1. German Cancer Research Center
Autoimmune Diseases
SS 2006
Adelheid Cerwenka, PhD
Innate Immunity
German Cancer Research Center

2. The dark
and the bright
side
of the
Immune system

3. 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

4. Loss of tolerance towards self-antigens.
Autoimmunity
Loss of tolerance towards self-antigens.

5. 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.

6. 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

7. Mechanisms of Tolerance
Central Tolerance:
negative selection in thymus (apoptosis)
Peripheral Tolerance:
Indifference
Deletion
Immuno Modulation:
Regulatory T cells
Cytokine Micromilieu
Immune-priviledged sites

8. Tolerance/Autoimmunity
Thymus
CD4-8-
TCR-
CD4+8+
TCR+
“self”
Present
Negative Selection
CD4+8- or
CD4-8+
TCR+
“foreign”
Absent
“foreign” (e.g., virus)
Activation
“self”
Absent
Tolerance/Autoimmunity
Periphery
CD4+8- or
CD4-8+
TCR+

9. Loss of Tolerance?

10. Autoimmune Diseases Risk Factors:
Hormons
genetic
environment

11. Genetic Risk Factors: Major Histocompatibility complex (MHC)
MHC genes are polygenic: several MHC class I and class II genes exist:

12. MHC genes are polymorphic: each gene consists of several allels:

13. MHC molecules are highly variable and each MHC protein binds a different set of antigens:

14. 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,

15. MHC Risk Factors for Diabetes
Juvenile Diabetes (IDDM):
MHC class II: e.g., HLA DQß
IDDM
risk
IDDM
resistence
position 57
Ala, Ser, Val
Asp
Additional 19 non MHC genetic regions
determine IDDM susceptibility!

16. 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
HA-
Specific
TCR X
RIP-HA
HA: influenza
hemagglutinin
T cells
Balb/c
B10.D2
T cell activation
yes
Diabetes no
yes
Th2 Phenotype
yes no
IL-4!
Cytokines play a critical role in autoimmunity!

17. TH1 and TH2 Cytokine-Profiles
IL-2, IFN-, TNF-
mediate cellular immunity
reciprocal
control
IL-4, IL-10, TGF-
TH2
mediate humoral immunity

18. Functional Imbalance BetweenTH1 and TH2 Cytokine Levels
Normal
homeostasis
Example:
autoantibody-
mediated
autoimmune
desease
Prone to
autoimmunity
Autoimmunity

19. Autoimmune Diseases Risk Factors:
hormones
genetic
environment

20. 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

21. Environmental Risk Factors for Autoimmune Diseases
Ref.: Conrad et al.
Nature, 1994, 371, P. 351
Infections can break self-tolerance!

22. Reactivity towards pathogens can cause autoreactivity.
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)

23. 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

24. Which autoimmune diseases do your know?
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

25. Examples for Autoimmune Diseases
Frequency [%]
Insulin-Dependent Diabetes Mellitus (IDDM)
0.4
0.1
1.0
Multiple Sclerosis (MS)
Rheumatoid Arthritis (RA)
Systemic Lupus Erythematosus (SLE)

26. Insulin-Dependent Diabetes Mellitus (IDDM): Selective Destruction of b Cells
Imbalance in glucose metabolism: blindness, renal failure

27. Insulin-Dependent Diabetes Mellitus: Mechanism?
T cell-mediated,
autoantibodies
Autoantigens:
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  cells unclear,
in humans: anti-GAD Ig serum levels are markers for IDDM

28. Transgenic Diabetes Mouse Model: RIP-NP Mice Develop Diabetes after Viral Infection

29. Spontaneous Diabetes Mouse Model: Nonobese Diabetic Mouse (NOD)
Spontaneous, accumulating -cell damage results in overt diabetes,
origins of autoreactivity not identified.
Phenotype
Age
Antigen
Peri-Insulitis
4-6 weeks
limited number of
primary antigens
Islet infiltration,
increasing -cell
damage
12 weeks
recruitment of T cells
with different
specificities
Diabetes
increase of blood glucose
levels due to massive -cell
damage (>90%)
18-20 weeks
“epitope-spreading”
observed

30. 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

31. Transfer Model for MS: Experimental-Autoimmune Encephalomyelitis (EAE)

32. Epitope Spreading I Induction of EAE in mice via injection of PLP: PLP
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,
Induction of EAE in mice via injection of PLP:
PLP
peptide recognition
early
early: EAE
late:
symptom-free
period, followed by
chronic EAE
late
NH2
COOH
MBP
NH2
87-99
COOH

33. Epitope Spreading II OR
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”.

34. 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

35. Antibody Deposition Causes Systemic Injuries

36. 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.

37. 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.

38. 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”

39. Oral Administration of MBP Protects from Experimentally Induced EAE

40. Conclusion: Autoimmune Diseases
Risk factors
Autoimmune Diseases
Insulin-Dependent Diabetes Mellitus (IDDM)
Multiple Sclerosis (MS)
Rheumatoid Arthritis (RA)
Systemic Lupus Erythematosus (SLE)
Therapy