aps 2006 refresher course common auto-immune signaling defects; what does gender have to do with it?...

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


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


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


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


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

APS 2006 Refresher Course APS 2006 Refresher Course


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


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


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)


Destruction of Memory T Cells

Defects in NF-B Activation

Rx #2

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



NF-B Precursor Proteins Are Not Processed Properly in NOD Mouse

Figure 2 from Hayashi and Faustman


Proteosomes from NOD Mouse Are Missing Key Subunit

Figure from Yan et al.


TNF- -induced Apoptosis

NF-B

NF-B

NF-B

IB

Survival factor

Survival factor

Nucleus

Cytosol

TNF-

TNF- receptor

NF- B activation

Transcriptional activation


Figure 5 A&B from Hayashi & Faustman


Nature Medicine 2002; 6:1065.


Autoimmunity

Target Organ

T Cells

Defects in tolerance are lineage dependent defects (only certain lymphocytes have the defect, not all lymphocytes)


Autoimmunity-Current Rx

Target OrganT Cells


Autoimmunity-New Rx

Target OrganT Cells

Rx #1 Rx #2TNF


Combination of Approaches

Permanent Disease Reversal


Combination Treatment

Rx #1- Cells w/ MHC class I and self peptide matched

Rx #2 TNF- Induction

Diabetic NOD Mouse

40 days

1 injection


Figure 3 from Ryu et al.



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


Far Side cartoon by Gary Larson of explorers in canoe entering the spleen


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


Hox11 expression in spleen of adult mouse but not the pancreas



Translation of TNF autoimmune treatment to humans with autoimmunity

Next step: Biomarker development

Uses: Design of rapid clinical trialsdugs

aps 2006 refresher course common auto-immune signaling defects; what does gender have to do with it?...

Documents

tnf receptors

linkage of tnf

tnf levels

essentialantitnf therapies

refresher coursefigure

refresher coursenf

refresher courseaps

refresher courseproteosomes