autoimmune diseases, their pathogenic …...1 autoimmune diseases, their pathogenic mechanisms and...

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Autoimmune diseases, their pathogenic

mechanisms and treatment of unwanted immune

responses (Janeway‘s Immunobiology)

Ann-Britt Schäfer

Faculty of chemistry and biochemistry

Molecular Immunology 2016

Date: Wed 29th June, 2016

Seminar facilitator: Dr. Peters

Picture source:

https://www.klini

kum.uni-

heidelberg.de/fil

eadmin/pressest

elle/PM_neu/20

13/05_2013/PM

_MS_EPO_Dieh

m_060513.jpg

(26.06.2016)

2

Overview

autoimmune diseases and pathogenic mechanisms

classification

involved components

chronic autoimmune diseases

mechanisms of tissue/cell damage

autoantibodies

T cells

Treatment of unwanted immune responses drugs

biologics



Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016

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general information

loss of self tolerance

autoimmunity can be provoked:

− proved by mouse models

self proteins are hard to eliminate





Picture source: http://histohal.uni-

halle.de/histopatho/histopics/s639.jpg (28.06.2016)

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Classification

Picture

source:

Murphy,

Kenneth;

Janeway;

8th Edition;

p.623





Organ-specfic: few organs are targeted

Systemic: many tissues effected

both can become chronical

clustering of autoimmune diseases

– classification into subtypes

Organ-specific autoimmune diseases

Type 1 diabetes mellitus

Goodpasture‘s syndrom

Multiple sclerosis

Crohn‘s disease

Psoriasis

Graves‘ disease

Hashimoto‘s thyroiditis

Autoimmune hemolytic anemia

Autoimmune Addison‘s disease

Vitiligo

Myasthenia gravis

Systemic autoimmune diseases

Rheumatoid arthritis

Scleroderma

Systemic lupus erythematosus

Primary Sjögren‘s syndrome

Polymyositis

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Classification

Picture

source:

Murphy,

Kenneth;

Janeway;

8th Edition;

p.623





Organ-specfic: few organs are targeted

Systemic: many tissues effected

both can become chronical

clustering of autoimmune diseases

– classification into subtypes

exceptions:

– inflamatory bowel disease (IBD)

– autoimmune hemolytic anemia

Organ-specific autoimmune diseases

Type 1 diabetes mellitus

Goodpasture‘s syndrom

Multiple sclerosis

Crohn‘s disease

Psoriasis

Graves‘ disease


Autoimmune hemolytic anemia

Autoimmune Addison‘s disease

Vitiligo

Myasthenia gravis

Systemic autoimmune diseases

Rheumatoid arthritis

Scleroderma

Systemic lupus erythematosus

Primary Sjögren‘s syndrome

Polymyositis

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involved components

Picture source:

Murphy,

Kenneth;

Janeway; 8th

Edition; p.625





autoantibodies (e.g. myastenia gravis)

– recognize: acetylcholine receptors

– damage: muscle weakness

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involved components

Picture source:

Murphy,

Kenneth;

Janeway; 8th

Edition; p.625





autoantibodies (e.g. myastenia gravis)

antibodies as immune complexes

– complement activation and ligation of

Fc-receptors

– damage: inflammation of tissue

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involved components

Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.626





effector T cells (e.g. type 1 diabetes)

– recognize: self peptides of commensal microbiota with self-MHC

– damage: local inflammation or dircet tissue damage

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involved components






pregnancy

– IgG can cross

placenta

– maternal IgG is

catabolized

– can cause chronic

organ injury

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involved components






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involved components






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high number of self antigen

– limiting of immune response is hardly possible

broken sequestration

13


Picture

source:

Murphy,

Kenneth;

Janeway; 8th

Edition;

p.628





autoimmune response

lead to production of

epitopes

– reveal cryptic

epitopes

– epitope of antigen

can be completly

different e.g. SLE

– can be linked to

the progress of a

disease e.g.

pemphigus

vulgaris

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Mechanisms of tissue/cell damage






15







16


Picture

source:

Murphy,

Kenneth;

Janeway;

8th

Edition;

p.630





Type III are

systemic diseases

Type IV are mainly

organ-specific

diseases

most diseases have

a more complex

response e.g. type 1

diabetes

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Autoantibodies against blood cells






self antigens on blood cells

trigger destruction e.g.

autoimmune hemolytic

anemia

destruction of blood cell in

MPS or through lysis

lysis of nucleated cells is

rare but possible e.g.


treatment:

– removal of spleen

– administration of lgG

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Autoantibodies against receptors

Picture

source:

Murphy,

Kenneth;

Janeway;

8th

Edition;

p.633





stimulation of receptor

through antibody binding

e.g. Graves‘ disease

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Autoantibodies against receptors

Picture

source:

Murphy,

Kenneth;

Janeway;

8th

Edition;

p.633





inhibition of receptor through antibody binding e.g. myasthenia gravis

– autoantibodies against α-chain of nicotinic acetylcholine receptors

– progressive muscle weakness

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Autoantibodies against extracellular antigens

Picture source:

http://library.med.utah.edu/WebPath/jpeg2/RENAL093.jpg

(25.06.2016)





is rare but harmful

Goodpasture‘s disease:

– antibodies against α3 chain of

basement membrane collagen

ligate Fcγ receptor

activation of monocytes,

neutrophils, tissue basophils and

mast cells

release of chemokines

influx of neutrophils

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3 failures in immune complex clearance

1. injection of large amounts of antigens

large amounts of immune complexes

overwhelming system (serum sickness)

2. chronic infections

incapability of clearing infection

– bacterial endocarditis: widespread immune complex injury

– mixed essential cryoglobulinemia: deposite immune complexes in

joint and tissues

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3. part of the pathogenesis of SLE

3 types of antigens: nucleosome subunit of chromatin, spliceosome

and small cytoplasmatic ribonucleoprotein complex

autoantigens are exposed by dying cells

large amounts of immune complexes are produced

activation of phagocytic cells

more nucleoprotein complexes

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T cells specific for self antigens





difficult to prove existence of autoreactive T cells:

– T cells recognition is MHC restricted

– difficult to identify targeted antigen

– antigens recognized by CD4 T cells are easier to identify than those

that are recognized by CD8 T cells

evidence through diseases like Typ 1 diabetes

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T cells specific for self antigens





evidence through diseases like Typ 1 diabetes


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T cells – Multiple sclerosis

Picture source: https://indianmedtrip.com/wp-

content/uploads/2016/02/multiple-sclerosis.jpg

(25.06.2016)





T cell mediated chronic neurological disease

affected antigens: - myelin basic protein (MBP)

- proteolipid protein (PLP)

- myelin oligodendrocyte

glycoprotein (MOG)

development of plaques

demyelination of nerve cells

inflammatrory infiltration along blood vessels

variety of neurological symptoms

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T cells – Multiple sclerosis






autoreactive B cells produce with help of T cells autoantibodies against

myelin antigens

demyelination

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T cells – Rheumatoid arthritis






progressive chronic disease

affected tissues: synovium, cartilage and bone

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Overview


classification

involved components


mechanisms of tissue/cell damage

autoantibodies

T cells

Treatment of unwanted immune responses drugs

biologics




29

general information




Treatment of unwanted immune responses


occur in

autoimmune

disease,

transplant

rejection and

allergy

aim: avoid tissue

damage and

prevent disruption

of tissue function

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drugs - corticosteroids

Picture source: Murphy, Kenneth; Janeway; 8th Edition;

p.670





cross plasma membranes

bind intercellular receptors of nuclear

receptor family

regulate approximately 20% of genes

expressed in leukocytes

side effects: toxic and develop tolerance

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drugs – cytotoxic drugs

Picture source: sigma aldrich





most commen: azathioprine, mycophenolate and

cyclophosphamide

target: DNA synthesis

side effects: toxic to all tissues

azathioprine: block de novo synthesis of AMP and GMP

mycophenolate: block de novo synthesis of GMP

cyclophosphamide: alkylates DNA

azathioprine

cyclophsphamide

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drugs – non cytotoxic drugs





most commen: cyclosporin A, tacrolimus (FK506) and rapamycin

interfere with T cell signaling

Picture

source:

Murphy,

Kenneth;

Janeway; 8th

Edition;

p.672

33






cyclosporin A and

tacrolimus inhibit

calcineurin

T cells are sensitve to

calcineurin

side effects:

– affect all immune

responses

– effect several tissues

– fine tuning of drug dosis

is neccessaryPicture source: Murphy, Kenneth; Janeway; 8th Edition; p.673

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rapamycin

– immunophilin complex inhibits mTOR

– reduces cell growth and proliferation

– increase number of regulatory T cells

fingolimod:

– inhibits migration of dendritic cells

– causes retention of effector

lymphocytesPicture source: Murphy, Kenneth; Janeway; 8th Edition; p.674

35

biologics – monoclonal antibodies





new class of therapeutic compounds

act by two general mechanisms:

– depleting antibodies (trigger destruction of lymphocytes)

– non depleting antibodies (blocking function of their target protein)

various approches to make them more compatible

Picture source:

Murphy,

Kenneth;

Janeway; 8th

Edition; p.675

36

biologics – monoclonal antibodies





Source:

Murphy,

Kenneth;

Janeway; 8th

Edition;

p.67600

Monoclonal antibodies developed for Immunotherapy

Generic name Specifity Mechanism of action Approved indication

Rituximab Anti-CD20 Eliminates B cellsNon-Hodgkin‘s

lymphoma

Alemtuzumab Anti-CD52Eliminates

lymphocytes

Chronic myeloid

leukemia

Muromonab Anti-CD3Inhibits T cell

activation Kidney

transplantationDaclizumabAnti-IL2R

Reduces T cell

activationBasiliximab

Infliximab

Anti-TNF-αInhibit inflamation

induced by TNF-α

Crohn‘s disease

Certolizumab

Rheumatoid arthritisAdalimumab

Golimumab

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biologic agents





immunomodulatory therapy:

– aim is to reduce tissue damage

– antibodies against activity of cytokines like TNF-α and IL-1

anti-TNF-α antibodies are used in rheumatoid arthritis

– block TNF- α activity

– neutralize TNF- α activity

problem: higher risk of infections e.g tubercolosis

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biologics





natalizumba is specific for α4 integrin subunit

blockade of α4:β1 integrin is not specific

side effect: reduced defence against infections

Picture source:

Murphy,

Kenneth;

Janeway; 8th

Edition; p.680

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biologics - antigens





change of immune response and reduction or elimination of pathogenic

features by antigen presentation

for example: peptides given orally can effect regulator T cells without

activating other T cells

peptide drugs (e.g. glatiramer acetat)

altered peptide ligands

– can be designed to be an antagonist, agonist or induce differentiation

of regulatory T cells

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take home messages


autoimmune diseases and pathogenic mechanisms:

classification of diseases in organ-specific and systemic

classification of tissue injury by scheme of hypersensitivity reactions

multiple components are involved

inducement of autoimmune response remains unclear

Treatment of unwanted immune responses:

conventional drugs:

– anti-inflammatory have a wide range

– cytotoxic kill all dividing cells

– immunosupressant drug intervene in intracellular signaling pathways

biologics:

– reduce, inhibit or prevent lymphocyte actions

– inhibition TNF-α

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Thank you for your

attention




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List of sources

M. KENNETH, Janeway’s Immunobiology, 8th Edition

http://www.niddk.nih.gov/Pages/default.aspx

http://www.mayoclinic.org




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