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What is X linked agammaglobulinanemia?

Condition which happens when you have an immunodeficiency

Symptoms: Repeated episodes of pneumonia, recurrent otitis media, streptococcal infection of skin

X-linked: Sex linked as much more prevalent in males

Cannot fight off extracellular infection e.g. pneumonia and ear infections BUT can control viral infections


What is the primary function of immunoglobulin?

AKA antibodies

Most effective against extracellular pathogens such as bacteria, some parasites, antigenic macromolecules and viruses

NOT toxic= Function is to help immune system react to specific antigens= Different reactions depending on what the antigen is


What happens when there is a bacterial toxin? How does the immunoglobulin react?

1) Bacterial toxins= Neutralisation
Antibodies would bind to molecular molecules causing the toxicity= Neturalise= Stop from binding to the cells


What happens when the bacteria is in extracellular space?

2) Act as opsonins to tag antigens for phagocytosis by neutrophils and macrophages
Coat targets (opsonise)= Macrophages can ingest them better as macrophages have Fc receptors= Can bind to complex structure immunoglobulin well= Helps them to digest the pathogen


What happens when the bacteria is in plasma?

3) Antibodies will activate complement to kill the pathogen directly e.g. NK cells
Recruit cytotoxic cells to kill them
Kills pathogens: by lysis and ingestion


What is the structure of immunoglobulins?

4 polypeptide chains linked to Y shape
-2 heavy chains= Bonded together by disulphide bonds
-2 light chains =covalent linked to heavy chain
Each arm is made up of 1 light and one heavy chain
-Stem of Y-shaped antibody molecule is Fc region= Determines which Ig class the antibody belongs to
-Hinge region: Between arms and stem= Allows flexible positioning of the arms as the antibody binds to antigen

Globular protein
Single B cell produces 1 antibody


Where does the variability of immunoglobulins come form?

Variability in V region is not randomly distributed

The 2 arms= Fab regions= form antigen-binding sites that confer with antibody specificity= V region
-V region variability is clustered around the antigen binding site
-In one antibody, the 2 light chains are identical and the 2 heavy chains are identical BUT between different antibodies, the chains are DIFFERENT
How does structure relate to function:
-The 2 antigen binding sites at the end of the arms are the IDENTICAL for each of the immunoglobulins= Want to bind to the same antigen


What are CDR regions?

Complementarity Determining Regions
Where the V region variability clusters around= offer the opportunity for variability= Specificity


How is the antibody variable regions created?

Created by random generation of variable regions by recombination of genomic elements= Editing process= Only one specificity is permitted for each B cell

Variable regions= Fab regions which are made by VDJ recombination is the process by which T cells and B cells randomly assemble different gene segments – known as variable (V), diversity (D) and joining (J) genes – in order to generate unique receptors (known as antigen receptors) that can collectively recognize many different types of molecule.


How is antibody produced in a secondary response qualitatively better at fighting infection?

Second time you get exposed= Antibody molecules are better
B cell clone= Produces the same specificity
Antibody structure used in secondary structure CAN CHANGE from primary response= Better


What is Hyper-IgM syndrome?

Can make B cells= Can make immunoglobulins
BUT have different profile of the type of immunoglobulin they make
Make different type of immunoglobulins:
IgM levels are high- ONLY make these
Germinal centres= Present if immune response is happening
Hyper-IgM= No germinal centres= Poorly able to respond to signals produced for adaptive immune response

Cant switch specificity to make other isotypes


What are the 5 isoTYPES of immunoglobulin?

1) IgG= Make up 75% of plasma antibody= Produced in SECONDARY immune responses
Can get into tissues and transfer via placenta
2) IgA= Found in external secretions e.g. saliva, tears= Bind to pathogens and flag them up for phagocytosis if they reach the internal environment
3) IgE= Targets gut parasites and are associated with ALLERGIC responses, mast cells --> bind to --> IgE and antigen= mast cells degranulate and release chemical mediators such as histamine
4) IgM= Antibodies are associated with primary immune response and with antibodies that react to blood group antigens= Strongly activate COMPLEMENT

5) IgD= Proteins that appear on surface of B-lymphocytes along with IgM= NO ONE KNOWS WHAT THEY DO SO JUST FORGET IT EXISTS

Fc is constant between the types
Types are present in different parts of the body- Distributed differently, but are produced by same cell


Which type is mainly dominant in primary response and what happens to it? What about during secondary?

IgM is the first type to be produced in immune response
IgM, drift to ---> IgG
Secondary: IgG, A or E
Secondary: Dominated by types on the right hand side of the genome
Variable elements (VDJ)= Excision and alternate splicing joins onto different C elements


What can IgM do?

Can form monomers and pentamers
Multimers: A, I and M

Cannot get into the foetus through placenta
Function: Acts as antigen receptor on B cell
IgM= Membrane bound Monomer= act as antigen receptor on B cells= Transduce the signal to interior of that the B cells must soluble make antibodies
Can co-exist with IgD= Same V regions and specificity, can be expressed at the same time as no chromosomal editing by alternate splicing

Immunoglobulin can have transmembrane regions and act as receptors OR can be secreted as soluble proteins in the absence of TM regions?
OVERALL: IgM secreted= Activated as receptor= B cells become plasma cells= Produce soluble immunoglobulin

IgM produced as pentamer= Very big molecule= Cannot leak out


What do pentameric IgM molecules to?

Bind to antigens on bacterial surface and adopt "staple" form= Cleaves and activate complement BUT can't get into tissues

IgG is also able to complement activation


What does IgA do?

Synthesised in blood more than any other immunoglobulin, but is lower level
Most of IgA is sucked out of blood= Secreted onto epithelial surface
Function: Actively transport out of blood into mucosal lining and surfaces
Babies take up IgA from breast milk
Extracellular epithelial surfaces

constant domain= J chain to dimerise it= able to be bound to plgR= and secreted into mucosa


What does IgG do?

GOOD AT: Activating NK cells
Able to get into tissues and activate complement which leaks out of activated tissues e.g. capillaries which are activated by cytokines
Leaks out well
Activates NK cells= Innate immune system recognise self by receptors which will bind to MHC
NK cells= Kill virally infected cells, use antibody as receptors by binding immunoglobulin which is complexed with target cell

Antibody binds antigens to surface of target cells --> Fc receptors on NK cells recognise bound antibody --> Cross-linking of Fc receptors signals the NK cell to kill the target cell --> Target cell dies by apoptosis

IgG can bind to low affinity for immunoglobulin Fc cells= ONLY when lots of IgG cluster together can the low affinity be overcome and bind= Can then get activation

IgG can bind to specific Fc cells which activate NK cells which can be mobilised and kill cells by apoptosis


How can Eosinophils use immunoglobulin cells?

Use IgG and IgA bound to Fc receptors to attack parasites

Have Fc receptors for IgG and IgA= Use complexed immunoglobulin to mobilise the degranulation of the parasites

Release big Granules= Erode away the parasite, immune cells can get in the parasite and kill them from inside


What do IgE do?

Good at activating mast cells
Activating mast cell does not stay activated for very long as they lose it straight away
Mast cells= Use IgE to mediate function

How does structure link to function: C region of IgE dictate binding to mast cells


What is the difference in NK cells, eosinophils and mast cells in their Fc receptors?

NK cells= Fc are low affinity= Needs a lot
Eosinophils= Fc are also low affinity receptors= Need complexed IgA and IgG= Need pre coating
Mast= High affinity Fc= Don't want for complex, will grab IgE when they found them
IgE= Antigen specific receptors for mast cells


What are the antibodies like which are produced in secondary responses?

Secondary response changes the isotype= Isotype becomes more effective

Example: IgM is great as receptor but cannot get into tissues, gut or epithelial = Switches to IgG for tissues, placenta, IgA for gut

Enhances immune response

ALSO: Affinity maturation= immunoglobulin binds more tightly= Clones of B cells in secondary responses produce antibody of higher affinity than in primary responses= Clones will get bigger