1. 4th LECTURE Public Health BSc CONNECTING INNATE AND ADAPTIVE IMMUNITY: ANTIGEN PRESENTATION Arpad Lanyi

2. MECHANISM OF DEFENSE IN GENERAL environmental changes (e.g. infection) recognition (by receptors) effector functions (e.g. to get rid of pathogens)

3. SENSINGRECOGNITION SIGNALING RESPONSE INNATE IMMUNITY CellsReceptors Signaling pathways Cell-Cell collaboration Effector functions DEFENSE SYSTEMS ADAPTIVE IMMUNITY SENSINGRECOGNITION SIGNALING RESPONSE

4. EFFECTOR MECHANISMS OF INNATE IMMUNITY NATURAL KILLER CELLS PHAGOCYTIC CELLS COMPLEMENT SYSTEM

5. PHAGOCYTIC SYSTEM NEUTROPHIL - MACROPHAGE - DENDRITIC CELL  Defense against infectious diseases  Elimination of tumor cells  Transplantation rejection Gatekeeper function Sensing commensals and pathogens Rapid activation of innate immunity Priming adaptive immune responses Maintenance of self-tolerance

6.  Infections  Trauma  Physical and Chemical agents (thermal injury, irradiation, chemicals)  Tissue Necrosis  Foreign bodies (splinters, dirt, sutures)  Hypersensitivity or autoimmune reactions  Increased vascular diameter  increased flood flow  Increased vascular permeability  edema  Migration of leukocytes from the blood to the affected tissue (diapedesis/extravasation), accumulation, effector functions MAJOR COMPONENTS OF INFLAMMATION: TRIGGERS OF ACUTE INFLAMMATION:

7. ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE

9. activating surface enzyme Activating surface required! inactive precursors limited proteolysis COMPLEMENT SYSTEM

10. THE EFFECTOR FUNCTIONS OF THE COMPLEMENT SYSTEM 1.help inflammatory processes: –increase vascular permeability –recruit leukocytes 2.opsonize pathogens  facilitate recognition by innate immune cells 3.direct lysis of pathogens/cells (Membrane Attack Complex – MAC)

11. SECONDARY LYMPHOID ORGANS/TISSUES LYMPH NODES SPLEEN TONSILS (Waldeyer’s ring) Diffuse lymphoid layers under the epithelial barriers: –SALT (skin-associated lymphoid tissue) –MALT (mucosa-associated lymphoid tissue) BALT (bronchus-associated lymphoid tissue) GALT (gut-associated lymphoid tissue) Sites of lymphocyte activation and terminal differentiation

13. THE MEETING OF INNATE AND ADAPTIVE CELLS

14. ACTIVATION OF T CELLS

15. T cells can only recognise antigens that are bound to MHC molecules!

17. THE OUTCOME OF INFECTION IN A POPULATION WITH POLYMORPHIC MHC GENESMHC-Gen v v v v v v v v v v v v v vvv v v v v v v v v v Example: If MHC X was the only type of MHC molecule Population threatened with extinction Pathogen that evades MHC X MHC XX Population is protected

18. MHCI Displays intracellular antigens to cytotoxic T cells

19. Peptides of endogenous proteins bind to class I MHC molecules presented to cytotoxic T cells Tc Endogenous Ag RECOGNITION OF ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES TCR Peptide MHCI APC MHCI is expressed by all nucleated cells

20. STRUCTURE OF CLASS I MHC MOLECULES A polymorphic α chain and and a non-polymorph β2 mikroglobulin α1 és α2 domains are responsible for peptide binding

21. MHC class I accommodate peptides of 8-10 amino acids Cleft geometry MHC class II accommodate peptides of >13 amino acids  -M  -chain Peptide  -chain  -chain Peptide

22. Synthesized antigens – endogenous antigens (virus, tumor) Internalized antigens – exogenous antigens (any protein) Degrade protein antigens to peptides = processing Protein-derived peptides are presented by MHC (HLA) membrane proteins  antigen presentation MHC molecules present both self and non-self protein-derived peptides MHC class I molecules are expressed in all nucleated cells MHC class II molecules are expressed by professional antigen presenting cells ANTIGEN PRESENTING CELLS

23. CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS

24. Degradation of endogenous proteins takes place in the proteasomes, they are presented on cell surface by MHC I

25. MHC do not recognize or distinguish self and nonself peptides Antigen presentation goes in the absence of pathogen or T cells as well !

26. System optimalization 2: MHCI present the intracellular area. Next step, how could the MHC molecules (and the T cells) monitor the extracellular enviroment?

27. 22 11 22 11 PEPTIDE STRUCTURE OF CLASS II MHC MOLECULES MHCII Expressed by professional antigen presenting cells Macrophage, dendritic cell, B cell

28. 22 11 22 11 PEPTID PEPTIDE α1 and β1 domens are responsible for peptide binding A polymorphic α and a polymorphic β chain STRUCTURE OF CLASS II MHC MOLECULES

29. MHC class I accommodate peptides of 8-10 amino acids Cleft geometry MHC class II accommodate peptides of >13 amino acids  -M  -chain Peptide  -chain  -chain Peptide

30. Presentation of extracellular peptides by MHCII

31. Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules Tc Endogenous Ag RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES Exogenous Ag Th Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules

33. The recognition of the MHC-presented peptide antigen is not enough for T cell activation!

35. DIFFERENTIATION OF CD4+ T CELLS The polarization of helper T cell response is regulated by multiple factors: –origin of the presented peptide –nature of the APC –microenvironment –etc. In case of an infection both Th1 and Th2 cells are generated in different sites of the secondary lymphoid organs Imbalance occurs in case of special disorers: –Th1 dominance: e.g. mycobacterial infection –Th2 dominance: e.g. allergy, SLE cellular, pro- inflammatory humoral, anti- inflammatory