller ones will pass right out.) the alpha2 band increases substantially relative to the others. it increases because of the alpha2 globulin macromolecule which remains b/c it is too large to pass through.
what do you see an hypogammagobulinemia or primary immune deficiency?
major loss of Ig
what proportion of plasma protein does albumin make up?
how would gamma bands appear early in an infection?
not too different than healthy, though alpha1+2 are elevated, and you will probably see a gamma increase
how would globulin bands appear during chronic lymphatic leukemia?
very low gamma/Ig
what are acute phase proteins, (APP)? can they change in chronic conditions? what is the time range for APP action? where are they generally produced?
proteins whose conc. increase, (+APP), or decrease, (-APP), by more than 25% or greater during inflammatory processes or disorders. APPs can also change in chronic conditions. APP action will be seen within the first 72 hrs. APPs are mostly synthesized in the liver, (except for gamma/Igs that are made by plasma cells/activated B cells)
what might APPs do that increase during inflammatory processes? what about those that decrease?
APPs that increase might have anti-microbial properties, increased phagocytosis, chemotaxis, complement activation. APPs that decrease might sequester iron, (or another molecule pathogens like to use), or simply be downregulated so other APPs can be upregulated.
which APP increases sharply within the first 24 hours of inflammation?
C-reactive protein and serum amyloid A
what does C-reactive protein respond to? when are these produced?
proinflammatory cytokines Il-1, TNF-alpha, Il-6 which are produced early in an inflammatory response.
what conditions will have substantial changes on APP levels?
infection, trauma, surgery, burns, infarction, inflammatory conditions, advanced cancer
what conditions will have moderate changes on APP levels?
strenous exercise, heatstroke, and childbirth
what conditions will have minimal changes on APP levels?
psychological stress, pyschiatric illness
how are APP regulated? are they coordinated? are there certain cytokines involved? what level are they regulated at?
regulation of APP is not coordinated, they each have their own control, however APP control involves cytokines, Il-6, Il-1 beta, and TNF alpha. they are mostly regulated at the transcriptional level, but some at post-transcriptional/translational levels
what are reasons for positive increase in APP?
they have roles in inflammation/reaction/recovery from trauma, for example c-reactive protein will work with complement even in the absence of pre-formed antibodies. serum amyloid A has protective effects, cell survival is increased over the short term.
what are reasons for negative decrease in APP?
molecules need to be sequestered such as iron, which can limit micro-organism growth. our body can make conditions bad for pathogens in certain area and still survive b/c other areas are unaffected. some APPs might simply be decreased in production b/c the AAs are needed for other APPs
what is the structure of C-reactive protein?
homopentameric, 5 non-covalently associated proteins arranged symmetrically around a central pore
how is C-reactive protein regulated? how fast can it be regulated? how does it behave in chronic conditions? where is it regulated on a genetic level?
CRP is regulated quickly, (can increase to 1000x within 24-48 hrs, and then drop again fast). it can be persistently elevated in chronic inflammatory conditions/advanced cancer. it is regulated at the transcriptional level, Il-6 induces, with other cytokines acting synergistically
what does CRP do? is it part of the innate immune response? what does it bind? how?
CRP is a part of the innate immune response. it binds to phosphocholine, (PCh) in a Ca++ dependent process. PCh is present on bacterial+fungal pathogens as well as apoptotic/necrotic human cells where CRP binds nuclear components.
how does CRP affect the classical complement pathway? how does it interact with phagocytes?
ligand-bound CRP is bound by C1q, activating the classical complement pathway. CRP may also help recruit phagocytes by binding Fc receptors
how is CRP used as a marker for inflammation? what are slightly elevated levels of CRP associated with?
CRP is used to monitor disease activity in chronic inflammatory conditions, and may replase erythrocyte sedimentation rate, (ESR). slightly elevated levels of CRP are associated with increased cardiovascular risk. it is
what is the structure of serum amyloid A, (SAA)?
it is a part of the family of apolipoprotiens, containing alpha helices with beta pleated sheets
how is serum amyloid A regulated? how does its release compare to CRP? what induces it?
SAA levels increase within hours of stimulus, to a magnitude sometimes larger than CRP. it is induced by synergistic action of cytokines, esp Il-1 and Il-6
what is the function of SAA?
serum amyloid A is a precursor of amyloid A protein, a major component of secondary amyloid plaques. it associates with HDL, replacing apolipoprotein A-1
what changes with HDL once SAA interacts with it in acute phase reactions?
HDL is cleared from circulation more quickly, its binding to macrophages is increased 5x, SAA also reduces storage of cholesterol esters in macrophages, (decreasing foam cells)
what is the structure of fibrinogen? is it homo- or heterogenous? why? where is it made?
2 symmetric half molecules, each consisting of one set of 3 different polypeptide chains. it is highly heterogenous due to alternative splicing, extensive post-translational modification, and proteolytic degradation. it is made in hepatocytes.
how is fibrinogen regulated? what level APP is it? what induces it? how much of it is found in plasma? what does it have its greatest effect on?
fibrinogen is a moderate APP, it is induced by Il-6, glucocorticoids, and oncostatin-M. it is abundant in plasma and has its greatest effect on ESR, (erythroctye sedimentation rate)
which of these: cell proliferation, immunosuppression, cell migration, angiogenesis, blood vessel tone, and hemostatsis does fibrinogen and its cleavage products affect?
all of them
what is the erythrocyte sedimentation rate, (ESR)? how is it done? what does it measure? what can affect the ESR?
most widely used marker of inflammation. blood+anti-coagulant are placed in a vertical tube, and the rate of fall is measured. this is an indirect measure of APP, especially fibrinogen’s activation state. increased aggregation of RBC, (into stacks called rouleaux), causes them to fall faster, as well as high Igs, (esp IgM), and aging. changes in rbc size and shape can affect ESR.
what is alpha 1 antiprotease/trypsin? what is its structure? how many forms does it come in? where is it made?
it is a serine protease inhibitor, (SERPIN) family. it is a single chain protein with 3 oligosaccharide side chains 75+ polymorphic forms. it is mostly made in the liver, w/~1% made in monocytes.
what is the most common form of alpha 1 antiprotease? what is a common abnormal form?
the normal alpha 1 antiprotease genotype is MM which makes PiM, (an inhibitor). ZZ is a common abnormal form which makes PiZ and is asssociated with emphysema. this is a result of missense mutation affecting folding and processing in the ER. <-good example of ER stress associated with apoptosis
how is alpha 1 anti-protease/trypsin regulated? what induces it?
in acute phase, levels increase 3-4x and it is induced by Il-6.
what does alpha 1 anti-trypsin/protease do?
it inhibits trypsin, elastase, other proteases by forming inactive compleses. it also protects elastic fibers in lung alveoli from excessive digestion by neutrophil elastase. alpha-1 antitrypsin mitigates collateral damage to human cells by their own body’s immune response.
what is the result of AAP deficiency, particularly alpha 1 antitrypsin in the lungs and liver? how do these deficiencies manifest themselves?
in pts with the ZZ genotype, mutant protein is not secreted properly and it forms aggregates in the ER of hepatocytes, leading to cirrhosis as well as emphysema in the lungs b/c the enzyme never makes it to the lungs -> overactivity of neutrophil elastase. methionine from cigarette smoke also compounds these problems by oxidizing the enzyme’s active site.
what is the structure of the alpha2-macroglobulin? what % of total plasma protein does it comprise? where is it made?
it is a very large glycoprotein with 4 identical subunits, comprising 8-10% of total plasma protein, it is made by hepatocytes, monocytes and astrocytes.
when are higher levels of alpha2-macroglobulin seen?
relative levels of alpha2 macroglobulin increase in nephrotic syndrome, due mainly to large size
what is the function of alpha2 macroglobulin in terms of protease activity? zinc transport? cytokine+growth factor activity?
it is a panprotease inhibitor. it transports ~10% of zinc in plasma. alpha2 macroglobulin binds cytokines and growth factors and appears to target them to particular cell types
what does albumin bind in the plasma? what other function does it perform?
divalent/trivalent cations such as Cu++ and Fe+++ it also can regulate osmotic pressure in the blood.
how is the transfer of iron from mucosal cell to capillary regulated?
by requirement and synthesis of apoferritin
where does transferrin bind Fe? where does it take it?
transferrin binds Fe in the capillaries and takes it to Fe-consuming tissues, (bone marrow/liver primarily)
what is the structure of transferrin?
transferrin is a single chain glycoprotein, (with 2 binding sites for Fe+++), beta globulin and functions as a negative acute phase protein.
what is the function of transferrin?
carries Fe in the blood, in acute inflammation, it carries Fe away from Fe-dependent pathogens. its level of saturation/iron binding capacity changes with Fe availability
what is TIBC?
transferrin iron binding capacity, which when high is a marker for iron deficiency
how is iron moved in and out of cells?
transferrin holding iron is taken into cells via clatharin-coated pits, the iron is stored as ferritin, and then if it needs to be released it is taken out of the cell via apotransferritin
what is the structure of ferritin? what does its blood level indicate?
24 subunits, (isoforms L+H), surrounding a core of 3-4000 Fe. ferritin is found mostly in tissues, but a small amount in blood, which is a marker for Fe reserves
how do increased iron levels affect ferritin and transferrin levels?
increased iron keeps a particular protein from binding to MRNA, and more ferritin is synthesized, less transferrin receptor is synthesized. (no iron=negative stimulus)
how do decreased iron levels affect ferritin and transferrin levels?
decreased iron levels lead to protein binding mRNA, less ferritin synthesis and more transferrin receptor synthesis. (iron=positive stimulus)
what is the structure of ceruloplasmin? what is another name for it? what does it bind and what % of the total?
ceruloplamin or ferroxidase 1 is an alpha2 globulin with 6 binding sites for Cu, to which it binds very tightly, (not readily exchangable). it carries 90% of plasma Cu, which albumin carries the other 10% of and is an easier donator
what is the function of ceruloplasmin/ferroxidase? what does Cu do? excess Cu? what happens in a Cu deficiency?
ceruloplasmin helps regulate Cu levels, and Cu accepts/donates e- in reactions involving dismutation, hydroxylation, and oxygenation. excess Cu can oxidize proteins, bind nucleic acids and enhance free radical production. if there is not enough ceruloplasmin, Fe builds up in tissues, b/c transferrin can’t move Fe2+, it needs to be changed to Fe3+ for transferrin to move it. (lack of ferroxidase activity)
what do increased ceruloplasmin levels correlate with?
increased ceruloplasmin levels correlate with cardiovascular risk, no clear correlation w/it and inflammation/atheroscelerotic plaques. both its anti-&pro-oxidant properties have been demonstrated in vitro.
what is haptoglobin? what kind of APP is it? what does it do? what can it stimulate?
an alpha2 globulin, a positive APP w/ antioxidant properties. it binds extra-corpuscular Hb and stimulates angiogenesis, (after inflammation is resolved, a new vascular network will be needed)
what is albumin? what % of plasma protein does it comprise? what important function does it perform generally in the blood? of protein synthesized in the liver, what % does albumin make up? what kind of APP is it? what does its rate of synthesis depend on?
albumin is small but it accounts for 50-60% of plasma protein. it is responsible for 80% of the blood’s osmotic pressure, (which allows for ions/antibodies/complement to flow from the vessels to the tissue when albumin drops as an APP), and transports numerous substances in the blood. it represents 25% of total liver protein production and it is a negative APP, (but not to great degree). its rate of synthesis depends on nutritional status.
what is transthyretin? what does it transport? does it inhibit anything/have a role in resolution of the acute inflammation phase? would it show up on a banding pattern? where does it appear in elecrophoresis in relation to albumin?
transthyretin or prealbumin is a negative APP that transports vit , (retinol) and some thyroxine. it inhibits Il-1 production by monocytes and endothelial cells.
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