AG MHC HLA APC Ii EPR TAP ABC CLIP TCR

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2 !! AG MHC HLA APC Ii EPR TAP ABC CLIP TCR Antigen Major Histocompartibility Complex Human Leukocyte Antigen Antigen Presenting Cell Invariant Chain Endoplasmatic Reticulum Transporters Associated with Antigen Processing ATP Binding Cassette Class II associated Invariant-chain Peptide T CellC Receptor

3 !!!" # proteins glycolipids carbohydrates nucleic acids But only proteins can cause adaptive immune response Sources: viruses, bacteria, protozoan parasites, microfungi, tumors, grass pollen

4 AG processing is a generation of peptides from intact proteins AG presentation is a display of the AG peptides in complex with MHC molecules on the surface of the cell

5 $! %"&# highly polymorphic glycoproteins encoded in a large cluster of genes Classes: MHC I (express in all nucleated cells) MHC II (express only in APC) Professional antigen presenting cells (APC): monocytes/macrophages dendritic cells B cells

6 ' &!( )

7 * && Membrane-bound glycoproteins & Peptide binding grove 2 1 & Peptide binding grove microglobulin APC membrane

8 &!( MHC I binds 8-10 amino acids by both ends MHC I binds peptides anchor residues Variants of peptides binding to the same MHC I allele by Garland Publishing Green - anchor aminoacids Main stabilizing contacts: 1 Amino and carboxy termini 2 Anchor aminoacids

9 &!( MHC II binds more than 13 amino acids Variants of peptides binding to the same MHC II allele Green and blue - anchor aminoacids 2001 by Garland Publishing Main stabilizing contacts: 1 Hydrogen bonds with peptide backbone 2 Anchor aminoacids

10 & Highly polymorphic gene families Chromosome 6 6p21.3 HLA gene complex DPA DQA DRA DPB DQB DRB Encoded and chains C4B C4BCYSP21 C4A C2 Bf HSP70 TNF B C E A G F Encoded chain HLA class II region Class III region (Non-HLA) HLA class I region

11 + 395 MHC I MHC II 323 Human MHC molecules are highly polymorphic B C A polygeny DP DP DQ DQ DR DR polymorphism polymorphism and polygeny Combination of MHC II chains enlarges MHC diversity

12 '($ endosome lysosome cytosol nucleus cytosol vesicular system Golgi apparatus secretory vesicle endoplasmatic reticulum Golgi apparatus endoplasmatic reticulum lysosomes other intracellular vesicles 2001 by Garland Publishing

13 && & & All intracellular antigens: viruses and bacteria, tumor Activation of cell death All extracellular antigens: bacteria and some parasites, toxins Activation of cell to kill intravesicular parasite Activation of B cell to secret Ig to eliminate extracellular AG 2001 by Garland Publishing

14 !& Protein degradation to peptides by the proteosome Peptides transportation to EPR by TAP; peptide binding and complete folding of MHCI calreticulin Cytozol EPR Export to the cell surface tapasin TAP2 TAP1 Erp57 MHC1 ABC Peptid binding peptide fragments protein proteosome peptide fragments

15 !& Invariant chain (Ii) forms complex with MHC II and block binding with peptide in EPR MHC II transportation to endocytic vesicle; Ii cleavege Endocytosis of AG and their degradation to peptides HLA-DM binds to MHC II, releasing CLIP and allowing AG peptide binding (Ii) 2001 by Garland Publishing

16 CD8 T cell activation CD4 T cell activation TCR TCR CD4 molecule AG CD8 molecule AG MHC I MHC II APC differentiation APC differentiation MHC restriction

17 &, &, -!&

18 ' Foreign peptide: self- MHC binding T cell Peptide dominant binding T cell MHC dominant binding T cell TCR TCR TCR self MHC2 nonself MHC2 nonself MHC2 APC APC APC 2001 by Garland Publishing

19 &. Autoimmune diseases Multiple sclerosis Systemic lupus erythematosus Rheumatiod arthritis Type I insulin-dependent diabetes Ankylosing spondylitis DR2 DR3 DR4 DR3/DR4 heterozygote B27 Allergic diseases Regulation of IgE in serum blood Atopic bronchial asthma DRB and DRQ, DPB DRQ, DRB - protective allele, - susceptible allele

20 &. Infection disease Prarazites Malaria Leishmaniasis B53, DRB1 A28, B22, DQ28, DR2, A11, B5, B7 DQ3 Viral infection Hepatitis B persistence Hepatitis C persistence DR7 DRB1, DR6, DR2 DR5 Bacterial infection Chronic Lyme disease DRB - protective allele, - susceptible allele

21 . Immunobiology 5 Janeway C.A., Travers P., Walport M., Sholomchik M P , P , P , P by Garland Publishing

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