APS 2006 Refresher Course
Common auto-immune signaling defects; what does gender have to do
with it?
Denise Faustman, M.D., Ph.D.
Director, Immunobiology Laboratory
Massachusetts General Hospital
Harvard Medical School
APS 2006 Refresher Course
Autoimmune Disease Incidence
0 10 20 30 40 50 60 70 80 90 100
Thromboangiitis obliterans
Goodpasture's syndrome
Ankylosing spondylitis
Polyarteritis nodosa
IgA nephropathy
Erythema multiforme
Ulcerative colitis
Sarcoidosis
Multiple sclerosis
Rheumatoid arthritis
Addison's disease
Thrombocytopenic purpura
Myasthenia gravis
Takayasu's arteritis
Erythema nodosum
Systemic lupus erythematosus
Au
toim
mu
ne
Dis
ease
% Females
APS 2006 Refresher Course
Autoimmunity
• Manifests itself as many different diseases– Type I diabetes, Reumaotid arhritis (RA), Crohn’s, Lupus, and
about 45 others
• Autoimmunity tracks in families, but target tissue differs
• Autoimmune patients often develop additional autoimmune disease
• Complex and inconclusive genetic picture-twins
APS 2006 Refresher Course
New Concepts
• Use of TNF not anti-TNF as a therapy
• For type I diabetes: regeneration is a method of restoring normal blood sugars in diabetes– Disease removal is essential
APS 2006 Refresher Course
Anti-TNF therapies: approved drugs for autoimmunity
• Approvals: Rheumatoid Arthritis(RA), Crohn's, Juvenile Rheumatoid Arthritis, etc
• Ex: infliximab, adalimumab, entanercept
• Proven efficacy
• Side effect: induction of new AI
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Death Receptors and Autoimmunity
BAFF/CD40L
FasL
LPS/Toll
TLR4
FAS
TNF R
BAFFR/CD40-R
NIK
TRAF
MyD88
Casp8RAIDDRIP2
RIP
IKK
NFkBp52/p50-RelA,B
NOD1NOD2
Casp9
FADD
TCR
Self Antigen with MHC
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Defects in TNF levels (decreased NFB activation) in murine autoimmunityNOD mouse - dysregulated NFkB
TNF gene polymorphismsExcess TNF-R
TNF or it’s induction is therapeutic (JCI 2001; Science 2003)
NZB mouse - dysregulated NFkBInduced decrease TNF, accelerated diseaseTNF is therapeutic
BB ratLow TNF productionTNF therapeutic
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Defects in NF-B in Human Autoimmunity
• A Frameshift Mutation in NOD2 Associated with Crohn’s Disease, Nature 411: 603 (2001), Nature 411: 599 (2001)
• Genetic linkage to NFkB modifier IkBa - Multiple Sclerosis, Ulterative colitis• Abnormal NF-kB Activity in T Lymphocytes from Patients with Systemic Lupus,
Wong, et al., Journal of Immunology 163: 1682 (1999)• Abnormalites in T Lymphocytes from diverse human diseases with TNF apoptosis
(Faustman lab)• Altered CD8 T cell apoptosis and low NFkB in Scleroderma, Kessel et al J Clin
Immun Vol 24, 30 (2004)• Functional variant of SUMO4, a IkBa modifier with IDDM
Nature Genetics 36, 837 (2004)• Many genetic papers with linkage of TNF and TNF receptors to autoimmune risk
– Met-196to Arg TNFR2 affects TNF apoptosis by impared NFkB signalling (Lupus, Rheumatoid arthritis) JBC 280: 5994 (2005)
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Destruction of Memory T Cells
Defects in NF-B Activation
Rx #2
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Figure 3A and B
1 2 3 4 5 6 7 8 9 10 11
- -M F M F
BALB/C NOD
N.E. from Spleen
- - + - + TNF-
1 2 3 4 5 6 7 8 9 10 11
TNF- Does Not Induce NF-B in NOD Mouse
TNF-
From Hayashi and Faustman
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NF-B Precursor Proteins Are Not Processed Properly in NOD Mouse
Figure 2 from Hayashi and Faustman
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Proteosomes from NOD Mouse Are Missing Key Subunit
Figure from Yan et al.
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TNF- -induced Apoptosis
NF-B
NF-B
NF-B
IB
Survival factor
Survival factor
Nucleus
Cytosol
TNF-
TNF- receptor
NF- B activation
Transcriptional activation
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Figure 5 A&B from Hayashi & Faustman
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Nature Medicine 2002; 6:1065.
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Autoimmunity
Target Organ
T Cells
Defects in tolerance are lineage dependent defects (only certain lymphocytes have the defect, not all lymphocytes)
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Autoimmunity-Current Rx
Target OrganT Cells
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Autoimmunity-New Rx
Target OrganT Cells
Rx #1 Rx #2TNF
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Combination of Approaches
Permanent Disease Reversal
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Combination Treatment
Rx #1- Cells w/ MHC class I and self peptide matched
Rx #2 TNF- Induction
Diabetic NOD Mouse
40 days
1 injection
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Figure 3 from Ryu et al.
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Irradiated Irradiated SplenocytesSplenocytes
LiveLiveSplenocytesSplenocytes
Pancreatic histology after treatment (I)Pancreatic histology after treatment (I)
#790#790#788#788#744#744
#699#699 #745#745 #752#752
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Far Side cartoon by Gary Larson of explorers in canoe entering the spleen
APS 2006 Refresher Course
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Hox11 transcription factor
• Fetal transcription factor for stem cell fate, patterning, neurogenesis
• Highly conserved in stem cells of sponges, newts
• Newt regeneration
• Transfection into ES cells to maintain undifferentiated state
• Hox11 stem cells in females and males
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Hox11 expression in spleen of adult mouse but not the pancreas
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Translation of TNF autoimmune treatment to humans with autoimmunity
Next step: Biomarker development
Uses: Design of rapid clinical trialsdugs