LECTURE 1 INTRODUCTION TO IMMUNOLOGY Jan Żeromski 200 13 /20 14

1. LECTURE 1INTRODUCTION TO IMMUNOLOGYJan Żeromski20013/2014

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

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

4. 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

5. 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 „ )

6. 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

7. 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

8. INNATE IMMUNITY

9. 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)

10. 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

11. Complement system

12. 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

13. Complement– bound and Complement – associated biologically 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):

14. 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

15. 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

16. 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

17. Cytokines

18. 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

19. 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)

20. 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.)

21. 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)

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

23. 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)

24. ADAPTIVE IMMUNITY

25. 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)

26. 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)

27. MAJOR HISTOCOMPATIBILITY ANTIGENS • Histocompatibility antigens are cell surface expressed on all cells (class I) – exception: red blood cellsand 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

28. 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

29. 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

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

31. EFFECTIVENESS OF VACCINES

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