Plasma Flashcards
What is plasma?
- the fluid left over after blood cells are removed
- it can clot
What is Serum?
-the fluid left after the blood clot (plasma) and cells are removed
The liver and chemical mediators of inflammation?
- liver is systemic source of some
- bacteria induces macrophages to make IL-6; acts on live to produce mediators
Mediators consitituvely produced or regulated?
-both; they are constitutively produces at low levels, but when PAMPs are activated, cascade events cause sliver to produce at much higher level
four mediators liver secretes? What are they in response to?
1) C-reactive protein (CRP)
2) Mannose-Binding Lectin
3) Serum Amyloid Portein
4) Fibinogen
-in response to systemic IL-6, IL-1, TNF (bacteria infection)
C-reactive protein (CRP)
- CRP binds phosphocholine on bacteria
- acts as opsonin
- activates complement
Mannose-binding lectin?
- mannose-binding lectin binds residues on bacterial surfaces
- acts as opsonin
- activates complement
What does high levels of CRP in the blood indicate?
- used as diagnostic measure of ongoing inflammation (acute/chronic)
How distinguish self mannose from bacteria?
-bacterial mannose is structurally different from how humans make it
What comprises the Pentraxin family?
1) CRP: opsonization; complement activation
2) SAP: opsonization, complement activation, binding of mannose/glucose
Serum Amyloid Portein (SAP)
- secreted by liver
- opsonization,
- complement activation
- binding of mannose/glucose
opsonin
-a molecule that binds a pathogen, coats it in opsin, and facilitates phagocytosis of the opsin coated pathogen
Opsonization
- the process by which a pathogen (virus, fungi or bacteria) is marked for ingestion and destruction by a phagocyte
- done by opsonin
What is the benefit of opsonization?
- so phagocytes only need receptors for opsin, and not for each individual type of pathogen
How do CRP/SAP do opsinization?
- CRP and SAP bind microbial cell walls, coating the pathogen and facilitating phagocytosis
Complement
- primary mechanism by which pathogen recognition is immedietly converted into an effective host defense against infection
What are the complement proteins? What form are these proteins typically in?
- numbered C1-C9
- are present as inactive forms in plasma
- get activated into proteolytic enzymes that degrade & activate downstream complement components
What do complement proteins trigger?
- trigger cascade amplification of inflammation
- by activating into protelotyc from, that degrade & activate downstream complement components
3 pathways that lead to complement activation
1) Classical Pathway
2) MB-Lectin Pathway
3) Alternative Pathway
all three lead to the single pipeline that is the complement pathway activation
Classical pathway, what is it dependent on?
- the first discovered
- activated by antigens binding to antibody & making a complex
- dependent on ADAPTIVE IMMUNITY (antibodies)
- leads to complement activation
MB-Lectin Pathway
- activated by lectin binding to pathogen surfaces
- activated complement pathway
alternative pathway
activated by the surface of pathogens
what are the three outcomes of complement activation? Do all 3 happen ALL the time when complement pathway is activated?
1) recruitment of inflammatory cells
2) opsonization of pathogens
3) killing of pathogens
YES, once complement activated ALL happen
What is the complement pathway?
-complement pathway is a single pipeline having three entry points and three exit points
What is the key step that the 3 complement pathways share? What is the result of this step?
- generation of protease C3 convertase which produces C3b
- once made, there are three outcomes (all happen)
3 outcomes after C3 convertase generation? Where is C3 convertase put?
1) inflammation
2) Phagocytosis
3) Lysis of Microbe
C3 convertase is deposited onto the microbe
C5A/C3a
- peptide mediators of inflammation
- promote phagocyte recruitment
- heavily involved with inflammation/anaphalaxsis
phagocytosis pathway steps after C3B generation? what pathways help with this outcome?
1) opsinozation of pathogens by addition of C3b coat
2) C3b binds to phagocyte
4) removal of immune complexes
*alternative & MBL pathway?
C3b
- activated by generation of C3 convertase
- binds to C3b receptors on phagocytes
- opsinozation of pathogen
- removal of immune complexes
lysis pathway steps after C3B generation? specific effectors used & their function?
1) C3b produces terminal complement components
2) these form the Membrane-Attack complex (MAC)
3) MAC causes lysis of certain pathogens & cells
MAC complex?
- a pore that goes into pathogen, pathogen guts leak out & pathogen lysed/dies
- allows fluid and ions to enter, causing cell lysis of pathogens
How C5A/C3a promote inflammation?
- cause vascular permeability/edema, icnrease cell adhesion moelcuels on vascualature which facilitate immune cells in blood to leave blood
- promote phagocyte recruitment
Does deficiencies leading to decreased formation of MAC cause major immune susceptibilities?
No -is primarily increased susceptibility to only one class of organisms, Neisseria
the single common wayC3a, C5a, C4a amplify inflammation?
all 3 cause histamine release from mast cells; increase vascular permeability, cause vasodilation
2 unique ways C5a amplify inflammation?
1) C5a activates lipoxygenase pathway of AA in neutrophils and monocytes
2) C5a a chemoattractant for monocytes, neutrophils, eosinophils, basophils
1 unique way C3 amplify inflammation?
C3 acts as opsonins when fixed to bacterial cell walls and promote phagocytosis by macrophages and neutrophils
anaphylatoxins
when histamine is stimulated to release from mast cells (increase vascular permeability, cause vasodilation)
What if fail to activate complement?
1) Increased susceptibilities to fatal infections
2) Deficiencies associated with decreased MAC formation
3) Deficiencies in C2 and C4
Deficiencies in C2 and C4 cause susceptibility to what?
associated w/ autoimmune disorders (lupus) cuz immune complexes can’t be efficiently cleared
how regulate C3 & C5?
- is key inhibitory point
- DAF or other host proteins increase decay rate of these two proteins
- by proteolytically cleaving C3b (factor I)
- to stop inflammation progression
how inhibit C1
- plasma protein C1 inhibitor (CiiNH) binds C1 & interferes with its enzyme activity
- CiiNH also inhibits Hageman Factor, Kallikrein & lectin as well
how inhibit MAC?
Several other host molecules inhibit MAC formation
What if you fail to inhibit the complement system C1?
- causes deficiencies in CiiNH
- lead to excessive production of vasoactive mediators causing episodic edema (fluid accumulation)
Specific mediator of edema in CiiNH deficiency?
bradykinin
2 possible activation pathways of chemical mediators in plasma?
1) Factor X11 (Hageman factor) activation
2) Complement Activation
Factor X11 (Hageman factor) activation and complement Activation
-can acitvate part of complement cascade & activate C3a to get anaphylaxis activation
Kinin system:
- enzymatic cascade triggered by tissue damage
- causes inflammation
Hageman factor (factor XII) & activation? What does it produce after activation?
- factor XII of intrinsic clotting pathway
- activation caused by contact w/ negatively charged surfaces (collagen & basement membrane)
- once activated produces Prekallikrein activator (factor XIIa
Prekallikrein activator (factor XIIa)?
-Prekallikrein activator produced by Hageman factor & converts inactive form of prekallikrein into the active protease: Kallikrein
How get negatively charged surfaces for Hageman factor to react to?
-due to tissue damage exposing the collagen/basement membrane
What does active protease Kallikrein do?
-Kallikrein cleaves high molecular weight kininogen to produce bradykinin
What does Bradykinin do?
-Bradykinin increases vascular permeability, causes contraction of smooth muscle, dilation of blood vessels & pain
What other function does high molecular weight kininogen (HMWK) cofactor do?
-acts as a co-factor promoting the activation of Factor XII (Hageman Factor)
What other function does high Kallikrein do?
1) activator of Hageman factor,
2) directly converts factor C5 to activated C5a which is the inflammatory response in the compliment pathway
inactivation of of Bradykinin?
1) activation of of Bradykinin is short lived so is partially self regulating
2) inactivated by Kininase in the plasma
3) inactivated by angiotensis-converting enzyme when passes through lung
Two types of clotting pathways?
1) Intrinsic clotting pathway
2) Extrinsic clotting pathway
Intrinsic clotting pathway
-damage to blood vessel causes cascade of clotting factors and activation of Hagemen factor (XII)
Extrinsic clotting pathway
- tissue damage outside blood vessel causes tissue thromboplastin release & activation of Hagemen factor (XII)
2 pathways that can transpire after Hageman factor activation?
Factor X11 (Hageman factor activation)–> Factor XIIa–>
1) Kinin cascade
2) Clotting cascade
Clotting cascade initiation?
1) inactive factor X
2) active factor X
3) cleaves pro-thrombin–>thrombin
4) thrombin activated fibrinogen to fibrin
5) Factor XIII converts fibrin into blood clot
thrombin roles? (x2)
1) generate fibrin from fibrinogen to make blood clot
2) promotes proinflammatory activation of multiple cells by activating their PARs (protease activated receptors)
Fibrinolytic pathway?
- pathway that counterbalances clotting
- activates enzymes that cleave & solubilize fibrin via the kinin cascade
How Fibrinolytic pathway work?
1) Kallikrein (from kinin cascade) acts to activate plasminogen into plasmin, 2) plasmin degrades fibrin and reverses clotting
2 roles of plasmin?
1) converts complement C3 to active C3a which causes inflammatory pathway
2) degrades fibrin and reverses clotting
Nitric Oxide and Free Radical Production are?
- inducible responses in the vicinity of the vasculature
- also occurs during local inflammatory responses within tissues
Nitric Oxide (NO)
1) Is a potent vasodilator
2) reduces platelet aggregation
3) inhibits mast cell inflammation
4) is microbicidal
How NO generated?
-from L-Arginine by the enzyme nitric oxide synthase (NOS)
what are the three forms of NOS?
1) eNOS =endothelial NOS: calcium dependent
2) nNOS = neuronal NOS: calcium dependent
3) iNOS = inducible NOS: calcium independent-activity is regulated by transcriptional regulation. Expression induced by TNF and other pro-inflammatory cytokines
eNOS
=endothelial NOS
- calcium dependent
- consittuviely made, but need high levels of Ca to be active
nNOS
=neuronal NOS
- calcium dependent
iNOS
= inducible NOS
- calcium independent; active as soon as made
- activity is regulated by trxn regulation
- expression induced by TNF and other pro-inflammatory cytokines
What does NO contribute to?
-both active pathogen defense and resolution of inflammation!
Oxygen derived free radicals
- released from leukocytes after exposure to:
1) microbes,
2) chemokines & cytokines
3) immune complex encounter
4) following phagocytic challenge
oxygen derived free radical production dependent on?
-activation of NADPH oxidative system
What are the major reactive oxygen species produced?
-Superoxide anion production, hydrogen peroxide and hydroxyl radical
what do reactive oxygen species interact with?
- NO to produce cytotoxic reactive nitrogen intermediates
- means that NO aren’t intrinsically bad, just their combination w/ ROS is really bad
