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Immunology > Adaptive Immunity > Flashcards

Adaptive Immunity Flashcards

1
Q

What is an antigen?

A

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.

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2
Q

What is the humoral arm of the adaptive immune response?

A

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.

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3
Q

What are the key features of the BCR or Ig?

A

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.

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4
Q

Explain the constant and variable regions of Ig:

A

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.

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5
Q

How does gene rearrangment of Ig occur?

A

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.

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6
Q

What are the following enzymes used for?

1) RAG
2) TdT
3) AID
4) BtK

A

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)

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7
Q

In what order is the Heavy chain assembled?

A

1) DJ

2) V+ DJ

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8
Q

How are B cells matured?

A

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.

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9
Q

Why doesnt IgM need high affinity?

A

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.

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10
Q

What are the four functions of Antibodies?

A
  • Opsonisation (IgG)
  • Neutralisation (IgA)
  • Complementation (IgM)
  • Antibody dependant cellular cytotoxicity (ADCC) (mainly IgG)
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11
Q

Where does somatic hypermutation take place?

A

In the secondary lympohoid tissues.

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12
Q

How are B cells activated?

A

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).

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13
Q

How does Isotype Switching occur?

A

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.

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14
Q

Why is isotype switching important?

A

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.

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15
Q

What are the processes in ADCC?

A

If the antigen is associated with a cell or a tissue toxic metabolites are released from macrophages. This occurs in three steps:

  1. Antibody binds to target cell via variable region (Ab binds virus infected cell)
  2. Antibody binds to NK cell via FcgRIII receptor (CD16)
  3. Cross linking of FcR triggers NK cell killing
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16
Q

Explain the process of Affinity maturation?

A

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).

17
Q

Where can variation arise from in antibody formation?

A

1) Heavy/Light chain maturation
2) variation within the ‘V’ region
3) Variation between ‘Snipping’
4) Somatic hypermutation

These all contribute to affinity maturation

18
Q

What three signals are required for isotype switching of antibodies?

A

1) MHC II molecule (on B cell) binding TCR (on T cell)
2) CD40 (on B cell) binding CD40L (on T cell)
3) Cytokines

19
Q

What does a mutation in CD40/CD40L interaction cause?

A

Hyper IgM syndrome because isotype switching is not able to occur

20
Q

What cytokines specifically induce the isotype switching to IgG, IgE and IgA?

A

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

21
Q

How do naive T cells mature?

A

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

22
Q

How are T cells activated to mature?

A

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)

23
Q

What type of cells are MHC class I and II displayed on?

A

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

24
Q

What are some features of the TCR?

A

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.

25
Q

What is the difference in MHC binding clefts for Class I and II?

A

MHC Class I: Peptide is embedded in MHC binding cleft - held in place by specific anchor residues. The small cleft/gap is where the antigen peptide binds.

MHC Class II: Peptide is embedded in MHC binding cleft - held in place by specific anchor residues. This class is made up of two alpha and beta chains. Unlike the Class I cleft, the Class II cleft has open edges allowing larger peptides to bind.

26
Q

What can HLA polymorphisms cause in terms of immune response?

A

An individual’s HLA halotype affects susceptibility to disease. Genetic polymorphisms in MHC affect:
- The ability to generate an adaptive response (T cell and antibody responses). T cells which recognise MHC and peptide are said to be ‘genetically or MHC
restricted’
- The resistance or susceptibility to infectious disease
- The resistance or susceptibility to allergic disease
- The resistance or susceptibility to autoimmune diseases
- transplantation responses

27
Q

Explain the antigen processing pathways of MHC Class 1 molecules?
(CYTOSOLIC)

A

Class I MHC proteins are synthesised.
There is an association between the class I and peptides
It is then transported from the ER where it is expressed on the cell surface.

Class I MHC:

- displays peptides from cytosolic compartments
- typically endogenous antigens (virus, tumor antigens, self MHC antigens)
- presents peptide to T cell receptors on CD8 T cells
28
Q

Explain the antigen processing pathways of MHC Class 2 molecules?
(ENDOSOMAL)

A

Synthesis of Class II molecule
Assembly of Class II (invariant li blocks peptide binding site in the ER)
Transported from the ER
The peptide associates with Class II and displaces the li which is endocytosed and the MHC class II goes on to be expressed on the cell surface.

Class II MHC:

- displays peptides from endosomal compartments
- typically extracellular antigens (generated outside cell and introduced by 	phagocytosis/endocytosis
- presents peptide to T cell receptors on CD4 T cells

Cross presentation delivers peptides from Class II processing pathway to the Class I pathway.

29
Q

What are the exceptions to the MHC presentation method?

A
  1. Superantigens - they bind directly to conserves regions of Class II beta1 chains together with the V-beta chain of many T cell receptors. Superantigens can bind one or more V-beta chains and do not rely on the antigen binding site, thus large numbers of T cells are activated. The response is ‘super’ and results in significant pathology.
  2. Some T cells don’t recognise classical MHC molecules or peptide (NKT and γδ T cells).

NKT cells - express a (semi-invariant αβ-chain dimer, as well as NK receptors. It is not MHC restricted, binding an MHC-I-like molecule called CD1d that presents glycolipid antigens. They produce large numbers of cytokines.

γδ T cells - express a γδ-chain dimer and is not classically MHC restricted. It has an unknown function to do with the skin and mucosa and the genes only rearrange and are transcribed if productive αβ gene rearrangements fail.

30
Q

How do APCs take up antigen?

A

Macrophages: engulfment of anytigens and receptor mediated endocytosis

Activated B cells: receptor mediated endocytosis

DCs: take up small soluble antigens, macropinocytosis and RME

31
Q

What interactions allow naive T cells to adhere with DCs?

A

1) LFA-1 (T) with ICAM-1 (DC)
2) ICAM-3 (T) with DC-SIGN (DC)
3) CD2 (T) with CD58 (DC)

which allows TCR to bind the MHC on the APC resulting in a conformational change in LFA-1 increasing the binding affinity

32
Q

How are Germinal Centres formed in the LN?

A

When B and T cells are both activated in their separate regions of the LN, they alter the concentrations of CCR7 and CXCR5 to allow the two cells to move toward the junction of the two zones creating the germinal centre.

The B cell:

  • Increases CCR7
  • Decreases CXCR5

The T cell:

  • Decreases CCR7
  • Increases CXCR5

This makes a gradient that move the two cells together.

33
Q

What is a Germinal Centre?

A

This is the site of intense B cell stimulation (proliferation and affinity maturation). Without T cell help, B cells will not reside here.

34
Q

What are follicular Dendritic Cells?

A

Follicular dendritic cells (FDC) (not dendritic cells, they are stromal cells) provide a source of antigen for affinity maturation.

- FDCs are found only in the lymphoid follicles and they capture immune complexes (Ag + Ab) by their FcR and C'R.
- Forms a long term antigen depot that drives B cell activation and affinity maturation

Immunology (8 decks)

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