Linking: Exceptions and MHC genetics Flashcards
What are the general rules - principle of mhc presentation
Exo= presented on mhc 2
Endo = mhc 1
Name 3 exceptions to the rules
Cross presentation
Presentation of cytosolic peptides by mhc class 2 molecules
Allorecognition
Describe cross presentation
Exogenous peptides presented on mhc class 1
What is the opposite of cross presentation
Presentation of cytosolic peptides by mhc class 2 molecules
What is cross presentation
Dendritic cells cross present antigens = take up exogenous antigens and redirect
Exogenous antigens redirected to endogenous pathway and presented on mhc1
Which cells can do cross presentation
Dendritic cells = only apcs so far that can cross present
Name and describe the 2 exs of cross presentation
Viruses phagocytosed by dendritic cells = exogenous antigens, when virus extra cellular and need c8+ cells
Virally infected cells are phagocytosed and viral peptides - release damps - presented on mhc molecules - class 1
Generally describe cross presentation mechanism
Actual redirection mechanism unclear
Dendritic cells need liscene
Describe dc licensing
Dc can present foreign antigen to cd4+ helper T cell and get licensed= to redirect exogenous antigen into endogenous pathway from T cells = thinks cd8+ would be better so cd4+ gives liscnece to dendritic cells = to go to endogenous pathway
What does license allow
Cytokine and ligand signalling between apc/helper T cell
Allows for their presentation on mhc class 1 = so can prime cd8+ t cell
What do we first need before licensing
Need to have activated cd4+ T cell first - then can license and cross present
How does presentation of cytosolic peptides by Mhc class 2 occur
Via autophagy= digestion and breakdown of a cell by its own organelles and proteins in lysosomes
Describe autohagosome
Specialized double membrane vesicles that contain cytoplasmic content and fuses with lysosomes = can be degraded
Describe steps of mechanism - autophagsome
Parts of cytoplasm taken into autopahgosome
Proteins degraded
Links up to exogenous pathway —> mhc2
Name EXAMPLE 1 of presentation of cytosolic peptides mhc2
Some pathogens = have adapted to resist intracellualr killing and the macrophages in which they live require stimulation by cytokines in order to kill pathogen (cannot do on own, this situation more common)
Describe further how macrophages help with cytosolic presentation of peptides by mhc 2
Will help redirect some of these peptides to be processed via exogenous and presented on mhc 2 = boost macrophages = fight against intracellualr parasite
T helper cell binds macrophage mhc class 2 with peptide
What is allorecognition
Tcr - recognize peptide in context of self mhc - mhc class 1
Describe h2k mouse exp
H2k mouse was injected with Lymphocytic choriomeningitis virus (LCMV). Days later, spleen cells, including cytotoxic T lymphocytes, from this mouse were incubated with LCMV-infected target cells of the same (H2k) or different haplotype (MHC alleles) (H2b). What do you observe?
= need T cells to be specific to mhc alleles = only h2b lcmv infected target cells = can kill cells, = release 51cr
Describe h2k mouse exp = conclusions
Tcrs not only specific to peptides but also specific to mhc
Wat are T cell responses
Mhc restricted
What does mhc restriction mean
A given T cell is able to recognize a specific peptide only when bound to a specific self mhc molecule
Describe ex of mhc restriction
Strain A animal only respond to at presnted by strain A apcs but not by strain B apc
When does recognition happen - mhc restriction
Tcr binds mhc AND peptide
If only specific to one or other = no recognition
What is allorecognition
Recognition of non self mhc by some T cells in body
How many T cells can react to allogenic mhc
1-10% of all T cells in an organism can react to non self (allogenic) mhc molecules (allo-mhc)
Describe why allorecognition important
Main mechanism of rejection of transplanted organs between genetically different individuals of same species = why ppl take immunosuppressants
If grant mhc a —> mhc b recipient = REJECTED
Describe allorecognition generally = images
Tcr= binds both mhc and peptide usually specific to both
But sometimes = non self mhc but doesn’t matter, T cells Will activate, proliferate and tru to get all cells with this non self mhc
Mhc dominant binding
Name the 2 types of allorecognition
Direct
Indirect
Describe direct allorecognition
Recipient T cell recognition of donor/transplant mhc molecules expressed on surface of donor cells = try to get rid of donor mhc protein
Describe indirect allorecognition
Recognition of processed donor peptides presented onto recipients own apcs via self mhc
Donor apc = shed parts of it = necrotic or apoptotic material shed mhc
Recipient apc takes up donor cells = include non self mhc —> process and present it to T cells
Donor peptide + recipient mhc = presnted on surface mhc = bc peptide non self mhc and not like pathogen = considered indirect allorecognition
Define gene
Segment of a chromosome that controls specific characteristics = encodes for protein
Define allele
One specific form of a gene
Define locus
Loci = Plural
Specific chromosomal location of a gene
What codes mhc molecules
Hla genes
Where mhc molecules found
In a cluster of genes on chromosome 6 in humans
Name classses mhc genes
2 main classes = class 1 class2
Describe mhc class 1 genes
Hla-a, hla-b, hla-c =
All encode for alpha chain
(Beta2micro= always the same, also on diff gene)
Describe mhc class 2 genes
Hla-dr, Hla-dq, Hla-dm, Hla-doa, Hla-dob
Encodes for alpha and beta chain
Define polymorphism
Multiple variations (forms) or alleles, exist for each gene
Describe polymorphism - allele
2 or more alternative forms of a gene at particular locus
How are alleles known
By number after locus = Hla-a1, hla-dr3 etc
Many mhc genes have >100 diff alleles
Give ex polymorphism
Hla-a= gene
Hla-a1 to hla-a2041 = alleles
Ex = inherited how-a1 and hla-a6 while someone else = inherited Hla-a2041 and hla-a200 = one from each parent
Provides variability in mhc molecules
Define haplotype
Particular combo of mhc alleles found on single chromosome
Each individual inherits one halpotype from each parent
How are mhc alleles expressed
Codominantly =
Both maternal and paternal mhc genes expressed in offspring cells
Best change of prensting all possible antigen peptides it encounters
Why is transplantation difffcult
Bc humans heterozygous at each locus
Define polygeny
Each individual has many copies of related genes
Multiple genes with same function but slightly diff structures
One haplotype form each parent = one of each hla with diff number (polymorphism) from each = 2x3 = 6
Describe ex polygeny
Inherit 3 diff mhc-1 alleles from each parent = so 6 alleles expressed in one person = (Hla-a, hla-b and hla-c allele per chromosome)
(Same for class 2)
What does polygeny result in
High degreee of variance in mhc expression in population
What does peptide binding groove have
Allelic variation (the most)
Differences clustered at aa locations within groove sites
Describe what peptide binding groove allelic variation causes = facilitates
Helps facilitate presentation of diff variety of peptides - diff peptide binding specificities
Describe what peptide binding groove allelic variation causes = folding
If areas outside of the binding groove altered too much = can affect structure conformation and folding of mhc molecule
What can a given mhc molecule bind
A given mhc molecule can bind numerous diff peptides - depends on type and size, and some peptides clad bind to diff mhc molecules
Define polygeny again
Hla-a hla-b hla-c
Same for class 2
Define polymorphism again
Multiple allelic variants of each of these genes in the population
Multiple alleles/forms of them
You transplant skin from the b/k progeny mouse into the b/b parent mouse. Will this transplant be successful? Why?
Noooo
Will reject k part of it
B/k can only give to b/k
Bb can give to bb or bk
Kk parent can give to b/k or kk only
You transplant skin from the b/k progeny mouse into the b/b parent mouse. Will this transplant be successful? Why?= compare to humans
Parent mice =have homologous chromosomes
But Humans heterozygous = even more difficult for transplantation of organs
Name EXAMPLE 2 of presentation of cytosolic peptides mhc2
Some viruses prevent presentation on mhc1 - if infect host cell - professional apc = chance that virus can inhibit presentation, so apc presents onto mhc2 to try to get help of cd4+ cells
