JPEMS Nantes, 2014- Basic Immunology Introduction to the immune system Definitions Structure and General Organization Teacher: Pr. Régis Josien, Laboratoire Immunologie and INSERM U1064, CHU Nantes Regis.Josien@univ-nantes.fr 1
Immunology and immunity: definitions Immunology: science of the immune system Immune system: a collection of tissues, cells and molecules which mediates the defense and protection of host against pathogens Immune response: coordinated reactions of the immune system to infectious microbes Immunity: state of protection or resistance against infections The physiological function of the immune system is to prevent or eradicate infections
Immune responses are diverse Diversity and complexity of the immune responses are mostly related to the diversity of pathogens (i.e. extra or intracellular bacteria, virus, etc..) and their adapta<on during evolu<on together with the fact that the immune system should not a>ack host <ssues (no<on of self- non self discrimina<on). 3
The importance of immunology in medicine Products of the immune system are rou5nely used in clinical laboratory and treatments: - monoclonal an<bodies - cytokines
Effec5veness of vaccina5ons for some common infec5ous diseases
Important dates in the history of immunology 1796 E. Jenner: vaccine protects against small pox 1886 L. Pasteur: vaccine against rabies 1885 E. Metchnikoff: phagocytosis/macrophages (Nobel 1908) 1890 R. Koch: hypersensitivity reaction (BK) (Nobel 1905) 1891 E. von Berhing: antitoxins (anticorps) (Nobel 1901) 1897 J. Bordet: complement (Nobel 1919) 1897 P Ehrlich: antibodies - side chain theory (Nobel 1908) vaccina5on 6
The 1908 Nobel prize in Medicine and Physiology Ilya Ilyich METCHNIKOV 1845-1916 Paul EHRLICH 1854-1915
Important dates in the history of immunology 1796 E. Jenner: vaccine protects against small pox 1886 L. Pasteur: vaccine against rabies 1885 E. Metchnikoff: phagocytosis (Nobel 1908) 1890 R. Koch: hypersensitivity reaction (BK) (Nobel 1905) 1891 E. von Berhing: antitoxins (anticorps) (Nobel 1901) 1897 J. Bordet: complement (Nobel 1919) 1897 P Ehrlich: antibodies - side chain theory (Nobel 1908) vaccina5on Cell- mediated immunity Humoral immunity 8
Important dates in the history of immunology 1796 E. Jenner: vaccine protects against small pox 1886 L. Pasteur: vaccine against rabies vaccina5on 1885 E. Metchnikoff: phagocytosis (Nobel 1908) Cell- mediated immunity 1890 R. Koch: hypersensitivity reaction (BK) (Nobel 1905) 1891 E. von Berhing: antitoxins (anticorps) (Nobel 1901) 1897 J. Bordet: complement (Nobel 1919) Humoral immunity 1900 P Ehrlich: antibodies - side chain theory (Nobel 1908) 1921 K. Landsteiner: haptens (Nobel 1930) 1963 F. MacFarlane Burnet: Clonal selection theory (Nobel 1960) 1958 J. Dausset: HLA (Nobel 1980) 1959 G. Edelman: Ig sequence(nobel 1972) 1963 J. Miller: fonctions of thymus T lymphocyte 1973 R. Steinman: dendritic cells (Nobel 2011) 1975 R. Zinkernagel et P. Doherty: allogeneic restriction (Nobel 1996) 1976 S. Tonegawa: organization of Ig genes (Nobel 1987) 1979 OMS: small pox eradication 1984 M. Davis et T. Mak: organization of TCR genes 1988 P. Marrack et H. van Boehmer: mechanisms of thymic selection 1991 T. Mossman: Th1 and Th2 cells 1997 C. Janeway, B. Beutler: Toll-like réceptors (TLR) (Nobel 2011) 9
BASIC CONCEPTS in IMMUNOLOGY 1. Components of the immune system 2. Principles of innate and adapative immunity 3. Recognition and effector mechanisms of adaptive immunity 10
BASIC CONCEPTS in IMMUNOLOGY 1. Components of the immune system 2. Principles of innate and adapative immunity 3. Recognition and effector mechanisms of adaptive immunity 11
Cells of the immune system Lymphoid progenitor HSC Myeloid progenitor GM precursor Gran. Prec. Monocytes- DC precursor Blood and lymph nodes Eosinophil Basophil Neutrophil Monocyte PreDC Blood Polymorphonuclear cells 12 Tissues Mastocyte Macrophage Dendritic cell
Myeloid cells of the immune system Polymorphonuclears Mastocyte 13
Cells of the immune system Hemogram: Leuk: 4000-10000/mm3 Neutr: 52-75% Lympho: 20-45% Lymphoid progenitor HSC Myeloid progenitor GM precursor Mono: 3-9 % Eosino: 0-5% Baso: 0-1,5 % DC: 0,1-0,5% Gran. Prec. Monocytes- DC precursor Blood and lymph nodes B T Lymphocytes NK ILCs Innate lymphoid cells Eosinophil Basophil Neutrophil Polymorphonuclear cells Monocyte PreDC Blood plasmocytes 14 Tissues antibodies Mastocyte Macrophage Dendritic cell
Principal cells of the immune system and their func5ons
More definitions ü Antigen (Ag): a molecule that binds to an antibody or a T cell receptor expressed by lymphocytes. Antigens that bind to antibodies include all classes of molecules. Most TCR bind only peptide fragments of proteins complexed with MHC molecules. ü Antigen receptor: membrane glycoprotein expressed by lymphocytes (T = T cell receptor (TCR); B = BCR) which can recognize antigens. ü Antibody (Ab): a type of soluble glycoprotein molecules, also called immunoglobulin (Ig), produced by B lymphocytes, that bind antigen, often with a high degree of specificity and high affinity. ü Effectors: cells or their products directly involved in the elimination of infectious microbes or antigens 16
Lymphoid organs and tissues Primary lymphoid organs sites of lymphocyte development Secondary lymphoid organs site of antigen capture and initiation of the adaptive immune response 17
Morphology of lymph nodes
Morphology of the spleen
Segrega5on of T and B lymphocytes secondary lymphoid organs
Naive lymphocytes trafic between blood and secondary lymphoid organs in which they meet antigens
BASIC CONCEPTS in IMMUNOLOGY 1. Components of the immune system 2. Principles of innate and adapative immunity 3. Recognition and effector mechanisms of adaptive immunity 22
The 3 phases of an immune response to infection Innate immune response Adap5ve immune response 23
The immune response 24
Innate and adaptive immunity 25
Principles of innate and adaptive immune responses Innate or natural immunity Poorly specific response Innate and therefore immediate Due to phagocytes (PMN, MØ), DC, NK cells, complement Use poorly specific and conserved receptors (PRR) recognizing pathogen associated molecular patterns (PAMPs) Constitute the first lign of defense against pathogens No memory (stereotyped response) 26
Recognition of microbes by the innate immune system: pattern recognition receptors (PRR) 27
Bacterial infection initiates inflammation 28
Principles of innate and adaptive immune responses Innate or natural immunity Poorly specific response Innate and therefore immediate Due to phagocytes (PMN, MØ), DC, NK cells, complement Use poorly specific and conserved receptors (PRR) recognizing pathogen associated molecular patterns (PAMPs) Constitute the first lign of defense against pathogens No memory (stereotyped response) Adaptive or specific mmunity Highly specific response Inducible and therefore delayed (>4d) Due to lymphocytes (T and B) and antibodies produced by B cells Use highly specific and diverse receptors (T cell receptor, TCR; B cell receptor, BCR) that recognize antigens Induce protection against reinfection (immune memory) with the same pathogen 29
Dendritic cells initiate adaptive immune responses 30
Principles of innate and adaptive immune responses Innate or natural immunity Poorly specific response Innate and therefore immediate Due to phagocytes (PMN, MØ), DC, NK cells, complement Use poorly specific and conserved receptors (PRR) recognizing pathogen associated molecular patterns (PAMPs) Constitute the first lign of defense against pathogens No memory (stereotyped response) Adaptive or specific mmunity Highly specific response Inducible and therefore delayed (>4d) Due to lymphocytes (T and B) and antibodies produced by B cells Use highly specific and diverse receptors (T cell receptor, TCR; B cell receptor, BCR) that recognize antigens Induce protection against reinfection (immune memory) with the same pathogen 31
Types of adap5ve immunity 2 classes of T lymphocytes: - Helper / CD4+: produce cytokines that help other immune cells to eliminate microbes - Cytotoxic /CD8+: kill virus infected cells
Clonal selec5on of lymphocytes
Origin of the diversity of lymphocyte antigen receptors TCR: T cell receptor (lympho T) BCR: B cell receptor (lympho B) 34
Development of lymphocytes Bone marrow CLP prob Elimination of autoreactive B cells B mature Blood Thymus prot Elimination of autoreactive T lymphocytes T mature Homeostasis of lymphocyte populations Secondary lymphoid organs (LN, spleen..) 35
Matura5on of lymphocytes
Steps in the activation of T lymphocytes Ag recognition Naive T cells APC (dendritic cell) Activation Clonal expansion/ proliferation IL-2 Differentiation cytokines Effectors Apoptosis Memory T cells Apoptosis 37
Migra5on of T lymphocytes
Stages in the life history of lymphocytes
Primary and secondary immune responses
Proper5es of adap5ve immune responses
Lymphocyte activation requires two signals T lymphocyte B lymphocyte 42
BASIC CONCEPTS in IMMUNOLOGY 1. Components of the immune system 2. Principles of innate and adapative immunity 3. Recognition and effector mechanisms of adaptive immunity 43
The different classes of pathogens will be cleared by different types of effector cells 44
Types of adaptive immunity 45
Antibodies eliminate extracellular pathogens and their toxins: mechanism of action as anti-infectious effectors 46
Cytotoxic T lymphocytes (CD8 T cells) eliminate virus-infected cells
Helper T cells eliminate intracellular bacteria 48
Classes of lymphocytes and their functions Helper T lymphocytes play a central role in the organisa5on of adap5ve immune responses 49
Effector Th cells and classes of pathogens Autoimmunity Inflammatory diseases Autoimmunity Allergy 50
Antigen recognition by lymphocytes B Lymphocyte BCR (surface Ig) recognize antigenic determinants (epitopes) in a native molecule (antigen) T Lymphocyte TCR regognize a protein fragment (peptide) presented by a molecule of the major histocompatibility complex (MHC)) requirement for an antigen-presenting cell (APC) 51
Class I MHC molecules present peptides to CD8 + T cells Class II MHC molecules present peptides do CD4 + T lymphocytes 52