Flashcards in innate receptors > INF IL cellular interactions and immune modulation Deck (56):
What does IL-5 do?
IL-5 is a Th2 cytokine similar to granulocyte stimulating factor. Eosinophiles have high concentration of IL-5 receptors which increases their numbers and ability to infiltrate. Asthma and allergic rhinitis depend on IL-5.
What are chemokines ?
Chemokines are named for chemotactic effect, recruiting immune cells to sites of infection.They are 8 – 10 kD , 70-100 aa sized proteins containing 4 cysteines which determine their 3 dimensional shape. Some are homeostatic and control cells during physiological activity. They are found in all vertebrates, some viruses and bacteria, but not invertebrates.
What is IL-13?
IL-13 is similar to IL-4 structurally, increases IgE and metalloproteinase production. It induces many features of allergic disease such as airway hyperresponsiveness, mucus hypersecretion, and Schistosoma granuloma formation.
What are some members of the IL-1 receptor family?
ILR (IL-1R like receptors) family includes signaling molecules (TIR8/Sig1RR, IL-1RAcPb, DIG1RR), + orphan receptors known ligand), as well as decoy receptors (IL-1R2, IL-18BP). Accessory proteins (AcP (accessory protein for IL-1α, beta, -18, -33, -36 ) are also included.
What happens in the SMAD pathway
SMAD (mothers against decapentaplegic- a Drosophila gene, small body size- a worm gene) proteins transduce extracellular signals from TGF-β activating downstream gene transcription.
What is CD30?
CD30 is TNFRSF8, present time activated but not resting T and B cells and is a positive regulator of apoptosis.
What is CD15?
CD15 is 3-fucosal-N-acetyl-lactosamine, a carbohydrate found within glycoproteins, glycolipids, and proteoglycans. It mediates phagocytosis chemotaxis and is a marker for Reed Sternberg cells, diagnostic of Hodgkin's disease.
what is GATA-3?
GATA-3 is the transcription factor inTh2 cells that stimulates the production of IL-4, IL 13, and IL-8.
What are some members of the IL-1 receptor family?
ILR (IL-1R like receptors) family includes signaling molecules (TIR8/Sig1RR, IL-1RAcPb, DIG1RR), + orphan receptors (no known ligand), as well as decoy receptors (IL-1R2, IL-18BP). Accessory proteins (AcP (accessory protein for IL-1α, beta, -18, -33, -36 ) are also included.
What transcription factors are generated by Toll and IL-1 receptors?
TIR (Toll IL-1) domain is on signaling IL-1 receptor and Toll-like receptors which then begins signaling pathways that generate NF-kB, JNKs, ERKs, and mAPKs transcription factors.
How does IL-1 work?
IL-1α is synthesized as a precursor protein and stored in mesenchymal and epithelial cells but must be synthesized de novo in response to stress. The precursor is modified into a 17-kDa transcription factor, and cytosolic protein which acts as a damage-associated molecular pattern molecule (DAMP). DAMP then stimulates pattern recognition receptors (PRRs) on innate immunity cells, and results in necrosis or pyroptosis of the originally stressed cell.IL-1α stimulates IL-1R
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.
TRAF (TNF receptor associated factor) has a C-terminal TRAF domain that mediates binding to TNF receptors and CD40.
what is T-bet (TBX21) ?
TBX21 is the gene for T-box transcription factor (T-bet), a member of the protein family that binds to DNA binding domain- T-box. It stimulates Th1 and NK cells to produce interferon gamma.
What proteins make up the T cell receptor complex?
TCR alpha and beta chains ( 95%) or epsilon and gamma (5%). 3 additional dimeric signaling molecules are associated, 2 types of CD3 (one chain each of CD3E (epsilon), CD3Z (Zeta), CD3D (delta), and CD3G (gamma)), and CD247 (zeta chain dimer).CD3 chains belong to the immunoglobulin superfamily. The transmembrane portion is negatively charged but associates with the positively charged TCR complex. Intracellular portion contains ITAM (immunoreceptor tyrosine-based activation motif) structure, which accounts for downstream T cell signaling.
What cytokines are included in the IL-10 superfamily?
IL-10 (CSIF cytokine synthesis inhibitory factor) family includes IL-19, IL-20, IL-24, IL-26, and sometimes IL-28 and IL-29. IL-10 down regulates Th1 responses, MHC class II expression, and costimulatory molecules on macrophages. It downregulates TNF alpha, interferon, and GM-CSF. It upregulates IL-6 in muscles during exercise.
What is the endogenous ligand that forms an inflammasome in response to bacterial and viral DNA?
Bacterial products flagellin and PrgJ are recognized by NAIP2 which then combines with 9 units of NLRC4 to form a 10 member ring. NLRC4 and CARD interact with caspase-1 forming the NAIP2-NLRC4 inflammasome. AIM2 is an interferon-inducible protein, 344 aa, which forms part of the inflammasome which then sets off pyroptosis and IL-1beta and IL-18 maturation.
AIM2 (absent in myeloma 2)
NAIP (NLR family apoptosis inhibitory protein recruitment domain)
NLRC4 (NOD-likereceptor), C(CARD caspase activation and recruitment domain
What is the receptor for MICA on NK cells?
DAPK1 (death-associated protein kinase 1) mediates gamma-interferon induced programmed cell death. It is a calmodulin dependent serine-threonine kinase, 160 kD, 8 ankyrin repeats, and a tumor suppressor candidate.MICA is one of the ligands.
What does thymic stromal Lymphopoietin do?
TSLP (Thymic Stromal Lymphopoietin) induces T cell-attracting chemokines from monocytes that increases maturation of CD11c+ dendritic cells.
What are the proinflammatory family members of the IL-1 superfamily?
Proinflammatory IL-1 family members include IL-1 alpha, beta, IL-18, IL 36 alpha, IL-36 Beta, IL-36 gamma and IL-33. Antagonists to other members include IL-1Ra, IL-36Ra, IL-37.
How many members are there in the IL-1 superfamily?
The IL-1 superfamily has 11 members currently identified as various forms of IL-1,33,36, 37, and 38. Each one may or may not have a co-receptor as well as a receptor. Some are proinflammatory (7) in some anti-inflammatory (3). 9 members are on chromosome 2q, 1 on chromosome 11, and 1 on chromosome 9.Nomenclature reflects common use rather than systematic structural similarities.
Are IL-1 transcripts active prior to proteolytic cleavage?
IL-1 alpha and IL-33 are stored in their long form and are capable of stimulating their receptor. IL-1 beta and IL-18 require proteolytic cleavage by caspace 1 to become active.IL-1 secretion occurs without use of the golgi apparatus.
Why is IL-1 alpha considered a dual function cytokine?
IL-1 alpha precursor protein contains a transcription factor (ppIL-1 alpha) released via calpain (calcium activated protease). This activates synthesis of NF-kB, IL-6, TNF alpha and INFγ.
how are Tregs cells produced in the gut which permit tolerance to most gastrointestinal antigens?
Tissue resident mononuclear phagocytes produce IL-1 beta which stimulates ILC3 cells (innate lymphoid) which then release Csf2 (GM-CSF). Phagocytes, and dendritic cells then produce IL-10 and retinoic acid which then cause naïve T cells to become Treg cells.ILC3 cells are ROR gamma t+ (RAR-related orphan receptor gamma).
What does the CD40-CD40L system do?
CD40 is a costimulatory protein on antigen presenting cells that binds to CD40L (CD154) on Th cells. CD40 is also present on dendritic cells, B cells, endothelial cells, smooth muscle cells, fibroblasts, epithelial cells, tumor cells-lymphoma, myeloma, and carcinoma. CD154 on B cells stimulates antibody class switching and differentiation into plasma cells. CD154 on T cells stimulates macrophages to produce reactive oxygen species and nitric oxide.
What is CD44 hyaluronic acid binding protein ?
cd44 is a cell surface glycoprotein (ch 1, cd44 gene), expressed on many cell types, that is a receptor for hyaluronic acid as well a collagen, MMPs, and osteopontin. Many post translational modifications alter function. Plays a role in lymphocyte maturation in thymus, splice variants occur in neoplastic markers.
What is CD62 cell binding domain?
CD62 refers to the 3 member L,E, and P selectin transmembrane adhesion molecules that contain a calcium dependent Ca binding domain, EGF domain.Subtypes serve different functions in different cell types.
What is the CD 138 plasma cell marker?
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 as tumor cells.
What is the NK receptor CD244?
cd244 is a NK cell receptor (SLAMF4, 2B4) that activates NK cell cytolytic activity.It is an RA susceptibility factor. Null mice develop anti DNA ab.
What does TBX21 regulate during the Th1 response?
TBX21 is T box (DNA-binding domain) transcription factor that regulates developmental processes especially Th1 INFG production.
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.
What does IL13 do for Th2 cells.
IL13 is a cytokine secreted by many cells especially Th2 cells and mediates allergic and inflammatory responses.
In what family of proteins does IL-33 belong?
IL-33 is a protein of the IL-1 family that drives Th2 cells and mast cells.
What does IL35 do?
IL35 is composed of EBI3 and p35, a subunit of IL-12. It is inhibitory via Treg cells and inhibits Th17 cellular activity.
What is a type 1 cytokine receptor?
Type 1 cytokine receptors respond to cytokines that contain 4 alpha chains. Receptor contains wsxws motifs close to the cell membrane.They respond to interleukins and colony stimulating factors.p
What interferon receptors respond to types 1, 2 and 3 interferons?
Type 2 IFN utilize IFNGR1 and IFGAR2 combination receptor, which utilize JAK2 and JAK1 cytoplasmic tails to stimulate STAT1. Type I INF utilize IFNAR 1 and 2 with TYK2 and JAK1 tails. Type 3 INF use IL-10R2 and IFNLR1 receptors the same tails as Type 1 to phosphorylate STAT1 and 2 which elicits a different cascade from Type 2 IFN.
What is MICA?
MICA (MHC class I polypeptide-related sequence A) encodes a highly polymorphic MHC class I protein that does not associate with beta-2-microglobulin. It is present on intestinal epithelial cells, broadly recognized by NK cells, NKT cells, and gamma delta T cells. It is the ligand that activates the NK cell receptor NKG2D. Alleles of this gene determine rheumatoid arthritis susceptibility.
What immune defect is caused by a congenital abnormality of the calcium release-activated calcium channel?
Severe combined immunodeficiency or SCID is due to a congenital defect in the ORAI1 gene that codes for a protein necessary for CRAC ( calcium release-activated calcium channel) and thus T cells cannot be activated.
How is the elevated calcium level in the cytoplasm maintained during T lymphocyte proliferation.
In stimulated T cells the ryanodine receptor on the endoplasmic membrane keeps the calcium level low near STIM1 which allows for keeping the CRAC channel open, and permitting prolonged hypercalcemia to stimulate T cell proliferation.
How can the Fc gamma receptor be stimulated to decrease antibody production.
A monoclonal antibody against CD 19 with an appropriate Fc tail will reduce immunoglobulin production.
What is CD2, a marker for lymphocytes?
CD2 is a single class type I membrane protein with a C2-type immunoglobulin like domain and Ig-like V-type domain.
It is present on T cells and NK cells and is responsible for forming rosettes with red cells.
What is the role of interferon inducible protein 1?
Interferon-inducible protein 1 (IFI1) may regulate autophagy in response to intracellular pathogens.
Polymorphisms expressing the gene IRGM (Immunity-Related GTPase Family M Protein) affect susceptibility to Crohn's disease and tuberculosis.
How many adenosine receptors are there?
There are 4 adenosine G protein-coupled receptor subtypes A1, A2a, A2b, and A3. Receptor A2a is abundant in basal ganglia, vasculature, T lymphocytes, and platelets and is responsible for anti-inflammatory effects, including cAMP. It is responsible for coronary artery vasodilatation, regulates glutamate and dopamine release in the brain, and decreases activity of dopamine D2 receptors.
Where does plasmin come from and what does it do?
Type I plasminogen contains two glycosylation moieties and type II contains one. Type I attach us to blood clots, and type II, the cell surface. Plasminogen is 88 kD and plasmin has a heavy and light chain, 63 and 25 KD. The proteolytic center is on the C-terminal region of the light chain.
Plasmin is a serine protease that activates collagenases, some mediators of the complement system, weakens the wall of the Graafian follicle permitting ovulation, and cleaves fibrin, fibronectin, thrombospondin, laminin, and von Willebrand factor.
How do intraepithelial lymphocytes increase epithelial cell bacterial resistance?
Innate lymphoid cells type 3 (ILC3) with the markers RORgamma t and cytokines IL 22 and lymphotoxin stimulate surface epithelial cells to fucosylate surface glycoproteins which encourages binding of helpful commensal bacteria. A
How are cytokine receptors classified?
Cytokine receptor classification is based on size and structure.
Type I and type II cytokine receptors are both heterodimers, transmembrane proteins, utilize JAK-STAT signaling.
Type I cytokine receptors possess the signature sequence WSXWS, and other conserved extracellular amino acid domains. They respond to cytokines with alpha helical strands, and are comprised of different chains (CD132, CD131, gp130, CD130, IL12RB1,+).
Type II cytokine receptor, have tandem Ig-like domains, respond mostly to interferons, no WSXWS domain, with intracellular domains associated with tyrosine kinase of the JAK family.
Immunoglobulin superfamily receptors with homology with immunoglobulins, cell adhesion molecules, and some cytokines.
Tumor necrosis factor receptor family have cystine-rich common extracellular binding domain such as for CD 27.
Chemokine receptors are seven transmembrane helix , e.g. for IL-8.
TGF beta receptors; combination of type 1 and type 2 receptors with serine/threonine kinase motifs.
How does CTLA for modulate immune responses?
CTL A4 (CD152, cytotoxic T-lymphocyte-associated protein 4) is a Th cell surface immunoglobulin superfamily protein receptor similar to CD28. Both CTL A4 and CD28 bind to (CD80-86) on activated B cells and monocytes. Binding to CTLA-4 inhibits T cells. Binding CD28 on on T cells by CD80 (B7.1-activated by Toll-like receptors) CD86 (B7.2-constitutive) on antigen presenting cells primes T cells, and leads to increased expression of CTLA-4.
CTLA-4 may work by capturing CD80-86 thus decreasing CD28 stimulation.
The intracellular domain of CLA-4 is similar to CD28 and can bind PI3K, PP2A, and SHP-2 thereby possibly dephosphorylating CD3 and LAT (linker of activated T cells).
PD-L1 (Programed Death-Ligand 1, CD274) also binds CD80, inhibits CD8 cytotoxic T cells, stimulates Treg.
Mutations in CTLA-4 are associated with diabetes knowledge is, cruise disease, possible thyroiditis, iliac disease, SLE, thyroid-associated or the top of the, primary biliary cirrhosis.
What is the nature of Fas and Fas ligand and protein?
Fas protein (CD95) is a 319 amino acid 48 kD trans membrane protein containing a death domain. It trimerizes when binding to Fas Ligand. It then forms the death-inducing signaling complex (DISC) by aggregating death domains with FADD which then activates caspase 8 eventually leading to apoptosis.
Fas ligand(CD95L) is a homotrimeric type II membrane protein expressed on cytotoxic T lymphocytes that binds to Fas protein.
Soluble Fas ligand is generated by MMP-7 cleavage.
What a immune abnormalities characterize rheumatoid vasculitis?
CD4 positive CD 28-null cells that express the KIR2DS2 stimulatory receptor are overrepresented in rheumatoid vasculitis. KIR2D receptors are selective for certain alleles of the HLA-C locus. chromogranin A Is increased in severe extra articular manifestations of RA.
Chromogranin a or parathyroid secretory protein 1 is a member of neuroendocrine signatory proteins which are precursors of vasostatin-1, vasostatin-2, pancreastatin, catestatin, and parastatin.
How does the glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR, TNFRSFS18) induce regulatory T cell tolerance?
Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR, TNFRSFS18) is a T cell receptor which increases upon activation. Regulatory T cells CD4+ CD25+ maintain self tolerance via GITR which also helps CD3 cells induce apoptosis.241 aa, last216 aa is TNF receptor.
What is the pathway by which tumor necrosis factor ligands induce inflammation?
tumor necrosis factors bind to their ligand which have terminal tim barrel death domain sequences->traf(TNF protein associated factor) induced activation of mek pi13 ikks->tf jnk-p38 akt/pkb nfkb transfer factors. I
What is the pathway by which tumor necrosis factor ligands induce apoptosis ?
TRAIL (TNF-related apoptosis-inducing ligand, CD253, TNFSF10)-> TLR 2,4,5 as well as FasL, TNFa, CD40L which stimulate additional death domain receptors which activate FADD (Fas Associated proteins with Death Domains) ->caspases-> apoptosis
What is the role of TRIF in interferon signaling.?
TRIF (TIR-domain-containing adapter-inducing interferon-beta) 712 residues, adapter protein used in downstream signaling cascades fallowing TLR 3 and 4 activation.
What tool like receptors are bound to the cell membrane?
TLR 1, TLR 2, TLR 4, TLR 5, TLR6, and TLR 10 are bound to the cell membrane.
What toll like receptors are intracellular
TLR 3, TLR 7, TR 8, TLR 9 bind to PAMPS-(pathogen associated molecular patterns) are intracellulat.
What are some intracellular proteins associated with TLR signaling?
Adapter proteins used by TLR include MYD88, TRIF, TIRAP, TRAF6, and TOLLIP and downstream proteins IRAK1, IRAK4, IRF3.