The Adaptive Immune System

Question 1

What’s the difference between an intracellular and extracellular pathogen?

Answer 1

Pathogens can be intracellular or extracellular in reference to where they divide. Our body recognises both types differently.

Question 2

How are T cell activated?

Answer 2

T cells are activated by antigen presenting cells.

Question 3

Where are APCs founds?

Answer 3

APCs are present in strategic locations to allow them to interact with both T and B cells: Lymphoid organs such as lymph nodes and spleen, skin (SkinALT), Mucous membranes (GutALT, NasalALT and BronchalALT) and blood circulation (plasmacytoid and myeloid DCs (dendritic cells).

Question 4

Describe the different types of specialised antigen presenting cells?

Answer 4

Dendritic cells - located in the lymph nodes, mucous membrane and blood - present to T and B cells

Langerhan’s cells - located in the skin - present to T cells

macrophages - located everywhere - present to T cells

B cells (BCR) - located in lymphoid tissue - present to T cells.

Question 5

What is special about dendritic cells?

Answer 5

Dendritic cells can detect both type of pathogens

Question 6

What does activation of the immune system result in with intracellular vs extracellular pathogens

Answer 6

Extracellular pathogens they activate the Humoral immunity – antibodies and complement

Intracellular pathogens they activate the Cell-dependant immunity – Tytotoxic T cells (CD8+ and T cells, macrophages and antibodies.

Question 7

How does antigen presentation occur?

Answer 7

Antigen presentation is done by the Major Histocompatibility Complex (MHC) or Human leukocyte antigen. Encoded by the short arm of chromosome 6. Class 1 molecules are found on all nucleated cells – HLA-A, HLA-C and HLA-B. Class 2 molecules (HLA-DR, HLA-DQ and HLA-DP) found on dendritic cells, macrophages and B cells only.

The more diverse the MHC molecules are the better for us.

Question 8

Describe the inheritance and expression of MHC genes

Answer 8

Co-dominant expression – both parental genes are expressed this increases the number of different MHC molecules. Polymorphic genes – many different alleles in the population different individuals increase the presentation of different antigens/microbes.

Question 9

What’s the difference between the Class I and Class II MHC molecules other than the cells they are expressed in?

Answer 9

MHC class 1 – present peptides from intracellular microbes responsive T cells are CD8+ T cells

MHC class 2 – present peptides from extracellular microbes responsive T cells are CD4+ T cells

Question 10

What is the peptide binding cleft?

Answer 10

The peptide bind cleft is a varibale region with highly polymorphic residues where the peptide is presented. Broad specificity – many peptides presented by the same MHC molecule

Question 11

Describe how the endogenous pathway for presentation of antigens works

Answer 11

This occurs in all cells. Virus or tumour antigens inside the cell – these will be targeted by ubiquitin for degredation by a complex called proteasome (LMP2) which will produce small antigenic peptides. These are collected inside the ER by a specific transporter called TAP1 and TAP2. An MHC complex will then bind one of these antigens peptides and move to the membrane to present it.

Question 12

Describe how the exogenous pathway for presentation of antigens works

Answer 12

This is for APCs only. Exogenous antigens are phagocytosed into the cell and digested as usual and parts of the pathgoenic proteins are stored in an endosome. This endosome binds with a larger endosome containing some MHC II complexes which have been activated by HLA-DM and HLA-DO complexes. If the peptide fits one of the MHC complexes then it is presented in the membrane.

Question 13

Is it just non-self antigens that are presented?

Answer 13

Both self and non-self peptides are presented but T cells are trained not to react to self material, all peptides from the same microbe are presented by different MHC molecules. Susceptibility to infection dependa on the types of MHC molecules.

Question 14

What’s the difference between elite controllers/long term non-progressors and rapid progressors?

Answer 14

Some patietns are elite controllers or long-term nonprogressors and can control viral replication. This is because the allele of MHC moleceules they posess present key peptides for the survival and replication for he virus that wont mutate whilst fast progressors only present mutatable peptides that aren’t critical for the virus.

Question 15

What is one major clincal importance of MHC genes?

Answer 15

MHC molecules are the major issues for organ transplant rejection. HLA mismatch between donor and recipient – graft verus host reaction.

Question 16

How are MHC molecules linked to some autoimmune diseases?

Answer 16

HLA association and autoimmune disease – ankylosing spondylitis, HLA-B27  90% of patients and Insulin dependant diabete mellitus , HLA-DQ2  50-75% of patients.

Question 17

What happens after the antigens are presented in the intracellular route

Answer 17

With intracellular microbes the antigen presenting cells (not normal cells) present proteins on both the MHC class one and two complexes activating both CD4+ and CD8+ cells. This is vital because to fully activate and differentiate CD8+ T cells you need CD4+ and this is the only way you can get Cytotoxic T cells.

Question 18

What does the CD8+ and CD4+ cells go onto do after being activated by the intracellular pathway?

Answer 18

If a T cell is stimulated by intracellular microbe, they will differentiate into TH1.
Once the CD8+ has been activated into a cytotoxic lymphocyte (requiring CD4+) they then go and recognise any body cells that are expressing the antigen that stimulated them in the first place. They bind to these cells with their TCR and cause the cell to die.

The TH1 CD4+ cells also stimulate B cells to synthesise antibodies (IgG) to this antigen that was presented. The antibodies opsonise the cells they recognise which are then killed by macrophages. The CD4+ cells also increase the activity of the macrophages.

Question 19

What happens after the antigens are presented in the extracellular route

Answer 19

The MHC class II molecules activate CD4+ cells which go on to activate the humoral immunity - antibodies and complement

Question 20

Where do T cell mature?

Answer 20

Thymus

Question 21

What is the TCR (T cell receptor)

Answer 21

The T cell receptor (TCR) recognises the antigens that are presented. The TCR diversity is created by gene rearrangement.

Question 22

What are the CD3, CD4 and CD8 receptors?

Answer 22

CD3 complex on the T cell membrane is what signals the T cell to become activated. CD4 and CD8 compexes are what recognise the MHC class one and 2 complexes and only one type can be present on a T cell.

Question 23

What is the final receptor that must be activated for a T cell to become activated?

Answer 23

As well as being activated by the MHC to beocme activated a T cell must also have a CD80/86 molecuels bind to it’s CD28 molecule this allows it to proliferate, differnetiate and persue its effector function.

Question 24

How is the cycle of activation of T cells arrested?

Answer 24

To arrest this cell cycle there is a second complex on the T cell membrane called CTLA-4 which also binds to CD80/86 and sends a negative signal to the cell causing it to arrest.

Question 25

What happens when a CD8+ T cell is stimulated by intracellular microbe?

Answer 25

If a T cell is stimulated by intracellular microbe, they will differentiate into TH1.
Once the CD8+ has been activated into a cytotoxic lymphocyte (requiring CD4+) they then go and recognise any body cells that are expressing the antigen that stimulated them in the first place. They bind to these cells with their TCR and cause the cell to die.

Question 26

What happens when a CD4+ T cell is stimulated by an extracellular microbe?

Answer 26

If a T cell is stimulated by extracellular microbe, they will differentiate into TH2 and TH17.
The TH2 cells stimulate eosinophils to kill parasites, B cells to produce antibodies (enhancing phagocytosis and complement) and also mast cells which stimulate a local inflammation (IgE and allergies occur here). The TH17 cells stimulate neutrophils which continue phagocytosis.

Question 27

How is an immunity created to this microbe after all the antigen presenting takes palce?

Answer 27

In both cases an immunity is created by memory cells.

Question 28

How do the different immunoglobulins rise between 1st and 2nd infections with a pathogen?

Answer 28

In the first response there are much more IgM which is a polymer of many antibodies. These are highly efficient at activating complement. IgG is low and rises slowly in the first response (if we look at this ratio we can tell if it’s the first time this infection has occurred).

In the second exposure the response IgG is created in much larger amounts and this is because it is made much faster, is stronger, lasts longer and has higher affinity (binds more efficiently.

To switch from producing IgM to IgG requires a process called isotype switching. This needs TH2 and CD4+ to occur.

Question 29

What are the differen immune functions of the different type of antibodies?

Answer 29

IgG – Fc-dependant phagocytosis, complement activation, neonatal immunity (transfer of maternal IgG) and toxinvirus neutralisation
IgA – mucosal (mucous membranes) immunity
IgE – immunity against helminths (worms) and mast cell degranulation (allergies)
IgM – complement activation