LECTURE 1 INTRODUCTION TO IMMUNOLOGY Jan Żeromski 200 13 /20 14
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LECTURE 1
INTRODUCTION TO IMMUNOLOGY
Jan Żeromski
20013/2014
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3 student groups
Subjects:1. 11 lectures – approach to basic and clinical
immunology2. 5 classes – approach to essentials of diagnostic
immunology 3. 7 seminars – clinical immunology
Evaluation:1. Midterm test2. Basic imm. test Final examination 3. Final test
Detailed schedule on the website: immuno.ump.edu.pl
Immunology Course Outline Immunology Course Outline
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Recommended books:Recommended books:
• Introduction to Clinical ImmunologyMedical University Press, 2009.
• Basic Immunology Abbas et al.. Elsevier 2013
• Male, Brostoff, Roth & Roitt Immunology Mosby, Elsevier
• Chapel: Essentials of Clinical Immunology Blackwell.
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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
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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 „ )
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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
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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
receptors
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,• Over 100 000 000 000 different
receptors
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INNATE IMMUNITYINNATE IMMUNITY
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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, c-reactive protein)
• Cytokines (TNF, IL-1- 25)
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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
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CComplement systemomplement system
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COMPLEMENT SYSTEM – MAIN STRUCTURAL FEATURES
Consists of about 30 serum proteins marked by C and arabic number (C1q, C2, C3 etc.)
Many C proteins are zymogens – proenzymes requiring proteolytic cleavage
Enzymes are often formed from several C molecules –eg. C4B2a cleaves C3
Activation of C is controlled by regulatory proteins – eg. DAF, CD59
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Complement– bound and ComplemeComplement– bound and Complemennt – associated t – associated biologically active moleculesbiologically active molecules
C3a i C5a (anafilatoxins) – mediators of inflammation,
Membrane attack complex (non-enzymatic assembly of C5b-C9) – responsible for cell lysis
Complement–inhibitory molecules; DAF,MCP, CD59
C receptors (CR) on various cells (B cells monocytes, neutrophils, some epithelial cells, erythrocytes etc):
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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
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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
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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
C3)– lung surfactant proteins A and D and also – C1q
• MBL binds mannose groups in the bacteria,yeast fungi, viruses cell walls and then activates serine proteinases (MASP), able to cleave C4 and C2 analogous to C1q interaction with C1r and C1s. Effect: C activation
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CCytokinesytokines
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CYTOKINESSIGNAL 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, TNF, TGF – involved in inflammation,
cytotoxicity and immunosuppression respectively
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CELLULAR MECHANISMS OF INNATE IMMUNITY - NEUTROPHIL ACTIVATORS
• Bacterially derived N-formylated
peptides (FMLP)
• Defensins (natural antibiotics)
• Products of complement (iC3b)
• Leukotrienes (products od arachidonic
acid metabolism)
• Cytokines ((TNF, IL-8, GM-CSF)
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RECEPTORS OF INNATE IMMUNITY-PATTERN 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, unme-thylated CpG nucleotides, glycolipids etc.)
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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 leucine-rich repeats (LRRs),In intracellular portion show high homology to IL-1R (TIR domain)
• Exist in families (TLR1-TLR-13)
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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
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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)
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ADAPTIVE IMMUNITY ADAPTIVE IMMUNITY
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ANTIGEN-ANTIBODY BINDING
• Non-covalent (hydrogen bonding, electrostatic, Van der Waals, hydrophobic)
• Antibody affinitythe strength of a single Ag-Ab bond
• Ab aviditythe sum of strength of all bonds
• Epitopeantigenic determinant able to bind antibody determinant (paratope)
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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)
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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
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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
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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
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IMMUNOPATHOLOGY
Hypersensitivity – overactive immune
response (IR)
Immunodeficiency – ineffective IR
Autoimmunity – reactivity to self antigens
Graft rejection
Malignancies of the immune system
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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
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THANK YOU FOR YOUR ATTENTION !
GOOD LUCK IN STUDYING IMMUNOLOGY!