Atopic Disease and Immune Tolerance Flashcards
Which cells are responsible for adative immunity?
- B lymphocytes
- T lymphocytes
What percentage of WBCs are lymphocytes?
~30%
Where do B and T lymphocytes form?
In the bone marrow
Where do B and T lymphocytes mature?
- B lymphocytes mature in the bone marrow.
- T lymphocytes mature in the thymus.
What are BCR and TCR?
- Each B and T lymphocyte has a unique surface antigen recognition receptor (BCR or TCR).
- BCR and TCR are expressed as part of conserved surface molecules that confer function to the antigen recognition site.
How are unique antigen recognition sites formed?
What does this result in?
- Unique antigen recognition sites by recombination of a single member multiple copies of the VDJ genes - the final arrangement codes for a unique region that is aligned to constant functional gene segments (BCR shown; same principle for TCR).
- The resulting unique antigen binding sites will capture most foreign antigens, BUT some will inadvertantly bind to host proteins.
Which part is the variable portion?
The variable portion is the sum of variability on the alpha and beta sites.
What is immune tolerance?
Removal of B and T cell clones that have antigen binding sites specific to self proteins / antigens.
Describe the removal of self-reactive B cell clones in the bone marrow.
- As pre-B cells develop in the bone marrow they encounter host cells and if they react they are removed.
- If the pre-B cell surface receptor recognises host cell receptors - e.g. MHC molecules, they are eliminated.
- Only the B cells that don’t react with anything in the bone marrow can leave the bone marrow.
- If the pre-B cell’s surface receptor recognises soluble host proteins they are rendered anergic.
- If a B cell looks activated it is cleaned out of the system.
Describe the B lymphocyte maturation which occurs in the bone marrow.
- B cell maturation in a radial direction with more mature cells located toward the centre of the bone.
- Endosteal (inner) surface of bone with a layer of osteoclasts.
- Macrophages phagocytose negatively selected cells.
- Immature B cells travel to the spleen via the circulatory system.
Describe the removal of self-reactive B cell clones in the spleen.
- Transitional not fully mature B cells enter the periphery and pass through the spleen - a second round of removal of B cells with self-reactive antigen binding receptors in the spleen.
Describe the removal of self-reactive T cell clones
- More complex than B cell clone removal - involves 3 organs:
- Bone marrow
- Thymus
- Two distinct thymocyte lineages develop in the thymus.
- Most thymocytes die and only approximately 5% enter the periphery as CD8+ cytotoxic T cells or CD4+ helper T cells - importantly they are positively and negatively selected to recognise foreign / altered peptides presented in host MHC1 (CD8+) or MHC2 (CD4+) molecules on infected cells or APC respectively.
- Spleen
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What are MHC class I and MHC class II?
- Major histocompatibility complex antigens - host specific.
- Encoded by multiple gene families and have variable antigen presentation domains and present antigen (peptides) to T lymphocytes.
Describe the antigen presenting site on MHC antigen grooves.
- MHC antigen presenting groove variability - evolved to bind to most peptides of foreign / abnormal origin.
- MHC class I variability in the antigen presenting groove is conferred by amino acid variability on the α 1 and 2 chain domains.
- MHC class II antigen binding groove variability is conferred by the β1 domain. The α is invariant.
What is T cell positive selection?
- T cells with TCR in the thymus that recognise MHC I develop into CD8+ cytotoxic T cells.
- T cells with TCR in the thymus that recognise MHC II develop into CD4+ helper T cells.
- All others are deleted.
What is negative T cell selection?
- MHC I and II in the thymus (only) present host peptides and T cells CD8+ or CD4+ that recognise host peptides are deleted.
- Only non-self reactive T cells enter the periphery.
What happens to MHC class I during successful antigen presentation and T cell activation?
CD8 co-receptor bind to MHC class I during successful antigen presentation and T cell activation.
What happens to MHC class II during successful antigen presentation and T cell activation?
CD4 co-receptor bind to MHC II during successful antigen presentation and T cell activation.
Describe T lymphocyte antigen recognition.
- B cell receptors (a cell surface copy of the antibody that will be made by plasma cells if activated) recognise soluble antigens.
- T cells recognise processed antigens presented on the surface of host cells in MHC molecules and with the T cell co-receptors CD4 or CD8.
