autoimmune diseases, their pathogenic mechanisms and ... · 1 autoimmune diseases, their pathogenic...
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1
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
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
3
general information
loss of self tolerance
autoimmunity can be provoked:
− proved by mouse models
self proteins are hard to eliminate
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
Picture source: http://histohal.uni-
halle.de/histopatho/histopics/s639.jpg (28.06.2016)
4
Classification
Picture
source:
Murphy,
Kenneth;
Janeway;
8th Edition;
p.623
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
5
Classification
Picture
source:
Murphy,
Kenneth;
Janeway;
8th Edition;
p.623
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
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
6
involved components
Picture source:
Murphy,
Kenneth;
Janeway; 8th
Edition; p.625
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
autoantibodies (e.g. myastenia gravis)
– recognize: acetylcholine receptors
– damage: muscle weakness
7
involved components
Picture source:
Murphy,
Kenneth;
Janeway; 8th
Edition; p.625
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
autoantibodies (e.g. myastenia gravis)
antibodies as immune complexes
– complement activation and ligation of
Fc-receptors
– damage: inflammation of tissue
8
involved components
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.626
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
effector T cells (e.g. type 1 diabetes)
– recognize: self peptides of commensal microbiota with self-MHC
– damage: local inflammation or dircet tissue damage
9
involved components
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.626
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
pregnancy
– IgG can cross
placenta
– maternal IgG is
catabolized
– can cause chronic
organ injury
10
involved components
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.627
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
11
involved components
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.627
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
12
chronic autoimmune diseases
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.628
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
high number of self antigen
– limiting of immune response is hardly possible
broken sequestration
13
chronic autoimmune diseases
Picture
source:
Murphy,
Kenneth;
Janeway; 8th
Edition;
p.628
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
14
Mechanisms of tissue/cell damage
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.572
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
15
Mechanisms of tissue/cell damage
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.630
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
16
Mechanisms of tissue/cell damage
Picture
source:
Murphy,
Kenneth;
Janeway;
8th
Edition;
p.630
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
Type III are
systemic diseases
Type IV are mainly
organ-specific
diseases
most diseases have
a more complex
response e.g. type 1
diabetes
17
Autoantibodies against blood cells
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.631
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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.
Hashimoto‘s thyroiditis
treatment:
– removal of spleen
– administration of lgG
18
Autoantibodies against receptors
Picture
source:
Murphy,
Kenneth;
Janeway;
8th
Edition;
p.633
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
stimulation of receptor
through antibody binding
e.g. Graves‘ disease
19
Autoantibodies against receptors
Picture
source:
Murphy,
Kenneth;
Janeway;
8th
Edition;
p.633
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
inhibition of receptor through antibody binding e.g. myasthenia gravis
– autoantibodies against α-chain of nicotinic acetylcholine receptors
– progressive muscle weakness
20
Autoantibodies against extracellular antigens
Picture source:
http://library.med.utah.edu/WebPath/jpeg2/RENAL093.jpg
(25.06.2016)
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
21
Autoantibodies against extracellular antigens
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
22
Autoantibodies against extracellular antigens
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
23
T cells specific for self antigens
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
24
T cells specific for self antigens
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
evidence through diseases like Typ 1 diabetes
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.636
25
T cells – Multiple sclerosis
Picture source: https://indianmedtrip.com/wp-
content/uploads/2016/02/multiple-sclerosis.jpg
(25.06.2016)
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
26
T cells – Multiple sclerosis
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.637
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
autoreactive B cells produce with help of T cells autoantibodies against
myelin antigens
demyelination
27
T cells – Rheumatoid arthritis
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.638
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
autoimmune diseases and pathogenic mechanisms
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
progressive chronic disease
affected tissues: synovium, cartilage and bone
28
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
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
29
general information
Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.670
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
occur in
autoimmune
disease,
transplant
rejection and
allergy
aim: avoid tissue
damage and
prevent disruption
of tissue function
30
drugs - corticosteroids
Picture source: Murphy, Kenneth; Janeway; 8th Edition;
p.670
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
32
drugs – non cytotoxic drugs
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
most commen: cyclosporin A, tacrolimus (FK506) and rapamycin
interfere with T cell signaling
Picture
source:
Murphy,
Kenneth;
Janeway; 8th
Edition;
p.672
33
drugs – non cytotoxic drugs
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
34
drugs – non cytotoxic drugs
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
37
biologic agents
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
38
biologics
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
39
biologics - antigens
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Treatment of unwanted immune responses
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
40
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
take home messages
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
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
41
Thank you for your
attention
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016
42
List of sources
M. KENNETH, Janeway’s Immunobiology, 8th Edition
http://www.niddk.nih.gov/Pages/default.aspx
http://www.mayoclinic.org
Molecular Immunology 2016
Seminar facilitator: Dr. Peters
Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses| Ann-Britt Schäfer| Bochum | 29.06.2016