Lecture 12; MHC structure, function, restriction, transplantation and disease implications. Flashcards
What was learnt about tissue transplantation in the crimean war?
Tissue transplantation between soldiers was rejected after a period of time, inflam etc
However if this soldier received a second transplant from the same donor, the tissue was rejected faster, but a different donor would take equally long as the first time.
i.e the immune system learned and adapted.
This means that whatever was causing the infection was unique to individuals
What was the cause of this tissue rejection?
Major Histocompatibility Complex
or
Original name = HLC or H2 in mice
What is essential for t cell pathogen recognition?
MHC
Describe transplantation and the H2 locus;
A -> B = rejection
B -> A = rejection
A -> AB = Acceptance (neonatal tolerance to A antigen)
AB -> A = rejection
What is MHC?
A cell surface antigen.
Expressed mainly on leukocytes, but some somatic cells too.
Describe the different types of tissue grafts;
Autograft
Allograft (b/w humans)
Xenograft (animals)
Isograft (twins)
Why are isografts and xenografts successful?
Isograft - twins, gentically identicle, therefore very similar MHC complexes
Xenograft = Less likely rejection b/c MHC is so different from humans
What causes tissue rejection?
T cells (Thymus derived)
- Express TcR
- Diverse receptor recognition b/c germline gene rearrangement
Describe the type of t cells;
CD4
- Th1->cytokines->(innate immunity, macrophage mediated, little AB)
- Th2->cytokines->(humoral- Adaptive immunity i.e AB produced and isotype switching)
CD8
- Cytotoxicity (NO cytokines)
What MHC molecules do CD4 and CD8 express?
CD8- recognise MHC class 1
CD4 - recognise MHC class 2
What are the types of CD4 and CD8 response?
CD4 = extracellular pathogens
CD8 = Intracellular pathogens
Whats a restriction of T cells and what does this mean?
T cells are MHC restricted meaning that their ability to recognise forien antigens is controlled by polymoprhic antigens encoded by a genome region (MHC locus)
i.e T cells = CD4 and CD8 antigens
Describe the Rolf Zinkernagel and Peter Doherty experiment;
Infected mice who had two different H2 mice strains that differed in MHC locus.
- Infected with LCMV (lymphocyte choriomeningitis Virus)
- Isolated CD8 cells from each mouse lymph
- Found that the CD8 cells would only kill infected cells from the strain which they originated (named this MHC restriction) (wouldnt recognise MHC of other patients cells)(LCMV is intracellular) Despite CD8 killing the same virus in either instance
i.e CD8 cells would only kill infected cells expressing the correct MHC antigens
Tissue rejection and virus protection were both controlled by MHC
What do T cells recognise?
Two components;
- Non self antigen derived from pathogen
- MHC antigens from host
What do polymorphisms in MHC regulated?
Regulate Immune protection against pathogen
Describe three features of MHC genes;
Polymorphic, polygenic and co-dominant
What is meant by polymorphic in terms of MHC genes?
Polymorphic - They vary widely in sequence between individuals but remain constant within each person
What is meant by co-dominant in terms of MHC genes?
Each person expresses both maternal and paternal copies
What is meant by polygenic in terms of MHC genes?
Each person has more than one version of class one and two antigens
Describe some of the CLASSIC MHC HLA polymorphisms in man;
MHC class 1
HLA-A
HLA-B
HLA-C
MHC class 2
HLA-DR (a Chain invariant
HLA-DQ
HLA-DP
MHC class 3 (includes TNF and compliment genes)
What are the non-classical MHC genes?
CD1 HLA-E HLA-F HLA-G HLA-H
Much less polymorphic
What are the min and max number of different MHC antigens a person can have?
Min 6 and max 12 (codominance)
Thus MHC locus has extreme variability
What drives the MHC genes to be polymorphic?
MHC molecules have become polygenic and polymorphic to ensures the species as a whole can cope with a common pathogen
thus different areas of the world possess different MHC’s
Describe MHC expression;
MHC molecules are deferentially expressed.
i.e
MHC class One is one all cells except RBC (imp tissue killing and CTL regulation
MHC class 2 are only on select APC’s.
- Macrophages
- B cells
- Dendritic cells
- Activated T cells also
MHC 1 and 2 have very different roles in CD8 + CD4
Describe MHC class one structure;
Two chains; H(c) non covalently associated with B-2 microglobulin
Heavy chain has 3 domains , a-1,2,3
- a-1,2 polymorphic
- a-3 binds B2M and CD8
Describe the MHC class one antigen binding cleft;
Formed by 8 beta strand antiparallel beta sheet floor over which two long alpah helices lie.
The groove created in MHC class one can bind small peptides (8-10) aa long. (polymorhpism groove)
Thus can bind many peptides as the binding domain is very polymorphic
Describe MHC class 2 structure;
2 chains = a and b. non covalently linked
Each has two domains i.e a1 a2
a chain is polymorphic thus forms the binding groove (open at both ends unlike MHC 1) thus can bind peptides of any length
Describe adaptive cellular immunity;
- T cells recognise antigens on a cell surface (MHC)
- Antigen recognition of t cells is goverened by MHC locus.
Describe MHC class one function;
MHC class one mediate CD8 (CTL) against INTRAcellular pathogens
- Infected cells MHC class one binds viral peptide produced inside the cell.
- This activates CD8 = cytotoxic activity and kills the cell and thus virus.
Describe MHC class 2 function;
MHC class 2 mediates CD4 helper t cell of extra cellular pathogens
- APC express pathogen material i.e bacteria, fungi, protozoa on MHC class 2 receptors. this activates CD4 that produce cytokines to help B cells produce antibody or drive CTL to expand and kill infected cells
i. e TH1 - cytokines - Innate immunity - Macrophage mediated
TH2 - cyotkines - humoral - adpative immunity,ab production
When a cell encounters a foreign peptide how does it express it with MHC
Foreign peptide is buried with MHC
subject of another lecture
Describe peptide binding motifs for MHC molecules;
Peptides bind by side chains into pockets in the MHC molecule (binding cleft)
For each allele the pocket differs
Each allele has a specific motif for binding
Describe CD4
Co-receptor of TcR
- 80% of resting t cells
- monomeric protein
- Binds to the two alpha domains of MHC class 2
- CD4 has tyrosine kinase domain attatched to its intracellular domain which triggers t cell activation through p/ph
Describe CD8
Co-receptor of TcR
- Heterodrimer
- 20% of resting peripheral t cells
- Binds a3 domain of MHC class 1
- has tyrosine kinase domain attatched to its intracellular domain which triggers t cell activation through p/ph of TcR
Describe MHC and disease susceptibility;
- because MHC locus is polymorphic, it is also strongly associated with disease
i. e Rheumatoid arthritis, type one diabetes, MS
