Prim a r y lymphoid organs : - B one marrow - T hymus

! ! LYMPHOID ORGANS Primary lymphoid organs: - Bone marrow - Thymus the cells of the immune system originate in and mature here Secondary lymphoid organs: - Spleen - Lymphatic vessels - Lymph nodes - Adenoids and tonsils - MALT (Mucosal AssociatedLymphoid Tissue) GALT (Gut Associated Lymphoid Tissue) BALT (Bronchus Associated Lymphoid Tissue) SALT (Skin Associated Lymphoid Tissue) NALT (Nasal Associated Lymphoid Tissue) not for cell development. (final differentiation, activation may be performed) The cells of the adaptive immune system recognize here the pathogens

! ! THE TWO ARMS OF THE IMMUNE SYSTEM Monocytes, Macrophages, Dendritic cells, Granulocytes, NK cells and Complement components Monocytes, Macrophages, Dendritic cells, Granulocytes, NK cells and Complement components B and T cells MEMORY

! ! Professional phagocytic cells macrophages neutrophyl granulocytes dendrtitic cells Professional antigen presenting cells macrophages B lymphocytes dendrtitic cells they express MHCII molecules the protein degradation products (peptides) can be presented to T lymphocytes by MHC molecules ! !

Cells of innateimmunesystem: • Macrophages: • Macrophages are constitutively present in tissues and recognizemicrobesthat enter these tissues and respond rapidly to thesemicrobes. Initiatetheimmuneresponse • Thesecellsare phagocytes (eliminatethepathogens) • Activatetheinnateimmuneresponse(bysecreted proteins, called cytokines) • Activatetheadaptiveimmunesystem. Macrophages serve as APCs that display antigens to and activate T lymphocytes • Dendriticcells • are constitutively present in tissues and recognizerapidlymicrobesthat enter these tissues. Initiatetheimmuneresponse. • They have phagocytic capabilities • migrate to lymph nodes, and display microbial antigens to T lymphocytes,professionalantigenpresentimgcells(APC) • Neutrophilgranulocytes arephagocytes, the main functiontoeliminatethepathogens • Appearonlyinthecirculationundernormalcondition Main actorsIninflammatoryprocesses ! !

! ! Innate immunity as a first line of defence Innate immune cells recognize frequently found structures of pathogens by PRRs , these are not found in human cells! PRRs (pattern recognition receptors) are responsible for recognize conserved structures of the microbes Examples of recognited structures: duple strain RNA bacterial cell wall components bacterial flagellin…. Recognition is inevitable

! ! Danger signal! The innate immune system also recognizes molecules that are released from damaged or necrotic cells. Such molecules are called damage-associated molecular patterns (DAMPs).

! OPSONIZATION ! Opsonization facilitate and accelerate the recognition of the pathogen by phaogocytes, opsonins form a bridge between pathogen and a phagocyte connecting them. Main opsonins: antibodies Complement fragments Acute-phase proteins

Specificity of innate immunity direct connetion between innate cells and pathogen ( ) Few receptors (20-30) are responsible for the recognition of all the pathogens

T cell receptor (TCR) The TCR, whichrecognizespeptideantigens displayed by MHC molecules ! ! V s H s s s s s s V s L C s H1 s s s s s s C s s L s s s s s s s s s C s s H2 s s C s s H3 BCR • : • membrane-bound heterodimer composed of an α chain and a β chain, each chain containing one variable (V) region and one constant (C) region Both the α chain and the β chain of the TCR participate in specific recognition of MHC molecules and bound peptides

! ! TCRs only function as membrane receptors Plasma cell B cell TCR T cell

ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES Cell surface MHC-peptidecomplex T-cell response ! ! T II soluble Ag Peptide antigen Native membrane Ag Cell surface peptides APC APC APC No T-cell response

! 2 1 2m 3 ! MHCI Expressed by all nucleated cells STRUCTURE OF CLASS I MHC MOLECULES PEPTIDE

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

ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES Cell surface MHC-peptidecomplex T-cell response ! ! T II soluble Ag Peptide antigen Native membrane Ag Cell surface peptides APC APC APC No T-cell response

! ! MHCI Displays intracellular antigens to cytotoxic T cells

! ! MHCII Displays extracellular antigens to helper T cells

! Th Endogenous Ag Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic T cells RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES ! Tc TCR Peptide MHCI TCR Peptide MHCII Exogenous Ag APC

! ! T cell receptor (TCR) recognizes peptide antigen and simultaneously also recognizes the MHC molecule that is displaying that peptide

Specificity of innate immunity Tc Tc peptid MHC APC APC Specificity of T cells Distinct T cell receptors Peptides derived from different microbes

Specificity of innate immunity T T peptid MHC APC APC direct connetion between innate cells and pathogen ( ) Specificity of T cells No direct connetion between T cell and pathogen APC-T cell connection Distinct T cell receptors Peptides derived from different microbes

! ! Immunoglobulin STRUCTURE • 2x identical Heavy chain (light blue) • 2x identical light chain (dark blue) • Variable regions  antigen binding • Constant regions disulfide bond carbohydrate CL VL CH2 CH3 CH1 hinge region VH

ANTIBODY DOMAINS AND THEIR FUNCTIONS ! ! Antigen recognition Variable domain Constant domain Effector functions

! ! Antibody BCR (B cell receptor) Transmembrane domain Associated chains for signaling Cytoplasmic domain SOLUBLE (freely circulating) MEMBRANE BOUND! Antigen recognition and effector functions. Produced by plasma cells Antigen recognition and B cell activation

! ! B cell epitop T cell epitop B cells recognize: proteins polysaccharides lipids DNS steroids drugs, etc Tissue or soluble antigens T cells recognize: peptides (8-23 amino acid) only when these peptides are presented by MHC molecules on APC cells

Receptors responsible for the recogniton of pathogens in the immune system

! ! Antibody BCR (B cell receptor) Transmembrane domain Associated chains for signaling Cytoplasmic domain SOLUBLE (freely circulating) MEMBRANE BOUND! Antigen recognition and effector functions. Produced by plasma cells Antigen recognition and B cell activation

! ! Several antibodies are expressed on B cells, (arround 100.000) but all of them with the same specificity

! Antigen recognition by specific BCR induces clonal expansion and differentiation of the sepcific B cells. ! Activation of specific B cells 1. Clonalexpansion MEMORY B CELLS Plasma cells, antibody production 2.Differentiation

Effector funtions Innate Adative B cells T cells Extracellular Intracellular pathogens

! ! • INNATE IMMUNITY II • Effector functions, elimination of pathogens • Phagocytosis • Killing with soluble mediators • Complement system • NK cell activation

! ! EFFECTOR FUNCTIONS OF ANTIBODIES Antibody-mediated immune responses • NEUTRALIZATION • OPSONIZATION • COMPLEMENT FIXATION • ADCC • MAST CELL DEGRANULATION

! ! T helper cells (TH cells) assist other white blood cells in immunologic processes Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells

! ! Activation of helper T cells results in cytokine production

THE MOST IMPORTANT FEATURES OF CYTOKINES • Cytokines are the most important mediators of indirect cell communication in the immune system („hormones” of the immune system). ! !

! ! MHCI is present in all the nucleated cells Intracellular pathogens can be presented on all the cells Any cell is infected, can be killed by cytotoxic T cells MHCII present extracellular antigens to helper T cells. Helper T cells direct the immun eresponse by the pruduced cytokines.

! ! B cell memory: Quicker response Increase in the number of specific B cells The amounts of antibody are biger Higher affinity antibodies (‘more specific’) Isotype switch In case of T dependent B cell activation

! ! T cell memory: Quicker response Increase in the number of responding cells

Active and passive immunization activepassive protection slowimmediate (2 weeks) Time-span longshort (years) ! ! passive protection active injection time

Prim a r y lymphoid organs : - B one marrow - T hymus