wednesday rds,mTOR,cytokine, IF

Question 1

What does mTORC2 do?

Answer 1

mTORC2 is an important regulator of cytoskeleton, F-actin stress fibers, PKC and PKB. MTORC2 binds MTORC1, MAPKAP1. PDPK1 phosphorylates PKB at serine 308 then MTORC2 phosphorylates PKB at serine 450, 473. PDPK-1 then phosphorylates PKB at S378 resulting in full PKB activation. Fully activated PKB can activate CREB, PI3K, and MTORC1. PKB inhibits p27, an inhibitor of cell cycle progression thus further stimulating growth. CREB (cAMP response element-binding protein) DEPTOR (DEP containing MTOR-inteacting protein) LST8, G protein beta subunit like, GbetaL, Gable MAPKAP1 mitogen activated protein kinase associated protein 1 p27 (CDKN1B gene product, cyclin dependent kinase inhibitor) PDPK1 (Phosphatidylinositol dependent kinase-1) can also phosphorylate other serine/threonine protein kinases SGK and atypical protein kinase C (aPKC, PRKCI gene). PI3K (phosphotidylinisotol 3 kinase) PKA (protein kinase A, cAMP dependent protein kinase) PKB (Protein kinase B, AKT, Akt-V-AKT murine thymoma viral oncogene homolog 3) PKC (protein kinase C) PROTOR protein observed with MTORC2 RICTOR rapamycin-insensitive companion of mammalian target of rapamycin SGK (serum/glucocorticoid -regulated kinase, first member of large subgroup of serine/threonine kinases). TEL2 telomere maintenance 2, homolog of TTI1 TTI1 TELO2-interacting protein 1

Question 2

What is the difference between cytochrome C oxidase-complex 4, cytochrome b-C1, and cytochrome c?

Answer 2

Cyotchrome C oxidase is complex IV, a large integral mitochondrial membrane complex composed of 28 cytochrome subunits (COX-1 through 8) containing two hemes (cytochrome a and a3) and two copper centers using 14 assembly subunits. Cytochrome b-C1 is Complex 3 and contains 11 subunits, 3 respiratory subunits, 2 core proteins, and 6 low molecular weight proteins. Reduced ubiquinol donates electrons to ferricytochrome c which passes them to complex 4. Cytochrome C is a small protein, 100 aa, 17k daltons, with 1 heme unit that uses its Fe to shuttles electrons from Complex 3 to Complex 4. COX can mean cytochrome oxidase or cyclo-ooxygenase, renamed PTGS (ProsTaGlandin Synthase).

Question 3

how does NF-kB work?

Answer 3

NF-kB refers to a cytoplasmic p50-RELA dimer generated from class I and II NFkB proteins. Both have N terminal DNA binding domains, class I has C terminal repressor activity, class II have activator domains. The DNA binding domains are bound by ikBa. NF-kB moves to nucleus when IkBa is phosphorylated and released. The preformed NF-kB transcription factor then binds response elements on multiple genes where additional factors mediate rapid transcription. p50-RELA dimer is the main TF combination. NFkB activates transcription of exogenous retroviruses. IkBa (Inhibitor of kappa B) NFkB (nuclear factor activated-kappa-light-chain enhancer of activated B cells) p50 generated by constitutive processing of p105, product of NFKB1 gene. relA product of RELA gene (V-Rel avian reticuloendotheliosis viral oncogene homolog A)

Question 4

What is the peroxisome?

Answer 4

Peroxisomes are single membrane organelles drived from the endoplasmic reticulum that replicate by fission. A target signal on a protein determines content. Peroxisomes are involved in long chain fatty acids catabolism, biosynthesis of plasmalogens (ether phospholipids), and 10% of pentose phosphate shunt enzyme activity. Peroxisome contain oxidative enzymes-catalase, D amino acid oxidase, uric acid oxidase producing H2O2 (absent human). Peroxisomes oxidize about 25% of ingested ethanol.

Question 5

What different types of blotting procedures are used to identify cellular molecules?

Answer 5

Southern blot uses known DNA and probes with DNA samples. A northern blot uses electrophoresis to separate cellular RNA, blots it onto nylon membrane, uses labeled RNA or DNA or oligonucleotide probes with at least 25 complementary bases to identify type of cellular RNA. A reverse northern plot uses isolated known DNA fragments on a membrane and probes with cellular RNA to develop an expression profile for that tissue. A Western blot separates unknown protein by electrophoresis on nitrocellulose and probes with a known antibody. Far-Western blotting probes a Western blot w post translational modification with a non-antibody binding protein to detect protein-protein interaction. An Eastern blot probes proteins separated by electrophoresis (SDS-PAGE gel) for post-translational modification to detect lipids, carbohydrates, or phosphorylation. A Far-Eastern blot (developed in Japan) uses (high-performance thin layer chromatography (HPTLC) to separate phospholipids which are then transferred to a membrane and probed by ligand binding or mass spectroscopy. Southern blot named after Edwin Southern.

Question 6

What enzyme does metformin activate to inhibit mTOR?

Answer 6

Metformin inhibits mTOR by activating AMPK which decreases glucose utilization. Activated AMPK inhibits MTOR resulting in decreased fatty acid and protein synthesis, mitochondrial respiration, and up regulation of glycolysis, and autophagy- decrease anabolism, increase catabolism. AMPK (adenosine monophosphate-activated protein kinase)

Question 7

What is the result of ROS generation by NADPH Oxidase?

Answer 7

ROS kills bacteria and fungi by inactivating critical metabolic enzymes, initiating lipid peroxidation, or liberating redox-reactive iron which then produces indiscriminate oxidants. SOD destroys ROS and inhibiting SOD increases ROS effectiveness. Knockout mice are more sensitive to lethal effects of superoxide inducing drugs. SOD (Superoxide dismutase)

Question 8

What metabolic defect in substrate utilization can affect the electron transport chain to increase reactive oxygen species production?

Answer 8

Any defect that decreases the concentration of mitochondrial matrix NADH will result in excess of direct oxidation at complex 1, and 3 with increased production of reactive oxygen species.

Question 9

How is tryptophan (C11H12N2O2) related to NAD?

Answer 9

Tryptophan is metabolized to kynurenine (C10H12N2O3) by tryptophan dioxygenase, an important step on the way to the synthesis of NAD (nicotinamide adenine dinucleotide-the nicotinic acid part).

Question 10

What is the role of kynurenine in the immune response?

Answer 10

Kynurenine (C10H12N203) is a metabolic product of tryptophan. Dependent biological functions include dilating blood vessels during inflammation, and regulating the immune response. Synthetic L-Kyn in coculture of bone marrow-derived dendritic cells skews the differentiation of T cells to Treg cells rather than Th17 cells. Formation depletes tryptophan stores which depress growth of T cells and bacteria.

Question 11

What is the difference between phospholipase C and protein kinase C?

Answer 11

Phospholipase C releases IP3 from PIP2 which then stimulates IP3 sensitive calcium channels on the ER. Protein kinase C is a serine threonine kinase that is activated by DAG and incased Ca++ (downstream from GPCR). It phosphorylates substrates near the cell surface and is important in signal transduction by phosphorylating ion channels.

Question 12

What factors bind to Ras and alter its GTPase activity?

Answer 12

The Ras GTPase is the Ga subunit of the heterotrimeric G protein large GTPase found in G protein receptors. GTPase activating proteins (GAPs) encourage GTP to GDP transition. Guanine nucleotide exchange factors (GEFs) release GDP which is then replaced by the abundant cytosolic GTP. Son of sevenless (Sos) and cdc25 have a RasGEF domain. Ras activity depends on GTP: GDP ratio as well as factors like PI3K.

Question 13

How do members of the Ras superfamily of proteins operate, and what do they do?

Answer 13

The Ras superfamily is a group of small GTPases related to the Ras subfamily (RAt Sarcoma source). Ras contains a GDP/GTP binding domain, and motifs for binding Mg, and guanine. The GTP form changes thnding affinity to other proteins that often increases that protein’s enzymatic activity. Receptor tyrosine kinases are a form of enzyme-linked receptors that activate Ras once phosphorylated by ligand binding. Members include: Ras controls cell proliferation, Rho controls cytoskeletal dynamics/morphology, Rab controls membrane trafficking, Rap controls cellular adhesion, Arf controls vesicular transport (ADP ribosylation factor), Ran controls nuclear transport, Rag RRAGA gene,Adenosine diphosphate ribosylation factor-1 GTPase ( member of the Arf small GTPase binding proteins of the Ras superfamily) is required for mTOR activation and lysosome localization by glutamine. Rheb activates mTORC1 kinase, and displays guanine nucleotide exchange activity. Miro controls mitochondrial transport.

Question 14

What happens to the heterotrimeric G protein of the G protein coupled receptor?

Answer 14

Ligand binding separates the heterotrimeric G protein into 2 pieces, G alpha, the G beta bound to G gamma. Down stream enzymes are activated or suppressed, ion channels may also be affected. The alpha subunit ~354 aa in the resting state binds GDP. There are 4 families of G alpha subunits based on sequence homology. Gi family inhibit adenylate cyclase or activate phosphodiesterase. Gs family activate adenylate cyclase, Gq family activate phospholipase C, and the G12/13 family activate the Rho family of GTPases. The G beta gamma complex can attach to ligand gated ion channels (G protein-coupled inward rectifying potassium channels) or L-type calcium channels, or bind to histamine receptors and activate phospholipase A2 (release arachadonic acid from c2 of glycerol).

Question 15

What are some downstream effects when AMPKK (AMPK kinase) activates AMPK? Not cAMP activated protein kinase (protein kinase A, PKA)

Answer 15

AMPK activation increases catoblism to create more ATP, and slows down anabolism to reduce ATP consumption. AMPK is activated when phosphorylated at threonine 172 by AMPKK, a complex of three proteins. Downstream effects include adipokines (Adiponectin and leptin) regulate appetite, metabolism, fatty acid catabolism, coagulation, and systemic inflammation may work through AMPK. Muscle cells upregulate oxidative metabolism via GLUT4, hexokinase 2, PPARalpha, PGC-1, UCP3, cytochrome C, and TFAM. AMPK (5’adenosine monophosphate-activated protein kinase) AMPKK AMPK kinase LKB1 a serine/threonine kinase MO 25 most protein 25 PGC-1 (peroxisone proliferator-activated receptor gamma co-activator 1-alpha) PPARalpha (peroxisone proliferator-activated receptor alpha) TFAM (mitochondrial transcription factor A) UCP3 (mitochondrial uncoupling protein 3)

Question 16

What are the phospholipases A-C and the phosphokinases A-C?

Answer 16

Phospholipase A1 catalyzes the cleavage of the sn-1 position of phospholipids, forming a fatty acid and a lysphospholipid. Phospholipase A2 cleaves the SN-2 position (release arachadonic acid). Phospholipase B can cleave both the SN-1 and SN-2 positions.Phospholipase C catalyzes the cleavage of I3P. Phosphokinase A does not exist, phosphokinase B is aKT and phosphokinase C is a serine/threonine kinase activated by binding to diacylglycerol.

Question 17

How does mTORC1 increase production of reactive oxygen species?

Answer 17

mTORC1 increases cytosolic glycolysis and decreases oxidative phosphorylation thus lowering O2 demand and allowing excess O2 to form reactive oxygen species.

Question 18

What is the difference in function between mTORC1 and mTORC2?

Answer 18

MTOR forms different complexes due to multiple protein binding domains (eg PH, TPR domains) that affects substrate access. mTORC1 acts as the nutrient/energy/redox sensor which is stimulated by insulin, growth factors, serum, amino acids, and oxidative stress. Phosphorylates S6 kinase 1 - S6 ribosomal protein. mTORC2 is an important regulator of cytoskeleton, F-actin stress fibers, PKC and PKB phosphorylation. MTOR -/- knockouts die as embryos, -/+ are normal and fertile. PKC (protein kinase C) PKB (protein kinase B, Akt) MTORC1 expands IL-4 double negative T cells, Th-17 cells, and contracts Tregs in SLE. PH domain- plextrin homology domain. TPR (tetratricopeptide repeat) ~34 aa seq;uence In SLE, rapamycin inhibits mTORC 1 in Tregs and promotes expansion of Tregs. -Kato

Question 19

How do tuberous sclerosis proteins affect mTOR?

Answer 19

TSC2 is a peripheral membrane protein that combines with TSC1 in cells to become a cytosolic dimer with GTPase activating protein (GAP) activity that inhibits rheb GTPase by dephosphorylatiion. TSC2 unbound by TSC1 activates Rheb (GTPase) which then activates mTOR by removing the inhibitory protein FKBP8 which binds FRB motif and prevents kinase activity. Otherwise amino acids can stimulate mTOR directly by Rag C/D binds GTP ->Rag A/B, binds to lysosome, attracts Rheb which activates mTORC1. The TSC1/TSC2 heterodimer is a sensitive to upstream signals (AKT) that result in increased or decreased mTOR activation and can function as a tumor suppression gene when dimerized. TSC2 (tiberpis sclerosis complex 2, tuberin, tuberous sclerosis complex refers to disease not a complex of proteins) TSC1 (hamartin, peripheral membrane protein) rheb (RAS homolog enriched in brain), membrane bound farsenylated FKBP8 (FK406-binding protein 8, FKBP8, 38KD, FKBP38)

Question 20

How does mTORC1 inhibit autophagy?

Answer 20

Activated mTORC1 phosphorylates Atg 13 which prevents autophagosome construction at the plasma membrane. Atg 13 (autophagy related protein 13)

Question 21

What does MLST8 (MTOR subunit LST8) do in the MTORC1 complex?

Answer 21

MLST8 binds to kinase domain of MTOR and stabilizes interaction with RPTOR (raptor). Necessary for phosphorylation of S6K1 and 4EBP1. MLST8 (mammalian lethal with SEC protein lethal 8) RPTOR (regulatory-associated protein of MTOR

Question 22

how are various domains distributed by location along the MTOR molecule?

Answer 22

The MTOR complex binds multiple proteins. N terminal end has multiple HEAT repeats comprised of TPR motifs, then one FAT domain, then FRB domain then more TPR repeats. A class IV PI3K/PI4K domain is near the C terminal end, then a cFAT domain. MTOR consists of 2,549 aa, and calculated mol wt of 300 kD. ATM (ataxia telangiectasia mutated) cFAT (C terminal FAT domain) FRB (FKBP12-rapamycin binding domain). FAT [FRAP-ATM-TRRAP) FRAP-(FKBP-rapamycin-associated protein) HEAT (Humtingtin, Elongation factor 3 (EF3), protein phosphatase 2A (PP2A), ATM, yeast kinase TOR1) PI3K/PI4K class IV phosphatidylinositide-3-kinase, serine/threonine kinase MTOR (Mechanistim Target of Rapamycin; MTOR Mammalian Target of Rapamycin, FRAP (FKBP12-binding protein, 12-rapamycin complex-associated protein 1), RAFT1) TPR (tetratricopeptide repeat) ~34 aa seq;uence TTRAP (transformation/transcription domain-associated protein member of the phosphatidylinositol 3-kinase-related kinase protein family)] domain.

Question 23

How does MTORC1 complex work?

Answer 23

MTORC1 works by having bound proteins that restrict serine/threonine enzymatic activity to proteins that stimulate cell proliferation and increase cell size only when metabolically appropriate. MTORC1 is 1Md in size, contains 2 hetero tetramers with rhomboid shape and central cavity formed by 2 MTOR and 2 RPTOR, MLST8 subunits, which form distal foot like processes. AKT1S1 is in central core and has 10 serine/threonine sites where phosphorylation by PKB, regulates kinase activity by causing AKT1S1 to leave the complex and permit substrate access to MTORC1. Also binds ATP, RNA polymerase, and attaches to mitochondria, endoplasmic reticulum, golgi. lysosomes, endosomes, pml body in nucleus. The FRB motif on MTOR binds FKBP1A (FKBP12), forming catalytic cleft in MTORC1. The FKBP1A-rapamycin complex does not form an enzymatic site. FKBP8 (FKBP38) is related to FKBP12 and inhibits MTORC1 similar to FKBP 12-rapamycin. Rheb contains 5 GTP binding repeats,- has GTPase activity, and once activated displaces FKBP8 and thus activates MTORC1. AKT1S1 (AKT1 Substrate 1, Proline rich, PRAS40) MLST8 (MTOR subunit LST8) MTOR ( mechanistic target of rapamycin, FKBP12-rapamycin complex-associated protein 1, (FRAP1)) PML (promyelocytic leukemia bodies) PKB (AKT1) RPTOR (regulatory-associated protein of MTOR 1335 aa)

Question 24

What is RPTOR?

Answer 24

RPTOR (regulatory-associated protein of MTOR) which regulates growth, survival, and autophagy. It serves as a scaffold for recruiting MTORC1 substrates, and various kinases. Binds 14-3-3 protein, protein kinase, RNA polymerase 3. Has 10 serines phosphorylated by MAPK8, RPS6KA1, MTOR. Insulin induced phosphorylation regulates MTORC1. Growth factors up regulate MTOR via RPS6KA1 by phosphorylating serines at 3 sites . Nutrient limitation results in RPTOR phosphorylation by AMPK which associates with 14-3-3 which down regulates MTOR. RPTOR binds directly to 4EBP1 and RPS6KB1, independent of MTORC1 . Interacts with SPAG5and G3BP1 which is increased by oxidative stress. Interacts with HTR6. Contains 7WD repeats 14-3-3 binds to over 200 signaling proteins MAPK8 mitogen activated protein kinase 8 RPS6KA1 ribosomal protein S6 kinase alpha 1 SPAG5 (Sperm associated antigen 5) G3BP1 (RasGTPase-activating protein-binding protein 1) HTR6 (5-HT (serotonin) receptor 6) WD repeats (about 40 amino acid motif culminating with tryptophan-aspartic acid-W-D) forms circular solenoid protein domain (WD-40 domain).

Question 25

how do amino acids activate mTOR?

Answer 25

In the presence of amino acids Rag proteins become RagC GDP and RagB GTP, and attracts mTOR and Rptor to become mTORC1. P62 associates with RagC GTP and RagG GDP on the surface of a lysosome. P62 (Sequestosome 1; SQSTM1 gene) rags (GTPase-activating protein for Rag subunits A/B)

Question 26

How do enzymatic complexes coordinate incoming signals prior to gene activation? What is the ragulator complex?

Answer 26

Enzymatic complexes coordinate different processes by binding different proteins according to different conditions resulting in different transcription factors. Conditions cause post transitional modifications -phosphorylation, GTP binding so that the complex localizes to different sites and attract different mix of activators and suppressors. The ragulator complex composed of MAPKSP1, ROBLD3 and c11orf59 interacts with Rag GTPasees to recruit mTOR to the lysosomal surface where it becomes active by binding Rheb. MAPKSP1 (Mitogen activated protein kinase scaffold protein 1) enhances signal. ROBLD3 (? p14, Lamtor2, endosomal?lysosomal adaptor MAPK and MTOR activator 2) c11orf59 (chromosome 11 open reading frame 59, late endosomal/lysosomal adapter, MAPK and MTOR activator 1)

Question 27

How do gator complexes affect rag activity?

Answer 27

Rag activity is regulated by GATOR complexes. GATOR1 contains DEPDC5, Nprl2 and Nprl3. GATOR2 complex contains Mios, WDR24, WDR59, Seh1L, and Sec13. GATOR1 inhibits Rags. GATOR2 activates Rags by inhibiting DDPDC5. DEPDC5 (DEP domain-containing protein 5) GTPase activator GATOR (GTPase activating protein activity towards RAGs) Nprl2 gene TUSC4(tumor suppressor candidate 4, protein phosphorylation, GTPase activator. Nprl3 (nitrogen permease regulator-like 3) Mios (missing oocytte/meiosis regulator, Drosophila, homolog of) WDR24 (WD repeat containing protein 24) WDR59 (WD repeat containing protein 59) rags (GTPase-activating protein for Rag subunits A/B) Seh1l (Seh1-like protein) localizes nucleoporins to nuclear envelope Sec13 (sec13-like protein 1,sec13L1) suppresses mTORC1 signaling.

Question 28

What is the role of GATA-3 in the Th2 response?

Answer 28

GATA-3 is a zinc finger transcription factor that promotes differentiation of Th2 cells and secretion of IL-4, -5, -8 and -13. Suppresses differentiation to Th1 cell line. Defects result in hypoparathyroidism with sensorineural deafness and renal dysplasia. Often expressed in breast cancer- luminal type. GATA-3 expression is increased in CD8 lupus T cells and is insensitive to rapamycin. IL-17 but not IL-4 induces suppression of GATA-3. GATA-3 (enhancer binding protein GATA-3, Trans acting T cell specific transcription factor)

Question 29

IL-23 Is composed of what proteins and stimulates what other interleukin?

Answer 29

IL-23 is composed of IL-12p40 subunit shared with IL-12 and the IL-23p19 subunit. IL-23 simulates T helper cells producing IL-17 and delayed type hypersensitivity. IL-23 contributes to experimental autoimmune inflammation in numerous models of encephalitis, arthritis, enteritis, and psoriasis.

Question 30

What is the result of IL-17 stimulation and which cells are most sensitive?

Answer 30

IL-17 induces production of cytokines IL-6, G-CSF, GM-CSF, IL-1 beta, TGF-beta, TNF alpha and chemokines IL-8, MCP-1, and prostaglandins PGE2 for many cell types including fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages. Stimulates Th17 cells linked to many autoimmune diseases. IL-17 expression is increased in CD4 positive T cells and is suppressed by rapamycin. Neutralization of IL 17 but not IL-4 expanded Tregs in SLE and HC subjects-Kato.

Question 31

What is the fate of immature B cells once they leave the bone marrow ?

Answer 31

Circulating immature B cells are CD45, CD19, CD40, IgM BCR+ that has undergoes deletion or receptor edit, before leaving the bone marrow. B-1a lymphocytes are CD5+CD11b/CD18+CD45RAlow, and produce low affinity poly-reactive IgM Ig using germline genes. They are self replenishing, are found in the blood in peritoneal cavity. CD5 ligation induces TNF and IL-2R. B-1b have inducible CD5, are CD11b/CD18 +, CD45RA low, produce high affinity IgG, IgM, and IGE immunoglobulins, found in the bone marrow and blood, and CD5 ligation causes apoptosis. B-2 lymphocytes are conventional, have inducible CD5, CD11b/CD18 -, CD45RA high, and undergo further differentiation in lymph nodes and apleen. Fo B express IgM, IgD, CD21, CD19, and CD81. organize into primary B follicles, white pulp spleen, cortical areas lymph node. freely recirculate. CD21 binds C3 and with CD19 and CD81 produce co-receptor complex which increasea BCR responsiveness. Fo B-follicular B cell CD5 has an ITIM motif which reduces antigenic responsiveness,. No confirmed ligand, may be homophilic and bind to itself. CD11b/CD18 (integrin alpha 1 ITGAM MAC-1 CR3) / CD1b (Thymocyte antigen) CD18 (integren beta chain beta 2) CD19 transmembrane Ig like extracellular, intracellular tyrosines affect BCR responsiveness once phosphorylated. CD21 complement receptor CR2 CD81 transmembrane glycoprotein, signal transducer CD45RA (Protein tyrosine phosphatase receptor type C PTPRC)

Question 32

What are the differences between B1, B2, and Fo B (follicular) lymphocytes?

Answer 32

B-1 cells have more IgM than IgG on the surface with low antigen avidity responding mostly to polysaccharides. Present in pleural and peritoneal cavities. B-2 cells are intended when B cell is otherwise unqualified. T follicular helper cells, help for primary immune response, isotype switching. no CD1 or CD5, different from B1 B cells, and marginal zone B cells.

Question 33

What does interferon inducible GTPase do?

Answer 33

Interferon inducible GTPase is a family of proteins primarily associated with the golgi apparatus and endoplasmic reticulum which affects intracellular membrane trafficking. Immunity-related GTPase family M protein (IRGM) is a member which regulates autophagy in response to intracellular pathogens.

Question 34

How does dsRNA stimulate an antiviral response?

Answer 34

RIG-I is a dsRNA helicase enzyme that participates in RNA binding and dsRNA recognition. Works with MDA5 to activate MAVS and increase expression of NFKB and interferon via irf3 and CREBB heterodimer transcription factor. MAVS (mitochondrial antiviral signaling protein), VISA (viral induced signal adaptor). MDA5 (melanoma differentiation protein 5, dsRNA helicase) RIG-I (rig-i, retinoic acid-inducible gene 1), recognizes 4000bp sections. IRF3 (interferon regulatory factor 3) CREBBP (CREB binding protein)

Question 35

What is the Mac-1 antigen ?

Answer 35

Mac-1 is a heterodimeric integrin is composed of CD11B (ITGAM (integrin alpha M, CR3A)). and Beta2 integrin. Beta2 integrin (CD1beta, related to class 1 MHC). Mac-1 (complement receptor 3 (CR3), macrophage-1 antigen, integrin alpha-M beta-2 complex)

Question 36

What is the CD 138 plasma cell marker?

Answer 36

cd138 is a transmembrane heparin sulphate proteoglycan of the syndecan family that participates in cell binding, signaling, and cytoskeletal functions. Serves as a marker for blood derived plasma cells.Required for internalization of HIV-1 tat protein. Variants occur on tumor cells.

Question 37

What are γδT cells?

Answer 37

γδT cells are not MHC restricted and seem to recognize whole proteins without digestion. They make up about 2% of peripheral blood lymphocytes. Most are CD4-CD8-.

Question 38

How does the Prdm1 (PR domain zinc finger protein 1) transcription factor stimulated by viral infection, increases IL 10 excretion and become a master regulator of hemetatopoetic stem cells?

Answer 38

Prdm1 is a transcription factor that binds to beta interferon promoter, represses beta-interferon expression, and increases IL-10 excretion. Transcription increases upon virus induction especially in B and T lymphocytes, NK cells, and is a master regulator of hemetatopoetic stem cells. Prdm1 (PR domain zinc finger protein 1, (Blimp1 B lymphocyte induced maturation protein 1))

Question 39

How does staining the Ki-67 nuclear protein identify cellular proliferation, even on fixed tissue?

Answer 39

Ki-67 is a nuclear protein associated with cellular proliferation especially ribosomal RNA transcription. It is absent during G0 and during mitosis is attached to chromosomes. The monoclonal antibody (Ki-67) works on fixed issue demonstrating the presence of proliferating cells.

Question 40

What is the role of fibrinogen like protein 2?

Answer 40

Fgl2 is a type II transmembrane protein found on the surface of macrophages and endothelial cells (mfgl2) and can be constitutively secreted by both CD4+ and CD8+ T cells (sfgl2 soluble). mfgl2 exhibits a prothrombinase activity inducing fibrin deposition. Treg cells secrete sfgl2 which helps to dampen inflammation once infection has cleared. Knockout mice have T cells that are hyper proliferative. Fgl2 (Fibrinogen like protein 2), 439 amino acid protein similar to beta and gamma chains of fibrinogen

Question 41

How does Bruton's membrane associated tyrosine kinase affect B cell development ?

Answer 41

Bruton's tyrosine kinase (Btk, BTK gene) as a pH domain which binds it to PIP3 which induces phospholipase C to cleave PIP2, releasing IP3 and DAG. Plays a critical role in early B cell development prior to expression of B cell receptor and heavy chains. Dysfunction causes X-linked agammaglobulinemia.

Question 42

How do fatty acids and their metabolites affect gene transcription?

Answer 42

Fatty acids and their metabolites bind to PPAR which then dimerize with RXR to form a transcription factor that recognizes PPRE DNA sequences. PPRE have 2 DNA-binding domains (DBD), One for RXR and the other bound to PPAR. There are 3 main forma of PPAR activated by a wide range of ecosanoids, leukotrienes, and fatty acids. Affect cellular differentiation, tumorigenesis, and metabolism. The Loss of function results in lipodystrophy, insulin resistance, acanthosis nigricans, gain of function mutations reduce risk of insulin resistance and increase risk of obesity. The DNA-binding domains recognize DNA-site consensus sequences arranged as inverted or direct repeats. These proteins are occupied by a co-repressor which upon ligand binding is replaced by a co-activator. PPAR (peroxisome proliferator--activated receptor) PPRE (Peroxisome proliferator response element) RXR (Retinoid X receptor bound to retinoic acid)

Question 43

What is the role of the CD5 glycoprotein on lymphocytes?

Answer 43

CD5 is a transmembrane glycoprotein, 54 kD, 455 aa, on T cells, B-1 cells and serves to lower B cell responsiveness via intracellular ITIM domain so that only strong stimuli become immunogenic. CD5 (Ly1, Leu1) ITIM (Immunoreceptor Tyrosine-based inhibitory motifs)

Question 44

what happens when CXCR4 on lymphocytes binds its ligand CXCL12 ?

Answer 44

CXCR4 is a chemokine receptor for CXCL12 (stromal derived factor I) which causes circulating cells to home to the bone marrow. It is also the major HIV receptor on lymphocytes.

Question 45

What happens to B cells when CXCL13 from T cells binds CXCR5?

Answer 45

CXCR5 is a 7 transmembrane G protein-coupled receptor for CXCL13, secreted by T cells. CXCR5 is important in B cell migration. CD4+ CXCR5+ T cells protect against tuberculosis. CXCL13 (BLC, B lymphocyte chemoattractant ) CXCR5 (C-X-C receptor type 5, CD185, (BLR1 Burkitt lymphoma receptor 1)) hint unlucky people (13) get Tb.

Question 46

What type of ROR (RAR related orphan receptor) is important in T cell transformation?

Answer 46

ROR (retinoid-related orphan receptor, 3 forms-alpha beta gamma) is a transcription factor that binds as a monomer to hormone response elements. RORGamma activation results in naïve T cells transforming to promote proinflammatory Th17 cells, or natural helper cells. Retinoic acid binds to alpha and beta.

Question 47

How does ATP get to the extracellular space and what is its fate?

Answer 47

Pannexin-1 is a cell membrane transporter that moves intracellular ATP to the extracellular space. Extracellular ATP can bind to P2X receptor. ATP breaks down to ADP and AMP. ATP, AMP, UTP, UDP, UDPglucose bind to P2Y type receptors. Adenosine derived from AMP binds to the adenosine receptor (4 types of g protein coupled receptors). P2X receptor (2 plasma membrane spanning domains, ligand gated ion channel) P2Y (g protein coupled receptor-12 genes)

Question 48

What interleukins stimulate what cells to generate what transcription factors to develop a Th1 response?

Answer 48

Th1 depends on IL-12, and IL-2 stimulation affecting macrophages, CD8 T cells, IgG B cells, to generate STAT4 and T-bet that transforms Tn cells into INTg producing Th1 lymphocytes. STAT4 (signal transducer and activation of transcription), necessary for IL-12 ability to induce INFg T-bet (T-box 21), produces transcription factor TBX21 which controls expression of INFg. Tn Naive T cells

Question 49

What cytokines do CD4+ Th17+ cells secrete after stimulation by IL-23?

Answer 49

TNF alpha, IL-17. IL-17 is produced by Th17 cells after stimulation by IL-23, and recruits monocytes and neutrophils to inflammatory sites and stimulates the production of IL-6, G-CSF, GM-CSF, IL-1 beta, TGF-beta, and TNF alpha as well as many chemokines, and prostaglandins. This pathway is active in psoriasis, autoimmune uveitis, juvenile idiopathic arthritis, rheumatoid arthritis, and Crohn's disease. IL-23 (heterodimer containing IL-12p40 and IL-23p19) stimulates IL-23 receptor (heterodimer IL12R and IL-23R) on T cells, and NK cells that stimulates the production of IL-17.

Question 50

What cytokines do CD4+ Th2 cells secrete?

Answer 50

IL-4, IL-5, IL-6, IL-10, IL-13Th2 response relies on B cells to produce IL-4-5-6-10-13 thus stimulating antibody class switching and neutralizing antibody production. IL-4 Starts the process which auto stimulates itself and other cytokines. IL-10 Inhibits IL-2 and interferon gamma.

Question 51

What cell types promote Th1 and Th2 type responses?

Answer 51

Macrophages promote Th1, B cells Th2.

Question 52

How many types of Treg lymphocytes are there?

Answer 52

nTregs are CD4+ CD25+ FoxP3+. iTreg develop outside the thymus from mature CD4+ T cells, and function to increase TCR diversity. Adaptive Treg cells are also known as Tr1, Th3, CD8+CD28+. Th3 cells at mucosal surfaces regulate responses with TGFbeta and IL-10 and are CD25+CD4+ without a specific marker. nTreg (Naturally occurring Treg cells) iTreg (Induced Treg cells)

Question 53

What sort of effectors are stimulated by interferons?

Answer 53

Type I and type III interferons induce 14 effectors including APOBECs, NOS2, Tetherin, TRIMs, and Viperin. Type II interferon (INFg) induces 15 effectors including NOXs, PKR, NOS2, Tetherin, TRIMs, and Viperin. APOBEC (APO protein B (apolipoprotein B) mRNA Editing enzyme, Catalytic protein like) NOS2 (nitric oxide synthase 2, inducible), L-arginine, NADPH,O2-\>citruline, NO., NOX (NADPH oxidase, 4 isoforms NOX1-4) PKR (protein kinase R, interferon induced ds-RNA activated protein kinase ), dsRNA bind, inhibit virus, pro-apoptotic. Tetherin-viral restriction factor preventing release TRIM (TRI partite Motif), pathogen recognition, transcription Viperin- (Virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) stimulates PKR.

Question 54

What is the result of FOXP3 mutations in man?

Answer 54

FoxP3 Mutations result in X linked immunodeficiency and endocrinopathies. IPEX syndrome of immunodisregulation, polyendocrinopathies, enteropathy, X linked. Promotor has NF-AT and AP-1 binding sites that up regulate FOXP3 expression. Epigenetic imprinting includes demethylation of CpG motifs and histone modification which stabilizes FOXP3 expression. AP-1 (activator protein-1, transcription factor controlling differentiation, proliferation, apoptosis). FoxP3 (FOrkhead bOX P3) gene is on X chromosome, ~1000 bp, ~400 aa protein transcription factor, with multiple splice variants-isoforms-alleles. NFAT (nuclear factor of activated T cells)

Question 55

What plasma components are increased by IL-6?

Answer 55

IL-6 increases complement levels, acute phase protein synthesis, and myelopoeisis. IL-6 stimulates prostaglandin synthesis in the hypothalamus..

Question 56

What is interferon gamma and what does it do?

Answer 56

Interferon gamma, a type 2 interferon, promotes NK cell activity, induces production of IgG2a, IgG3 from plasma cells, promote Th1 differentiation, increases class I and 2 MHC expression, promotes adhesion and binding required for leukocyte migration, increases lysosomal activity of macrophages, activates iNOS, increases resistance to retroviruses via TRIM5alpha, APOBEC, and tetherin. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polyprotein like) editing C-to-U errors. Interacts with RNA binding protein form editosome. INFg 6 alpha helices, mw ~17k, Tetherin ( BST 2 gene, CD317) is expressed on mature B cells, plasma cells, and dendritic cells following IFN stimulation. Inhibits retroviral budding and release from cell membrane. TRIM5 (tripartite motif-containing protein 5) is a retrovirus restriction factor blocking retrovirus infection. Part of innate immune system.

Question 57

What cell types produce IL-22 (IL-10 related T cell inducible factor) and what does it do?

Answer 57

IL-22 is produced by dendritic cells and T cells as part of an innate immune response. It affects epithelial cells not immune cells. Increases S100 protein production, and defensins,

Question 58

What pathways does TGF-beta affect?

Answer 58

TGF-β induces apoptosis through the SMAD and DAXX pathways, regulates the cell cycle through c-myc suppression, and the immune system by blocking activation of lymphocytes and monocyte derived phagocytes. upregulation results in inflammation, autoimmune disorders, fibrosis, cancer and cataracts DAXX (death associated protein 6) binds symoylated transcription factors SMAD transcription factor related to MAD (mothers against decaplegic) c-myc resembles v-myc myelomatosus viral oncogene

Question 59

What is the structure of TGF-beta family proteins?

Answer 59

TGF-beta refers to a superfamily of structurally related regulatory proteins that form disulfide linked homo or heterodimers with intra-chain disulfide bonds. TGF-beta-1 has 22 aa derived from C-terminal proteolytic cleavage of 412 gene product. Family members use serine/threonine kinase receptors to activate various's SMAD pathways. TGF alpha is an epithelial growth factor, both discovered as the active ingredient in sarcoma growth factor.

Question 60

How do various alpha and beta chains combine to form the IL-12 family (IL-35, IL-27, IL-23, IL-12)?

Answer 60

Each component of the IL-12 dimer is part of the other 3 interleukins. IL-35 is a dimer containing p35 (IL-12 alpha) and EBI3 (Ebstain Bar virus Induced 3) chain that binds to gp130 . IL-27 is a dimer containing P28 (IL-27)and EBI3. IL-12 is a dimer containing p35 (IL-12 beta 2) and p40 (IL-12 beta1). IL-23 is a dimer containing p19(IL-23), and p40 (IL-12 beta 1 ). The chains associate via Jak and Tyk motifs which phosphorylate STAT 3 and 4 transcription factors Tyk motif.

Question 61

What does the alpha chain of the IL-2 receptor (CD25) do?

Answer 61

The alpha chain of the IL-2 receptor is present on activated T and B lymphocytes, thymocytes, myeloid precursors, and oligodendrocytes. It associates with CD122 (beta chain of IL-2R) and the GAMMA chain (CD132) to form a high affinity IL-2 receptor, commonly expressed on Treg cells as well as resting memory T cells. CD122 has JAK1 , and gamma chain JAK3 kinase capacity. The complex stimulates JAK-STAT, PI3K, and MAP kinase pathways. CD132 also participates in 6 other receptors: IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK1 Janus kinase 1, tyrosine kinase PI3K (phosphatidylinositol-4, 5-biphosphate 3-kinase)

Question 62

What is the role of phosphatidylinositol in cell signaling?

Answer 62

PI3K acts on membrane phosphatylinositol to generate PI(3)P, PI(3-4)P2, and PI(3,4,5)P3. These compounds can then activate PDPK or be the substrate for phospholipase C to generate IP3. PDPK1 activates AKT and IP3 activates receptors on the sarcoplasmic membrane among other effects. PI3K is activated by G protein-coupled receptors and tyrosine kinase receptors. Phosphorylated phosphatidylinositol can then attract other proteins with PH (plextrin homology) domains to facilitate further signaling. PI3K (phosphatidylinositol-4, 5-biphosphate 3-kinase) PI(3)P (phosphatidylinositol 3-phosphate) PI(3-4)P2 (phosphatidylinositol (3-4) biphosphate) PI(3,4,5)P3 (phosphatidylinositol (3-4-5) triphosphate) PDPK1 (3-Phosphoinositide-dependent protein kinase-1)

Question 63

What activates PKB and what does activated PKB do?

Answer 63

PKB is a serine/threonine-specific protein kinase that participates in cytoplasmic signaling downstream from PDPK1 which phosphorylates serine 308 of PKB for partial activation. MTORC2 phosphorylates PKB at serine 473 which then phosphorylates CREB, and MTORC1. Its PH domain binds phosphatidylinositides, a membrane localizing factor which affects access to substrates. PKB inhibits p27, an inhibitor of cell cycle progression thus promoting cell growth.. PKB (Protein kinase B, AKT, Akt-V-AKT murine thymoma viral oncogene homolog) PDPK1 (3-Phosphoinositide-dependent protein kinase-1) CREB (cAMP response element-binding protein) PH domain- plextrin homology domain. p27 (CDKN1B gene product, cyclin dependent kinase inhibitor), an inhibitor of cell cycle progression.

Question 64

What are the components of MTORC1 and MTORC2?

Answer 64

MTORC1 complex contains MTOR, RPTOR, MLST8, PRAS40, FKBP8 and DEPTOR. MTORC2 contains LST8 and DEPTOR like MTORC1 as well as RICTOR, MAPKAP1, PRR5, TTl1, TELO2, and mSIN1. DEPTOR (DEP containing MTOR-inteacting protein) MAPKAP1 Mitogen-activated protein kinase-associated protein 1 MLST8 (MTOR subunit LST8 (mammalian lethal with SEC protein lethal 8), GBL) MTOR ( mechanistic target of rapamycin, FKBP12-rapamycin complex-associated protein 1, (FRAP1)) MTORC1 (MTOR complex 1) PRAS40 (AKT1 Substrate 1, Proline rich AKT substrate) Protor 1/2 (protein observed with RICTOR). PRR5- proline rich protein 5, RICTOR rapamycin-insensitive companion of mammalian target of rapamycin RPTOR (RAPTOR, regulatory-associated protein of MTOR) mSIN1 mammalian stress activated protein kinase interacting protein 1 TTI1 TELO2 interacting protien 1 TELO2 TEL2 telomere maintenance 2 MTORC1 size is 1Md, contains 2 hetero tetramers with rhomboid shape and central cavity formed by 2 MTOR and 2 RPTOR and MLST8 subunits which form distal foot like processes. PRAS40 is in the central core.

Question 65

What is the structure of Rheb?

Answer 65

Rheb is a monomeric small lipid anchored GTPase containing 5 RAS related GTP binding repeats. Once activated it displaces FKBP8 on MTORC1 and thus improves substrate access and serine/threonine kinase activity..

Question 66

What role does phosphorylation play in PKB (protein kinase B) activation.

Answer 66

Protein kinase B is a serine/threonine-specific protein kinase, is phosphorylated at serine 473 by MTORC2, and threonine 308 by PDPK1. Once phosphorylated PKB activates MTORC1 by releasing RHEB from TSC inhibition. RHEB then activates MTORC1 perhaps by removing FKBP8 or otherwise improving access of substrates to the kinase binding site. Protein kinase B (PKB, Akt-V-AKT murine thymoma viral oncogene homolog 3, AKT1) PDPK1 (phosphoinositide dependent kinase 1) AKT named after transforming retrovirus AK8 with t added for thymus..

Question 67

What is the role of CD45 (PTPRC, protein tyrosine phosphatase receptor type C) on T and B cells?

Answer 67

CD45 is a transmembrane protein that modifies tactivity of both T and B cell receptors and activates src kinases and suppresses JAK kinases. Used to differentiate lymphocytes from carcinomas. CD45 (PTPRC, protein tyrosine phosphatase receptor type C, leukocyte common antigen), type 1) CD45RA is a longer isoform of CD45. src family kinases are non non receptor tyrosine kinases (Src,Yes-1, Fyn, Fgr, Lck, Hck, Blk, Lyn) in vertebrates and Frk in flies and worms.

Question 68

What does TIGIT (T cell immunoreceptor with Ig and ITIM domains) ligation on Treg cells do to Fgl2 (Fibrinogen like protein 2) production and activity of effector cells?

Answer 68

Ligation of TIGIT (T cell immunoreceptor with Ig and ITIM domains) on Treg cells induces expression of Fgl2 which suppresses the effector cell population. Th1, Th17. Th2 cytokine production is not affected. PVR (polio virus receptor) is one ligand for TIGIT

Question 69

What characterizes the binding sites of integrins, cadherens, selectins, and syndecan ?

Answer 69

integrins are obligate heterodimers with large glycosylated binding sites. cadherins are immunoglobulin transmembrane then external Ca++ binding cadherin motifs. selectins are transmembrane, CHO binding via Ca++ binding similar to C-type lectins syndecan are single pass transmembrane receptor with terminal heparin sulfate and chondroitin sulfate chains that bind TGFbeta, fibronectin, and VEGF. Ligands for integrins include fibronectin, vibonectin, collagen, and laminin

Question 70

What are M1 and M2 macrophages, what stimulates their development .and what do they produce?

Answer 70

M1 macrophages are inflammatory and . M1 respond to INFg, GM-CSF, lipopolysaccharide,, and adding fucose to glycan termini by fucosaltransferases. M1 macrophages produce IL-12, TNF, NO, reactive O2 species, Adding encourages M1 phenotype. encourages M1 and encourages M2. M2 macrophages are polarization by IL-4,10,18, M-CSF, and are associated with down regulation of CD25, TLR2, CD127, CD64, CCR7, CD16, and CD36 and up regulation of CD86, CD14, CD209, CXCR4, and CD206 with an overall anti-inflammatory effect. CCR7 (C-C chemokine receptor type 7) CD14 (coreceptor with TLR4 for lipopolysaccharide) CD16 (Fc IgG receptor) CD25 (alpha chain IL-2 recptor) CD36 (thrombospondin receptor) CD64 (monomeric IgG Fc receptor) CD86 (ligand for CD28 and CTLA4) CD127 (IL-7 receptor subunit alpha) cd206 (c type lectin, mannose receptor) binds N-accetylglucosamine, fucose CD209 (C type lectin receptor) cxcr4 (CD184, fusion, binds SDF-1 stromal derived-factor-1 or CXCL12), HIV binding site on T cells.

Question 71

What is the effect of rapamycin on macrophages?

Answer 71

Rapamycin caused M2 apoptosis, Rapamycin treatment induces a quantitative shift to M1 and induces a mild systemic inflammation. Rapamycin induces NF-kB, blocks STAT3, glucorticoid effect,emergence of distinct inflammatory disease-interstitial pneumonitis, glomerulonephritis, and systemic inflammatory response syndrome.

Question 72

How many T helper cells are there, how do they develop, and what are the major results?

Answer 72

Naive T cells are stimulated by cytokines in different combinations which lead to different transcription factors which different cytokines tailored for different situations. Th1 cells develop via INFg and IL-12 stimulation producing Tbet transcription factor-\> increase INFg and macrophage activation Th2 develop via IL-4 and IL-2 stimulation producing GATA3 transcription factor with increased IL-4 and IL-13 affecting intracellular parasites, and B cell antibody production TH 17 cells developed by a TGF-beta, IL-6, IL-21 inducing RORg which then produces IL-17, and IL-21 affecting extracellular bacteria and fungi and neutrophil activation. Tfh follicular helper T cells develop via IL-6 and IL 21 producing Bcl6 which then produces IL 10, IL-21 and IL-4 with simulation of long-term humoral mmunity Bcl6 (B cell lymphoma protein 6) RORg (RAR related orphan receptor gamma, retinoic acid binding receptor gamma)

Question 73

How does rapamycin treatment inhibit MTORC2?

Answer 73

MTORC2 is insensitive to rapamycin but rapamycin binds to newly formed MTOR and prevents formation of new MTORC2. MTOR -/- knockouts die as embryos, -/+ are normal and fertile.

Question 74

How does rapamycin suppress MTORC1 and RHEB activate MTORC1 ?

Answer 74

In the presence of rapamycin, an FKBP1A (FKBP12)-rapamycin complex binds the FRB motif on MTOR thus inhibiting MTORC1 by blocking access to the enzymatic site. FKBP8 binds MTOR similar to the FKBP 12-rapamycin complex. Activated RHEB inhibits FKBP8 binding in a GTP dependent fashion, which removes the blocking of the MTORC1 enzymatic site. FKBP1A ((FK506-binding protein, 12-KD, FKBP12), FK506-binding protein 1, FKBP1) FKBP8 (FKBP38) is related to FKBP12

Question 75

What was the small GTPase RAB4 do in endosomes ?

Answer 75

LIC1 and RAB4A localize to endosomes in a matter dependent upon intact microtubules. The complex controls recruitment of dynein to early endosomes and regulates transport and sorting of early endosomes via direct interaction with LIC1. LIC1 (dynein, cytoplasmic 1 light intermediate chain 1; DYNC1LI1) RAB4A (RAS associated protein RAB4, HRES-1 (Human T cell lymphotropic virus (HTLV)-related endogenous sequence))

Question 76

How does overexpression of RAB4 in T lymphocytes aggravate SLE?

Answer 76

Overexpession of RAB4A increases mitochondrial mass, causing depletion of Drp1 which leads to further mitochondrial dysfunction. Drp1 (Dynamin related protein 1,) gene is DNM1L

Question 77

What does the bodipy dye consist of?

Answer 77

boron-dipyrromethene fluorescent dye

Question 78

What is the relationship of BNip3 to NiX

Answer 78

BNip3 is an outer membrane mitochondrial protein, induced by fasting that stimulates mitophagy. NIX is the ligand. BNIP3 BNIP3L BCL2/Adenovirus E1B 19-kD protein-Interacting Protein 3 NIX (BNIP3L BCL2/Adenovirus E1B 19-kD protein-Interacting Protein 3-Like, nip3-like protein X)

Question 79

What does the TUNEL acronym stand for?

Answer 79

Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick and labeling, used to detect apoptosis.

Question 80

How are B cell formed in the bone marrow?

Answer 80

Early pro B cell. IL-7R, CD43, CD45, class II MHC Late pro B cell. As in early pro B + CD19, CD40, surface IgD Large pre-B cell- as late pro B but pre-BCR IgM rather than IgD. -VDJ recombination of Hv. Small pre-B cell-CD45, CD19, CD40, class II MHC, more advanced pre-BCR -Light chain recombination. Lose IL-7R. immature B cell. CD45, CD19, CD40, IgM BCR undergoes deletion or receptor edit, end of bone marrow maturation.

Question 81

What does CD81 do?

Answer 81

cd81 member of transmembrane 4 superfamily where both amino and carboxy terminals are intracellular. Surface glycoprotein can complex with integrens. Transduce signals important in development, activation, growth, and motility. On T cells associates with CD4 and CD8 and provides co-stimulatory signal with CD3. On B cells participates in co-stimulatory complex sensitizing BCR.

Question 82

How does mTOR effect CD8+ T cells?

Answer 82

Adenosine monophosphate-activated protein kinase (AMPK) inhibits mTOR and thereby increases autophagy. In Drosophila sestrins accumulate from mTOR activation as do triglycerides, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction which are inhibited by AMPK suppression of MTOR. Using Rag2 -/- mice Rao PubMed: 15146184 showed that IL-12 enhanced CD80 expression and MTOR activity and locating implicating MTOR as a regulator of CD8 + T cell maturation to effect her or memory cells. Afaki showed that mTOR C1 regulates memory T cell differentiation and increases antibody levels and CD8 T cell activity in CMV infected mice. PubMed: 19543266,

Question 83

What is HMGB1 (I-mobility group box 1 protein) and how does it make human DNA proinflammatory?

Answer 83

HMGB1 (high-mobility group box 1 protein) is a non-histone nuclear protein released along with DNA during apoptosis that has alarmin activity, that interacts with nucleosomes, transcription factors, and histones, regulates transcription, bends DNA which facilitates protein binding. Hyper acetylation of lysine residues causes it to translocate to the cytosol. When released from cells binding to RAGE (receptor for advanced glycan end products) and/or TLR 4, 2 may induce inflammation via MyD88. Complexes may act as a DAMP (damage-associated molecular pattern). Pisetsky DS

Question 84

Where does extracellular DNA come from and what may it cause?

Answer 84

Extracellular DNA comes from a apoptosis, necrosis, and netosis. Apoptosis produces characteristic laddering by DNA size, necrosis, and netosis comes from granulocyte disintegration that traps and kills bacteria. Apoptosis is not inflammatory, human DNA has few CpG motifs and needs modification to become inflammatory.