Flashcards in Tn > Th > IL-# ,apop autoph, Immune and inflammatory mechanisms Deck (35):
How many binding sites must connect to stimulate T helper cell activation?
The beta chain of the T cell receptor must recognize the antigen in the MHC class 2 groove and CD4 must associate with the T cell receptor and bind to the beta-2 domain of the MHC class 2 complex.
How strong is the attachment of the T cell receptor to the immunogen on the MHC molecule?
The binding is weak permitting easy on easy off interrogation of multiple receptors. Additional binding such as CD4 and presence of appropriate cytokines determines the T cell response.
What pathways are stimulated after IL-1 receptor activation?
IL-1 stimulates the transmembrane receptor IL-1R, which has many associated proteins including ACCP1, MyD88, IRAK and TRAF6. MyD88, IRAK and TRAF6 also associate with Toll like receptors. These complexes stimulate NIK which then phosphorylates IkB-alpha which is then ubiquinated and destroyed releasing p65 (RelA) and p50 (NF-kB1), transcription factors for inflammatory response-TNFα, INF.
How many types of selectins does CD62 cell binding domain refer to, and what does it do ?
CD62 refers to the 3 member L (lymphocytes) ,E (endothelial cells), and P (platelets and endothelial cells) selectin transmembrane adhesion molecules that contain a calcium dependent Ca binding domain, EGF domain.Subtypes serve different functions in different cell types.
What cytokines are produced by sarcoid granulomas?
Sarcoid granulomas show RNA expression for IL-6, MCP-1 (monocyte chemotactic protein 1, CCL2, Cox-2, INF gamma, T-bet, IRF-1 (interferon regulatory factor 1), IP-10 (interferon gamma induced protein 10, CXCL10), Nox2 (subunit of NADPH oxidase), but not beta actin, IL-13, IL-33.
Granulomatous inflammation usually shows a Th1 mediated response with increased production of TNF, INF gamma, IL-2, IL-8, IL 10, IL-12, IL-18, IL-23, and TGF beta.
What is CXCL10 chemokine related to INFG.
CXCL10 is C-X-C chemokine 10 (IP-10 interferon gamma-induced protein 10) and is produced by several cell types in response to interferon gamma (INFG). Binds to receptor CXCR3 on Th1 cells, NK cells resulting in chemotaxis.
What is the difference between apoptosis, necroptosis, pyroptosis, and netosis?
Apoptosis depends upon TNF and caspase 8 whereas necroptosis relies on RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, as well as TLR3, TLR4 and the T cell antigen receptor. In the absence of active caspase 8 RIP1 phosphorylates RIP3 which activates MLKL (protein mixed lineage kinase domain-like) which leads to cell membrane rupture.
Pyroptosis is a form of apoptosis due to PAMPs (pathogen-associated molecular patterns), NOD-like receptors within the cytoplasm unlike TLR on the cell membrane.
Netosis comes from granulocyte disintegration wherein nuclear debris traps and kills bacteria.
How do CpG sequences in bacterial and viral DNA activate macrophages?
TLR9 responds to unmethylated CpG sequences common in bacterial and viral DNA. TLR9 signaling induces IRF5 (Interferon regulatory factor five). This group of transcription factors promote virus mediated activation of interferon, modulation of cell growth, differentiation, apoptosis, and immune system activity. Members contain a conserved N-terminal DNA-binding domain containing tryptophan repeats. The main effect is to promote or inhibit macrophages from inducing inflammation.
What are the main complement pathways generating C3b?
The classical pathway starting with activated C1 then C-4 and C2 result in C3b. The lectin pathway uses mannan associated serine protease (MASP) to activate C1 or C4 and C2 to produce C3b. The alternative pathway continuously generates C3b (tickover) in which C3bBb convertase is formed.
What results from excessive C3b accumulation?
Inflammation due to C3a/C5a, membrane attack due to C5b to C9, and opsonizaton due to C3b/C4b.
C3a degranulates mast cells and increases chemotaxis. Carboxypeptidase B generates C3adesArg (acylation-stimulating-protein, ASP) which affects triacylglycerol synthesis and adipocytes and fibroblasts through the G protein receptor.
C5a releases histamine and TNF alpha from mast cells, recruits phagocytes to sites of inflammation, and antigen-presenting cells to lymph nodes. It upregulates integrin activity, activates lipoxygenase, and arachidonic acid metabolism. It increases activating versus inhibitory IgG Fc receptors on leukocytes.
C4b binds to complement receptor 1 (CR1), a single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, podocytes, hyalocytes, and splenic follicular dendritic cells.
C3a and C4a have a direct antimicrobial properties.
What immunoglobulins are responsible for fixing complement?
IgM and what immunoglobulins are responsible for fixing comps?IgG subclass 1 and 3 fix complement well, IgG4 does not, and IgG2 is intermediate.
How does the lectin pathway work to fix complement?
The lectin pathway utilizes mannose-binding protein (MBP), this binds to sugars on pathogens, utilize associated serine proteases that function similar to C1 activating C2 and C4.
Arginine can generate citrulline via deimination, which might generate auto antigens from what sources?
Citrulline modified auto antigens include filaggrin, fibrin, vimentin, collagen, and alpha enolase. Filaggrin is a protein in the stratum granulosum of the skin, vimentin is in intermediate filaments, and alpha enolase is a glycolytic enzyme (2Phospho Glycerate->PEPyruvate). Thought to be an auto antigen in Hashimoto's encephalopathy, severe asthma, and Behcet's disease.
How does homocysteine cause vascular injury?
Homocysteine induces vascular injury by promoting :
activate factor 7A and five, inhibit protein C and heparin sulfate, increase blood viscosity,
leukocyte recruitment via chemoattractant protein-1 and interleukin 8 expression and secretion.
Increase oxidative stress.
Platelet aggregation directly or via the impaired endothelium-mediated platelet inhibition.
A thiolactone metabolite produces intimal foam cells.
Increases smooth muscle cell proliferation and collagen production.
Attenuates endothelial tissue plasminogen activator binding sites, change thrombomodulin function.
Decreased nitric oxide synthase
How do platelets behave immediately after endothelial injury?
After endothelial injury, platelets bind to collagen via multiple surface receptors glycoprotein 1a/2a. Von Willebrand factor (vWF) assists in binding glycoprotein 1b/9/5 which promotes collagen interaction with platelet glycoprotein 6. This activats of platelet integrins causing tight binding. Platelet granules are released-ADP, serotonin, platelet-activating factor, vWF, platelet factor 4, and thromboxane A2 (TXA2). Platelet intracellular calcium increases via Gq-linked protein receptor cascade that activates protein kinase C, then phospholipase A2 which modifies glycoprotein 2b/3a which strengthens fibrinogen binding, and platelet aggregation.
How does the extrinsic coagulation system work?
Stromal fibroblasts and leukocytes express tissue factor (TF) that combines with FVII forming TF-FVIIa which activates FIX and FX. This extrinsic route to FXa is immediately inhibited by tissue factor pathway inhibitor (TFPI). FXa and its cofactor FVa form prothrombinase which splits prothrombin into thrombin. Thrombin activates most other factors and releases FVIII binding to vWF. FVIIIa and FIXa form tenase which activates FX.
How does the intrinsic coagulation system work?
Intrinsic system relies on collagen activation of high-molecular-weight kininogen (HMWK,644aa, inhibitor thiol protease), prekallikrein (serine protease), and FXII (serine protease) to eventually form the tenase complex. Deficiencies in this pathway affect inflammation but not coagulation.
What does the transglutaminase motif of factor VIII do?
FVIIIa is a transglutaminase which attaches the amino group of lysine of protein1 to the amine group of glutamine on protein2. In the coagulation cascade this works to cross-link fibrin to alpha2-antiplasmin, as well as FV, platelet actin, and von Willebrand factor. It also cross-links fibronectin, vitronectin (pexin, cell adhesion, membrane protector from C') , collagen, and lipoprotein. This helps to organize inflammation and wound healing. Macrophages in some tumors can produce factor VIII to form protective fibrin meshes.
How is factor 8 synthesized, and what does it do?
Factor 8 has 2351 AA, cleaved by thrombin, 1-19 signal peptide, 20-2351 coagulation F8, 20-1332, F8 200 kDa, 20-759 heavy chain 92 kDa, 760-1332 factor 8 B chain, 1668-2351 F8 light chain. Expressed in human liver, spleen, lymph nodes not bone marrow, peripheral blood lymphocytes, or endothelial cells. Synthesized primarily in the liver. F 8 polypeptide A1 has transglutaminase activity Isoform a, encodes a large glycoprotein which circulates in the plasma with von Willebrand factor, undergoing multiple cleavage events. Isoform b is smaller, consisting of a phospholipid binding domain of factor VIIIc, essential for coagulant activity.
Thrombin releases factor VIII which then binds to factor IX which then activates factor X which along with factor Va generates more thrombin.
Protein C and factor IXa destroy factor VIII.
Elevated factor 8 predisposes to thromboses. Copper is needed is a cofactor and copper deficiency increases factor 8 levels.
What genetic problem results in hyperprothombinemia?
Prothrombin G2O210A is carried by 3% of Caucasians and increases the risk of thrombosis especially if protein C or protein S are deficient (5-10 fold). The mutation is in the non-coding region and may prolong the mRNA resulting in elevated prothrombin levels.
How does protein C work?
Protein C binds to thrombin and the combination with protein S and phospholipid binds to thrombomodulin where protein C becomes a serine protease and destroys factors 5a and 10a. Factor 5 Leiden does not split and therefore is a procoagulant.
What is thrombomodulin?
Thrombomodulin (CD141) , is a 74 kDa glycoprotein, expressed on mesothelioma cells, monocytes and dendritic cells that binds thrombin which then activates protein C, an anticoagulant effect. It also cleaves thrombin-activation fibrinolysis inhibitor, a pro-coagulant effect.
What cytokine does Oncostatin M (IL-6 group) resemble?
Oncostatin M is a member of the IL-6 group of cytokines closely related to leukemia inhibitory factor. The receptor contains the GP130 chain. Monoclonal antibody induces minimal effect in rheumatoid arthritis.
What is fibrinogen, and how does it form fibrin?
There are three fibrinogen genes-FGA, FGB, and FGG (gamma), each forming chains producing the fibrinogen hexamer, linked by disulfide bonds, with globular domains at both ends (D) and centrally (E). Thrombin removes 38 amino acids from the N-terminus, the monomers polymerize end to end forming fibrin fibers. Factor XIII, a transglutaminase, is necessary to form a stronger mesh.
Other motifs on fibrinogen include recognition sites for angiopoietin, carbohydrates, and sequences that prevent spontaneous polymer formation.
How do endosomal TLR'S operate.
TLR3,8,7,and 9 are intracellular endosomal receptors that face the lumen, respond to endosomal contents and stimulate cellular pathways to generate transcription factors for interferons and other cytokines.
TLR3 attracts TRIF which then produces IRF3 (interferon regulatory factor 3) and IRF7 which transcribe type I INF.
TLR 8, TLR7, and TLR9 attract MyD88 (myeloid differentiating factor 88) which in combination with TRIF from TLR3 produces NF-kB to transcribe inflammatory cytokines, MyD88 alone generates IRF 7, transcription factor for type I IFN.
TRIF (TIR-domain-containing adapter-inducing interferon beta ) is an adapter protein activated by TLR. MyD88 is a cytosolic platform that starts another cascade in response to pathogens
MxA is a GTPase (Myxovirus resistance A) which is an interferon-inducible factor similar to APOBEC 3G with broad antiviral effect..It is important in suppressing endogenous human retroviruses.
How does IL-1 stimulate prostaglandin release?
IL-1 sensitizes cells to bradykinin by up regulating to bradykinin receptors, which then induce prostanoid release.
Bradykinin is a peptide (C50H73N15O11) that causes blood vessels to dilate due to release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor.
What apoprotein accounts for resistance to infection as well as chronic renal disease in West Africans?
APOL1 gene codes for Apolipoprotein L1 which occurs only in African primates with a BH3 domain associated with programmed cell death and a PFD domain (pore forming). The protein accounts for West African resistance to trypanosomiasis wherein parasite lysosomes become excessively permeable to chloride and burst. It also accounts for focal glomerular sclerosis which is increased in blacks and HIV infection.
What proteins make up the cytoplasmic NFkB complex?
Cytoplasmic NFkB consists of a heterodimer p50 and Rel held together by IkB
How does mTOR effect CD8+ T cells?
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,
What is HMGB1 (I-mobility group box 1 protein) and how does it make human DNA proinflammatory?
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 nucleosome's, transcription factors, and histones, regulates transcription, Ben's 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).
Where does extracellular DNA come from and what may it cause?
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 (few CpG motifs) needs modification to become inflammatory.
What is the origin of anti-RNA antibodies?
RNA binding proteins (RBP) are immunogens accounting for anti-Sm antibodies,. Although specific for SLE these antibodies do not correlate with disease activity nor do they arise in lupus prone mice.
What needs to happen so DNA can become an immunogen?
Extracellular DNA and histones might well form nucleosomes (electrostatic binding) and provoke anti-DNA antibody production as DNA alone is a very poor immunogen. DNA structure matters however-sequence (CpG motif), base methylation, backbone structure, strandedness, protein binding, and intracellular location. Mammalian DNA no CpG-can interfere with immunogenicity of bacterial DNA.
What Needs to happen to PGAM ( to result in necroptosis?
Necroptosis relies on phosphorylation of PGAM on the mitochondrial surface by complex RIP1, RIP3, and MLKL leading to binding Drp1 leading to mitochondrial fission then necrosis.
RIP1 (receptor-interacting protein) is recruited by TRIF for NF-kB activation from TLR3 stimulation. Other TLR's use IRAK.
MLKL (mixed linkage kinase domain-like protein) 471-aa, C-terminal kinase domain which lacks several residues required for activity. Requires phosphorylation to be active.
PGAM (phosphoglycerate mutase) transfers phosphate from C3 toC2 through a 2, 3-biphosophglycerate intermediate.
Drp1 is a member of the Dynamo superfamily of large GTPases which pinches the stock separating 2 daughter mitochondria.