MHC Flashcards
What does MHC stand for?
Major histocompatibility complex
What is MHC?
Complex of genes that defines a genetic locus
Highly polymorphic (causes diversity)
Where is MHC class I expressed and what is it recognised by?
Expressed on most cells except neurones
Recognised by cytotoxic T-cells expressing CD8 +
How does the MHC conveyor belt work?
MHC conveyor belt loads self proteins that can be degraded in the cell - these proteins are identified by T-cells
If the T-cell identifies MHC + self peptides it ignores the cell
But if T-cell recognises non-self peptides ie will respond:
- CD8+ cytotoxic T-cell binds to MHC I peptide and kills infected cells
- CD4+ helper t-cells bind to MHC class II on APC (antigen presenting cell) and help B cells
Where are T-cells educated?
Thymus
Describe the role of MHC in immune tolerance?
Immature T cells (before leaving thymus) are presented to thymus epithelial cells (MHC I) and thymus dendritic cells (MHC II)
thymus uses these cells to present self proteins (peptides) to T-cell receptor by immature T cells
These T-cells have CD4 and CD8 - called double positive immature T-cells
Positive selection - when immature T-cells have weak binding to MHC self protein it survives
Negative Selection - when immature T-cells have strong binding to MHC self protein it dies
What is negative selection?
When immature T-cell has strong binding to MHC self protein it dies
What is positive selection?
When T-cell has weak binding to MHC self protein it survives
What causes autoimmune diseases?
Some helper T-cells arable to leave thymus, despite having strong biding to self MHC proteins
These T-cells help B-cells produce antibodies against some self proteins
These are called autoantibodies
What is HLA?
Human leukocyte antigens
Same as MHC but in humans not mice
What is a HLA gene? And why is it important?
Defines a genetic locus that varies by individuals
Important in understanding increasing risk of autoimmune diseases and understanding the immune response of a population to a vaccine
What is the action of MHC I?
Kills infected cells
What is MHC II expressed by and recognised by?
Expressed by APCs
Recognised by T-helper cells via CD4+
What is the action of MHC II ?
T-helper cells bind to MHC II on APCs and provide help to B-cells
What is the function of T-helper 1 cells?
Aid effector functions of antibodies by allowing isotope switching to make different classes of antibodies
What is the function of T helper 2 cells?
Aid B-cell differentiation
Aid plasma cell generation - secretes antibodies
Important during vaccination - TH2 stimulated in good vaccination
How is a single gene able to generate a vast number of antigen biding specificities?
Ig gene rearrangement
A whole range of variable, diversity and joining regions can be spliced together to generate Ig’s with different antigen binding regions
How do B and T cells find each other to agree on antigens?
Lymph nodes act as a funnel to concentrate antigens and immune cells
Antigens get to the lymph node via dendritic cells which take up antigens by phagocytosis, dendritic cells make lots of MHC I which binds peptides
What are adaptions of dendritic cells ?
Massive surface area for engulfing pathogens
Make large quantities of MHC I to bind peptides
Express lots of peptides on their plasma membrane
What is the action of dendritic cells?
- PAMPs recognised by TLRs in innate immunity - triggers phagocytosis, triggers delivery of pathogen to lysosomes for degradation, enhances uptake into dendritic cells
- Dendritic cells take up antigens at sites of infection and present peptides on MHC II
- Change the expression of cell adhesion molecules allowing them to migrate through lymphatics to find T-cells
4.Dendritic cells present antigen to helper T-cells, which divide if see non-self peptide - T-cells help B cells to make antibodies
How do B and T cells fins the vaccine antigen when it is injected into the arm?
- Vaccines contain adjuvants that activate TLRs and increase phagocytosis by APCs
- Adjuvants contain: PAMPs, precipitate antigens to increase phagocytosis, encapsulate antigens in nano materials, to: activate TLRs, increase phagocytosis by APCs
What are two mechanism of tolerance?
Central tolerance
Peripheral tolerance
What are the 4 major peripheral tolerance mechanisms? And how do they work?
1.T regulatory cells - inhibit response of all other immune cells be expressing CTLA-4 receptors, which inhibit co-stimulatory B7 on APCs
2. Colonial anergy - occurs due to lack of co-stimulation, decreased expression and availability of B7 in presence of self-antigens
3. Peripheral depletion - cells are induced to die by up regulation of cell surface marker FAS
4. Peripheral tolerance in B cells - via anergy due to lack of activating stimulus
What are steps of recombination of B cells?
- Recombination first occurs for the heavy chain in pro-B cells
- If the heavy chain is ok the pro-B cell becomes a pre-B cell and rearranges the light chain (if not the cell dies)
- If the heavy and light chains assemble properly the B-cell becomes an immature B-cell with a B-cell receptor
- If B-cells make a self-reactive B-cel. Receptor that binds to self-proteins, B-cell cannot leave bone marrow and dies
Describe the steps of T cell maturation/education
- T cell pre-cursors from bone marrow and liver have not rearranged genes
- T cells migrate to thymus
- VDJ recombination occurs in the thymus before the T cells get to the lymph nodes
- Self reactive T-cells are removes in the thymus
- Early progenitor T cells arriving from bone marrow to thymus encounter adhesion molecules that stimulate the proliferation of immature T cell and stimulate the TCR gene rearrangement
- Thymic medulla cells use MHC to educate T cells by presenting self proteins to immature T cells and their newly rearranged receptors
- CD4 and CD8 determine thee type of T cell emerging from thymus
What is the limitation of self-reactive T cells in the thymus called?
Central I cell tolerance
