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

LECTURE 1

INTRODUCTION TO IMMUNOLOGY

Jan Żeromski

20013/2014

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

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.

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

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

INNATE IMMUNITYINNATE 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, c-reactive 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

CComplement systemomplement system

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

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):

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

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

CCytokinesytokines

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

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)

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.)

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)

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 ADAPTIVE IMMUNITY

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)

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!