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What is adaptive immunity?

‘Specialised’ immune response with set tasks to give a more powerful response

Occurs when innate immunity can no longer cope or has failed to remove infection - After the initial ‘innate’ defences are either compromised or overwhelmed

Highly specific

Can distinguish between closely related pathogens

Delayed initiation

Executed by specialised cells / molecules

Powerful elimination tool

Memory Recall function


What is the order of lymphocyte Generation and where do each cell type mature?

Haematopoietic stem cell (HSC)
Multipotent Progenitor (MPP)
Common lymphoid progenitor (CLP)
| | |
B cell T cell NK cell

Production site – Bone marrow
Maturation site – Bone marrow

Production site – Bone marrow
Maturation site – Thymus


What happens when lymphocytes encounter antigens?

Naive lymphocytes [B+T cells] circulate via the blood and lymphatic system, but up until this point they have never encountered an antigen. In circulation they continuously survey the host for invaders.

Antigen encountered in the secondary lymphoid organs:
lymph nodes, spleen, mucosal lymphoid tissues [gut, respiratory, nasal & urogenital tracts]

Naive cells see an antigen and can go through two stages upon activation. They can either mature into their effector form, most often, or they can go on to become memory cells that are able to remember that specific pathogen is that if there is ever a second exposure the immune response is faster and more effective.


What is the colonial selection hypothesis?

Colonial selection hypothesis: The lymphocyte precursor allows generation various different types of immune mature cells with different receptors on their surfaces.
Once the antigen is encountered only the cell that recognises it is gets selected and activated by a cycle of rapid proliferation (this is why this stage takes days - lag phase), as this is the cell required to mount the adaptive immune response.
This gives us a large abundance of effector cells that either kill organism/cells infected with organism or produce molecules such as antibodies.

Colonial selection states that you have a large pool of cells with different receptors but only after an antigen is encountered and a specific receptor cell selected will this rapid proliferation take place in order to generate effector cells.


How does B cell differentiation occur?

Plasma cells (soluble form)
Produce antibodies which:
- Neutralise the microorganism
- Coat the pathogen for destruction
- Activate complement (classical pathway)– to kill the pathogen

Memory B-cells
- Provide long-term protection against the same exact pathogen - not
mutated forms
- Critical for reinfection with the same pathogen = very specific!


What do T cells differentiate into?

Cytotoxic T cells (CD8+):
- Kill virus-infected cells
- Release toxic granules from cytoplasm that can kill the target
(infected cell)
- They then undergo apoptosis
- CD8 marker that allows lab detection

Helper T cells (CD4+):
- Provide ‘help’ to the B-cells which then make antibodies
(the humoural side)
- Secrete messengers (cytokines) that direct B cells to develop into
plasma cells
- If macrophages get infected so can't kill effectively they are able to
activate the macrophages and enhance their intracellular killing
- Main type - CD4 marker allows lab detection


What is the difference between an antigen and an epitope?

Antigen – any molecule capable of inducing an immune response.
Foreign part of the pathogen that is recognised by immune system. But the immune cell's defined receptors can't recognise the whole large antigen which can be a:
Protein, glycoprotein, polysaccharide, chemical.

Epitope – part of the antigen [short peptide] which is recognised by the immune cells.
Many diff cells (receptors) can recognise one molecular antigen, but at different epitope sites - how you can mount different immunological responses to one antigen.

E.g. a football is an antigen but each hexagon on it is an epitope. Each epitope (hexagon) is different, therefore the same antigen (football) can be recognised by lots of different immune cell receptors from different angles.


What is the difference between direct and indirect antigen recognition?

Directly recognising different parts of the antigen:
e.g. Polysaccharide antigens are recognised by B-cell receptors (b cells are recognition cells and effector cells)

In-direct antigen recognition:
the microbe has already been processed by different cells in the immune system (APCs), but is presented as a small peptide to the T cells
Eg mainly with proteins, so viruses infect host cells and use host cell machinery to produce proteins which are then degraded the immune cells and are then presented on the host cell surface and recognised by T cells which mount a response against the infected cell.

e.g. Microbial peptide bound to host protein and presented to T-cells by specialised cells


What are antigen presenting cells and how do they allow indirect antigen presentation?

APCs are specialised cells; e.g. dendritic cells, macrophages
and B-cells. Their function is to take up any antigen that is not a self antigen and present it to cells of the immune system.

Macrophages phagocytose the microbe then go through processing of antigen peptides then present them on their surface. In order to do this they must have a specific mechanism so that other immune cells then know to act on that cell in an in-direct immune response.
To do this they present the antigen alongside an MHC molecule, this is the self molecule but what it presents is the foreign peptide.

Hence the process is:
- Micropinocytosis/Phagocytosis /Endocytosis
- Degrade / process into peptides
- Assembly into a complex
- MHC + Peptide


What is a major histocompatibility complex (MHC)?

AKA Human Leucocyte Antigen (HLA)

Germline encoded on chromosome 6

Highly Polymorphic

Responsible for graft-rejection

Two forms:
- MHC class I – on all nucleated cells (All uncleared cells need the
ability to present an antigen if they are infected)
- MHC class II – on professional APCs (Only present on certain T cells
that are professional antigen presenting cells, such as B cells,
macrophages, dendritic cells. They have class one and two)

Present antigen to different T-cell types. So CD4 and 8 both recognise antigens but in the context of different classes of MHC -


What are the features of MHC class I?

HLA-A, HLA-B, HLA-C: Basic structure is an alpha 1, 2 and 3 chain that spans the transmembrane region and an associated beta-2 microglobulin.

The associated β-2 microglobulin protein is not highly polymorphic, unlike the other regions

Expressed on all nucleated cells

Presents endogenous antigens: hence displays internal status of a cell - if infected this may mean viral antigens
- e.g. Viral derived peptides: presents antigens to CD8+ T cells because
their main job is to fight viral infections.


What are the features of MHC class II?

HLA-DP, HLA-DQ, HLA-DR - but there are other subtypes

Expressed only on APCs: Macrophages, B-cells, Dendritic cells

Presents exogenous peptides - anything taken up by cell, degraded and loaded onto MHC

2 transmembrane regions - alpha 1, 2 and beta 1,2 chains, al together they form the peptide binding groove where the peptide is expressed.
- e.g. Bacterial toxins derived peptides: Presents antigen to CD4+ T cells


How does each MHC class interact with T cell subgroup?

Two ways peptides are recognised - these peptides could be on each MHC class on one cell.

Class 1 activates CD8 T cells that then release their granules to target and kill the infected cell. They also release cytokines that have an effect on other cell types, signalling that other neighbouring cells require immune response.

The same, or different, cell can also express MHC Class 2, activating CD4 T cells that can mature into effector cells and help B cells develop into plasma cells and produce antibodies against the organism, or cytokines that help macrophages phagocytose or NK cells get rid of the organism, etc. So depending on which cell types are activated it can have various different results, all with the end goal being to get rid of the infectious organism.


What happens after the infection has been eliminated?

To keep homeostasis, the effector cells undergo apoptosis leaving only the memory cells.
Memory cells survive in order to provide a quicker response in the future


Why is regulation important?

Don't want immune response constantly activated, need a way to dampen the immune system and end the response.

Regulatory cells do this, eg reg T cells block B cells from proliferating/producing antibodies/releasing cytokines which in turn prevents the continuation of inhibit other areas of the immune response eg the complementary pathway.

Otherwise would lead to tissue injury.


What is the humoral mechanism?

Humoral Immunity is the soluble immune response: e.g. antibodies produced by plasma cells (hence, B-cell mediated)
Basic structure of BCR
BCR Diversity
Antibody classes
Affinity vs avidity
Antibody production
Effector functions
Role in Disease


What is the nature of a B-cell receptor/antibody?

Y shape protein with two identical heavy chains (mainly 5 diff types) and two identical light chains (two different types). Both chains have domains (regions)

The hinge region:
Provides flexibility to recognise epitopes on the antigen surface

The outermost region is variable:
Recognises the antigen and forms the antigen-binding sites

Innermost region is constant:
elicits and performs the effector function

For one B cell receptor (BCR) there are two antigen recognition sites - can recognise two epitopes at once.
The antigen is in a soluble form, same as an antibody, but in order to be expressed on the B cell surface it must also have an extra transmembrane region which is transcribed, translated and exported to expressed in the surface. Otherwise is in exactly the same form both in secretion and in expression.


How do B cell receptors function?

B cell receptors on the surface allows association with other surface proteins which have further extension into the cytoplasm - this is where signalling takes place.
The antigen is recognised and the signal is transferred through these coreceptor proteins. This is how it is then transferred through the cytoplasm to the nucleus resulting in effector function (proliferation etc...)


How do BCRs and antibodies have such diversity?

Within the genes that encode the heavy and light chains is divided up into segments.
The heavy chain has a variable, diversity and junctional region - of which there are several different types for each.
Then there is the constant region, for which there are also several different types - but only one per chain.
These allow the immune system to generate various different combinations together to get the final product. You only ever have one of each region. Any of the heavy chains then combine with light chains to give further variation.

Genes are on diff chromosomes - heavy chain on humans is on chromosome 14. 2 light chains are on chromosome 2 or 22.


How is antibody diversity achieved?

Antibody diversity occurs when different gene segments come together.
Gene rearrangement allows the formation of the variable regions. For example, light chain gene rearrangement forms the variable region of the light chain; these come together to form the antigen binding site.
In the constant regions, there are multiple possible gene rearrangements to five variable constant regions c(mew) , delta, etc - which constant region is selected determines which antibody class it is.
It's this region that carrier out the effector function (not recognition).
For example, if C new is chosen then you produce an IgM, usually the first antibody as it is the first constant region after the VDJ segments within the gene. Whereas if gamma 3 is selected you get aN IgG3 antibody... This can then rearrange into other antibody forms.


How do antibodies form isotypes and what are the differences between antibody types?

Structure may be similar but how they arrange themselves is different, for example IgA forms a dimerise via a J chain and IgM forms a pentamer.

Each isotope has a different effector function:

IgM is a pentamer with 10 binding sites, hence is very good at recognising foreign epitopes - could be different ones on the same antigen.

The pecentage in the serum varies too. Mainly will find IgG, followed by A and M. So only very minute concentrations of IgE and IgD, where D tends to be mainly expressed as the B cell receptor (alongside IgM), so isn't secreted in large amounts under normal healthy circumstances.

IgG can pass the placenta giving babies immunity before it has its own effective immune system.

IgM and G are the most effective at activating the complement pathway.


How can antibodies switch between classes?

Antibody classes can be produced in different OR the same cells.

You have the VDJ combinations of the variable region (forming the antigen recognition site), then a constant region (determines antibody class - and effector function).

Usually M is made first, as Cmew is the first constant region. But the same cell can then switch to a different class by selecting different constant genes and deleting the previous.

Eg switching from M to G to A. This is a class switching event, important in infection as although M may be the first one produced, a mucosal infection requires A, so it is important to be able to switch. So that the body can adapt and produce the best antibodies against infection.


Which antibodies are necessary in which type of infection?

Depends on the sort of infection and site of infection as to which immunoglobulin is most necessary.

Type of infection:
Primary infection – IgM produced
Secondary infection – IgG produced as you need memory cells and quick activation
Mucosal – IgA is found in secretions – mucous, saliva.
Parasitic – IgE
During pregnancy – IgG crosses placenta

Depending on which Ig is produced will depend on the function that is elicited as each is slightly different.
Effector function:
Activation of complement – IgG
Activation of mast cells in allergic reaction – IgE
Antibody-dependent NK-cell killing - IgG (antibody dependent NK cell cytotoxicity - only IgG can do this)


What is the difference between affinity and avidity?

- Strength of binding
- Lock-key hypothesis (higher affinity increases association and
decreases dissociation)
- IgG usually has high affinity, but isn't often secreted just remains
on cell surface

- Overall binding capacity
- The more complex the structure the higher the avidity
- No of binding sites /antibody molecule, e.g. IgM pentamer (x5 abs -
each could recognise diff epitopes)


How, why and when are antibodies produced?

Naïve B-cells [will become mature cells in upon antigen interaction]
Antigen encounter in the secondary lymphoid organs
Activation and help by CD4 T-cells; deliver the second signal necessary for proliferation, division and expansion
Proliferation: rapid cell division – clonal expansion
Differentiation: B-cells -> Plasma cell (secrete antibodies)
Antibody secretion: same antigenic specificity as the cell receptor that recognised it in the first place


What is the role antibodies in allergy?

People who for various reasons (e.g. Genetics) are more prone to allergies will have more IgE in circulation than healthy people.

IgE bind to mast cells and cause them to de-granulate releasing mediators (eg triptane, prostaglandin, etc) when they recognise the epitope of a known allergen.

Inflammatory mediators act on various organs and tissues that lead to common symptoms of allergy.


What is the role antibodies in autoimmunity?

For example: Lupus (making antibodies against self proteins)

Normally B and T cells in development are made non-responsive to self antigens and proteins.

Discrimination breaks down and antibodies produced towards self proteins and receptors, they bind and cause tissue damage.


What is the role antibodies in immunodeficiency?

For example CVID (common variable immunodeficiency - don't make enough antibodies due to genetic defects)
- Inability to produce antibodies
- Recurrent bacterial infections


What is the role antibodies in overexpression?

For example Hyper IgM syndrome (still classed as an immunodeficiency)
- Dis-regulated production due to defects in other genes (ie when the class switch event cannot occur, so you make lots of just IgM, can't go anything further)
- Unable to ‘switch’ to other antibody classes


What is the Cellular immune response mechanism?

Cellular Immunity (T-cell)
- Basic TCR structure
- Antigen recognition
- MHC [class I & II]
- T-cell activation & Differentiation
- Effector functions
- Role in Disease


What is the structure of a T-cell receptor?

Very similar structure to the B cell receptor except that it has two transmembrane spanning protein chains:
- α and β chains [majority]
- γ and δ chains [minority]

Variable region (Ag-binding)
Constant region
Transmembrane region

* Note – only ONE antigen-binding site per TCR
[contrast BCR has two] This is important because of the way it recognises the antigen.


How does antigen recognition occur with the antigenic peptide – MHC complex?

Dendritic cell’s for example, express both MHC class I and MHC class II. The MHC class 1 presents the antigenic peptide, which is recognised by the T cell receptor of a cytotoxic T cell. The dendritic APC also presents MHC class 2, which is recognised by t helper cells. The T cell receptor recognises both of these together or separately.

Other surface bound molecules interact with the dendritic cell and the T cells to drive the immune response to the next stage of differentiation. The two T cell types also interact via IL-2.

T-cell activation via MHC class I and II peptide complex binding has various outcomes.


Which other surface bound molecules are involved in T cell activation?

4 co-receptor molecules are involved in down stream signalling leading to effector function:
- these are the subunits of CD3, made up of epsilon/ gamma/ delta chains. CD3 is the main coreceptor for T cells. Once you recognise the antigen these CD3 molecules get intracellularly activated to you get transcription of target genes, which may lead to development into effector cells or lead to release of cytokines that increase the immune response.
- leads to responses such as complex intracellular signalling, TCR receptor associated proteins, phosphorylation, activation of downstream proteins and transcription factors (genes)


How does CD8 T-cell Effector Function occur?

- Cytotoxic activity is launched
- Releases granules containing perforin ( binds to target cell and
forms pore in target cell - viral, tumour, etc.) and granzyme (lytic
- Target cell is killed: i.e. Virus-infected host-cell or a modified host
cell (tumour)
- Also secrete cytokines
- Act on innate and adaptive components
- Enhances immune response


How does CD4T-cell Differentiation occur?

CD8+ can only be memory or effector but CD4+ can develop into various different subtype effector cells finetuned towards different pathways.

Th1 and 2 are the most common, however more recently Th17 has also been described, among others. Each has a different target organism or function.
- In a viral infection you will produce Th1 cells, which activate viral infection pathways, by producing cytokines like gamma interferon.
- In a bacterial infection you will drive production of Th2 cells, that will produce cytokines interleukin -4 and -13 to initiate an antibody response against a bacterial infection.
- During fungal infections Th17 production is driven and Ror(gamma)t is produced as a response.

If there is a defect in the genes that produce any of the components of these pathways it will make you more vulnerable to that particular type of infection.


How do CD4 T-cell (Th1) elicit their Effector Function?

As well as CD4's function of helping B cell antibody production, macrophages are also APCs.
- Helper-T cell binds antigen displayed by the macrophage
- Macrophage is activated
- Enhancing intracellular killing of micro-organisms by activating

e.g. Mycobaterium tuberculosis establishes intracellular infection. It is phagocytosed, but can resist the killing function of the macrophages so survives and travels from one cell to another spreading infection. So phagocytosis is not able to eliminate infection. Helper T cells secrete cytokines that activate the infected macrophage causing fusion of vesicles containing the mycobacterium with lysosomes containing breakdown enzymes.


How do CD4/T-cell (Th2) elicit their Effector Function?

Recall B-cells are APCs so present MHC and peptide derived from endocytosed bacterial toxin
Th2 (CD4 T cell subset) cells recognise this, and bind to the antigen displayed, then drive production of cytokines that act on this cell
B-cell is activated undergoes rapid proliferation forcing it to differentiate into a plasma cell that can secrete antibodies against this bacterial toxin.


How do T cells play a role in disease?

T cells play a key role in the adaptive immunity
Absent – severe immunodeficiency (e.g. SCID) cant activate macrophages, cant stimulate B cells to produce further antibodies. Actually better to have absent B cells than T cells as T cells as even with the B cells present they are not able to do their full job without T.
Defective – affects other cell functions (Ab prod)


How does HIV lead to AIDS?

HIV specifically targets CD4 T cells in the immune system.

The virus enters T cells and makes proteins establishing infection. As a result the CD4 T cells apoptosose setting off a cycle of inflammation, producing cytokines that pull more healthy cells to that site that are then also infected - this is a vicious cycle.

Later in the infection, there is a much lower number of CD4 T cells, which can be measured as a good indicator of infection.

Throughout this, the CD8 T cells will be being mass produced to try and kill the infected cells, but these can't do this effectively. Since you then have no T helper cells you cant help your B cells fight different infections, which is why HIV patients are so immunodeficient.


What happens if there is an imbalance between the humoral (Th2) and Cellular (Th1) responses?

Th1 dominance: you can fight viral infections well, but it will cause T cell mediated autoimmunity etc...
- T cell mediated Autoimmunity
- Graft rejection
- Delayed hypersensitivity reactions

Th2 dominance:
- Antibody mediated Autoimmunity
- Allergy