extracellular immune agonists Flashcards
keep track of extracellular immune effectors generated by the immune system
What are chemokines ?
Chemokines are a type of cytokine, 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.
β γ
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 is the IL-1 receptor type 1 (IL1R1)?
IL1R1 is a transmembrane protein with an immunoglobulin external portion and a TIR (Toll/Interleukin-1 Receptor) intracellular portion that binds accessory proteins to provoke many inflammatory and immune responses. CD121a refers to IL1R1 which binds IL1A, IL1B, and IL1RA with a TIR domain that binds accessory protein MyD88 which then binds IRAQ1 which activates NFkβ. CD121b refers to IL1R2, a decoy receptor as it cannot bind accessory proteins.
ILR (IL-1R receptor) family includes additional receptor protein variations that allow additional cytokine binding (IL-18, IL-33) and accessory protein activation that result in vaariable effects including inhibition.
TIR - Toll/Interleukin-1 Receptor
MyD88 - MYeloid Differention primary response 88
IRAK1 - IL-1 Receptor Associated Kinase 1
What happens in the SMAD pathway
SMAD codes for transcription factors that transduce extracellular signals from TGF-β activating downstream gene transcription.
SMAD - Small body size- a worm gene, Mothers Against Decapentaplegic- a Drosophila gene,
TGF-β - Transforming Growth Factor Beta
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.
3-fucosal-N-acetyl-lactosamine - a tetrasaccharide carbohydrate usuall attached to surface of cells-Sialyl-Lewis blood group antigen
what is GATA-3?
GATA-3 is the transcription factor in Th2 cells that stimulates the production of IL-4, IL 13, and IL-8.
GATA - a group of transcription factors capable of binding GATA DNA sequence. A wide variety of physiologic and pathologic consequences result from this group.
IL-4 - cytokine that induces Th0 to Th2 probably initially formed in basophils, then autokine
IL-13 - similar to IL-4 structurally, increases IgE and metalloproteinase production. Induces allergic disease
IL-8 - a C-X-C cytokine (CXCL8 gene.) Stimulates chemotaxis and angiogenesis usually in response to TLR stimulation. IL-8 binds to G protein coupled receptors CXCR1 and CXCR2.
How is IL-1α synthesized?
IL-1α is synthesized in mesenchymal and skin epithelial cells continuously, and in response to stress by many other cells. The precursor protein is digested by proteases and finally a Ca++ sensitive cysteine protease (Calpain) into active IL-1A, The receptor ( IL-1R) generates a 17-kDa transcription factor, which acts as a DAMP by stimulating innate immunity cells, resulting in necrosis or pyroptosis of the originally stressed cell.
DAMP - damage-associated molecular pattern molecule
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 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. PMID: 26494742 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+ (Retinoic Acid Related orphan receptor gamma).
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.
