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Pathogen Recognition
Fichas del conjunto (93)
- 1What is a PRR?Pathogen recognition receptor
- 2What is the immune system?The tissues, cells and molecules that protect the body from infection
- 3Describe innate immunity- the early phase of the host response
- present in all individuals at all times
- does not increase with repeated exposure
- discriminates between groups of pathogens
- predates separation of animal and plant lineages
- very good at recognising bacterial byproducts and cellular debris due to pathogens causing host cell lysis - 4Describe Adaptive Immunity- generated by specific lymphocytes
- discriminates between individual pathogens
- associated with immunological memory
- appears abruptly in evolution in the cartilaginous fish - 5What is a PAMP?Pathogen Associated Molecular Pattern
- 6What is the first layer of immunity?The anatomical barrier provided by the body's epithelial surfaces
- 7What is the second layer of immunity?Various chemicals and enzymatic systems (including complement) act as an immediate antimicrobial barrier near the epithelia
- 8What is the third layer of immunity?If epithelia is breached, various nearby innate lymphoid cells can coordinate a rapid cell mediated defences
- 9What is the fourth layer of immunity?If the pathogen overcomes all other barriers, the slower acting defences of the adaptive immune system are brought to bear
- 10What are inflammatory inducers?Chemical structures that indicate the presence of invading microbes or the cellular damage produced by them
- 11What is the function of sensor cells?Detect inflammatory inducers by expressing various innate recognition receptors and in response produce a variety of mediators
- 12What is the function of mediators?Act directly in defence or further propagate the immune response
They act on various target tissues to induce antimicrobial proteins and resist intracellular viral growth; or on other immune cells that produce other cytokines that amplify the immune response - 13What are the three responses of the immune system?- the innate phase
- the early induced innate response
- the adaptive immune response - 14what are mucins?Anti-microbial agents that may prevent adhesion to epithelium by micro-organisms.
They are proteins found in the mucus of the respiratory tract and the gastrointestinal tract - 15What are lysozymes?Glycosidases that attack peptidoglycans in bacterial cell wall to kill the invading bacterium
- 16What is the function of defensins?Disrupt cell membranes of bacteria and fungi via pore formation
- 17What is the function of a cathelicidin?Disrupt cell membranes of a wide range of microorganisms
- 18What are histatins active against?Pathogenic fungi
- 19What is the REG III family?C type lectins which target peptioglycans promoting pore formation
- 20What is the complement system?A collection of soluble proteins present in blood and other bodily fluids.
Comes into play when pathogen breaches host epithelial barriers and initial anti-microbial defences. - 21How can pathogen recognition lead to activation of complement?- mannose binding lectin: recognise sugars such as fructose, mannose
- ficolin: recognises oligosaccharides containing acetylated sugars
- c-reactive protein: recognises phosphorycholine, which is found on the surface of gram positive bacteria - 22What type of receptor does the innate immune system use?Germline-encoded receptors
- 23What type of receptor does the adaptive immune system use?Antigen receptors of unique specificity assembled from incomplete gene segments during lymphocyte development
- 24How are the receptors of the adaptive immune system distributed?Clonally distributed on individual lymphocytes
- 25How are the receptors of the innate immune system distributed?non-clonally, expressed on all cells of a given cell type
- 26How are individual NK cells different from one another?NK cells express various combinations of NK receptors from several families, a particular NK receptor may not be expressed on all NK cells
- 27State the macrophage receptors for microbial constituents- mannose receptors
- Toll-Like receptors
- scavenger receptors
- glucan receptors
- NOD receptors - 28What are TLRs?Important family of pattern recognition receptors present on macrophages, dendritic cells and other immune cells
Recognise different microbial components - 29State the four types of pathogen recognition receptors?C-type Lectin Family
Scavenger Receptors
Complement and Fc Receptors
Toll-Like Receptors - 30Describe the function of the C-type lectin family PRRs?Dectin-1: recognises beta-1,3-linked glucans common components of fungal cell walls
Mannose receptor: may recognise mannose containing structures on pathogens but also plays a role in clearance of host proteins - 31Describe the function of scavenger receptorsStructurally heterogenous, recognise various anionic polymers and acetylated low-density lipoproteins
May bind to the pathogen or host products - 32What is the function of complement and Fc receptor PRRs?Recognise complement-coated and antibody-coated organisms
- 33What do TLRs recognise?Molecular patterns not found in healthy vertebrate cells
- 34What are the ligands for TLR-4 and what is its cellular distribution?LIGANDS: LPS (gram -ve) and lipoteichoic acid (gram +ve)
CELLULAR DISTRIBUTION: macrophages, dendritic cells, mast cells, eosinophils - 35Describe the location of TLRsTransmembrane proteins whose extracellular region contains 18-25 copies of the leucine-rich repeat
Some TLRs are located on the cell surface of dendritic cells, macrophages and other cells where they are able to detect extracellular pathogen molecules
TLRs located intracellularly in the walls of endosomes can recognise microbial components such as DNA that are accessible only after the microbe has been broken down - 36How does binding to lipopeptide of TLR1 and TLR2 induce dimerisation?The convex surfaces of TLR1 and TLR2 have binding sites for the lipid side chains of triacyl lipopeptides
Binding of each TLRto the same lipopeptide induces dimerisation, bringing their cytoplasmic TIR domains into close proximity - 37Describe how LPS binds to MD-2 and TLR-4LPS has multiple fatty acid chains linked to a glycan head
Five acyl chains can bind to a pocket within MD-2 but one acyl chain is free
The free acyl chain of an LPS molecule then binds to the outer convex surface of another TLR-4 molecule, inducing a dimer
An LPS molecule bound to the second TLR-4/MD-2 molecule stabilises the dimer - 38What are the four adaptor proteins used by mammalian TLRs?MyD88
MAL
TRIF
MAL TRIF - 39How does TLR-3 induce IFN gene expression?TLR-3 expressed by dendritic cells and macrophages senses dsRNA
TLR-3 signalling uses the adaptor protein TRIF which recruits the E3 ligase TRAF3 to generate K63-linked polyubiquitin chains
This scaffold recruits NEMO and TANK which associate with the serine-threonine kinases IKKe and TBK1
TBK1 phosphorylates the transcription factor IRF3 and IRF3 enters the nucleus and induces expression of type I interferon genes - 40How does TLR-7 induce IFN gene expression?TLR-7 expressed by plasmacytoid dendritic cells detects ssRNA and signals through MyD88
IRAK1 directly recruits and phosphorylates IRF7 which is also highly expressed in plasmacytoid dendritic cells
IRF7 then enters the nucleus to induce expression of type I interferons - 41What do NOD-like receptors do?Recognition of bacterial cell wall peptidoglycan fragments
Cause activation of NFkB - 42What is the function of NLRP proteins?Activated in response to pathogen or host-driven cellular damage
Contributes to multiprotein complex (inflammasome) that drives pro-inflammatory cytokine production or induces cell death - 43What is the function of RIG-I-Like receptors?Sense viral RNAs produced within cells
Activation results in production of type I interferons - 44What is the function of cytosolic DNA sensors?Innate sensor of pathogen cytoplasmic DNA eg bacterial cyclic dinucleotides
- 45Explain how binding of bacterial ligands to NOD proteins leads to the activation of NFkBNOD proteins reside in an inactive state in the cytoplasm where they serve as sensors for various bacterial components
The binding of ligands to NOD1 and NOD2 induces aggregation, allowing CARD-dependent recruitment of the serine-threonine kinase RIP2
RIP2 associates with E3 ligases including: XIAP, CIAP1 and CIAP2
This recruited E3 ligase activity produces a polyubiquitin scaffold and the association of TAK1 and the IKK complex with this scaffold leads to the activation of NFkB - 46What are protein-interaction domains and give examples?Signalling proteins contain protein-interaction domains that mediate the assembly of larger complexes; proteins may have more than one domain
Examples include: TIR; CARD; Pyrin; DD (death domain); DED (death effector domain) - 47Explain how NOD receptors are involved in the production of cytokinesActivation of the P2x7 receptor by extracellular ATP allows efflux of K+ ions from the cell
Induce multiple NLRP3 molecules to aggregate through interactions of their NOD domains
The aggregated NLRP3 conformation brings multiple NLRP3 pyrin domains into close proximity which then interact with the pyrin domains of the adaptor protein ASC
This conformation aggregates the ASP CARD domains which in turn aggregate the CARD domains of pro-caspase 1
Aggregation of pro-caspase 1 induces proteolytic cleavage of itself to form the active caspase 1, which cleaves the immature forms of pro-inflammatory cytokines
Mature cytokines are secreted - 48Describe antigensAntigens can be complex macromolecules such as proteins
Most antigens are larger than the sites on the antibody/antigen receptor that they bind to
The portion of the antigen that is bound is called the epitope or the antigenic determinant
Large antigens can contain more than one epitope and may bind different antibodies
Antibodies generally recognise epitopes on the surface of the antigen - 49Describe the basic structure of antibodiesMade up of two hinged heavy chains and two light chains joined by a disulphide bond
Each heavy chain is linked to a light chain and the two heavy chains are linked together
Has a constant region and a variable region - 50Describe antibody domainsLight chains have two domains
Heavy chains can have four (IgG, IgA, IgD) or five (IgM, IgE) domains
All antibody domains share significant homology suggesting they evolved from an ancestral gene - 51Where else in the immune system can the antibody domain structure be found?T Cell Receptor
MHC Molecules
Adhesion Molecules - 52What domains make up the antigen binding site?The light chain variable (VL) and heavy chain variable (VH) together
- 53Describe how antigen:antibody complexes can be formedAn antigen consisting of two hapten molecules that can cross-link two antigen-binding sites is used to create the complex
Linear, triangular and square forms exist with short projections - 54How are the short projections on antigen:antibody complex removed?Limited pepsin digestion removes the spikes that therefore correspond to the Fc portion of the antibody
F(ab)'2 pieces remain cross-linked by antigen - 55Describe the carbohydrates found on antibodies State their functionA small amount is found on all antibodies which may be N- or O- linked
FUNCTIONS:
Addition of carbohydrates affects antibody secretion, solubility and catabolic rate - 56What is another name for hypervariable regions?Complementarity-Determining Regions (CDRs)
- 57What are the regions between CDRs called?framework regions
- 58What is the paratope?The CDRs that make up the antibody combining site
- 59What is the degree of variability at each amino acid sequence?The ratio of the number of different amino acids seen in all the sequences together to the frequency of the most common amino acid
- 60How is the antigen binding site formed?The pairing of a heavy chain and a light chain brings together the hypervariable loops from each chain to create a single hypervariable surface
- 61What are the averaged CDR contribution to antigen binding?HCDR1: 29%
HCDR2: 23%
LCDR3: 21%
HCDR1: 10%
LCDR1: 9%
LCDR2: 4%
Framework residues: 4% - 62What are the four types of binding sites in a Fab fragment of an antibody?Pocket
Groove
Extended Surface
Protruding Surface. - 63What are the five types of non covalent forces involved in antibody binding?Electrostatic forces
Hydrogen bonds
Van der Waals forces
Hydrophobic forces
Cation-pi interaction - 64Describe electrostatic forcesAttraction between opposite charges
- 65Describe hydrogen bondsHydrogen shared between electronegative atoms (N O)
- 66Describe van der waals forcesFluctuations in electron clouds around molecules polarise neighbouring atoms oppositely
- 67Describe hydrophobic forcesHydrophobic groups interact unfavourably with water and tend to pack together to exclude water molecules
The attraction also involves van der waals forces - 68Describe cation-pi interactionsNon-covalent interaction between a cation and an electron cloud of a nearby aromatic group
- 69How do electrostatic forces diminish?The inverse square of the distance separating the charges
- 70How do van der waals separate?The sixth power of separation
Operate only over very short ranges - 71How is the variable region of a light chain formed?A complete light chain variable region encoding the CDR1, CDR2 and CDR3 loops resides in a single exon
The complete variable region is derived from distinct germline DNA sequences
A V gene segment encodes the CDR1 and 2
CDR3 loop is formed by sequences from the end of the V gene segment and the beginning of the J gene segment, and by nucleotides added or lost when these gene segments are joined during lymphocyte development - 72How is the CDR3 loop of the heavy chain formed?The joining of sequences from V, D and J gene segments
- 73Describe the process of light-chain V-region constructionConstructed from two gene segments
A variable and a joining gene segment in the genomic DNA are joined to form a complete light chain V region exon
Immunoglobulin chains are extracellular proteins and the V gene segment is preceded by an exon encoding a leader peptide which directs the protein into the cells secretory pathways and then cleaved
The light chain c region is encoded in a separate exon and is joined to the v region exon by splicing of the light chain RNA to remove the L-V and J-C introns - 74Describe how heavy chain v regions are constructedConstructed from three gene segments
The diversity and j gene segments join, and then the V gene segment joins to the combined DJ sequence, forming a complete VH exon
C region exons, together with the leader sequence, are spliced to the v domain sequence during processing of the heavy-chainRNA transcript
The leader sequence is removed after translation and the disulphide bonds that link the polypeptide chains are formed - 75Why will the number of functional gene segments in human immunoglobulin loci not be the same for all people?Genetic polymorphism
- 76Describe the structure of a recombination signal sequencesComposed of heptamer and nonamer sequences that are separated by either 12 bp or 23 bp of nucleotides
- 77What is the 12/23 rule?Joining of gene segments almost always involves a 12 bp RSS and a 23 bp RSS
- 78What is the function of RAG1 recombinase?Cuts the DNA precisely between the last nucleotide of the V gene segment and the first C if the heptamer
Or
Between the last G of the heptamer and the first nucleotide of the D or J gene segment - 79What is V(D)J recombinase?The complex of enzymes that act in concert to carry out somatic V(D)J recombination
Lymphoid specific RAG-1 and RAG-2 are essential components expressed in developing lymphocytes only when recombination occurs
Ubiquitously expressed members of non-homologous end joining pathway of DNA repair known as double strand break repair
Lymphoid specific terminal deoxynucleotidyl transferase (TdT) adds nucleotides randomly to single strand ends - 80Describe the process of DH to JH rearrangementFormation of DNA hairpins
Two heptamer sequences are ligated to from the signal joint
Artemis:DNA-PK complex cleaves DNA hairpin at random site to yield a single stranded DNA end
single stranded DNA end may contain nucleotides that were complementary in the double stranded DNA and therefore form short DNA palindromes
Where the enzyme TdT is present nucleotides are added at random to the end of the single stranded segments
Two single strands then pa
Exonuclease trimming of unpaired nucleotides and repair of the coding joint by DNA synthesis and ligation leaves both P- and N-nucleotides in the final coding joint - 81State the sources of variation in CDRs of antibodiesCDR1: somatic hypermutation
CDR2: somatic hypermutation
CDR3: (VDJ or VJ junction) gene segment recombination, P- and N-nucleotide addition, somatic hypermutation - 82What is the fab fragment of an antibody molecule?A disulphide linked heterodimer, each chain of whichcontains one immunoglobulin C domain and one V domain
The juxtaposition of the V domains forms the antigen binding sites - 83What are the differences in antigen recognition between B cells and T cellsB cells bind directly to intact antigens, typically interacting with the surface of proteins, contacting amino acids that are discontinuous in the primary structure but are brought together in the folded protein
T cells interact with short continuous amino acid sequences which may be buried within the protein, thus proteins must be digested into fragments and presented by MHC molecules for recognition by T cells - 84Why do the epitopes recognised by T cell receptors not need to lie on the surface of the molecule?The T cell receptor recognises not the antigenic protein itself but a peptide fragment of the protein
- 85How can T cell receptors recognise epitopes that are buried within antigens?Antigens must first be degraded by proteases and the peptide epitope delivered to a MHC molecule
in this form, as a complex of peptide and MHC, antigens are recognised by T cell receptors - 86Describe the structure of MHC class IIComposed of two transmembrane glycoprotein chains, alpha and beta
Each chain has two domains, and the two chains together form a compact four domain structure similar to MHC class I - 87What are the differences in the peptide binding cleft in MHC class I and MHC class IIMHC Class I: peptide is bound in an elongated conformation with both ends tightly bound at either end of the cleft
MHC Class II: peptide is bound in an elongated conformation but the ends of the peptide are not tightly bound and the peptide extends beyond the cleft - 88How to MHC class I molecules interact with a bound peptide?A series of hydrogen bonds with the backbone of the peptide and ionic interactions at the end of the peptide
The amino acid residues in the MHC molecule that form these bonds are common to all MHC class I molecules
A cluster of tyrosine residues common to all MHC class I molecules forms hydrogen bonds to the amino terminus of the bound peptides
A second cluster of residues forms hydrogen bonds and ionic interaction with the peptide backbone at the carboxy terminus and with the carboxy terminus itself - 89How do MHC class II molecules interact with peptides?A peptide is bound through a series of hydrogen bonds distributed along the length of the peptide
Hydroogen bonds at the amino terminus are made with the backbone of the polypeptide chain
Throughout the peptide's length bonds are made with the residues that are highly conserved in MHC class II molecules - 90Where are MHC class I molecules expressed?On all nucleated cells, but more highly expressed in hematopoietic cells
- 91Where are MHC class II molecules expressed?Only on a subset of hematopooietic cells and by thymic stromal cells
May be expressed on other cell types on exposure to the inflammatory cytokine IFN-gamma
In humans activated T cells express MHC class II - 92How are the alpha chains of TCRs generated?A Va gene segment rearranges to aJa gene segment to create a functional V-region exon
Transcription and splicing of the VJa exon to Ca generates the mRNA that is translated to yield the TCR alpha chain protein - 93How is the beta chain of TCRs generated?The variable domain is encoded in three gene segments: VB, DB, JB
Rearrangement of these gene segments generates a functional VDJB v region exon that is transcribed and spliced to join to CB
The resulting mRNA is translated to yield the TCR beta chain
Información
- Descripción
- 3 BM325 Fichas sobre Pathogen Recognition, creado por Caitlin M el 03/11/2017.
- Creado por
- Caitlin M
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