Immunobiology

The role of the immune system

The defence against: (1) pathogenic organisms (viruses, bacteria, fungi, unicellular organisms, worms)(2) Tumor cells

Malfunctioning: Autoimmune disease (e.g. rheumatoid arthritis

type 1 diabetes)

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IMMUNE SYSTEM

1. Innate (nonspecific)1st line of defence

Cellular components

Humoral components

2. Adaptive (specific)2nd line of defence

Cellular components

Humoral components

2Two subdivisions of the

immune system

Innate immune responses are activated directly by pathogens and defend all multicellular organisms against infection. In vertebrates, pathogens, together with the innate immune responses they activate, stimulate adaptive immune responses, which then work together with innate immune responses to help fight the infection.

Two subdivisions of the immune system3

FeaturesInnate immune system Adaptive immune system

Response is antigen-independent Response is antigen-dependent

There is immediate maximal response There is a lag time between exposure and maximal response

Not antigen-specific Antigen-specific

Exposure results in no immunologic memory Exposure results in immunologic memory

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Two subdivisions of the immune system

IMMUNE SYSTEM

Myeloid cells

GranulocyticNeutrophils

BasophilsEosinophils

MonocyticMacrophagesKupfer cells

Dendritic cells

Lymphoid cells

T cellsHelper cells

Suppressor cellsCytotoxic cells

B cellsPlasma cells

Memory cells

NK cells

Cells of immune system5

I. Innate Immune System

Innate Immune System

A. Anatomical barriers

Mechanical factors: skin, cilia, mucus, peristaltics, flushing of tear and salivaChemical factors: low pH in the stomach and sweatBiological factors: natural flora of skin and intestines

B. Humoral barriersComplement systemCoagulation systemOthers: lactoferrin, interferon, lyozyme, defensin

C. Cellular barriersNeutrophil and eosinophil granulocytesMacrophagesNatural killer (NK) cells

Membrane-attack complex

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Inhibition of host complement factors by viruses7

Bloodcapillary

Skin

Bacteria introducedby splinter

Splinter

Mast cell

Damaged tissues attract mast cells which release histamine, which diffuses into the capillaries.

Inflammation X

Histamine causes the capillaries to dilate and become leaky; complement proteins leave the capillaries and attract phagocytes.

Blood plasma and phagocytes move into infected tissue from the capillaries.

Complementproteins

Phagocyte

Inflammation X

Deadphagocyte

Phagocytes engulf bacteria and dead cells.

Histamine and complement signaling cease; phagocytes are no longer attracted.

Signaling molecules stimulate endothelial cell division, healing the wound.

Inflammation X

II. Adaptive Immune System

Adaptive immune responses

Cellular response

Humoral response

2 main classes:(1) Humoral immune response (= antibody response, B cell-mediated response)

(2) Cellular immune response (=T cell-mediated immune response)

The T cells …(1) induce apoptosis?(2) activate macrophages phagocytosis(3) activate B cells antibody production

B cell T cell

antibody

virus-infected

cell

virus

virus-infected cell

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The antibodies…(1) block the ability of viruses to bind to receptors (2) block the effect of toxins by masking them(3) mark pathogens for destruction

LIMPHOCYTES

Against extracelluláris parasites

Against intracelluláris parasites

Human lymphoid organs 9

nasopharyngeal tonsil(adenoid) tonsil

lymphatic vessels

lymphatic nodes

spleen

thymus

Peyer’s patches in small intestines

appendix

bone marrow

2x1012 lymphocyte in the body

The innate and adaptive immune system work together10

Pathogen-associated molecular patterns (PAMPs) pattern recognition receptors

Pattern recognition receptors:(1) Located on the surface of phagocytes

(2) Secreted receptors (marking the pathogens through binding them)

(3) Located on the surface of e.g. dendritic cells (Toll-like receptors), which activate intracellular signal molecules that lead to the secretion of extracellular signal molecules that promote inflammation and help activate adaptive immune responses

Dendryticcell

The innate and adaptive immune system work together11

(1) Dendritic cells ingest invading microbes or their products at the site of an infection. (2) The microbial PAMPs activate the dendritic cells (through toll-like receptors) to express co-stimulatory proteins on their surface and (3) to migrate in lymphatic vessels to a nearby lymph node, where (4) the activated dendritic cells activate the small fraction of T cells that express a receptor for the microbial antigens displayed on the dendritic cell surface. (5) These T cells proliferate and some then migrate to the site of infection, where they help eliminate the microbes, by either helping to activate macrophages or killing infected cells .

1.2.

3.

5.

4.

HUMORAL IMMUNE RESPONSE

HelperT cell (TH)

T cellreceptor

Macrophage

The antigen is taken up by phagocytosis and degraded in a lysosome.

Interleukin-1 (a cytokine)activates a TH cell.

Cytokines re-leased by the TH cell stimulate it to proliferate.

A T cell receptor recognizes an antigenic fragment bound to a class II MHC protein on the macrophage.

ACTIVATION PHASEClass II MHCprotein

Antigen

Y

HUMORAL IMMUNE RESPONSE

The TH cell proliferates and forms a clone.

Y

HUMORAL IMMUNE RESPONSE

EFFECTOR PHASE

B cell

The binding of antigen to a specific IgM receptor triggers endocytosis, degradation, and display of the processed antigen.

Cytokines activate B cell proliferation.

TH cell

A T cell receptor recognizes an antigenic fragment bound to a class II MHC protein on a B cell.

Y

HUMORAL IMMUNE RESPONSE

B cells proliferateand differentiate.

The plasma cellproduces antibodies.

Plasma cell

Memory cell

Y

CELLULAR IMMUNE RESPONSE

ACTIVATION PHASE

Infected cell

CytotoxicT cell (TC)

T cellreceptor

Antigen

Class I MHCprotein

A viral protein made in aninfected cell is degraded into fragments and pickedup by a class I MHC protein.

A T cell receptor recognizesan antigenic fragment boundto a class I MHC protein onan infected cell.

Y

CELLULAR IMMUNE RESPONSE

The TC cell proliferates and forms a clone.

Y

CELLULAR IMMUNE RESPONSE

EFFECTOR PHASE

The T cell releases perforin…

A T cell receptor again recognizes an antigenic fragment bound to a class I MHC protein.

Infected cell(one of many)

Y

CELLULAR IMMUNE RESPONSE

…which lysesthe infected cell before the viruses can multiply.

Y

The development of T and B cells 12

1. central lymphoid organs

2. peripheral lymphoid organshematopoetic tissues thymus

common lymphoid progenitor cell

thymocytehematopoetic stem cell

common lymphoid progenitor cell

developing B cell

T cell

B cell

ANTIGEN

T cell-mediated immune response

Antibody response

B cells plasma cells: - make antibodies- make memory cells

T cells (1) cytotoxic T cells:- directly kill infected host cells (2) helper T cells: - secret cytokines thereby activate macrophages,

dendritic cells, B cells, and cytotoxic T cells (3) regulatory T cells: - inhibit the function of helper T cells,

cytotoxic T cells, and dendritic cells

maturation effector cells

B cells can act over long distances by Secreting antibodies that are widely distributed by the bloodstream

T cells can migrate to distant sites, but, once there, they act only locally on neighboring cells

HematopoesisDevelopment of blood cells

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Hematopoesistranscription factors

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PU.1

GATA-1

Ikaros, Aiolos, Helios

TRANSCRIPTIONFACTORS

GROWTH FACTORSNames are not needed to study!

The clonal selection theoryprecursor cell

different resting cells

antigen

antibody-secreting effective B cells

secreted antibodies

ANTIGEN BINDING TO SPECIFIC B CELL (B) IN PERIPHERAL LYMPHOID ORGAN

PROLIFERATION (CLONAL EXPANSION)AND DIFFERENTIATION OF B CELLS

PROLIFERATION AND DIVERSIFICATIONIN BONE MARROW

McFarlene Burnet

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Epitopes

antibody A

antibody Bantibody C

Epitopes(antigenic determinants)

antigen

Epitopes: those parts of an antigen that bind to the antigen-binding site on either an antibody molecule or a lymphocyte receptor

Immunodominant epitopes: epitopes producing a greater immune response than others

antigen-binding site

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naive cell

1st exposure to antigen

memory cells effector cells

memory cells

effector cells

2ndexposure to antigen

Both B and T cells

Immunological memory

Prim

ary

imm

une

resp

onse

Seco

ndar

y im

mun

e re

spon

se

Immunological tolerance to self antigens17

Central lymphoid organ

Peripheral lymphoid organ

Immaturelymphocytes

Mature naivelymphocytes

Lymphocyte withaltered specificity

Self antigens

Dead lymphocyte

RECEPTOREDITING

CLONALDELETION

CLONALDELETION

CLONALINACTIVATION

CLONALSUPPRESSION

Foreign antigen

Foreign antigen

Co-stimulatory signal

Self antigen

Effector or memorylymphocytes

Effector or memorylymphocytes

Dead lymphocyte

Inactivated lymphocyte

Suppressedlymphocyte

Regulatory T cell

David Nemazee Martin Weigert receptor editing

Autoimmune diseases – 2 examples18

Myasthenia gravis: immune reaction against acetylcholine receptor

Diabetes type 1: immune reaction against insulin-secreting cells in the pancreas

The membrane-bound and secreted antibodies made by a B cell clone

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antigen

antigen receptor resting cell

PROLIFERATIONAND

DIFFERENTIATION

effector B cells

secreted antibodies

Antibodies

variable

constant

light c

hain

Hea

vy c

hain

antigen-binding site antigen-binding site

hinge region

light chainlight chainheavy chainheavy chain

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Antibody–antigen interactions21

The 5 classes of antibodies22

The main stages in B cell development

Plasma cell

Memory cell

ANTIGEN EFFECT

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A pentameric IgM molecule24

IgG: antibody-activated phagocytosis25

Dimeric IgA molecule26

The role of IgE in histamine secretion by mast cells27

Antigen binding to antibody28

Molecules with multiple antigenic determinants29

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Heavy and light chains

Constant and variable regions of immunoglobulin chains31

Antibody hypervariable regions32

Immunoglobulin domains

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The organization of the DNA sequences that encode the constant region of an antibody heavy chain, such as that found in IgG

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Immunogenetics

Human antibody genes

Z

Heavy chain Light chain

Light chain

The V–J joining process involved in making a human k light chain

Primary antibody repertoire

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The human heavy-chain locus

The heavy-chain VDJ recombination 36

The role of recombination signal sequences in RAG-mediated gene segment joining

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Allelic exclusion: Selection of antibody loci during B cell development in the bone marrow

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Some ways in which AID can cause mutations during somatic hypermutation

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An example of the DNA rearrangement that occurs in class switch recombination

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The main mechanisms of antibody diversification in mice and humans

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A T cell receptor (TCR) heterodimer

chain: VJ régió chain: VDJ régióNo somatic hypermutation

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Three types of proteins on the surface of an activated dendritic cell involved in activating a T cell

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Two strategies by which effector cytotoxic T cells kill their target cells

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Differentiation of naive helper T cells into either TH1 or TH2 effector helper cells in a peripheral lymphoid organ

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Recognition by T cells of foreign peptides bound to MHC proteins

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Class I and class II MHC proteins

MHC-I protein

MHC-II protein

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Human MHC genes

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The interaction of a T cell receptor with a viral peptide bound to a class I MHC protein

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CD4 and CD8 co-receptors on the surface of T cells49

The processing of a viral protein for presentation to cytotoxic T cells – MHC-I system

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Some effects of interferon-g (IFNg) on virus-infected cells51

The processing of an extracellular protein antigen by a dendritic cell for presentation to a helper T cell –

MHC-II system

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Selection of T cells

1.

2.

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