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Exogenous processing
initiated outside the cell, involving professional antigen (dendritic cells, macrophage, B cells)
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How are microorganism ingested in exogenous processing?
phagocytosis--->lysosome--->phagosome--->MHC-2 presentation
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Where are MHC-2 molecules made?
rER--->golgi--->transport vesicle--->fuses with phagosome---->exocytosis
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What are the subunits for MHC-2?
heterodimeric glycoprotein subunits: 2 alpha, 2 B
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alpha and beta chains of MHC-2
- alpha 1 and 2
- beta 1 and 2
- #2's closer to PM of APC
- peptide binding groove in #1's
- both alpha 2 and beta 2 have TM/cytoplasmic tail
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How are MHC-2's plugged in rER?
an invariant chain is placed into peptide binding site of MHC-2
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How is invariant chain removed?
once transport vesicle w/ MHC-2 fuses with phagosome, invariant chain degraded into fragment, CLIP; CLIP removed by HLA-DM; Ag can now bind to peptide binding site of MHC-2
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What are the 3 isotypes of MHC-2?
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What type of cells can present MHC-2 molecules?
"professional" APCs (dendritic cells, macrophages, B cells)
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How many genes are there for MHC-2 isoforms?
7: DP-alpha, DP-beta, DR-alpha, DR-beta', DR-beta, DQ-alpha, DQ-beta
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What are some characteristics of MHC-2 molecules?
- polygenic (isoforms)
- polymorphic (diff alleles)
- co-dominant expression
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Where does Ag bind in MHC-2?
polymorphic regions of alpha helical walls in alpha 1 and beta 1 domains
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What is the first signal for exogenous processing T-cell activation?
dual recognition of Ag to TCR and polymorphic regions of alpha-1 and beta-1 domains on MHC-2 molecule
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What is the co-receptor for exogenous processing activation pathway?
CD4; binds to non-polymorphic region of beta-2 on MHC-2 molecule
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What is the second signal needed for full activation of T cell in exogenous processing pathway?
co-stimulatory molecules: CD28 and B7
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CD28
co-stimulatory molecule for T cell in exogenous processing pathway
has two TM/cytoplasmic tails in TCR; binds to B7
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B7
co-stimulatory molecule for T cell in exogenous processing pathway
has two TM/cytoplasmic tails in APC; binds to CD28
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What are the subsets of activated CD4+ T cells?
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What are the cytokines produced by TH1?
TNF-alpha, IL-2, IFN-gamma, IL-3
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What are some direct effector functions of TH1?
- increase nitric oxide, increase proteases
- stimulate phagocytic cells
- support T cell growth (via IL-2)
- stimulate hematopoeisis (via IL-3)
- macrophage activation (via IFN-gamma, TNF-alpha)
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What effect does stimulating phagocytic cells have on TH1 cells?
phagocytic cells increase MHC-2 presentation which increases CD4+ T cells which in turn can make more TH1 cells
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How does TH1 support T cell growth?
- via IL-2
- via macrophage activation (MHC presentation)
- via phagocytic cells (CD4+ activation)
- via IL-3 (hematopoeisis...diff of stem cells into other blood cells types...poss lymphoid lineage and then poss T cell activation)
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How can TH1 growth and support be suppressed?
- IgE isotype of IL-4
- IL-10 (TH2)
- TGF-beta (TH2)
- IL-6+TGF-beta (TH17)
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How can hematopoeisis be stimulated?
IL-3 via TH1 and TH2
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What are the cytokines that TH2 makes?
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What does IL-4 do?
- uses an IgE isotype to suppress TH17 and TH1 growth/diff; stimulates B cell activation and growth
- drives TH2 diff
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Why does fox P3+ make IL-4, IL-10, and TGF-beta?
to inhibit effector mech of TH1 in the inflammatory response to prevent septic shock
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What are the functions of IL-17?
- induce IL-6
- induce acute phase proteins
- induce chemokines for neutrophil recruitment
- cooperate with IFN-gamma, IFN-alpha in macrophage activation
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What does IL-23 do?
- stim TH17 diff
- prod by dendritic cells
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What does IL-12 do?
- activates NK cells
- prod by dendritic cells
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How do dendritic cells and macrophages play a part in THp differentiation?
whether they produce IL-12 (NK) or IL-23 (TH17)
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SIRS
Systemic Inflammatory Response Syndrome: systemic inflammation that may be assoc w/ a variety of causes, including infection
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Sepsis
SIRS in assoc w/ infection...septic shock
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Superantigens
can activate a large number of T cells by binding to non-polymorphic regions outside peptide binding site of MHC-2 molecule
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Granuloma formation
due to mult rounds of macrophage activation which results in additional T cell activation via IFN-gamma and TNF-alpha.
originally started by chronic maintenance of a microbial pathogen in macrophage endosomes, leading to continuous exogenous processing and MHC-2 presentation...T cell activation...TNF/IFN
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Treg
CD4+ T cell capable of modulating cytokine levels; prevents excessive inflammation and autoimmunity
high levels of IL-2R and fox P3+
functions to suppress TH1 via IL-4, IL-10, TGF-beta
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Linked recognition
B cells can produce MHC-2 and consequently activate T cells; T cells provide second signal for B cells (CD40/CD40L=CD154) which causes B cell to become APC and activate T cells...cyclical activation!
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gamma/delta T cells
has gamma/delta chains instead of alpha/beta chains
- in skin and mucosal layers
- early adaptive immunity
- produces cytokines
presentation is by non-polymorphic CD1 (similar to MHC-1 in structure) although uses exogenous mode of presentation
presents glycolipids and phospholipids common to mem of bact
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What is located in the thymic cortex?
developing thymocytes, branched epithelial cells, macrophages
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Positive selection
selection of immature T cells that are capable of recog self-MHC
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Where does positive selection begin?
thymic cortex w/ T cells who have just arrived from bone marrow
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What does positive selection involve?
after TCR gene rearrangements, T cells selected that can bind w/ high to int aff to self-histocompatability molecules (MHC1/2); remainders die
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What is unusual about thymic cortex epithelium?
it expresses BOTH MHC1/2...usually only done by professional APCs
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Negative selection
T cells that can bind w/ self molecules w/ int aff only move forward
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Where does negative selection occur?
cortical-medullary junction: contains dendritic cells, marcrophages w/ MHC molecules, MHC/self peptide complexes
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Central tolerance
ability of T cells to respond to all foreign antigens and unable to respond to self antigen
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When do thymocytes begin prod CD4 and CD8 molecules?
thymic cortex; they can express both at the same time early on in dev (cortex)
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How is one receptor (CD4 vs CD8) down-regulated against the other?
as thymocytes mature, the CD4 and CD8 molecules interact with either circulating MHC-1 or MHC-2; which ever one is bound makes the thymocyte send a signal within the cell to down-regulate expression of the other molecule
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Dendritic cells (as an APC)
most effective APC; move through tissues in an inactive/ immature state
activates T cells in lymph nodes via DC-SIGN (bound by ICAM-3 on T cell)...T cell then leaves lymph node to look for origin of Ag/infection
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Macrophages (as an APC)
"tissue fixed"; sample antigenic env, process, present to local T cells
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B cells (as an APC)
can bind, via their Ab receptor for Ag, the exact Ag against which they wish to respond, following by endocytosis, processing via exogenous pathway, and presentation as MHC-2/peptide complexes to TH2 cells. (remember how these TH2 cells can now activate B cells?....co-stim CD40/CD40L=CD154 molecules as second signal for B cells!)
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