Lecture 2 Flashcards
dWhen are commensal bacteria acquired?
Starting at birth and the development of the immune system is influences by the microbiota
->1000 species of bacteria inhabit the human gut
What hydrophobic proteins are involved in host defense?
SP-A and SP-D
What pathogens induce phagocytosis by alveolar macrophages?
Agglutinate pathogens
What is unique about viruses compared to other pathogens?
Can replicate and assemble and kill host cell
What is the complement system?
a system of plasma proteins that mark pathogens for destruction
Where are soluble proteins produced in?
liver
Where are plasma proteins found?
found in blood, lymph, and extracellular fluids and they coat the surface of pathogens-targets for destruction
What does the cleavage of C3 form?
C3a and C3b
What bond is exposed after cleavage of C3b protein?
thioester bond
What happens when the thioester bond ofd C3 is attacked by water?
a soluble C3 protein is formed
What happens when the C3 protein is attacked by a carboxyl group or amine group?
C3 protein becomes insoluble and bounds to the pathogen surface
What is the first complement pathway to act and what does it do?
Alternative pathway and the pathogen surface creates local environment conducive to complement activation
What is the second complement pathway to act?
Lectin pathway; mannose binding lectin binds to pathogen surface
What is the last complement pathway to act?
Classical pathway; C-reactive protein or antibody binds to specific antigen on pathogen surface
What is the result of complementation?
cleavage of C3 into C3a and C3b
C3b covalently bounds to surface components of pathogen
what are the three fates of the complement system?
recruitment of inflammatory cells
opsonization of pathogens, facilitating uptake and killing by phagocytes
perforation of pathogen cell membranes
What inititiates the alternative pathway?
formation and action of the soluble C3 convertase iC3Bb
Is iC3Bb soluble or insoluble?
soluble
Is C3b soluble or insoluble?
insoluble
What reaction occurs between C3 and iC3?
spontaneous hydrolysis
What enzyme is responsible for the possible positive feedback?
iC3Bb convertase
What are used to control the alternative pathway?
regulatory proteins, they determine the extent and site of C3b deposition
What does properdin do?
Binds C3bBb, preventing degradation
What does Factor H do?
binds C3b and induces cleavage to iC3b by factor I-decreases amount of C3b on pathogen surface
What does DAF do?
binds C3b and causes dissociation and inactivation Bb fragment
MCP-binds C3b and makes it susceptible to cleavage by factor I
What does DAF and MCP do?
disrupt C3 convertase C3bBb
What is opsonization?
coating of a pathogen with protein that facilitates phagocytosis
Why is phagocytosis necessary?
Phagocytois by macrophages provides a first line of cellular defense against invading microorganisms
What is CR1 and why is it unique?
the receptor on macrophages that bind to C3b protein to initiate phagocytosis.
CR1 protects expressing cells-makes C3b susceptible to cleavage by Factor I
What is a Phagolysosome?
A fusion of lysosome and phagosome
How do complement proteins lyse pathogens?
The terminal complement proteins lyse pathogens by forming membrane pores
What is C5 and why is it important?
involved in lysing of pathogens and binds to the C3b2Bb protein on the pathogen surface
How is the alternative C5 convertase formed?
C3b binds the alternative C3 convertase= alternative C5 convertase
What is C5b?
initiates the formation of a membrane attack complex
What does C6 do?
binds to and stabilizes C5b. Forms a binding site for C7
What does C7 do?
Binds to C5b6 and exposes a hydrophobic region that permits attachment to the cell membrane
What does C8 do?
Binds to C5b67 and exposes a hydrophobic region that inserts into the cell membrane
What does C9 do?
Polymerization on the C5b678 complex forms a membrane-spanning channel that disrupts the cell’s integrity and can result in cell death
What is CD59?
protein that binds to the C5b678 complex and prevents the recruitment of C9 to form a pore in human cells
What is a protectin and example?
protein that prevents destruction of cell integrity (eg CD59, HRF)
What is paroxysmal nocturnal hemoglobinuria?
disorder where patients cannot prevent against cell death through membrane pores
What do small peptides do during complement activation?
induce local inflammation
What are anaphylatoxins?
act on blood vessels to increase vascular permeability
What leads to an increase in release of histamine and other vasoactive substances
contraction of smooth muscle and degranulation of mast cells and basophils
What increase phagocytic capacity?
Chemoattractant for phagocytes
What does increased permeability allowed?
allows increased fluid leakage from blood vessels and extravasation of complement and the plasma proteins at the site of infection
-migration of monocytes and neutrophils from blood into tissue is increased. microbicidal activity of macrophages and neutrophils is also increased
what is the importance of alpha 2-macroglobulin and protease?
- ) the protease cleaves bait region, causing a conformational change
- ) alpha 2 macroglobulin enshrouds the protease and is covalently bonded to it
after conformational change, the complex will bind receptors on hepatocytes, fibroblasts, and macrophages and be cleared
How do antimicrobial peptides kill pathogens?
by perturbing their membranes
- they are amphipathic
- charged and uncharged regions
- secreted at mucosal surfaces-epithelial cells and neutrophils
What are the main source of defensin in the intestine?
Paneth cells
What brings defensins together?
electrostatic attraction and the transmembrane electric field
What do defensins do?
form pores to destroy cell membrane
What are pentraxins?
plasma proteins of innate immunity that bind microorganisms and target them to phagocytes
- ‘antibodies” of the innate immune system
- bridging molecules that bind pathogens to human cells (phagocytes)
Long Pentraxin
eg. PTX3 from monocytes, macrophages, dendritic cells, endothelial cells, epithelial cells
Short Pentraxin
eg. Serum amyloid P component from liver hepatocytes
What are the stages of immediate innate immune response (0-4 hours)?
- ) pathogen invades tissue and proliferates
- ) pathogen is recognized by preformed soluble effector molecules and resident effector cells in the infected tissue
- ) pathogen is eliminated and infection ends
- ) very minor tissue damage is repaired
What are the stages of induced innate immune response (4 hours to 4 days)?
- ) pathogen invades tissue and proliferates
- ) activation of cells resident in the infected tissue. Recruitment of effector cells to the infected tissue. Inflammation, fever, the acute phase response
- ) soluble effector molecules and effector cells recruited to the infected tissue recognize and attack the pathogen
- ) pathogen is eliminated and infection ends
- ) minor tissue damage is soon repaired
What are the stages of the adaptive immune response (4 days until death of the pathogen, defeat of the host, or the truce of chronic disease)?
- ) pathogen invades tissue and proliferates
- ) secondary lymphoid tissue close to the infected tissue is made aware of the infection
- ) pathogen-reactive B and T cells are identified in secondary lymphoid tissue
- ) B and T cells proliferate and mature to become effector cells
- ) effector molecules (antibodies) and effector T cells travel to the site of infection
- ) pathogen is eliminated and infection ends
- ) major tissue damage is gradually repaired
How do cells of innate immunity distinguish themselves?
Through receptors (over 100 receptors)
- macrophage receptors recognize the cell-surface carbohydrates of bacterial cells but not those of human cells
- NK cell receptors recognize changes at the surface of human cells that are caused by a viral infection
What is unique about toll-like receptors (TLR)?
induces signaling while the others induce phagocytosis
What is CTLD?
Carbohydrate recognition domain (C-type lectin domain)-requires calcium
-mannose receptor
What is RTLD?
Ricin-type lectin domain
-recognizes sulfated galactosamine residues
mannose receptor
What is SR?
scavenger receptor
- recognizes negatively charged microbial ligands
What are toll-like receptors?
Family of 10 genes-TLR 1-10
TIR- toll interleukin-1 receptor
-LRR-leucine-rich repeat-20-29 aminoacids-caries-pathogen recognition domain
- Homodimer or heterodimers-TLR4 only homodimerizes
What are allotypes?
proteins encoded by different alleles of the same gene
What does TLR4 recognize?
LPS
What binds LPS on the macrogphage receptor?
CD14
What protein binds TLR4 and LPS?
MD2
What is MyD88?
adaptor protein-binds TIR domain and IRAK4
What is IRAK4?
autophosphorylates, then phosphorylates TRAF6
What is IKK?
inhibitor of IkB- Phosphorylation releases NFkB
What is NEMO disorder?
lack an IKK subunit-impaired NFkB response
abnormalities in tissues taht arisw from ectoderm
What do NOD like receptors do?
recognize bacterial degradation products in the cytoplasm
What do LRRs in NOD domain do?
recognize degradation products of bacteria (degraded peptidoglycan)
What do CARDs do?
caspase recruitment domain
- NOD receptors DO NOT recruit caspases-recruit proteins with CARD domains
What is RIPK2?
phosphorylates TAKI which phosphorylates and activates IKK-NFkB activation
What do inflammasomes do?
amplify the innate immune response by increasing the production of IL-1B
Describe the assembly of inflammasome?
- ) IL-1B binds to IL-1 R1 and IL-1 RAcP (dimerizes)
- ) MyD88 binds to TIR domain
- ) transcription and translation of IL-1B leads to pro-IL-1B
- ) active caspase 1 binds to pro-IL-1B
- ) release IL-1B
ATP release causes activation of potassium channels to decrease K+ conc. causes NLRP3 (no CARD) to bind adaptor protein with CARD -binds procaspase 1
positive feedback-loop-IL1B binds IL1R
*** adapter protein and NLRP3 and procaspase 1
What are chemokines?
direct the flow of leukocytes in the body
Where are adhesion molecules found?
leukocyte and tissue surface
What is inflammation?
blood vessels dilate and vascular endothelial cells selectins
What does TNF do to ICAM-1 and ICAM2?
increases and vascular endothial cells upregulate ICAM-1 and ICAM-2
Describe how neutrophils attend to infected cells?
- CXCL8 binding leads to changes in integrins (LFA-1)-bind ICAM1
- basement membrane-neutrophils secrete elastase to degrade laminins and collagen
- neutrophil follows chemical trail to source of CXCL8 in tissue (macrophages)
CRP
binds pathogen-opsonin-triggers the innate immune response
-may deliver pathogens to phagocytes
Serum amyloid amyloid A
interacts with HDL, binds TLRs and CD36 (induces cytokines)
What initiates the lectin pathway?
the mannose-binding lectin
-binds mannose containing carbohydrates on pathogens
- mutipotent attachment is critical
- lectin pathway of complement activation triggered
- opsonin- induces monocytes in blood to uptake
What cytokine induces lectin pathway and where?
IL-6 and the liver
What does C-reactive proteins bind to?
-CRP binds phosphocholine on bacterial surfaces, acting as an opsonin and as a complement activator
What does mannose binding lectin bind to ?
binds carbohydrates on bacterial surfaces , acting as an opsonin and as a complement
Describe lectin pathway?
Activated MASP-2 cleaves C4 to C4a and C4b
- ) C4b binds covelently to the microbial surface
- ) Activated MASP-2 also cleaves C2 to C2a and C2b
- ) C2a binds to surface C4b forming the clasical C3 convertase, C4b2a
- ) C4b21 binds C3 and cleaves it to C3a and C3b. C3b binds covalently to the microbial surface
What does C4a do?
recruits leukocytes (weaker than C3a and C5a)
What is the C3 convertase for lectin pathway?
C4b2a
What triggers the classical pathway
C-reactive proteins
What does C-0reactive protein bind to on pathogen?
phosphocholine
What components make up C-1 protein?
C1r
C1q
C1s -binds C4 protein and cleaves into C4a and C4b
Where is TLR3 receptor located?
endosomes
Where are TLR1 and 2 found?
membrane or endosome
What cells have type 1 interferon?
all human cells
Describe the process of detection of viral infection?
- ) Viral replication in cytoplasm produces uncapped RNA with a 5’-triphosphate
- ) RLR binding to viral RNA induces association with MAVS and dimerization
- ) dimerization initiates signaling pathways that activate IRF3 and NFkB
- ) IRF3 causes synthesis and secretion of type I interferons, and NFkB causes synthesis and secretion of inflammatory cytokines
What results from interferon response?
- ) induce resistance to viral replication in all cells
- ) increase expression of ligands for receptors on NK cells
- ) Activate NK cells to kill virus-infected cells
What are plasmacytoid dendritic cells?
factories for making large quantities of type I interferons
-helps to prevent the systemic spread of infection
What are the main circulating lymphocytes that contribute to the innate immune response?
Natural killer cells
- kill cells infected with virus
- maintain/increase the state of inflammation (increase phagocytosis)
- CD56 positive, lack CD3
- 5-25% of blood lymphocyte population
Describe the NK cell cytotoxicuty at the sites virus infection?
- ) virus infection of cells triggers the interferon response
- ) Type I interferon drives the proliferation of NK cells
- ) Type I interferon drives the differentiation of NK cells into cytotoxic effector cells
- ) Effector NK cells kill virus infected cells by inducing them to undergo apoptosis
Describe the NK cell cytotoxicuty at the sites virus infection?
- ) virus infection of cells triggers the interferon response
- ) Type I interferon drives the proliferation of NK cells
- ) Type I interferon drives the differentiation of NK cells into cytotoxic effector cells
- ) Effector NK cells kill virus infected cells by inducing them to undergo apoptosis
