Innate Immunity and Complement Flashcards
What are the three main barriers of the innate immune system?
Mechanical - i.e. fluid / mucus
Chemical - i.e. lysozyme / defensins
Microbiological - normal flora
List some receptor types used by the host cells to recognize invading pathogens after barriers have been broken? What do they recognize
TLRs - recognize PAMPs (pathogen-associated molecular patterns)
C-type Lectin Receptors - recognize sugars
NOD-like - intracellular nucleic acid detecting
RIG-1 like - recognize RNA
f-Met-Leu-Phe - detect chemotaxic moeity on bacteria
What cytokine do dendritic cells produce in response to viral invasion?
Type 1 interferon
How does a monocyte entering the tissue know to differentiate into a macrophage or DC?
Depends on cytokine environment
What is an opsonin?
A protein that binds a microbial cell surface and aids in immune system targeting for phagocytosis (opsonization)
What syndrome results from being unable to make superoxides in phagocytes?
Chronic granulomatous disease
What is an important sugar to bind on bacteria?
Mannose - includes Mannose binding lectin (MBLs) and receptors for mannose
Where are TLRs located?
Some are on outer cell membrane, some are intracellular
What are the two most important TLRs and what do they bind? These receptors give some specificity to innate immune system
TLR4 - binds bacterial LPS (part of gram(+)) and leads to activation of defends genes by activating NFkB
TLR3- binds viral dsRNA, triggers interferons synthesis, preventing viral replication
What are examples of other TLR specificities?
- Flagellin
- Unmethylated CpG (human DNA is methylated)
- Peptidoglycan
- Zymosan - yeast
What are three proinflammatory cytokines released by activated macrophages? What do they do?
IL-1 - activates endothelium and lymphocytes, induces fever and IL-6 production
IL-6 - activates lymphocytes and induces liver APPs
TNF-alpha - induces fever and activates endothelium, increases permeability of endothelium for diapedesis
What is an important new treatment for rheumatoid arthritis?
Antibody for TNF-alpha in synovial fluid
What are the functions of IL-8 and IL-12?
IL-8 - chemokine for attracting PMNs
IL-12 - activates NK cells, and induces Th0 cells to become Th1
What is the positive feedback loop between macrophages and NK cells?
Macrophages produce IL-12, inducing NKs. NKs produce IFN-y, further inducing macrophages.
What are acute phase proteins in general?
Produced in liver in response to infectious agents, especially IL-6 induction. Can also induce clotting in inflammatory response via fibrinogen
List the two major APPs and their function?
C-reactive protein - sign of inflammation, binds bacteria as an opsonin and also activates complement
Mannose-binding lectin (MBL) + SPs A&B - opsonin and complement activation
What are the major actions of the inflammatory response?
Increased blood flow by dilation of capillaries, expresion of adhesion molecules for leukocyte binding, secretion of vasoactive peptides for diapedesis (IL-1/TNFa), clot formation to prevent spread of pathogen
What are selectins and what is their function?
A type of lectin, an adhesion receptor on endothelium which binds carbohydrates on leukocytes and slows them
What are integrins and ICAMs?
Adhesion molecules. Integrins are expressed on leukocytes and bind the ICAMs (intracellular adhesion molecules) on the endothelium and DCs strongly to stop their movement
ICAM = receptor, Integrin = ligand
What induces the production of IFN-alpha and beta, and what is their three functions?
Induced by viral dsRNA binding by TLR3
Functions
- Inhibit translation of viral mRNA
- Activate NK cells which kill virus infected cells
- Increase expression of MHC1 to promote cytotoxicity of CD8-T cells towards them
What is the function of NK cells?
kill virus-infected and tumor cells which are deficient in MHC Class 1, due to downregulation via mutant DNA
What are the three main functions of the complement (C) system?
- Attracting phagocytes via anaphylatoxins
- Assisting phagocytosis via opsonization
- Direct killing of pathogens
In what way does complement interact with both innate and adaptive immune systems?
Innate - activated by microbial products or APPs (lectin / alternative pathway)
Adaptive - activated by Ag-Ab complexes - classical pathway
Which two Ig types can activate complement?
IgM and IgG (classical pathway)
What are the steps up to C3 in the classical pathway?
- Ab binds the pathogen.
- C1 binds the Fc of the Ab.
- C1s cleaves C4 into C4a and C4b
- C4b is attached to pathogen, cleaves C2 to C2a and C2b.
- C4b2b complex is C3 convertase
What is the only change between classical and lectin pathway?
Lectin - MBL replaces the antibody as what ultimately binds the C1.
Mannose binding lectin binds the mannose residues of the pathogen
What is the alternative pathway up to C3?
C3 is spontaneously hydrolyzed and sticks to pathogen surface. C3b works with Factor B to be activated by factor D (activated factor B = Bb).
C3bBb = C3 convertase
What is the classical / lectin pathway through C5?
- C4b2b cleaves C3 into C3a and C3b.
- C3b attaches and makes C5 convertase
- C5 convertase cleaves C5 into C5b and C5a.
- C5b initiates assembly of membrane attack complex of C6-9
- C3a / C5a are vasoactive, and C5a attracts PMNS
What is the alternative pathway through C5?
All the same steps since its a C3 convertase, except the C3bBb complex is stabilized by Properdin and leads to extra deposition of C3b and amplification of alternative pathway on pathogen
How is complement regulated?
Host cells have regulatory proteins as well as in plasma to prevent accidental activation of the cascade, which are not present on pathogens
What is hereditary angioneurotic edema and what causes it?
Lack of C1 inhibitor which causes C1 to dissociate and prevents excessive activation of complement. Too much C2b causes swelling in these patients
What are some other regulatory proteins of complement?
DAF, Factor I, and Factor H which inactivate C3b
C4b binding protein
What is factor P?
Factor which stabilizes the MAC for full lysis
What does a mutation in CD59 cause?
Paroxysmal nocturnal hemaglobinuria - mutation lets immune system attack RBCs due to lack of CD59
