Summary IID

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Summary - IID

  • 1 Innate immuntity

  • What are the components of innate immunity?
    1. Cells
    - Epithelial barriers – Defensins and cathelicidins (antibiotics)
    • Phagocytes and other cells – Macrophages – Neutrophils – Dendritic cells
    • Specialized lymphocytes with limited diversity (“innate lymphoid cells”) – NK cells, iNKT cells – B1 and Marginal Zone B cells
    2. Soluble components - Complement, pentraxins (CRP), collectins (MBL), cytokines/chemokines (e.g. TNF/IL-8)
  • 1.1 Phagocytosis

  • Which cells are capable of phagocytosis?
    Monocytes/macrophages, neutrophils and dendritic cells. 
    In special circumstances, eosinophils, B-cells and epithelial cells are also able to do phagocytosis
  • What are the stages of phagocytosis?
    1. Recognition
    2. Chemotaxis and adherence of microbe to phagocyte
    3. Ingestion of microbe by phagocyte
    4. Formation of a phagosome
    5. Fusion of the phagosome with a lysosome ot form a phagolysosome
    6. Digestion of ingested microbe by enzymes
    7. Formation of residual body containing indigestible material
    8. Discharge of waste materials
  • 1.1.1 Pinocytosis

  • What is pinocytosis?
    Cell-drinking
  • What is the function of pinocytosis?
    Bring in nutrients and aid cell osmoregulation
  • What is the mechanism of pinocytosis
    The internalisation of molecules by non-specific invagination of the plasma membrane dependent on external concentration
  • 1.3 Receptors

  • What is the ligand of TLR-1: TLR-2 heterodimer?
    - Lipomannans (mycobacteria)
    - Lipoproteins (diacyl lipopeptides; triacyl lipopeptides)
    - Lipoteichoic acids (gram-positive bacteria)
    - Cell-wall beta-glucans (bacteria and fungi)
    - Zymosan (fungi)
  • What are the ligands of TLR-2: TLR-6 heterodimer?
    - Lipomannans (mycobacteria)
    - Lipoproteins (diacyl lipopeptides; triacyl lipopeptides)
    - Lipoteichoic acids (gram-positive bacteria)
    - Cell-wall beta-glucans (bacteria and fungi)
    - Zymosan (fungi)
  • What are the ligands of TLR-3?
    Double-stranded RNA (viruses), poly I:C
  • What are the ligands of TLR-4 (plus MD-2 and CD14)?
    - LPS (Gram-negative bacteria)
    - Lipoteichoic acids (Gram-positive bacteria)
  • What is the ligand of TLR-5?
    Flagellin (bacteria)
  • What is the ligand of TLR-7?
    Single-stranded RNA (viruses)
  • What is the ligand of TLR-8?
    Single-stranded RNA (viruses)
  • What is the ligand of TLR-9?
    DNA with unmethylated CpG (bacteria and herpesviruses)
  • What is the ligand of TLR-10?
    Unknown (human only)
  • Which TLRs are only known in mouse?
    TLR-11, TLR-12, and TLR-13
  • Which TLRs are located on the plasma membrane?
    TLR-1:TLR-2 heterodimer, TLR-2:TLR-6 heterodimer, TLR-4 and TLR-5
  • What is a broad name for all the ligands recognised by TLRs?
    pathogen-associated molecular patterns (PAMPs)f
  • Which TLRs are located on the endosome?
    TLR-3, TLR-7, TLR-8 and TLR-9
  • What is the main component of the extracellular region of a TLR?
    leucine-rich repeat (LRR)
  • Describe the activation of NFkB through TLR signalling
    1. Dimerised TLRs recruit IRAK1 and IRAK4 through the MyD88 death domain, activating the E3 ubiwuitin ligase TRAF-6
    2. TRAF-6 is polyubiquitinated, creating a scaffold for activation of TAK1
    3. TAK1 associates with IKK and phosphorylates IKKb, which phosphorylates IkB
    4. IkB is degraded, releasing NFkB into the nucleus to induce expression of cytokine genes
  • Which proteins contain TIR?
    MyD88, MAL, TRIF, TRAM, all TLRs
  • Which proteins contain CARD?
    Caspase 1, RIP2, RIG-I, MDA-5, MAVS, NODs, NLRC4, ASC, NLRP1
  • Which proteins contain Pyrin?
    AIM2, IFI16, ASC, NLRP1-14
  • Which proteins contain a DD (death domain)?
    MyD88, IRAK1, IRAK4, DR4, DR5, FADD, FAS
  • Which proteins contain DED (death effector domain)?
    Caspase 8, caspase 10, FADD
  • What does NOD1 recognise?
    y-glutamyl diaminopimelic acid (iE-DAP), which is a breakdown product of Gram-negative bacterial cell walls.
  • What does NOD2 recognise?
    muramyl dipeptide, which is a degradation product of bacterial cell0wall peptidoglycans.
  • What does binding of bacterial ligands to NOD induce?
    1. Binding induces aggregation, which stimulates CARD-dependent recruitment of RIP2.
    2. RIP2 associates with E3 ligases (XIAP, cIAP1 and cIAP2)
    3. E3 ligase activity produces a polyubiquitin scaffold which associates with TAK1 and the IKK complex
    4. NFkB activation
  • Describe the stimulation of type 1 interferon production through activation of RIG-I-like receptors
    1. detection of uncapped 5'- triphosphate RNA by RIG-I or viral dsRNA by MDA-5.
    2 Conformational chage of the CARD domains, to become free to interact with the amino-terminal CARD domain of MAVS.
    3. Generation of K63-linked polyubiquitin from E3 ligases (TRIM25 or Riplet).
    4. Aggregation induces a proline-rich region of MAVS to interact with TRAFs and leads to the generation of additional K63-linked polyubiquitin scaffold
    5. Scaffold recruits TBK1 and IKK complexes that activate IRF and NFkB, producing type I interferons and pro-inflammatory cytokines
  • Describe the activation of type 1 interferon production through cGAS
    1. Binding of dsDNA from a virus to cGAS
    2. Stimulation of the enzymatic activity of cGAS leading to production of cyclic GMP-AMP (cGAMP)
    3. Bacteria that infect cells produce second messengers like c-di-GMP and c-di-AMP
    4. cGAMP and these bacterial cyclic dinucleotides bind and activate STING dimer present on the ER membane
    5. STING activates TBK1
    6. Active TBK1 activates IRF3 through phosphorylation, which enters the nucleus and induces expression of type I interferon genes
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Describe the activation of type 1 interferon production through cGAS
1. Binding of dsDNA from a virus to cGAS
2. Stimulation of the enzymatic activity of cGAS leading to production of cyclic GMP-AMP (cGAMP)
3. Bacteria that infect cells produce second messengers like c-di-GMP and c-di-AMP
4. cGAMP and these bacterial cyclic dinucleotides bind and activate STING dimer present on the ER membane
5. STING activates TBK1
6. Active TBK1 activates IRF3 through phosphorylation, which enters the nucleus and induces expression of type I interferon genes
Describe the stimulation of type 1 interferon production through activation of RIG-I-like receptors
1. detection of uncapped 5'- triphosphate RNA by RIG-I or viral dsRNA by MDA-5.
2 Conformational chage of the CARD domains, to become free to interact with the amino-terminal CARD domain of MAVS.
3. Generation of K63-linked polyubiquitin from E3 ligases (TRIM25 or Riplet).
4. Aggregation induces a proline-rich region of MAVS to interact with TRAFs and leads to the generation of additional K63-linked polyubiquitin scaffold
5. Scaffold recruits TBK1 and IKK complexes that activate IRF and NFkB, producing type I interferons and pro-inflammatory cytokines
What does binding of bacterial ligands to NOD induce?
1. Binding induces aggregation, which stimulates CARD-dependent recruitment of RIP2.
2. RIP2 associates with E3 ligases (XIAP, cIAP1 and cIAP2)
3. E3 ligase activity produces a polyubiquitin scaffold which associates with TAK1 and the IKK complex
4. NFkB activation
What does NOD2 recognise?
muramyl dipeptide, which is a degradation product of bacterial cell0wall peptidoglycans.
What does NOD1 recognise?
y-glutamyl diaminopimelic acid (iE-DAP), which is a breakdown product of Gram-negative bacterial cell walls.
Which proteins contain DED (death effector domain)?
Caspase 8, caspase 10, FADD
Which proteins contain a DD (death domain)?
MyD88, IRAK1, IRAK4, DR4, DR5, FADD, FAS
Which proteins contain Pyrin?
AIM2, IFI16, ASC, NLRP1-14
Which proteins contain CARD?
Caspase 1, RIP2, RIG-I, MDA-5, MAVS, NODs, NLRC4, ASC, NLRP1
Which proteins contain TIR?
MyD88, MAL, TRIF, TRAM, all TLRs