Immunobiology

The role of the immune system The role of the immune system The defence against: (1)pathogenic organisms (viruses, bacteria, fungi, unicellular organisms, worms) (2)Tumor cells Malfunctioning: Autoimmune disease (e.g. rheumatoid arthritis type 1 diabetes) 1

IMMUNE SYSTEM 1. Innate (nonspecific) 1 st line of defence Cellular components Humoral components 2. Adaptive (specific) 2 nd line of defence Cellular components Humoral components 2 Two subdivisions of the immune system

Innate immune responses are activated directly by pathogens and defend all multicellular organisms against infection. In vertebrates, pathogens, together with the innate immune responses they activate, stimulate adaptive immune responses, which then work together with innate immune responses to help fight the infection. Two subdivisions of the immune system 3

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IMMUNE SYSTEM Myeloid cells Granulocytic Neutrophils Basophils Eosinophils Monocytic Macrophages Kupfer cells Dendritic cells Lymphoid cells T cells Helper cells Suppressor cells Cytotoxic cells B cells Plasma cells Memory cells NK cells Cells of immune system 5

I. Innate Immune System

Innate Immune System A. Anatomical barriers Mechanical factors: skin, cilia, mucus, peristaltics, flushing of tear and saliva Chemical factors: low pH in the stomach and sweat Biological factors: natural flora of skin and intestines B. Humoral barriers Complement system Coagulation system Others: lactoferrin, interferon, lyozyme, defensin C. Cellular barriers Neutrophil and eosinophil granulocytes Macrophages Natural killer (NK) cells A. Anatomical barriers Mechanical factors: skin, cilia, mucus, peristaltics, flushing of tear and saliva Chemical factors: low pH in the stomach and sweat Biological factors: natural flora of skin and intestines B. Humoral barriers Complement system Coagulation system Others: lactoferrin, interferon, lyozyme, defensin C. Cellular barriers Neutrophil and eosinophil granulocytes Macrophages Natural killer (NK) cells Membrane-attack complex Membrane-attack complex 6

Inhibition of host complement factors by viruses 7

Blood capillary Skin Bacteria introduced by splinter Splinter Mast cell Damaged tissues attract mast cells which release histamine, which diffuses into the capillaries. Inflammation X X

Histamine causes the capillaries to dilate and become leaky; complement proteins leave the capillaries and attract phagocytes. Blood plasma and phagocytes move into infected tissue from the capillaries. Complement proteins Phagocyte Inflammation X X

Dead phagocyte Phagocytes engulf bacteria and dead cells. Histamine and complement signaling cease; phagocytes are no longer attracted. Signaling molecules stimulate endothelial cell division, healing the wound. Inflammation X X

II. Adaptive Immune System

Adaptive immune responses Cellular response Humoral response 2 main classes: (1)Humoral immune response (= antibody response, B cell-mediated response) (2)Cellular immune response (=T cell-mediated immune response) 2 main classes: (1)Humoral immune response (= antibody response, B cell-mediated response) (2)Cellular immune response (=T cell-mediated immune response) The T cells … (1)induce apoptosis? (2)activate macrophages  phagocytosis (3)activate B cells  antibody production The T cells … (1)induce apoptosis? (2)activate macrophages  phagocytosis (3)activate B cells  antibody production B cell T cell antibody virus-infected cell virus virus-infected cell 8 The antibodies… (1)block the ability of viruses to bind to receptors (2)block the effect of toxins by masking them (3)mark pathogens for destruction The antibodies… (1)block the ability of viruses to bind to receptors (2)block the effect of toxins by masking them (3)mark pathogens for destruction LIMPHOCYTES Against extracelluláris parasites Against intracelluláris parasites

Human lymphoid organs 9 nasopharyngeal tonsil (adenoid) nasopharyngeal tonsil (adenoid) tonsil lymphatic vessels lymphatic nodes spleen thymus Peyer’s patches in small intestines Peyer’s patches in small intestines appendix bone marrow 2x10 12 lymphocyte in the body

The innate and adaptive immune system work together 10 Pathogen-associated molecular patterns (PAMPs)  pattern recognition receptors Pattern recognition receptors: (1)Located on the surface of phagocytes (2)Secreted receptors (marking the pathogens through binding them) (3)Located on the surface of e.g. dendritic cells (Toll-like receptors), which activate intracellular signal molecules that lead to the secretion of extracellular signal molecules that promote inflammation and help activate adaptive immune responses Pattern recognition receptors: (1)Located on the surface of phagocytes (2)Secreted receptors (marking the pathogens through binding them) (3)Located on the surface of e.g. dendritic cells (Toll-like receptors), which activate intracellular signal molecules that lead to the secretion of extracellular signal molecules that promote inflammation and help activate adaptive immune responses Dendrytic cell Dendrytic cell

The innate and adaptive immune system work together 11 (1) Dendritic cells ingest invading microbes or their products at the site of an infection. (2) The microbial PAMPs activate the dendritic cells (through toll-like receptors) to express co-stimulatory proteins on their surface and (3) to migrate in lymphatic vessels to a nearby lymph node, where (4) the activated dendritic cells activate the small fraction of T cells that express a receptor for the microbial antigens displayed on the dendritic cell surface. (5) These T cells proliferate and some then migrate to the site of infection, where they help eliminate the microbes, by either helping to activate macrophages or killing infected cells

HUMORAL IMMUNE RESPONSE Helper T cell (TH) T cell receptor Macrophage The antigen is taken up by phagocytosis and degraded in a lysosome. Interleukin-1 (a cytokine) activates a T H cell. Cytokines re- leased by the T H cell stimulate it to proliferate. A T cell receptor recognizes an antigenic fragment bound to a class II MHC protein on the macrophage. ACTIVATION PHASE Class II MHC protein Antigen Y

HUMORAL IMMUNE RESPONSE The T H cell proliferates and forms a clone. Y

HUMORAL IMMUNE RESPONSE EFFECTOR PHASE B cell The binding of antigen to a specific IgM receptor triggers endocytosis, degradation, and display of the processed antigen. Cytokines activate B cell proliferation. T H cell A T cell receptor recognizes an antigenic fragment bound to a class II MHC protein on a B cell. Y

HUMORAL IMMUNE RESPONSE B cells proliferate and differentiate. The plasma cell produces antibodies. Plasma cell Memory cell Y

CELLULAR IMMUNE RESPONSE ACTIVATION PHASE Infected cell Cytotoxic T cell (TC) T cell receptor Antigen Class I MHC protein A viral protein made in an infected cell is degraded into fragments and picked up by a class I MHC protein. A T cell receptor recognizes an antigenic fragment bound to a class I MHC protein on an infected cell. Y

CELLULAR IMMUNE RESPONSE The TC cell proliferates and forms a clone. Y

CELLULAR IMMUNE RESPONSE EFFECTOR PHASE The T cell releases perforin… A T cell receptor again recognizes an antigenic fragment bound to a class I MHC protein. Infected cell (one of many) Y

CELLULAR IMMUNE RESPONSE …which lyses the infected cell before the viruses can multiply. Y

The development of T and B cells central lymphoid organs 2. peripheral lymphoid organs hematopoetic tissues thymus common lymphoid progenitor cell thymocyte hematopoetic stem cell common lymphoid progenitor cell developing B cell T cell B cell ANTIGEN T cell-mediated immune response Antibody response B cells  plasma cells: - make antibodies - make memory cells T cells  (1) cytotoxic T cells:- directly kill infected host cells  (2) helper T cells: - secret cytokines thereby activate macrophages, dendritic cells, B cells, and cytotoxic T cells  (3) regulatory T cells: - inhibit the function of helper T cells, cytotoxic T cells, and dendritic cells B cells  plasma cells: - make antibodies - make memory cells T cells  (1) cytotoxic T cells:- directly kill infected host cells  (2) helper T cells: - secret cytokines thereby activate macrophages, dendritic cells, B cells, and cytotoxic T cells  (3) regulatory T cells: - inhibit the function of helper T cells, cytotoxic T cells, and dendritic cells maturation effector cells B cells can act over long distances by Secreting antibodies that are widely distributed by the bloodstream T cells can migrate to distant sites, but, once there, they act only locally on neighboring cells

Hematopoesis Development of blood cells Hematopoesis Development of blood cells 13

Hematopoesis transcription factors Hematopoesis transcription factors 13 PU.1 GATA-1 Ikaros, Aiolos, Helios TRANSCRIPTION FACTORS TRANSCRIPTION FACTORS GROWTH FACTORS Names are not needed to study!

The clonal selection theory precursor cell different resting cells antigen antibody-secreting effective B  cells antibody-secreting effective B  cells secreted antibodies ANTIGEN BINDING TO SPECIFIC B CELL (B  ) IN PERIPHERAL LYMPHOID ORGAN ANTIGEN BINDING TO SPECIFIC B CELL (B  ) IN PERIPHERAL LYMPHOID ORGAN PROLIFERATION (CLONAL EXPANSION) AND DIFFERENTIATION OF B  CELLS PROLIFERATION (CLONAL EXPANSION) AND DIFFERENTIATION OF B  CELLS PROLIFERATION AND DIVERSIFICATION IN BONE MARROW PROLIFERATION AND DIVERSIFICATION IN BONE MARROW McFarlene Burnet McFarlene Burnet 14

Epitopes antibody A antibody B antibody C Epitopes (antigenic determinants) Epitopes (antigenic determinants) antigen Epitopes:those parts of an antigen that bind to the antigen-binding site on either an antibody molecule or a lymphocyte receptor Immunodominant epitopes:epitopes producing a greater immune response than others antigen-binding site 15

16 naive cell 1 st exposure to antigen memory cells effector cells memory cells effector cells 2 nd exposure to antigen Both B and T cells Immunological memory Primary immune response Secondary immune response

Immunological tolerance to self antigens 17 Central lymphoid organ Peripheral lymphoid organ Immature lymphocytes Immature lymphocytes Mature naive lymphocytes Mature naive lymphocytes Lymphocyte with altered specificity Lymphocyte with altered specificity Self antigens Dead lymphocyte RECEPTOR EDITING RECEPTOR EDITING CLONAL DELETION CLONAL DELETION CLONAL DELETION CLONAL DELETION CLONAL INACTIVATION CLONAL INACTIVATION CLONAL SUPPRESSION CLONAL SUPPRESSION Foreign antigen Co-stimulatory signal Self antigen Effector or memory lymphocytes Effector or memory lymphocytes Effector or memory lymphocytes Effector or memory lymphocytes Dead lymphocyte Inactivated lymphocyte Inactivated lymphocyte Suppressed lymphocyte Suppressed lymphocyte Regulatory T cell David Nemazee Martin Weigert  receptor editing

Autoimmune diseases – 2 examples 18 Myasthenia gravis: immune reaction against acetylcholine receptor Diabetes type 1: immune reaction against insulin-secreting cells in the pancreas Myasthenia gravis: immune reaction against acetylcholine receptor Diabetes type 1: immune reaction against insulin-secreting cells in the pancreas

The membrane-bound and secreted antibodies made by a B cell clone The membrane-bound and secreted antibodies made by a B cell clone 19 antigen antigen receptor resting cell PROLIFERATION AND DIFFERENTIATION effector B cells secreted antibodies

Antibodies variable constant light chain Heavy chain antigen-binding site hinge region light chain heavy chain 20

Antibody–antigen interactions 21

The 5 classes of antibodies 22

The main stages in B cell development Plasma cell Memory cell ANTIGEN EFFECT ANTIGEN EFFECT 23

A pentameric IgM molecule 24

IgG: antibody-activated phagocytosis 25

Dimeric IgA molecule 26

The role of IgE in histamine secretion by mast cells 27

Antigen binding to antibody 28

Molecules with multiple antigenic determinants 29

30 Heavy and light chains

Constant and variable regions of immunoglobulin chains 31

Antibody hypervariable regions 32

Immunoglobulin domains 33

The organization of the DNA sequences that encode the constant region of an antibody heavy chain, such as that found in IgG 34

Immunogenetics

Human antibody genes Human antibody genes Z Z Heavy chain Light chain  Light chain

The V–J joining process involved in making a human k light chain Primary antibody repertoire 35

The human heavy-chain locus The heavy-chain VDJ recombination 36

The role of recombination signal sequences in RAG-mediated gene segment joining 37

Allelic exclusion: Selection of antibody loci during B cell development in the bone marrow 38

Some ways in which AID can cause mutations during somatic hypermutation 39

An example of the DNA rearrangement that occurs in class switch recombination 40

The main mechanisms of antibody diversification in mice and humans 41

A T cell receptor (TCR) heterodimer  chain: VJ régió  chain: VDJ régió  chain: VJ régió  chain: VDJ régió No somatic hypermutation 42

Three types of proteins on the surface of an activated dendritic cell involved in activating a T cell 43

Two strategies by which effector cytotoxic T cells kill their target cells 44

Differentiation of naive helper T cells into either TH1 or TH2 effector helper cells in a peripheral lymphoid organ 45

Recognition by T cells of foreign peptides bound to MHC proteins 46

Class I and class II MHC proteins MHC-I protein MHC-I protein MHC-II protein MHC-II protein 47

Human MHC genes 47

The interaction of a T cell receptor with a viral peptide bound to a class I MHC protein 48

CD4 and CD8 co-receptors on the surface of T cells 49

The processing of a viral protein for presentation to cytotoxic T cells – MHC-I system 50

Some effects of interferon-g (IFNg) on virus-infected cells 51

The processing of an extracellular protein antigen by a dendritic cell for presentation to a helper T cell – MHC-II system 52

Selection of T cells