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Transcript of mci.img.cas.czmci.img.cas.cz/pdf/AG presentation.pdf · MHC2 nonself MHC2 TCR TCR nonself MHC2 APC...
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AGAG
MHCMHC
HLAHLA
APCAPC
IiIi
EPR EPR
TAPTAP
ABCABC
CLIPCLIP
TCR TCR
– AAntiggen
– MMajor HHistocompartibility CComplex
– HHuman LLeukocyte AAntigen
– AAntigen PPresenting CCell
– Invariant Chain
– EEndopplasmatic RReticulum
– TTransporters Associated with AAntigen PProcessing
– AATP BBinding CCassette
– ClClass II associated IInvariant-chain PPeptide
– T CT Cell RReceptor
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�� proteinsproteins� glycolipids� carbohydrates� nucleic acids
ButBut only proteinsonly proteins can cause adaptive immune response
Sources:Sources: viruses, bacteria, protozoan parasites, microfungi, tumors, grass pollen
AG processingAG processing is a generation of peptides from intact proteins
AG presentationAG presentation is a display of the AG peptidesAG peptidesin complex with MHCMHC molecules on the surface of the cell
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� highly polymorphic glycoproteins� encoded in a large cluster of genes
Classes:Classes:MHC IMHC I (express in all nucleated cells)
MHC IIMHC II (express only in APC)
ProfessionalProfessional antigen presenting cells (APC)antigen presenting cells (APC):� monocytes/macrophages� dendritic cells� B cells
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�2
Membrane-bound glycoproteins
�2 �1
�3 �2- microglobulin
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APC membrane
Peptide bindinggrove
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�2
Peptide bindinggrove
Peptide bindinggrove
�2
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MHC I binds 8-10 amino acids by both ends
Variants of peptides binding to the same MHC I allele
Green - anchor aminoacids
123
MHC I binds peptides anchor residues
Main stabilizing contacts:Main stabilizing contacts: 1 Amino and carboxy termini
2 Anchor aminoacids
© 2001 by Garland Publishing
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MHC II binds more than 13 amino acids
Main stabilizing contacts:Main stabilizing contacts: 1 Hydrogen bonds with peptide backbone
2 Anchor aminoacids
Green and blue - anchor aminoacids
123
Variants of peptides binding to the same MHC II allele
© 2001 by Garland Publishing
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Highly polymorphic gene families
Chromosome 6 6p21.3
DPB
DPA
DQB
DQA
DRB
DRA
C4B
C4B
CY
SP
21
C4A
C2
Bf
HS
P70
TNF
AB C E G F
HLA gene complex
HLA class II region Class III region (Non-HLA) HLA class I region
Encoded � and � chains Encoded � chain
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Human MHC molecules are highly polymorphic
89
1945
20
323
2
MHC IIMHC II
DP� DP� DQ�DQ� DR� DR�
395
395
93
195
MHC I
C AB
polymorphismpolygenypolymorphism and polygeny
Combination of MHC II chains enlarges MHC diversity
� cytosol
� vesicular system
Golgi apparatus endoplasmatic reticulumlysosomes other intracellular vesicles
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lysosomeendosome
secretory vesicle
Golgi apparatus endoplasmatic
reticulum
nucleuscytosol
© 2001 by Garland Publishing
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All intracellular antigens: viruses and
bacteria, tumor
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All extracellular antigens: bacteria and some parasites, toxins
Activation of cell to kill intravesicular
parasite
Activation of B cell to secret IgIg to eliminate
extracellular AG
Activation of cell death
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© 2001 by Garland Publishing
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Protein degradation to peptides by the proteosome
peptide fragments
Export to the cell surface
Peptides transportation to EPR by TAP; peptide binding and
complete folding of MHCI
Peptid binding
EPR
protein
proteosome
peptide fragments
TAP1
Erp57
calreticulin
tapasinTAP2
ABC
Cytozol
MHC1
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Endocytosis of AG and their degradation to
peptides
MHC II transportation to endocytic vesicle;
Ii cleavege
Invariant chain (Ii) forms complex with MHC II and
block binding with peptide in EPR
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(Ii)
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HLA-DM binds to MHC II, releasing CLIP and
allowing AG peptide binding
© 2001 by Garland Publishing
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MHC restrictionMHC restriction
APC
TCR
MHC I
APC
CD8 T cell
TCR
MHC II
AGCD8 molecule
activation activation
differentiation differentiation
AG AG
CD4molecule
CD4 T cell
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TCR
self
MHC2nonself
MHC2
TCR TCR
nonself
MHC2
APC APC APC
T cellT cell T cell
Foreign peptide: self-MHC binding
MHC dominant binding
Peptide dominant binding
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© 2001 by Garland Publishing
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B27�Ankylosing spondylitis
DR3/DR4 heterozygote �Type I insulin-dependent diabetes
DR4�Rheumatiod arthritis
DR3�Systemic lupus erythematosus
DR2�Multiple sclerosis
Autoimmune diseases
Allergic diseases
DRQ� , DRB�Atopic bronchial asthma
DRB� and DRQ� , DPB�Regulation of IgE in serum blood
� - protective allele, � - susceptible allele
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DRB �Chronic Lyme disease
Bacterial infection
DR5 �Hepatitis C persistence
B53� , DRB1�Malaria
A28� , B22� , DQ28� , DR2� , A11� , B5� , B7�DQ3�
Leishmaniasis
DR7 �DRB1 �, DR6 �, DR2 �
Hepatitis B persistence
Viral infection
Prarazites
Infection disease
� - protective allele, � - susceptible allele
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Immunobiology Immunobiology 55
Janeway Janeway C.A., Travers P., C.A., Travers P., Walport Walport M., M., Sholomchik Sholomchik M.M.
2001. 2001. –– P. 105 P. 105 –– 120, P. 155 120, P. 155 –– 182, P. 504 182, P. 504 –– 507, 507,
P. 523 P. 523 -- 526526
© 2001 by Garland Publishing