Download Autoimmune Diseases

Autoimmune Diseases
SS 2006
Adelheid Cerwenka, PhD
Innate Immunity
German Cancer Research Center
The dark
and the bright
side
of the
Immune system
First Observations on Tolerance I:
Early 1900:
• Paul Ehrlich: Horror autotoxicus
Effector mechanisms used in host defense may be turned against
the host and cause severe tissue damage (Horror autotoxicus).
However, animals avoid self-destructive processes.
The dark
and the bright
side
of the
Immune system
Autoimmunity
Loss of tolerance towards self-antigens.
Autoimmune Diseases
Loss of tolerance leads to autoimmunity
towards self-antigens and consequently to
pathological damage of one organ or
several tissues within the body.
Autoimmune Diseases
“ Over the past century, there have been
almost as many theories about the origins
of autoimmunity as there are autoimmune
diseases.”
Yehuda Shoenfeld
Nat. Med. 10, 2004
Mechanisms of Tolerance
Central Tolerance:
•
negative selection in thymus (apoptosis)
Peripheral Tolerance:
•
Indifference
•
Deletion
•
Immuno Modulation:
–
Regulatory T cells
–
Cytokine Micromilieu
•
Immune-priviledged sites
Thymus
CD4-8TCRCD4+8+
TCR+
CD4+8or
CD4-8+
TCR+
“foreign”
Absent
“self”
Present
“self”
Absent
Negative Selection
Periphery
CD4+8or
- +
CD4 8
TCR+
“foreign” (e.g., virus)
Activation
“self”
Tolerance/Autoimmunity
Loss of Tolerance?
Autoimmune Diseases
Risk Factors:
Hormons
genetic
environment
Genetic Risk Factors: Major Histocompatibility
complex (MHC)
MHC genes are polygenic: several MHC class I and class II genes exist:
MHC genes are polymorphic: each gene consists of several allels:
MHC molecules are highly variable and each MHC protein binds a different set
of antigens:
Population studies show association of susceptibility to IDDM
with HLA genotype
Affected siblings share 2 HLA haplotypes
much more frequently than expected
Certain HLA genotype are
frequently found in diabetic patients
DR3/4 tight linkage to DQb,
MHC Risk Factors for Diabetes
Juvenile Diabetes (IDDM):
MHC class II: e.g., HLA DQß
position 57
IDDM
risk
IDDM
resistence
Ala, Ser, Val
Asp
Additional 19 non MHC genetic regions
determine IDDM susceptibility!
Genetic Risk Factors: Non-MHC
A Role for Non-MHC Genetic Polymorphism in Susceptibility to
Spontaneous Autoimmunity
B. Scott, R Liblau, S. Degermann, L. A. Marconi, L. Ogata, A. J. Caton, H.O. McDevitt, D. Lo
Immunity 1994, volume 1,p 73-82.
T cells
HASpecific
TCR
X
HA: influenza
hemagglutinin
RIP-HA
Balb/c
B10.D2
T cell activation
yes
yes
Diabetes
no
yes
Th2 Phenotype
yes
no
IL-4!
Cytokines play a critical role in autoimmunity!
TH1 and TH2 Cytokine-Profiles
TH1
IL-2, IFN-, TNF-
reciprocal
control
TH2
mediate cellular immunity
IL-4, IL-10, TGF-b
mediate humoral immunity
Functional Imbalance BetweenTH1 and TH2 Cytokine Levels
Example:
autoantibodymediated
autoimmune
desease
Normal
homeostasis
Prone
to
autoimmunity
Autoimmunity
Autoimmune Diseases
Risk Factors:
hormones
genetic
environment
Example environmental factors:
Goodpasture s disease
• Autoantibodies against type 4 IV collagen (distibuted
widely in basement membranes)
• Manifeestation: often glomerulonephritis, and
pulmonary hemorrhage
• pulmonary hemorrhage: ofen found in smokers:
inflammation of alveoli
Environmental Risk Factors for Autoimmune
Diseases
Ref.: Conrad et al.
Nature, 1994, 371, P. 351
Infections can break self-tolerance!
Molecular Mimicry
Reactivity towards pathogens can cause autoreactivity.
Epitopes derived from the pathogen are sufficiently homolog with
host self-epitopes to cause cross-reactivity, but different enough
to break tolerance.
Example: Juvenile Diabetes (IDDM)
Summary:
Risk Factors for Autoimmune Diseases
•
Genetic Factors: MHC
•
Genetic Factors: non-MHC
Hormones/sex
Th1 versus Th2 cytokine production
Regulatory T cells
•
Environmental Factors: Infections
„Molecular Mimicry“
Superantigens
Disruption of tissue barriers
Group Work
Discuss the following questions within your group:
Which autoimmune diseases do your know?
What mechanisms might cause autoimmunity?
Use the scheme of a human body to indicate diseased organs
Examples for Autoimmune Diseases
Autoimmune Disease
Frequency [%]
Insulin-Dependent Diabetes Mellitus (IDDM)
Multiple Sclerosis (MS)
0.4
0.1
Rheumatoid Arthritis (RA)
Systemic Lupus Erythematosus (SLE)
1.0
0.1
Insulin-Dependent Diabetes Mellitus (IDDM):
Selective Destruction of b Cells
Imbalance in glucose metabolism: blindness, renal failure
Insulin-Dependent Diabetes Mellitus:
Mechanism?
T cell-mediated,
Autoantigens:
autoantibodies
Insulin:
early antigen,
insulin-specific CD4+ T cells transfer diabetes in NODScid mice,
in humans: anti-insulin antibodies found in
50 % of patients just diagnosed with IDDM.
GAD: glutamic acid decarboxylase,
catalyses synthesis of the neurotransmitter GABA in the brain,
function in b cells unclear,
in humans: anti-GAD Ig serum levels are markers for IDDM
Transgenic Diabetes Mouse Model:
RIP-NP Mice Develop Diabetes after Viral Infection
Spontaneous Diabetes Mouse Model:
Nonobese Diabetic Mouse (NOD)
Spontaneous, accumulating b-cell damage results in overt diabetes,
origins of autoreactivity not identified.
Phenotype
Age
Peri-Insulitis
4-6 weeks
limited number of
primary antigens
Islet infiltration,
increasing -cell
damage
12 weeks
recruitment of T cells
with different
specificities
18-20 weeks
“epitope-spreading”
observed
Diabetes
increase of blood glucose
levels due to massive -cell
damage (>90%)
Antigen
Multiple Sclerosis (MS):
Selective Destruction of the Myelin Sheath in the
Central Nerveous System
T cell-mediated,
autoantibodies
Motory and sensory disturbances,
Episodes of relapse followed by remission.
Antigens:
MBP: myelin basic protein
PLP: proteo lipid protein
Transfer Model for MS:
Experimental-Autoimmune Encephalomyelitis (EAE)
Epitope Spreading I
Spontaneous Regression of Primary Autoreactivity during Chronic
Progression of Experimental Autoimmune Encephalomyelitis and Multiple
Sclerosis
By Vincent K. Tuohy, Min Yu, Julie. A. Kawczak, and R. Philip Kinkel
J. Exp. Med., Volume 189, Number 7, 1999, 1033-1042.
Induction of EAE in mice via injection of PLP:
PLP
peptide recognition
early
late
late
early: EAE
NH2
104-117
139-151
late
MBP
NH2
87-99
178-191
COOH
late:
symptom-free
period, followed by
chronic EAE
COOH
Epitope Spreading II
A) Epitope-spreading can enhance clinical symptoms by inducing
autoreactive T cells, which recognize novel self-peptides.
OR
B) Epitope-spreading leads to regression of clinical symptoms by
inducing regulatory T cells, which suppress autoreactive T cells
by a mechanism called:
“Bystander Suppression”.
Systemic Lupus Erythematosus: SLE
Systemic Autoimmune Disease
Autoantibodies
CD4+ T cells
complement
Heterogeneous clinical symptomes:
– skin rash
– joint pain
– disturbances of the central nerveous system
– renal disfunction (Glomerulonephritis)
Structures recognized by autoantibodies:
– double stranded DNA
– nuclear constituents
Antibody Deposition Causes Systemic Injuries
Animal Models for SLE
Spontaneous animal models:
Lpr and gld mice:
–lpr: mutation of Fas
–gld: mutation of FasL
-
-
Defect in apoptosis leads to accumulation of CD4 /CD8 T
cells and production of autoantibodies.
Symptomes: glomerulonephritis, vasculitis
Experimental animal models:
Knock-out mice:
e.g., TGF-ß, CTLA4
Molecules involved in T cell priming.
Therapy in Autoimmune diseases
•
Unspecific suppression of the immune system.
•
Monoclonal antibodies, specific for effector cells, e.g.,
anti-CD4, anti-VLA, anti-IFN-g
•
Modified peptides: blocking of peptide presentation by
MHC molecules or blocking of TCR signaling.
Most autoimmune diseases show reactivity towards multiple antigens, which is
enhanced by epitope spreading.
It is therefore unlikely that blocking of only one T cell population is
therapeutically successful.
Oral Tolerance
Oral uptake of antigen leads to immune suppression:
Induction of regulatory T cells, which migrate to the
attacked organ and secrete inhibitory cytokines.
The inhibitory cytokine milieu down-modulates the activity
of T cells with the same or diverse antigen specifity.
“Bystander Suppression”
Oral Administration of MBP Protects from
Experimentally Induced EAE
Conclusion: Autoimmune Diseases
Risk factors
Autoimmune Diseases
Insulin-Dependent Diabetes Mellitus (IDDM)
Multiple Sclerosis (MS)
Rheumatoid Arthritis (RA)
Systemic Lupus Erythematosus (SLE)
Therapy