0515 - MHC Revision and Graft Vs Host Flashcards
Outline Endogenous (MHCI) presentation.
Protein digested in proteosome, with peptide fragments delivered to ER (transporter-antigen processing - TAP). There it links with a new MHCI Molecule, and the complex is exported to the cell surface.
How is MHCI formed (genetically)?
3 alpha portions coded by HLA-A, B, and C in the MHC cluster on Chromosome 6. Non-polymorphic (doesn’t need to touch the antigen) Beta portion coded on chromosome 15.
How is MHCII formed genetically?
Coded by the HLA-D region, DP, DQ, DR, on Chromosome 6. Consists of alpha and beta chains.
Outline Exogenous (MHCII) presentation.
Pathogenic protein enters via phagocytosis. Enters phagolysosome and is degraded. Degraded peptide fuses with MHCII in vesicles in cytoplasm, and is exported to the cell surface.
What is the role of CD4/CD8 in antigen presentation?
T-cell receptor/MHC-peptide interaction is stabilised by CD4 (MHCII) or CD8 (MHCI). Low affinity, so CD stability is very important.
What are some important differences between MHC I and II
I - Endogenous, II Exogenous
I - CD8, II - CD4
I - Expressed on all nucleated cells, II - Expressed on APCs (Dendritics, Macrophages, B-cells).
MHCI coded by ABC, MHC II coded by DP, DQ, DR
MHC I and II are both are heterodimers. What is their structural difference?
MHC I - Has B-2 Microglobulin as smaller peptide 3:1, which is not involved in polypeptide binding domain, but MHC2 has both of them as histocompatibility antigens 2:2. (Therefore, heavy chain is important polymorphism for Class I)
What is polymorphism? How does it relate to the MHC?
Polymorphism - Variation within genome across population of same species. MHC has the greatest polymorphism in the genome.
Important because it provides a genetic basis for different MHCs, rather than just somatic mutations.
How does MHC polymorphism interact with transplant medicine?
Provides genomic basis for immunity. Want to get as little polymorphism as possible, as some individuals have anti-HLA antibodies.
Use the polymorphisms to understand a tissue type.
What is the genetic basis of HLA?
Genetics are HLA-A, B, C (MHCI), and HLA-DP, DQ, DR (MHCII). Each person has two copies of each (one per chromosome). As a result, you inherit the ‘set’ of A, B, C, DP,DQ,DR. As a result, there are four possible HLA patterns you could inherit from your parents - Dad=AB, Mum = 12 (A1, A2, B1, B2). The genes are co-dominant.
Given this, there is a ¼ chance that siblings will have a perfect match, a 50% chance they will match 1, and a ¼ chance they won’t match at all.
What is allorecognition?
Recognition of graft antigen-MHC complexes (or the MHC’s themselves) by the host tissue.
What is direct allorecognition?
Host T cells recognise the allogenic (donor) MHC itself as foreign. Involves both CD4 and CD8 T-cells and thus triggers both a cytokine response and a CD8-cytotoxic response against the graft.
What is the indirect pathway of allorecognition?
Host APC uptakes allogenic (donor) MHC as a foreign antigen, processes it, and presents a peptide fragment on host MHC.
Outline GvHD
A disease that occurs when immunocompetent cells are transferred into immunosuppressed individuals, and recognise the individual’s MHC’s as foreign. Mediated by T-cells, and can come in acute and chronic forms.
Outline acute GvHD
Occurs within days-weeks of allogenic bone marrow transplantation. Involves immune system, and epithelia of skin, liver, and intestines. As a result, typically presents with rash, jaundice, and bloody diarrhoea. Damage comes directly from CD-8 T-cells, and indirectly from cytokines released by CD-4’s.
