Adaptive Immunity Flashcards
(34 cards)
What is an antigen?
Antigen (simple or complex) is the target of an immune response.
The site that the TCR or BCR binds on the antigen is called the epitope or determinant. one antigen can have many epitopes.
Protein determinants can be linear or discontinuous and antibodies bind to conformational shapes.
What is the humoral arm of the adaptive immune response?
B Cells express receptors for antigen recognition, known as the BCR, Ig or antibody. The BCR/Ig carry a high level of diversity in their specificity for antigen.
Each cell has multiple copies of a single receptor specificity and this receptor determines the antigens that the B cell can bind.
What are the key features of the BCR or Ig?
There are two forms of immunoglobulin:
- Surface Ig: embredded in the B cell membrane which is the B cell antigen receptor
- Secreted/soluble Ig: secreted by B cells (plasma cells) when they bind their antigen. (controls extracellular microbes and mediates effector functions)
Each B cell expresses multiple copies of Ig which all bind the same antigen.
Explain the constant and variable regions of Ig:
Consists of two identical heavy chains and two identical light chains.
Antigen binding involves the variable region of the H and L chain (F(ab) domain) and the sequence determines the specificity of those regions.
The constant region (Fc) can take on one of five forms: IgM, IgG, IgA, IgD, IgE. This domain is also involved in:
- Mediating effector function - recognition via Fc receptors
- Activation of classical complement cascade - Ag:Ab complexes
- Delivery of Abs through the active transport to various compartments.
Antibody diversity is mainly generated in the bone marrow during B cell development.
How does gene rearrangment of Ig occur?
Heavy Chain V-region consists of 3 segments: Variable (V). Diversity (D) and Joining (J). The V-Region (VDJ) connects to a constant (c) gene.
Light Chain V-regions consists of 2 segments: Variable (V) and Joining (J). The VJ region connects to a constant region.
Rearrangement is mediated through various enzymes such as RAG.
Diversity: is achieved via altering the V-region, Junctional diversity, combinatorial diversity and somatic hypermutation.
What are the following enzymes used for?
1) RAG
2) TdT
3) AID
4) BtK
1) cutting between V, J & D in gene rearrangement/ enables splicing (Mutations in RAG can cause SCID)
2) Joining the V, J & D elements while adding random nucleotides for variation
3) Used in somatic hypermutation (Activation induced deaminase introduces random nucleotides that either increase or decrease affinity that forces natural selection in the lymph node)
4) responsible for making a surrogate light chain to pass the checkpoints for maturation (Mutations in BtK can cause XLA- no mature B cells formed)
In what order is the Heavy chain assembled?
1) DJ
2) V+ DJ
How are B cells matured?
Progenitor B cells undergo heavy chain maturation to become pro-B cells, which eventually become Pre-Bcells. These Pre- B cells undergo light chain amturation to become immature B cells that reside in the LN and secrete IgM.
Why doesnt IgM need high affinity?
IgM is a pentomer and doesn’t have high affinity with any given antigen because it needs to elicit a response to anything that new that it encounters (the common elements of foreign invaders). As a result it has a very high avidity as a pentomer that overcomes the single lack of affinity.
What are the four functions of Antibodies?
- Opsonisation (IgG)
- Neutralisation (IgA)
- Complementation (IgM)
- Antibody dependant cellular cytotoxicity (ADCC) (mainly IgG)
Where does somatic hypermutation take place?
In the secondary lympohoid tissues.
How are B cells activated?
Once a B cell is activated it has one of two fates. It proliferates and differentiates into either a plasma cell or a memory B cell.
Maturation of the B cell response is associated with memory. The response needs to be stronger, faster and more specialised in its approach. This is acheived through memory and is the driving mechanism behind vaccinations.
The key process underpinning this capacity is proliferation/increased magnitude (to be stronger and faster), affinity maturation (to be stronger and more specific) and isotype switching (to be specialised further).
How does Isotype Switching occur?
There are five variations (classes/isotypes) possible, determined by the constant region of the heavy chain (IgM, IgG, IgA, IgD, IgE).
Individual B cells may change their antibody isotype after antigen encounter. The constant region determines the antibody isotype function.
There is an affinity between primary and secondary responses during isotype switching of antibodies. The antibody response matures via isotype class switching and affinity maturation.
IgM → IgG → IgE → IgA
Isotype switching occurs in the secondary lymphoid tissue only after B cells have been stimulated by antigens. It involves the irreversible recombination events and ‘switch regions’, together with enzymes (activated induced deaminase AID)
The microenvironment determines the isotype produced (CD4, TFH, NKT), cytokines control isotype switching and is completely dependant on T cell help.
Why is isotype switching important?
Isotypes are important because they are highly specified for the invading pathogen and help the immune system more easily and quickly eliminate the threat before it is able to cause damage.
What are the processes in ADCC?
If the antigen is associated with a cell or a tissue toxic metabolites are released from macrophages. This occurs in three steps:
- Antibody binds to target cell via variable region (Ab binds virus infected cell)
- Antibody binds to NK cell via FcgRIII receptor (CD16)
- Cross linking of FcR triggers NK cell killing
Explain the process of Affinity maturation?
High affinity antibodies are most effective because they bind faster and they saturate binding sites at lower concentration.
Affinity Maturation is the process by which B cell increases its affinity for a particular antigen as the immune response progresses.
It is dependant upon the high frequency of somatic mutations (somatic hypermutation) in the V-region of the H & L chains as well as the continued antigen stimulation.
It requires T cell help and as antigen levels decrease during an immune response, B cells with mutations that result in high affinity surface Ig are preferentially selected for survival (clonal selection).
Where can variation arise from in antibody formation?
1) Heavy/Light chain maturation
2) variation within the ‘V’ region
3) Variation between ‘Snipping’
4) Somatic hypermutation
These all contribute to affinity maturation
What three signals are required for isotype switching of antibodies?
1) MHC II molecule (on B cell) binding TCR (on T cell)
2) CD40 (on B cell) binding CD40L (on T cell)
3) Cytokines
What does a mutation in CD40/CD40L interaction cause?
Hyper IgM syndrome because isotype switching is not able to occur
What cytokines specifically induce the isotype switching to IgG, IgE and IgA?
IgG - IFN alpha - monomer that is mainly for bacterial infections
IgE - IL4 - monomer that is mainly with autoimmune responses such as asthma
IgA - TGF beta - dimer that can cross the gut and therefore combats mostly gut bacteria in the lining of the GIT
How do naive T cells mature?
This requires three signals:
1) TCR binding MCH class II molecule + antigen
2) CD28 binds to CD80/CD86 (on APCs)
3) Cytokines released by the invading agent
The type of cytokine determines the outcome of the T cell:
IL-12 -> Th1 T cell which produces IFN alpha, IL2, LTs
IL-4 -> Th2 T cell which produces IL-4, IL-5, IL-13
TGFbeta -> Treg T cells which produce TGFbeta
How are T cells activated to mature?
An injury/infection occurs which causes PAMPs to be recognised by the dendritic cells via pinocytosis.
Once the DC finds an antigen, it causes the dendritic cell to do the following:
1) Upregulate chemotaxin receptor (enables migration to the LN)
2) Upregulate MHC class I & II
3) Downregulate pinocytosis (this allows lymphocyte maturation)
4) Downregulate adhesion molecules (enables migration to the LN)
What type of cells are MHC class I and II displayed on?
MHC I: CD8 - to kill intracellular pathogens so it is expressed on all cells
(Subtypes A, B, C)
MHC II: CD4 - only on APCs (B cells, Macrophages, DCs)
(Subtypes DP, DQ, DR)
Subtypes are expressed codominantly
What are some features of the TCR?
Extracellular-acting toxins have many targets:
- intact host cells such as haemolysin, leucocidins
- extracellular matrix such as hyaluronidase, collagenase
- other host molecules such as lipid, fibrin, nucleic acids etc.
Intracellular-acting toxins can be either cytotoxic which kills the cells (diphtheria toxin, shiga toxin) or cytotonic which are stimulatory (cholera enterotoxin, heat stable enterotoxin). They can be either simple (uncommon) for example the heat stable enterotoxin or bi-functional (A-B type - A is the active fragment and the B fragment is the binding fragment which is the part that antibodies target) such as the diphtheria toxin or the cholera toxin.
