5 Recognition of Extracellular Pathogens Flashcards
Briefly describe the stages involved in a normal immune response”
- Pathogen recognition
- Inflammation
- Antigen presentation
- Adaptive response
Describe Pathogen Associated Molecular Patterns (PAMPs) and Pattern Recognition Receptors (PRRs)
PRRs are encoded within the genome and require no additional modification
- these PRR are in soluble form as complement and bound to specific cells
- PRRs detect and bind PAMPs
PAMPs
- Pathogen Associated Molecular patterns (antigens)
- Because the host does not produce PAMPs
- the innate immune system is able to discriminate between self and nonself
Several of these receptors can be found on the same cell
Describe some Pattern Recognition Receptors (PRRs) as Toll-like receptors
Some of the PRRs are Toll-like receptors (TLR)
- when bound to PAMPs
- they initiate the production of cytokines
- to trigger inflammation
- and attract neutrophils, macrophages, dendritic cells, and Natural-Killer cells (chemokines attract)
They also can trigger phagocytosis
Describe the association of Toll-like receptors (TLRs) with Lipopolysaccharide and Peptidoglycan
Bacterial Lipopolysaccharide (LPS)
- is a major constituent of the outer cell membrane of gram -ve bacteria
- TLR-4 binds to this
Peptidoglycans
- are major components of gram +ve bacteria
- recognised by TLR-2 receptors on host phagocytic cells
So, as a result of receptor engagement
- the microbes are ingested and degraded
- the macrophage is activated
- and cytokine production and inflammation result
Describe Scavenger receptors
Scavenger receptors
- are involved in binding of modified low-density lipoproteins (LDL), some polysaccharides, and some nucleic acids
- they are involved in the internalisation of bacteria
- and in the phagocytosis of host cells undergoing apoptosis
Describe Opsonins
Opsonins are molecules that, when attached to the surface of microbes
- make them more attractive to phagocytic cells
- this facilitating microbe destruction
Opsnonins bind to microbial surfaces
- receptors for opsonins are present on phagocytic cells
- and the subsequent increased phagocytic destruction of microbes is termed OPSONISATION
e.g. bound Ab and bound complement
Give examples of proteins that are made which can activate PRR when bound to PAMPs (other ones)
Examples:
- Mannose-binding lectin
- C-reactive protein
Describe Mannose-Binding Lectin
and the pathway in which it helps to fight infection
Mannan-binding lectin pathway
- lectins are proteins that bind to specific carbohydrates
- this pathway is activated by the binding of Mannan-binding lectin (MBL)
- to Mannose-containing residues of glycoproteins on certain microbes (Listeria, Salmonella, Candida Albicans)
MBL
- acute phase protein
- one of a series of proteins whose levels can rise rapidly in response to infection, inflammation, or other stresses
MBL, once bound to appropriate Mannose-containing residues
- can interact with MBL-activated serine protease (MASP)
- Activation of MASP leads to subsequent activation of complements C2, C4, and C3
Describe an acute-phase protein
An acute-phase protein is produced by the liver
- in response to IL-6, which is produced by activated Macrophages
- who are activated by cytokines (like INF-y, and bacterial LPS)
Describe C-reactive proteins (CRP)
CRP
- is one of a set of serum proteins known as acute-phase proteins
- that inhibit the spread of infectious organisms
- and also include (complement components, INF-type 1, fibronectin, and protease inhibitors)
CRP levels increase greatly within 24-48 hours of infection
- CRP readily binds to phosphocholine (a molecule expressed on some microbes)
- and acts as an OPSONIN
Describe the clinical relevance of CRP levels
CRP is used to chart response to therapy
- CRP fluctuations are an accurate reflection of inflammatory disease activity
- CRP levels rise within 4-6 hours, with a half-life of 12 hours
Describe how PAMPs activate Macrophages/Dendritic Cells (DCs)
[events last 1-2 days]
- Immature DC’s are activated by PAMPs, in the tissue binding to a PRR on DC’s
- The immature DC is a small, rounded cell that develops dendrites upon activation
- and secretes an enormous amount of INF-a (a potent-anti-viral and pro-inflammatory cytokine)
- On activation, the DC migrates to the local lymph node with the engulfed pathogen
- One in the lymph node, the DC is matured
- the matured DC interacts with naive T cells (antigen presentation), resulting in 2 key outcomes:
- Activation of T-cells, with the ability to recognise peptide fragments (epitopes) of the pathogen
- Polarisation of the T-cell towards a functional phenotype
Describe how the Maturated Dendritic Cell communicates with the Naive T cell
(3 signals)
The mature DC provides 3 major signals to naive T cells:
- Presentation of peptide fragments from the pathogen bound to surface HLA molecules
- Co-stimulation through CD80 and CD86 interacting with CD28 on T-cells (co-stimulation)
- Secretion of cytokines, notably IL-12
Describe an antigen
and what it can bind to
An antigen is a fragment
- that binds to an immunoglobulin (Ig)
- simple or complex protein/carbohydrate
An antibody and Immunoglobulin both bind to Antigen
- Antibody (Ab) is free in the blood
- Ig is membrane-bound (to B-cells)
Describe Immunoglobulins
- how they are synthesised
Immunoglobulins are synthesised by
- and are present on the surfaces of B-cells
Each B-cell synthesised immunoglobulins of a single specificity that bind to a specific molecular structure
- (epitope - smallest individually identifiable part of antigen)
Describe the actions that occur when an antibody binds to an antigen (non-self)
- action of Antibody
Antibodies bind to antigens non-covalently
- to immobilise them, render them harmless
- or TAG the antigen for destruction and removal by other components of the immune system
Because Ab are often in soluble form, they are an important component of the humoral (soluble) immune responses
Describe antigen binding
- how this occurs
- what can bind to it
- what results after
Antigen binding triggers the activation of leukocytes
- the complementary shapes of the ligand and its receptor are critical
- The effectiveness of interaction often increases with the affinity/strength of interaction between ligand and receptor
Different lymphocytes, each with a unique set of receptors, may recognise different epitopes on the same antigen
- B cells can recognise their specific epitopes (even if it is free-soluble molecules, surface-bound molecule, or even degraded (proteolytic) fragments of antigen)
- T cells can bind only to epitopes that are on small fragments - MHC - and presented to them
Describe the basic structure of Immunoglobulins (Ig)
Human Ig contains 4 polypeptides:
- 2 identical light chains
- 2 identical heavy chains
Which are linked by disulfide bonds to form a monomeric unit
One light and one heavy chain form the
- Epitope-binding site
Each heavy and light chain can be subdivided (Isotopes):
- Light chains - k (kappa) or Lambda (λ)
- 5 heavy chain types (mu, delta, gamma, epsilon, alpha)
Describe the structure of the light chain of an Immunoglobulin
Light chains
An immunoglobulin monomer contains:
- 2 Identical Kappa k chains OR
- 2 identical Lambda λ chains
- BUT never 2 of each
Light chains contain a:
- Variable region (both heavy and light chains)
- due to their variation in amino acid sequences between Ig’s synthesised by different B-cells
Describe what Immunoglobulin domains are
Immunoglobulin Domains
- Light chains are of two types (k and λ)
- but there are 5 types of heavy chains (α, δ, ε, γ, μ)
Immunoglobulin light and heavy chains are:
- divisible into domains that consist of approx. 100 aa’s
- and contain an interchain Disulfide bond (S=S)
- light chain variable domain - V(L)
- heavy chain variable domain - V(h)
- light chain constant domain - C(L)
- heavy chain constant domain - C(h)
Describe the structure of the heavy chain of an Immunoglobulin
Heavy chains
- contain one variable (Vh) domain
- and 4/3 constant domains (Ch)
Heavy (H) chain variable domains (Vh) are very diverse
- and constant domains (Ch) show limited variability for members of an isotope
- the
Describe the nature of the Antigen-binding site on an Immunoglobulin
Antigen-binding site
- A light chain variable domain + a heavy chain variable domain together form
- a pocket that constitutes the antigen (epitope)-binding region of the Ig molecule
Because an Ig monomer contains 2 identical light and heavy chains
- the 2 binding sites on each monomeric Ig are also identical
The variability in the amino-acid sequences of the V(L) and V(h) domains
- together with the random pairing of light and heavy chain that occurs from one B cell to another
Creates a pool of binding sites
- that can recognise a very large number of different epitopes
Describe the role of Heavy-chain isotopes in the determination of Ig isotope/class
Heavy chain isotopes (α, δ, ε, γ, μ) also determine Ig isotope or class
- γ δ μ α ε [Heavy chain isotope]
- IgM, IgD, IgG, IgA, IgE [Ig class]
Humans produce all 5 Ig isotopes:
- Mature B cells express IgM and IgD
> IgM produced first - found in the blood
> IgD - bound to B cells
Other Ig isotopes:
- IgG - dominant class, can cross the placenta
- IgA - found in mucous membrane secretions
- IgE - responsible for allergy - in mast cells
Describe adaptive immune system receptor formation
how each lymphocytes gets a different receptor
B and T cells - generate distinct receptors during development (somatically generated)
Each lymphocyte randomly generates a unique receptor
- through the rearrangement and rejoining of a small number of genes
- into a merged gene encoding the receptor
Specificity is conferred by two types of receptor:
- the TCR on T-cells (different to Ig on BCR)
- the BCR on B-cells (surface immunoglobulins)
- Plasma B-cells also secrete antibodies (an Ig)
A subsequent process, in which the receptors are uniquely vetted by each individual
- results in the retention of a set of receptors that is individualised to that self, and non-self environment
