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Medicine 1 - 10 Blood and Immunity > 5 Recognition of Extracellular Pathogens > Flashcards

5 Recognition of Extracellular Pathogens Flashcards

1
Q

Briefly describe the stages involved in a normal immune response”

A
  1. Pathogen recognition
  2. Inflammation
  3. Antigen presentation
  4. Adaptive response
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2
Q

Describe Pathogen Associated Molecular Patterns (PAMPs) and Pattern Recognition Receptors (PRRs)

A

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

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3
Q

Describe some Pattern Recognition Receptors (PRRs) as Toll-like receptors

A

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

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4
Q

Describe the association of Toll-like receptors (TLRs) with Lipopolysaccharide and Peptidoglycan

A

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
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5
Q

Describe Scavenger receptors

A

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
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6
Q

Describe Opsonins

A

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

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7
Q

Give examples of proteins that are made which can activate PRR when bound to PAMPs (other ones)

A

Examples:

  • Mannose-binding lectin
  • C-reactive protein
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8
Q

Describe Mannose-Binding Lectin

and the pathway in which it helps to fight infection

A

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
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9
Q

Describe an acute-phase protein

A

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)
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10
Q

Describe C-reactive proteins (CRP)

A

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
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11
Q

Describe the clinical relevance of CRP levels

A

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
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12
Q

Describe how PAMPs activate Macrophages/Dendritic Cells (DCs)

A

[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:
  1. Activation of T-cells, with the ability to recognise peptide fragments (epitopes) of the pathogen
  2. Polarisation of the T-cell towards a functional phenotype
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13
Q

Describe how the Maturated Dendritic Cell communicates with the Naive T cell

(3 signals)

A

The mature DC provides 3 major signals to naive T cells:

  1. Presentation of peptide fragments from the pathogen bound to surface HLA molecules
  2. Co-stimulation through CD80 and CD86 interacting with CD28 on T-cells (co-stimulation)
  3. Secretion of cytokines, notably IL-12
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14
Q

Describe an antigen

and what it can bind to

A

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)
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15
Q

Describe Immunoglobulins

  • how they are synthesised
A

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)

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16
Q

Describe the actions that occur when an antibody binds to an antigen (non-self)

  • action of Antibody
A

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

17
Q

Describe antigen binding

  • how this occurs
  • what can bind to it
  • what results after
A

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
18
Q

Describe the basic structure of Immunoglobulins (Ig)

A

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)
19
Q

Describe the structure of the light chain of an Immunoglobulin

A

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
20
Q

Describe what Immunoglobulin domains are

A

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)
21
Q

Describe the structure of the heavy chain of an Immunoglobulin

A

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
22
Q

Describe the nature of the Antigen-binding site on an Immunoglobulin

A

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

23
Q

Describe the role of Heavy-chain isotopes in the determination of Ig isotope/class

A

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
24
Q

Describe adaptive immune system receptor formation

how each lymphocytes gets a different receptor

A

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

25
Q

Describe the Cell lineage of Lymphocytes (and the previous generations of cells that make this)

A 
Haematopoietic Stem Cell
                        \/
Common Lymphoid Progenitor
                        \/
Lymphocyte cells (B, T, NK, Nk-T)
                               \/
                       (Plasma cells)
26
Q

Describe the maturation of T cells

A

T cell precursors (prothymocytes)

  • migrate from the Bone Marrow
  • to the Thymus
  • (attracted by thymic molecules - lymphotactin)

The prothymocytes enter the cortical region of the Thymus - known called Thymocytes
- but lack the TCR’s, CD3, CD4, and CD8 surface molecules

The newly arrived thymocytes

  • acquire the TCRs, CD3, CD4, CD8 molecules
  • and now MUST PASS a series of selective tests as they migrate from the thymic cortex to the medulla

The selection process is demanding
- only 1-5% of all thymocytes are allowed to leave as T cells
- other 95-99% either leave as
> γδ (gamma-delta) T cells (without undergoing selection)
> or die an apoptotic death after failing one of the selective tests

27
Q

Describe the selective tests that T-cell’s must undergo and pass in the thymus

(and significance of these tests)

A

Within the cortex of the Thymus

aß thymocytes undergo positive selection
- to make sure they recognise MHC’s

The survivors of positive selection then undergo a negative selection
- to remove cells that are potentially autoreactive
- it does this by presenting a self protein, and the aim is to NOT interact with self protein
> if they do, the thymocytes undergo apoptosis

Mature single-positive (SP) thymocytes cross the endothelium of a venule
- and exit the Thymus as T-Cells

28
Q

Describe the maturation of B cells (cell lineage)

A

B cell lineage remains in the Bone Marrow for development
- unlike T-cells

Mature B cells (fraction F) co-express IgM and IgD on the cell surface

They undergo the same selection tests as T-cells (positive and negative selection)

  • If the IgM on developing cells binds to self-epitopes
  • they will undergo apoptotic death to prevent the production of autoreactive B cells
29
Q

Describe the B-cell receptor

and how/what happens when it gets activated

A

B-cell is activated when multiple binding sites are occupied

  • it endocytoses the antigen, processes (cuts) it into peptides, which it presents
  • on Class II HLA molecules to the
  • Helper CD4 T-cells

If the antigen is recognised

  • the T-cell may be activated
  • and secrete cytokines which complete the activation of the B-cells

The B-cell can now form a clone cell
- antibody production follows after receiving the ‘permission’ from the helper T-cell

30
Q

Describe the process of T-cell independent B-cell activation

A

Rare - SPECIAL CASE

The capsule of pneumococcus is a clinically significant T-independent antigen
- Most antigens do not have this repetitive structure (most are T-independent antigens)

So, B cells are activated independently of T-helper cells,
- this is rare

31
Q

Describe the process of T-cell dependent B-cell activation

adaptive immune system, memory etc.

A

Most antigens do not have repetitious structure and are T-cell dependent antigens

So, the B-cell must present the antigen to the helper T-cell of the correct specificity

  • The B-cell endocytoses and processes the antigen
  • Fragments of the processed antigen are presented on the B-cell surface on MHC-II to the T-cells

The T-helper cells respond by:

  • Secreting lymphokines (cytokines)
  • B-cell growth factors (IL-2, IL-4, IL-5, IL-6)
  • which push the B-lymphocyte over the activation threshold

Which then leads to clonal expansion

  • Plasma cells - release Antibodies
  • Memory cells - for secondary response
32
Q

Describe Immunoglobulin class switching

  • and outline how this determines the quality of the antibody response
A

Because of its particular combination of V(L) and V(H) regions and the effect of allelic exclusion
- an individual B cell synthesises Ig of ONLY a single specificity

Immunoglobulin Isotope Switch

  • when stimulated, B cells may change the isotope, but not the epitope specificity, of the Ig they produce
  • It influences the ultimate nature of the humoral immune response

Isotype switching permits the adaptive immune system to produce antibodies with identical specificity
- that are capable of initiating various different immune responses

33
Q

Describe the consequences of isotype switching (memory cells)

A

Not all B-cells initially stimulated by antigen (primary response) become Plasma cells

  • some stimulated B cells - B-memory cells
  • are held in reserve against future exposures to an antigen

So, when the antigen is encountered again

  • the B-memory cell can switch isotope
  • so that instead of producing only the IgM
  • it can start producing the correct immunoglobulins and antibodies, with identical specificity
34
Q

Describe allergy as an example of an immunopathological disorder

A
  • First exposure to the allergen (dust)
  • Antigen activation of T-helper 2 cells
  • and stimulation of IgE class switching in B-cells
  • production of IgE
  • binding of IgE to mast cells
  • repeat exposure to the same allergen
  • activation of mast cell release of mediators:

Vasoactive mediators:
- immediate hypersensitivity reaction
Cytokines:
- late-phase reaction

35
Q

Describe transplant rejection as an example of an immunopathological disorder

A

CD8-mediated cytotoxicity:

  • destruction of virus-infected, neoplastic
  • or donor graft cells

Medicine 1 - 10 Blood and Immunity (6 decks)

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