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Transcript
4th LECTURE Public Health BSc CONNECTING INNATE AND ADAPTIVE IMMUNITY: ANTIGEN PRESENTATION Arpad Lanyi MECHANISM OF DEFENSE IN GENERAL • environmental changes (e.g. infection) • recognition (by receptors) • effector functions (e.g. to get rid of pathogens) DEFENSE SYSTEMS ADAPTIVE IMMUNITY INNATE IMMUNITY SENSING Cells SENSING RECOGNITION Receptors RECOGNITION SIGNALING Signaling pathways SIGNALING Cell-Cell collaboration RESPONSE Effector functions RESPONSE EFFECTOR MECHANISMS OF INNATE IMMUNITY NATURAL KILLER CELLS PHAGOCYTIC CELLS COMPLEMENT SYSTEM PHAGOCYTIC SYSTEM NEUTROPHIL - MACROPHAGE - DENDRITIC CELL Gatekeeper function Sensing commensals and pathogens Rapid activation of innate immunity Priming adaptive immune responses Maintenance of self-tolerance Defense against infectious diseases Elimination of tumor cells Transplantation rejection TRIGGERS OF ACUTE INFLAMMATION: Infections Trauma Physical and Chemical agents (thermal injury, irradiation, chemicals) Tissue Necrosis Foreign bodies (splinters, dirt, sutures) Hypersensitivity or autoimmune reactions MAJOR COMPONENTS OF INFLAMMATION: 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 ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE COMPLEMENT SYSTEM inactive precursors enzyme limited proteolysis activating surface Activating surface required! 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) SECONDARY LYMPHOID ORGANS/TISSUES Sites of lymphocyte activation and terminal differentiation • 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) THE MEETING OF INNATE AND ADAPTIVE CELLS ACTIVATION OF T CELLS T cells can only recognise antigens that are bound to MHC molecules! THE OUTCOME OF INFECTION IN A POPULATION WITH POLYMORPHIC MHC GENES Example: If MHC X was the only type of MHC molecule MHC-Gen MHC XX v v Pathogen that evades MHC X v Population threatened with extinction v v v v v v v v v v v v v v v v v v v v v v Population is protected MHCI Displays intracellular antigens to cytotoxic T cells RECOGNITION OF ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES MHCI is expressed by all nucleated cells Tc TCR Peptide MHCI Endogenous Ag APC Peptides of endogenous proteins bind to class I MHC molecules presented to cytotoxic T cells 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 Cleft geometry a-chain a-chain Peptide b2-M MHC class I accommodate peptides of 8-10 amino acids Peptide b-chain MHC class II accommodate peptides of >13 amino acids ANTIGEN PRESENTING CELLS • 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 CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS Degradation of endogenous proteins takes place in the proteasomes, they are presented on cell surface by MHC I MHC do not recognize or distinguish self and nonself peptides ! Antigen presentation goes in the absence of pathogen or T cells as well System optimalization 2: MHCI present the intracellular area. Next step, how could the MHC molecules (and the T cells) monitor the extracellular enviroment? MHCII Expressed by professional antigen presenting cells Macrophage, dendritic cell, B cell STRUCTURE OF CLASS II MHC MOLECULES PEPTIDE b1 a1 b2 a2 STRUCTURE OF CLASS II MHC MOLECULES A polymorphic α and a polymorphic β chain PEPTID b1 a1 b2 a2 α1 and β1 domens are responsible for peptide binding PEPTIDE Cleft geometry a-chain a-chain Peptide b2-M MHC class I accommodate peptides of 8-10 amino acids Peptide b-chain MHC class II accommodate peptides of >13 amino acids Presentation of extracellular peptides by MHCII RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES Tc Th Exogenous Ag Endogenous Ag Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules The recognition of the MHC-presented peptide antigen is not enough for T cell activation! DIFFERENTIATION OF CD4+ T CELLS cellular, proinflammatory humoral, antiinflammatory • 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