Innate Immunity Part I Flashcards
How do B and T cells migrate to different zones of the LN?
By chemokines that are produced in specific areas.
How do Ag-loaded DCs enter the lymph node?
Though afferent lymphatic vessels that come from sites of Ag entry.
Once DCs are in the lymph node, what regions of the lymph node do they migrate to?
T-cell rich areas of the node.
How do naive T lymphocytes home to lymph nodes?
Via L-selectin binding to peripheral lymph node addressin on the HEV.
Are HEVs present in primary or secondary lymphoid organs?
Secondary.
Which chemokines are displayed on the surface of the HEV?
Chemokines CCL19 and CCL21
What must chemokines bind to in order to activate integrins?
CCR7
What receptor is necessary for effector T cells to exit the LN?
S1PR1. Effector T cells sense a gradient that the receptor produces, which allows them to leave the lymph node.
If an S1P gradient is produced in lymph nodes, what type of T cell will respond to it (and subsequently leave the LN)?
Effector T cells.
How do Ag-activated T cells respond to S1P?
They do not respond to it, and hence stay in the lymph node.
Ag-activated T cells have low levels of S1PR1 and cannot exit the lymph node.
Activated effector T cells home to sites of infection in peripheral tissues. Cell migration into tissue is mediated by what substances?
E-selectin, P-selectin, integrins and chemokine (CXCL10) that are produced at sites of infection.
Many chemokines and chemokine receptors are involved in what process?
They are involved in effector/memory T cell migration.
What ligand on the endothelial cell does L-selectin bind to?
PNAd
What is the function of L-selectin/PNAd?
Initial weak adhesion of naitve T cells to the HEV in the lymph node.
What ligand on the endothelial cell does CCR7 bind to?
CCL19 or CCL21
What is the function of CCR7/CCL19 & CCL21?
Activation of integrins and chemokinessis
What is the function of LFA-1/ICAM-1?
Stable arrest of cells on HEV in the LN.
What do E and P selectin ligands bind do on endothelial cells?
E or P selectin
What is the function of E/P selectin ligands and E/P selectins?
Initial weak adhesion of effector and memory T cells to cytokine activated endothelium at peripheral site of infection.
What is the function of CXCR3/CXCL10?
Activation of integrins and chemokinesis
What is the function of CCR5/CCL4?
Activation of integrins and chemokinesis
What is the function of LFA-1 or VLA-4/I-CAM1 or VCAM-1?
Stable arrest of cytokine-activated endothelium at peripheral sites of infection.
What are the three bonds made during jrolling and arrest of an effector T lymphocyte on endothelial cells?
PSGL-1 & Psel/Esel
CD44 & CD 44
VLA-4 & VCAM
What receptor is important for the mobilization of effector T cells in sites of infection and inflammation?
CD44
What do endothelial cells secrete that facilitate the homing mechanism of effector T lymphocytes?
Chemokines
E & P selectin
Hyaluronic acid
What must vascular endothelial cells express in order for CD44 to mediate rolling interactions?
Hyaluronic acid
Natural ligans
E-selectin
Chemokine signaling via ____ results in increased integrin affinity, such as VLA-4, which enhances adhesiveness.
GPCRs (G protein coupled receptors)
True or false: naive B cells use the same basic mechanisms as do naive T cells to home to secondary lymphoid tissues throughout the body.
True
What is the migration pathway of immature B cells?
Bone marrow -> blood -> red pulp of spleen -> white pulp of spleen.
As B lymphocytes mature, what receptor do they express that promotes their movement into the white pulp?
Chemokine receptor CXCR5.
The migration occurs in response to chemokine CXCL13.
Once maturation of B cells is completed within the white pulp, where do they migrate to?
They reenter circulation and home to lymph nodes and mucosal lymphoid tissues.
What does homing of mature naive B cells from the blood into LNs involve?
Rolling interactionf of HEVs, chemokine activation of integrins, and stable arrest.
Homing of mature naive B cells from the blood into LNs involves what chemokines?
CXCL12 and CCL19/CCL21 on HEV, as well as their chemokine receptors CXCR4 and CCR7 on naive B cells.
In the stroma, B cells migrate into follices driven by what receptor?
CXCL13.
It is recognized by CXCR5 expressed on naive B cells.
What is a process that may occur when B cells enter a follicel?
They may encounter Ag and become activated.
What are the cirulating effector cells involved in innate immunity?
Neutrophils, macrophages and NK cells
What are the circulating effector proteins involved in innate immunity?
Complement
Mannose-binding protein lectin
C-reactive protein
What is the function of complement?
It kills and opsonizes microbes.
It also activates leukocytes.
What is a common function of mannose-binding lectin and C-reactive protein?
Both activate complement.
What is opsonization?
The process by with a pathogen is marked for elimination.
Which cytokine in innate immunity causese inflammation?
TNF, IL-1 cytokines
Which cytokine from innate immuity shows resistance to viral infection?
IFN-alpha, beta
What cytokine from innate immunity activates macrophages?
IFN-gamma
What cytokine from innate immunity faciliates IFN-gamma production by NK cells and T cells?
IL-12
Which cytokine from innate immunity causese the proliferation of NK cells?
IL-15
Which cytokine from innate immunity causes control of inflammation?
IL-10, TGF-beta
What are three functions of innate immunity?
It is the initial host defense response to pathogens
It eliminates damaged cells and initiates tissue repair
It controls adaptive responses to intracellular vs. extracellular pathogens.
True or false: innate immunity has the ability to discriminate between self and nonself.
True
The basic mechaism of discriminating between self and nonself involves receptors which recognize what?
Pathogen associated molecular patterns (PAMPs)
What is the erm for cell receptors that recognize PAMPs?
Pattern recognition receptors (PRRs).
What is a general property of PRRs on the surface of bacteria and viruses?
They have mannose-tailed glycans.
What does it mean when a PRR is germ-line encoded?
It refers to sequences that are found in gamete producing cells.
Why do phagocytes use PRR-triggered responses?
To help distinguish self from non-self.
True or false: N-formylmetionyl peptide (fMet) is present in prokaryotes, but not eukaryotes
True
What do polymorphonuclear cells use fMet for?
The initiation of phagocytosis.
What are two functions of PRRs?
They trigger phagocytosis and kill microbes.
What is iNOS?
Inducible nitric-oxide synthase.
What are toll like receptors (TLR)?
Receptors that recognize extracellular pathogens.
They recognize products of extracellular microbes.
What do endosomal TLRs only respond to?
Nucleic acids
TLRs recognize ____ and activate ____
TLRs recognize pathogens and activate inflammation.
What is the outcome of signaling of extracellular TLRs?
Pro-inflammatory cytokine secretion.
TLRs 1, 2, 5 and 6 use the adaptor protein ____ and activate the transcription factors, NF-KB
MyD88
TLR3 usese the adaptor protein ___ and activates the IRF transcription factors
TRIF
TLR4 can activate what signaling pathways of TLRs?
Both pathways
What do TLRs 7 and 9 activate?
NF-KB and IRF
TLRs are important for what type of immune response?
Innate immune response
TLRs are expressed on immune cells. What specific immune cells are they expressed on?
Monocytes, neutrophiles, macrophages and dendritic ells.
TLR-dependent signaling pathways activate NF-KB. What is the function of NF-KB?
It results in the transcripton of pro-inflammatory genes.
Which cytokine controls the adaptive T-cell immune response?
Cytokine IL-12
What does the activation of TLRs result in?
The activation of antimicrobial pathways that directly kill a pathogen.
Activation of TLRs can be detrimental to the host. What can they specifically do?
Contribute to tissue injury by inducing apoptosis
Can lead to symptoms of septic shock.
TLR4 eventually leads to the transcrption of genes for what substance?
Inflammatory cytokines.
They are synthesized in the cytoplasm and secreted in the ER.
What are some inducers of innate immunity?
PAMPs
Nucleic acid
Lipid A
Protein PGN
What are some sensors of innate immunity?
Toll-like receptors
NOD-like receptors
C-type lectin
What are some mediators of innate immunity?
TNF alpha
IL-6
IL-1 beta
What do PAMPs and DAMPs (damage associated molecular patterns) trigger?
Inflammation
What does necrosis generate?
DAMPs
Why is necrosis detrimental to other cells?
Necrosis involves swelling and rupture of the cell membrane. This may cause inflammation or harm other neighboring cells.
What is inflammation?
An innate reaction caused by:
An increased blood supply to the affected area
Increases capillary permeability
Massive influx of neutrophils
Arrival of macrophages
Distortion of homeostasis and loss of function
What are some physiological consequences of inflammation?
Heat
Redness
Swelling
Pain
Loss of function
What do DAMPs activate?
NF-KB
What protein activates the NF-KB pathway?
HMGB1 (high mobility group box 1). It is a protein passively released during necrosis.
Uric acid and HSPs also activate the NF-KB pathway.
HSP induces the release of inflammatory cytokines.
What are nucleotide oligomerization domain-like receptors?
A specialized group of intracellular proteins.
What is the function of NOD-like receptors (NLRs)?
They play a critical role in the regulation of the host innate immune response.
They also act as scaffolding proteins that assemble signaling platforms that trigger NF-KB and MAPK signaling pathways.
What do NLRs control?
The activation of inflammatory responses.
How do NLRs respond to PAMPs and DAMPs?
By binding other proteins and forming signaling complexes called inflammasome.
What do inflammasomes activate?
Caspase-1
What is the main function of caspase-1?
To cleave the inactive cytoplasmic precursor forms of two homologous cytokines (IL-1beta and IL-18).
What process occurs from secreted forms of proinflammatory cytokines IL-1 beta and IL-18?
Inflammation.
Where are sereted forms of IL-1beta and IL-18 produced?
In the inflammasome
What three receptors are part of the scavenger receptor family?
SR class A type 1 (SR-A 1)
SR class A type 2 (SR-A II)
MARCO
What is the function of SRs? (Scavenger receptors)
They mediate the uptake of oxidized lipoproteins into cells.
They are expressed on macrophages and mediate recognition/phagocytosis of microorganisms.
They also bind various bacterial constituents based on negative charges of bacterials LPs.
Receptors for carbohydrates blong to what family?
C-type lectin family.
They contain a conserved carbohydrate recognition domatin for recognition of microbial mannose, N-acetylglucossamine and B glucans.
Most eukaroytic cell carbohydrates are most often terminated by what acids?
Galactose and sialic acid
What are functions of leptin receptors?
They facilitate the phagocytosis of microbes.
They also trigger secretion of cytokines that promote adaptive immune responses.
Mannose receptors on phagocytes are involved in what process?
The phagocytosis of microbes.
What is soluble mannose-binding lectin?
It is a protein that is involved in complement activation via the lectin pathway.
What is the importance of epithelium in innate immunity?
They provide physical barriers, produce antimicrobial substances, and harbor intraepithelial lymphocytes that are believed to kill microbes and infected cells.
What are defensins?
Small cationic peptides that contain both cationic and hydrophobic regions.
What are defensins produced by?
Epithelial cells of mucosal surfaces and by granule-containg leukocytes (neutrophils, NK cells and CTLs)
What is the synthesis of denfensis stimulated by?
Cytokines and microbial plroducts.
What happens when defensins are exposed to microbes?
The microbes will die, since defensins are toxic to them.
The affected microbes include bacteria, fungi and enveloped viruses.
How do defensins kill microbes?
By inserting into and disrupting functions of the microbial membranes.
What is a function of defensins?
They regulate activation of immune cells involved in the inflammatory response to microbes.
What are cathelicidins?
They are antimicrobial peptides. They also activate leukocytes and can bind and neutralize LPs.
They also plan an anti-inflammatory role by binding to DNA and blocking inflammasome activation.
What molecules releases anti-microbial peptides? (AMPs)?
Phagocytes
AMPs recruit T cells, neutralize inflammatory cytokines, and recruit immature dendritic cells.
Interesting.
How do naive lymphocytes enter the lymph node?
Through an artery.
They leave the circulation by moving across the wall of the HEV.
