21

CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

  • Upload
    others

  • View
    1

  • Download
    0

Embed Size (px)

Citation preview

Page 1: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

����������������� ��������� �������������������� ��������� ���

���� ���� ��

�������

������������������ ���������

��� �� ������������ � ��������� �

��������

�� ����������������� ����������������

Page 2: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�!!��� �����!!��� ����

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

Page 3: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�������������� ��� �����!�� ������ ��!������������� ��������������� �������� ���!�����"����#�

�� proteinsproteins� glycolipids� carbohydrates� nucleic acids

ButBut only proteinsonly proteins can cause adaptive immune response

Sources:Sources: viruses, bacteria, protozoan parasites, microfungi, tumors, grass pollen

Page 4: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

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

������������ ��������� ��������������� ��������� ���

Page 5: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

� $�� $�������� ��!������������ ��!����������%�"�&�#������%�"�&�#�

� 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

Page 6: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

'������� ��������&�����'������� ��������&�����

!�������(����� ���������������!�������(����� ���������������

))

Page 7: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

*����������&���� ����&������ �������*����������&���� ����&������ �������

�2

Membrane-bound glycoproteins

�2 �1

�3 �2- microglobulin

�&����&��� �&�����&����

APC membrane

Peptide bindinggrove

�1 �1

�2

Peptide bindinggrove

Peptide bindinggrove

�2

Page 8: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�&����!�������(������������&����!�������(�����������

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

Page 9: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�&�����!�������(������������&�����!�������(�����������

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

Page 10: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�&��������������&�������������

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

Page 11: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

+�������� � ���+�������� � �����������������

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

Page 12: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

� cytosol

� vesicular system

Golgi apparatus endoplasmatic reticulumlysosomes other intracellular vesicles

'(�� $������� ��� � �� ����'(�� $������� ��� � �� ����

lysosomeendosome

secretory vesicle

Golgi apparatus endoplasmatic

reticulum

nucleuscytosol

© 2001 by Garland Publishing

Page 13: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

����������

All intracellular antigens: viruses and

bacteria, tumor

�&����&��� �&�����&����

����������������������������������

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

�&���� ����&���������������������� ��&���� ����&���������������������� �

��������������� ��� � �� ������������������� ��� � �� ����

© 2001 by Garland Publishing

Page 14: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�����������������!���&��������������������!���&���

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

Page 15: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�����������������!���&���������������������!���&����

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

���

�������������

(Ii)

� � � �� � � ���� � � ��� �

� �� �� �� �

� � ���� � ����

HLA-DM binds to MHC II, releasing CLIP and

allowing AG peptide binding

© 2001 by Garland Publishing

Page 16: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�������������� ����������������� ���

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

Page 17: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

�&����������,�&����������,

���������������-������� �� ����������

!������������&��� �������

Page 18: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

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

' ���� �� ������������' ���� �� ������������

© 2001 by Garland Publishing

Page 19: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

&.�� ������� ���&.�� ������� ���

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

Page 20: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

&.�� ������� ��&.�� ������� ��

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

Page 21: CAS presentation.pdf · 2016-04-21 · AG MHC HLA APC Ii EPR TAP ABC CLIP TCR – Antigen – Major Histocompartibility Complex – Human Leukocyte Antigen – Antigen Presenting

.��� ���.��� ���

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