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IM1003: Medical Immunology Introduction to immunological disease principles Prof. L. Ziegler-Heitbrock. The complement system. C1qrs. C3. C4C2. antibody. C3a. C3b. C56789. bacteria. C5b678. C5a. PolyC9. chemotaxis. Membrane attack complex. MBL: mannose binding lectin.

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IM1003: Medical Immunology

Introduction to immunological

disease principles

Prof. L. Ziegler-Heitbrock


The complement system

C1qrs

C3

C4C2

antibody

C3a

C3b

C56789

bacteria

C5b678

C5a

PolyC9

chemotaxis

Membrane

attack

complex


MBL: mannose binding lectin

Ante-antibody

Hoffman et al. (1999) Science 284:1313-8


granulocytes

macrophages

Phagocytosis and intracellular killing


Innate immune response

Innate Immune Response

Invasion

of the same

Microbe

Invasion

of Microbe


2 systems of immune defence

2 systems of immune defence

Innate

(present from the beginning)

Fixed repertoire

Recognises rough differences

Soluble mediators

(complement, MBL)

Cells

(granulocytes, macrophages)

Adaptive

(acquired during life)

Flexible repertoire

Recognises subtle differences

Memory

Soluble mediators

(antibodies)

Cells

(B cells, T cells)


B

T

Effector Cells of the Adaptive Immune System

B cell receptor

Proteins

Sugars

Lipids

Anything

T cell receptor

Proteins


Fab

Fab

Fc

Antibody

Immunoglobulin (Ig)


B

1 B cell makes 1 Antibody

During an immune response many different B cells making many different antibodies are activated; the response is polyclonal.

For diagnostic and therapeutic purposes a monoclonal antibody may be advantageous.

How can monoclonal antibodies be generated?


T cell receptor (TCR)

recognises foreign peptide together with an MHC class I or II molecule (also termed HLA molecule)

MHC molecule

T cell receptor

Foreign peptide

Major Histocompatibility Complex, Human Leukocyte Antigen


Adaptive immune response

Adaptive Immune Response

More and better

B and T cells

Invasion

of the same

Microbe

Invasion

of Microbe


Immune Defence Against Infection

T

T

Extracellular bacteria

anti-bacterial antibody

C

lysis, phagocytosis

Intracellular bacteria

CD4+

helper

cell

macrophage is activated

to kill mycobacteria

IFNg

Viruses

CD8+

killer

cell

infected cell is killed


What can go wrong with the immune response

What can go wrong with the immune response ?

a) Hyper reactivity

Allergy

Autoimmunity

  • Immunodeficiency

  • Malignancy



type I

antigen

Type I allergy

house dust mite

IgE

Fc receptor

mast cell degranulation


type II

Self cell surface antigen

IgG

target cell

K cell

Anti-erythrocyte antibodies leading to hemolytic anemia

cytotoxic action

IgG

target cell

complement mediated lysis


type III

Lupus erythematodis

immune complex deposition

tissue

C3a

C5a

basement

membrane

polymorphs


type IV

CD4+ T helper cell

activated macrophage or dendritic cell

IFNg

Type IV (delayed) allergy

latex


Antibody against TSH receptor

TSH

TSH receptor

Thyroid epithelial cell

Thyroid hormones

Thyroid hormones

Excessive stimulation of thyroid epithelial cells by antibodies against TSH receptors (Grave’s disease)


Nerve ending

Acetyl choline (Ach)

Antibody against

Ach receptor

Ach receptor

Muscle

Contraction

No contraction

Inhibition of neuromuscular transmission by antibodies against the acetylcholine receptor (myasthenia gravis)


type I

type II

antigen

IgE

IgG

target cell

K cell

Self cell surface antigen

cytotoxic action

Fc receptor

IgG

target cell

Mast cell degranulation

complement mediated lysis

type III

type IV

immune complex deposition

Helper T cell

activated macrophage or dendritic cell

tissue

C3a

C5a

IFNg

basement

membrane

polymorphs

type II

Stimulating

antibody

Blocking

antibody


What is the basis of tolerance ?

Autoreactive

Deletion

B

Receptor down

regulation

B

Blockade of

signalling

B

IL-10

Suppression by

Cytokines

B


Usually tolerance is intact

CH2OH

CH2OH

OH

OH









NHCOCH3

CH2

OH

H

OH

OH

CH2OH

CH2OH

CH2OH

OH

OH

OH

A



A

NHCOCH3

NHCOCH3

CH3

OH

A

Anti-B

OH

OH

CH2OH

CH2OH

CH2OH

A

OH

OH

OH



OH

NHCOCH3

CH3

OH

B

OH

OH

B


If tolerance breaks down antibodies against self are produced.

(TSHR), (AChR) = Autoimmune disease


Immunodeficiencies produced.

Innate system

Adaptive system

Inborn

MBL deficiency

(airway infection)

NADPH-oxidase deficiency in phagocytes

(chronic granulomatous disease)

(bacterial abscesses)

Acquired

Chemotherapy induced agranulocytosis

(severe bacterial infection, sepsis)

Inborn

Selective IgA deficiency (1/600)

(airway infection)

X-linked agammaglobulinemia

(XLA)

(airway infection, enteroviruses)

Acquired

AIDS: CD4 helper cell depletion

(Pneumocystis, CMV)

Almost every element of the immune system can be defective, some deficiencies are amenable to gene therapy.


Malignancies of the Immune System produced.

Termed Leukemia or Lymphoma

Granulocytes Myeloid Leukemia

T Lymphocytes T cell Leukemia

B Lymphocytes B cell Leukemia

B Lymphocytes B cell Lymphoma

(Leukemia: increased numbers of white blood cells;

Lymphoma: increased size of lymph nodes)

Monoclonal antibodies against the normal leukocytes are used to classify the leukemias and lymphomas.


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