Innate Immunity Flashcards
Endotoxins
Heat-stable (pyrogen) cell-associated toxin
NOT directly TOXIN
Induces body to produce toxic molecules
LPS
Endotoxin on gram - bacteria
Pathology of LPS
LPS responsible for many of the body’s responses to gram negative bacteria
- profound inflammatory response
- infiltration of neutrophils and MOs
- increases permeability
- swelling
Septic shock
Endotoxin shock - associated w/ gram - infection
- lethal
- can lead to DIC, necrosis, ARDS
How to avoid Endotoxins
Test for pyrogen using LAL
-if dev DIC - there is LPS present
What toxic about LPS?
Proteins produced by LPS-stimulated MOs are the endogenous mediator (inflammatory cytokines)
- *IL-1
- *TNF-Alpha
TNF-Alpha
Important cytotoxic molecule produced by MO and is an important immunoregulator molecule
- Has overlapping function w/ IL1
- -stimulating B and T cells
- -inducing fever
IL-1
Cytokine secreted by activated and stimulated MOS
_produced as a pro-cytokine (must be cleaved prior to release)
_cleavage often by caspase 1 activated by inflammation sensitive complex (inflammasome)
Super Agtigenic Toxins
TSST-1 - endotoxin causing toxic show syndrom
-In response to the binding of toxin
__both T cells and APC produce many cytokines
–>TNF-alpha and IL1
Complement System
- Much more than lead to cell lysis
- Imp inflammatory mediators
- Role in opsonization
- Imp in clearing immune complexes
- Terminal complement imp in killing Neisseria
Complement
Is the collective term for a complex of sequentially interacting serum proteins
What occurs as a result of complement activation cascade?
Cell lysis Increased phagocytosis Increased vascular permeability Enhance leukocyte chemotaxis Functional stimulation of MOs
What are the two PWs for complement?
Classical PW
Alternative PW
**both lead to cleavage of C3 –>C3a and C3b
C3b attaches to surface of pathogen
Classical PW
- Initiation by IgM or IgG binding to Ag on a pathogen surface
- C1 binds single molecule of IgM (pentamer) or 2 or more IgG
- Activated C1s cleave C4 and C2
- C2a binds to surface C4b - forming C3b convertase (C4b2a)
- binds to C3b and cleaves it
- C3b binds covalently to microbial surface
Alternative PW
Formation and action of the soluable C3 convertase iC3Bb that initiates this PW
- -formation and action of the C3 convertase (C3bBb) at a pathogen surface
- -C3 continuously cleaved and C3b put on pathogen surface
Inactivation of C3b
- Inactivation of C3b by factor H and factor I to give fragments iC3b
- DAF and MCP disrupt C3 convertase C3bBb on a human cell surface
How are bacteria recognized by INNATE immune response?
By Endotoxins and Complement
–w/o them you DON’T get ADAPTIVE immune response
What do phagocytes do when react with bacteria?
Release cytokines
-too many is bad
Release of cytokines
Locally - its good
Systemically - its bad–> they become part of pathology
What are the receptors that interact with LPS ?
Recognized by the complex TLR4, MD2, and CD14 (part of LPS receptor - TLR4)
- leads to engulfment and digestion of bacteria
- lead to transcription of inflammatory cytokines
TLR’s
Diff TLRs are recognize diff things and respond differently
Why is inflammasome important?
Important for IL1 production
Both complement PWs lead to C3b on pathogen surface in order to…?
Amplify C3b
What does C3b lead to?
Binding to complement receptors
- ->Opsonization
- ->Clearance of immune complexes
What occurs when IgG binds to SOLUABLE multivalent Ag?
- C1 binds to soluable immmune complex (Ag:Ab) and initiates complement rxn
- Immune complex coated with covalently bound C3b
- C3b binds to receptor on erythrocyte surface
- Erythrocyte takes them to spleen/liver where they are removed by phagocytic cells
- *classical PW clears complex
What imp role does classical PW play?
Clear immune complexes out of blood
C5 Convertase
Activated by both PWs
**IMP Chemotactic Factor (attracts MO, nuetrophills, etc)
Lytic PW
Contains C5-C9
- Components binds to surface of pathogen or RBC coated w/ Ab
- Forms pores
- Cell dies
What are the biological active peptides?
C3a and C5a = anaphylatoxins
- make cell leaky
- draw monocytes/nuetrophils to site
What are ANAPHYLATOXINS?
Make blood vessels leaky around where complement being fixed
- causes them to be more fluid
- complement, Ab, and more cells come to site of infection
Inhibitors of complement system?
- C1INH inhibits C1
- C4BP binds to C4 in classical PW and makes it a target for factor I inhibition
- Factor H binds C3b and makes it target for factor I - inactivates C3b –> iC3b
- DAF and MCP disrupt C3 convertase C3bBb
What is C59?
Binds to C5b678 complex and prevents recruitment of C9 to form pore
C1, C2, C4 deficiency causes?
Immune-complex disease
-cant clear immune complex from blood
C3 deficiency causes?
Susceptible to capsulated bacteria
C5-C9 deficiency causes?
Susceptible to Neisseria
Factor D and Factor P deficiency causes?
Susceptible to capsulated bacteria and Neisseria but not immune-complex disease
Factor I deficiency causes?
Susceptible to capsulated bacteria
DAF or CD59 deficiency causes?
Auto-immune like conditions
C1lNH deficiency causes?
HANE
