LECTURE 1 INTRODUCTION TO IMMUNOLOGY Jan eromski 200132014

LECTURE 1 INTRODUCTION TO IMMUNOLOGY Jan Żeromski 20013/2014

Immunology Course Outline 3 student groups Subjects: 1. 11 lectures – approach to basic and clinical 2. 3. immunology 5 classes – approach to essentials of diagnostic immunology 7 seminars – clinical immunology Evaluation: 1. Midterm test 2. Basic imm. test 3. Final test Final examination Detailed schedule on the website: immuno. ump. edu. pl

Recommended books: • Introduction to Clinical Immunology Medical University Press, 2009. • Basic Immunology Abbas et al. . Elsevier 2013 • Male, Brostoff, Roth & Roitt Immunology Mosby, Elsevier • Chapel: Essentials of Clinical Immunology Blackwell.

INTRODUCTION TO IMMUNOLOGY • Immune system (IS): innate and adaptive immunity • Development of IS • Cells and tissues of IS • Soluble mediators of immunity • Antigens • Immunopathology • Modern approaches to study immunology

Immunologic concept of self • Recognizing self –whether an encountered molecule is a part of the body • Recognizing of absence of self – loss of some surface molecules such as transplantation antigens in cancer • Recognizing nonself - such as pathogens or foreign grafts • Recognition possible by: - via pattern recognition receptors (innate recognition) - via somatically generated receptors (adaptive „ )

TWO TYPES OF IMMUNITY Non-specific (innate) • Physical and chemical agents • Lysozyme • Acute phase proteins • Complement system • Cytokines (chemokines) • Phagocytes (granulocytes, macrophages) • Natural killer (NK) cells • Dendritic cells • Pattern recognition receptors (PRR) Specific (adaptive) • Antibodies (B lymphocytes) • T lymphocytes and their subsets

Major differences between innate and acquired immunity (acc. to U. Koedel & W Pfister 2005) Innate immune system • Immediate maximal response • No immunological memory • Not antigen specific • Receptors: germ line encoded, • In almost all multicellular organisms, • Recognition of conserved molecular patterns, • Perfect self/non-self discrimination • Only hundreds of different Acquired immune system • Lag time (3 -4 days) between exposure and max. response • Immunological memory • Antigen specific • Receptors: generated somatically, • Only in vertebrates, • Recognition of details of molecular structure, • Imperfect self/non-self discrimination,

INNATE IMMUNITY

Components of Innate Immunity • Barriers (epithelia, defensins) • Circulating effector cells (neutrophils, eosinophils, basophils, mast cells, NK cells, monocytes/macrophages) • Circulating effector proteins (complement, mannose-binding lectin, creactive protein) • Cytokines (TNF, IL-1 - 25)

Receptors of innate immunity • Pattern recognition receptors (TLRs, NLRs, Rig-1), • NK cells: killer activated R. (KAR) and killer inhibitor R. (KIR), • Complement receptors (on phagocytic cells) • Fc receptors – for Fc fragment of Igs • Scavenger receptors

Complement system

COMPLEMENT SYSTEM – MAIN STRUCTURAL FEATURES Consists of about 30 serum proteins marked by C and arabic number (C 1 q, C 2, C 3 etc. ) Many C proteins are zymogens – proenzymes requiring proteolytic cleavage Enzymes are often formed from several C molecules –eg. C 4 B 2 a cleaves C 3 Activation of C is controlled by regulatory proteins – eg. DAF, CD 59

Complement– bound and Complement – associated biologically active molecules C 3 a i C 5 a (anafilatoxins) – mediators of inflammation, Membrane attack complex (non-enzymatic assembly of C 5 b-C 9) – responsible for cell lysis Complement–inhibitory molecules; DAF, MCP, CD 59 C receptors (CR) on various cells (B cells monocytes, neutrophils, some epithelial cells,

EFFECTS OF ACTIVATION OF COMPLEMENT SYSTEM Chemotaxis (attraction of cells to sites of infection Opsonization (facilitation of phagocytosis) Promotion of killing of microorganisms Increased blood flow Increased blood vessel permeability Damage to plasma membranes Release of inflammatory mediators from mast cells

BIOLOGICAL EFFECTS OF COMPLEMENT Promotion of killing of bacteria Clearing of immune complexes The induction and enhancement of antibody responses Detrimental if activated on a large scale, e. g. in Gram negative septicaemia, in tissue necrosis, in autoimmunity

COLLECTINS (COLLAGEN LECTINS) – CALCIUM BINDING LECTINS • Lectins: proteins binding shugars in non-enzymatic way. • Collectin family includes: – mannan binding lectin (MBL), – Conglutinin (bovine globulin able to react with bound C 3) – lung surfactant proteins A and D and also – C 1 q • MBL binds mannose groups in the bacteria, yeast fungi, viruses cell walls and then activates serine proteinases (MASP), able to cleave C 4 and C 2 analogous to C 1 q interaction with C 1 r and C 1 s. Effect: C activation

Cytokines

CYTOKINES SIGNAL TRANSDUCING MOLECULES Interleukins (IL) • directing other cells to divide and differentiate Interferons (INF) • type I (alpha/beta), type 2 -gamma Colony stimulating factors (CSF) • directing bone marrow stem cells Chemokines • directing cell movement Other • TNF , TGF – involved in inflammation, cytotoxicity and immunosuppression respectively

CELLULAR MECHANISMS OF INNATE IMMUNITY - NEUTROPHIL ACTIVATORS • Bacterially derived N-formylated peptides (FMLP) • Defensins (natural antibiotics) • Products of complement (i. C 3 b) • Leukotrienes (products od arachidonic acid metabolism) • Cytokines ((TNF, IL-8, GM-CSF)

RECEPTORS OF INNATE IMMUNITYPATTERN RECOGNITION RECEPTORS • Expressed on cells of innate immunity • Encoded in the germline and not by somatic recombination of genes • Recognize structures of microbes essential for the survival and infectivity • Recognize less than a thousand microbial patterns (LPS, double stranded RNA, unmethylated Cp. G nucleotides, glycolipids etc. )

TOLL-LIKE RECEPTORS (TLRs) • Strongly conserved in evolution • Initially detected in fruit fly Drosophila melanogaster • Recognize Pathogen-Associated Molecular Patterns (PAMPs), absent in mammals • In extracellular portion contain multiple leucinerich repeats (LRRs), In intracellular portion show high homology to IL-1 R (TIR domain) • Exist in families (TLR 1 -TLR-13)

FUNCTIONAL FEATURES OF TLRs Their stimulation leads to: 1. Augmented inflammatory reaction via activation of NF-kappa B transcription factor and increased synthesis of proinflammatory cytokines (IL-1, TNF-alpha, IL-12) 1. Increased expression of MHC antigens 1. Enhancement of maturation of dendritic cells 1. Induction of apoptosis

FEATURES OF ANTIGEN-PRESENTING CELLS • Capacity for antigen uptake and partial degradation • Expression of MHC molecules (class I and class II • Expression of accesory cell interaction molecules • Cytokine secretion (IL-12 and others)

ADAPTIVE IMMUNITY

ANTIGEN-ANTIBODY BINDING • Non-covalent (hydrogen bonding, electrostatic, Van der Waals, hydrophobic) • Antibody affinity the strength of a single Ag-Ab bond • Ab avidity the sum of strength of all bonds • Epitope antigenic determinant able to bind antibody determinant (paratope)

ANTIGEN-BINDING MOLECULES Cell membrane Ig Ab - Antibody Free Ab in body fluids T-cell receptors (TCR) HLA - Human Leucocyte Antigens (MHC) – Major Histocompatibility Complex - class I HLA (MHC) class II Molecules of innate immunity (lectins and others)

MAJOR HISTOCOMPATIBILITY ANTIGENS • Histocompatibility antigens are cell surface expressed on all cells (class I) – exception: red blood cells and on APC, B cells, monocytes/macrophages (class II) • They are targets for rejection • They are inherited from both parents as MHC haplotypes and are co-dominantly expressed

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) Is located on short arm of chromosome 6 It includes 3 regions: class Ia (loci A, B, C) class Ib (loci E, F, G, H), class II (loci DR, DQ, DP) and class III Genes of class Ia and class II are highly polymorphic, while those of class Ib and class III are not Polymorphism means occurence of several allelles ie. genes encoding various qualitatively distinct MHC antigens located at the same locus

MAJOR FUNCTIONS OF CELLS PARTICIPATING IN IMMUNE RESPONSES • B cells • • • - recognize antigens and produce antibodies Plasma cells - produce antibodies Th cells - help in immune response, produce cytokines Treg cells - inhibit immune response, produce cytokines Tc cells - kill target cells NK cells - able to to kill virally infected and transformed cells Dendritic cells- present antigens to Th cells

IMMUNOPATHOLOGY Hypersensitivity – overactive immune response (IR) Immunodeficiency – ineffective IR Autoimmunity – reactivity to self antigens Graft rejection Malignancies of the immune system

EFFECTIVENESS OF VACCINES Disease Number of cases (year) Number of cases in 2004 Diphteria 206, 939 (1921) 0 Measles 894, 134 (1941) 37 Mumps 152, 209 (1968) 236 Rubella 57, 686 (1969) 12 Polio (paralytic) 21, 269 (1952) 0

THANK YOU FOR YOUR ATTENTION ! GOOD LUCK IN STUDYING IMMUNOLOGY!