il sistema maggiore di istocompatibilita’ - unicz.it course mhc.pdf · the mhc is a region of...
TRANSCRIPT
IL SISTEMA MAGGIORE DIISTOCOMPATIBILITA’
ENNIO CARBONEUNIVERSITA' DEGLI STUDI DI CATANZARO
"MAGNA GRÆCIA”Catanzaro
KAROLINSKA INSTITUTETMicrobiology and Tumor Biology Center MTC
Stockholm
SCOPO DELLA LEZIONE FORNIRE INFORMAZIONI AGGIORNATE SUL SIGNIFICATO BIOLOGICO DELL’MHC
ANALIZZARE LA GENETICA E GLI ASPETTI MOLECOLARI DEL FUNZIONAMENTO DELL’MHC
LE MOLECOLE MHC CLASSICHE E NON CLASSICHE LORO FUNZIONI
INTEGRARE CON UN SURVEY DELLA LETTERATURA RECENTE LE INFORMAZIONI OTTENIBILI DAI TESTI ADOTTATI
Struttura della lezione•Definizione e significato biologico.•Genetica del sistema maggiore di istocompatibilità. •Struttura molecolare.•Presentazione degli antigeni•Riconoscimento da parte dei linfociti.•MHC e Patologia
MHC-structure
Major Histocompatibility Complex (MHC): linked cluster of genes, which products play a role in intercellular recognition between self and nonself.
The MHC is a region of multiple loci that playmajor roles in determining, whether transplantedtissue is accepted as self (histocompatible) or rejected as foreign (histoincompatible)
The concept of Histocompatibility
A skin-graft transplanted from A donor to a genetically identical recipient is accepted, to a genetically disparate recipient is rejected
• MHC = Major Histocombitibiliy Complex• Minor Histocompatibility Antigens: proteins, which
are cell surface expressed and their peptides are loaded into MHC molecules
• MHC is a generic name • HLA = Human Leucocyte Antigen, eg SLA = Swine
Leucocyte Antigen• Mouse: MHC has an historical name = H2 (H-2)
stands for histocompatibility 2
Nomenclature
1.) Cell cell contact via cell surface receptors:cell surface proteins have been classified as CDs (=cluster of differentiation)
CD2
DCT cellMHCTCR
B7CD28
2.) Cell to cell contact via soluble mediators such as cytokines (interleukins-IL) or chemokines (CCR, CXCR)
DCT cellMHCTCR
B7CD28
IL-12
IFN-γ
Communication of cells in the body
Host defense
Against intracellular infection by viruses Against intracellular infection by mycobacteria
Structure of MHC class I
Computer graphic representationand ribbon diagramms of of the human MHC class I moleculeHLA-A2.
Heterodimer: α chain (43 kDa): polymorphicβ2-microglobin (12 kDa): non-polymorphic, non-covalently bound
α1 and α2: peptide binding, cleftformed by single structureα3: transmembrane
Structure of MHC class II
Computer graphic representationand ribbon diagramms of of the human MHC class II molecule, HLA-DRI
Heterodimer, 2 transmembrane chains:α chain (34 kDa)b-chain (29 kDa)
β1 and α1: peptide binding, not joinedby covalent bondΑ2 and b2 : transmembrane
Peptide binding groove is the MHC class II molecules is open at both ends
Peptide binding sites and binding sites for CD4 or CD8 on MHC class I and MHC class II
The binding sites for CD4 and CD8 on MHC class II molecules or MHC class I lie in the immunoglobulin domain, nearest to the membrane
Base ofβ2 domain(green)
β chain (white)
α chain(purple) β2-
Microglobuline(purple)
α−Chain (white)
Base of α3 domain(green)
Peptides bind to MHC I molecules through structurally related anchor molecules
Free amino and carboxytermini are stabilizing contacts
Peptides eluted from twodifferent MHC class I molecules are shown.
Anchor residues in green:Not identical but related:
eg: F and Y are both aromaticamino acids
V, L and I are large hydrophobic amino acids
MHC class I without peptideinstable
Pockets in the MHC molecules are lined by polymorphic amino acids.
Peptides that bind MHC class II are variable in length and anchor residues lie at various distances
from the ends of the peptide
Peptides that bind to mouse MHC II Ak allele, or human MHC II HLA-DR3Peptides that bind to MHC class II are at least 13-17 AA long, Ends of peptides are not conserved. Ends do not bind, binding pockets more permissiveBlue: negatively charged residue D, aspartic acid, E glutamic acid, green: hydrophobic residues
Peptide presentation MHC-I
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Peptide presentation MHC-II
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
THE EFFECT OF PEPTIDE LOADING
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Kb conformationalPeptide induced changes
Peptide presentation requirement
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
La conformazione del peptide
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
The expression of MHC molecules differs between tissues
MHC class I:Expressed on all nucleated cells
MHC class II: Expressed on surface of APCs(antigen presenting cells)
Viruses can infect all types of cellsPlasmodia (malaria)live in red blood cells
• MHC class I and II molecules have different structure, different distribution on cells in the body, and different function
• Peptides, that bind to MHC class I or II are derived of different compartments and are of different length
• The expression of MHC class I molecules can be regulated by interferon-γ.
Conclusion: Structure of MHC molecules
γδ T cells are not restricted by classical MHC molecules
• They may be specialized to bind certain types of ligands (heatshock proteins, mycobacterial lipid antigens) directly or presented by non-classical MHC molecules.
T cells bearing a γδ T cell receptor
Regulation of MHC class I expression
Expression of MHC class I regulated by sequences upstream of the coding part. MHC enhancer segment: enhancer A, IRE interferon response element, enhancer BMHC class I expression can be regulated by Interferon (IFN-γ). IFN-γ also induces the key components of the intracellular machinery thatenables peptides to be loaded onto MHC class I molecules
IL POLIMORFISMO DEI GENI DELL’ MHC
Gli alleli sono varianti molecolari della stessa sequenza genicaGeni che posseggono varianti comuni all’ interno della popolazioneSono detti Polimorfici
MHC classe I : HLA-A 95 alleli, HLA-B 207 alleli, HLA-C 50 alleli
MHC classe II: HLA-DR, HLA-DQ, HLA-DP sono polimorfici
Ogni individuo esprime 6 diversi geni HLA-Classe I e 6 diversi geni Per HLA-Classe II
Queste caratteristiche dei geni HLA sono alla base del rigetto dei trapianti
MHC diversity
MHC is polygenicmeans that it containsseveral different MHC class I and class II genes
MHC is polymorphic(poly=manyMorphic=shape, structure):
means that there aremultiple variants of a gene withina population as a whole
IL SISTEMA MAGGIORE DI ISTOCOMPATIBILITA’
Polimorfico e Poligenico
CROMOSOMA 6 UOMO,17 TOPOGrandezza 4 CentimorganContiene 200 geni
Detailed map of the human MHC
MHC class IB genes=Non-classical MHC Molecules=Non-conventional MHClass I molecules
• Ligands of inhibitory (HLA-G) or activating (MIC) Natural Killer cell receptors
• Presentation of non-conventional peptides to ?? Cells: In mice, the H-2M locus encodes a nonconventional MHC class I molecule that present peptides that have a formylated methionin (eg also found in prokaryotic organisms such as mycobacterium tuberculosis, listeria, Salmonella)
• Presentation of lipid antigens (CD1)
Function of non-conventional MHC molecules
MHC class I receptors on human Natural killer cells
Receptors……………………………Ligands effectKIR receptors(Killer immunoglobulin receptors)…HLA-C mostly
inhib.
NKG2A/CD94………………………..HLA-E mostlyinhib.
NKG2D……………………………….MIC activ.