Human Disturbances of Apoptosis: ALPS and beyond

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Human Disturbances of Apoptosis ALPS and beyond

• João Bosco Oliveira, MD, PhD
• National Institutes of Health

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Clinical History

• White, non-consanguineous parents
• Linphadenopathy since 1st year of life
• Splenomegaly
• Coombs hemolytic anemia
• Immune thrombocytopenia

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Lab Studies

• Initially investigated for chronic EBV
• Negative serologies
• Funny immunophenotype.

CD3TCRalfa/beta CD4CD80.2
CD3TCRalfa/beta CD4CD837.1
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Autoimmune Lymphoproliferative Syndrome (ALPS)

• Described by Canale and Smith in 1967 Sneller
  1992 Fas 1995
• Chronic benign lymphocyte accumulation
  (splenomegaly, linphadenopathy)
• Elevated DNT (gt1)
• Apoptotic defect in vitro (/-)
• Autoimmunity and lymphoma.

Oliveira JB and Fleisher TA. Curr Opin Allergy
Clin Immunol. 2004..
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EXTRINSIC
INTRINSIC
Fas L
NRAS
Death receptor
Cytokine withdrawal BIM Growth
factors BAD DNA damage NOXA, PUMA
Death domain
Death-inducing Signaling complex
FADD
Death effector domain
BAX BAK
Caspase-8, -10
BID
BCL-2 BCL-XL MCL-1
Caspase-3 and other effector caspases
Cytochrome c
Caspase-9
APOPTOSIS
Apoptosome
Apaf-1
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Etiology of ALPS

• Most cases (148/240, 62) caused by mutations in
  FAS (TNFRSF6)
• Minority associated to somatic Fas mutations
  (10), caspase-10 (4), caspase-8 (2), FasL (3) and
  NRAS (1)
• Around 23 (NIH) unknown defect

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Molecular Classification

• ALPS tipo Ia FAS
• ALPS tipo Ib FasL
• ALPS tipo Im somatic FAS mutation (mosaic)
• ALPS tipo II CASP10 (CASP8?)
• ALPS III Unknown
• ALPS IV NRAS (intrinsic apoptosis defects)

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ALPS Type Ia

• Mutations in FAS (TNFRSF6)
• Most common form
• DD mutations higher penetrance and risk of
  complications
• Aut.Domin Dom.negative effect
• Other modifiers HLA-B44, CASP10 SNPs.

Fisher, GB. Cell. 1995 81(6)935-46
Rieux-Laucat, etal. Science. 1995
268(5215)1347-9.
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ALPS Type Ib

• Mutations in Fas ligand
• Normal apoptosis assay
• 1996 atypical, male, LES-like, 84 bp deletion in
  exon 4, nl FasL expression
• 2006 female, homozygous, no FasL expression
• 2007 heterozygous, DN effect.

Bi, LL., et al. BMC Med Genet. 2007 Del-Rey M,
et al. Blood 2006 Wu J, et al. JCI 1996.
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Tipo I mosaic

• Typical phenotype
• Second most common
• Mutation in DNT and some CD4, CD8 and CD34
  cells (10-20)
• Normal apoptosis in vitro

Holzelova E, et al. N Engl J Med, 2004
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ALPS Type II

• Caspase-10 mutations
• Typical phenotype
• Three patients I406L and L285F, not V410I
• Nice defective dendritic cell apoptosis.

Wang, J.et al. Cell. 199998(1)47-58.
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ALPS Type IV

• First intrinsic apoptosis defect
• Single patient
• Chronic lymphadenopathy
• Leukemia and lymphoma
• Autoantibodies.

Oliveira JB, et al. Proc Natl Acad Sci U S A,
2007.
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Low BIM Levels in P58
Resting PBLs
Purified T cells
NL NL P58
NL NL P58
BIM
actin
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NRAS Mutation
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Caspase Eight Deficiency Syndrome - CEDS

• Two siblings
• Moderate splenomegaly and lymphadenopathy
• Recurrent cutaneous herpes infection
• Low Ig levels
• Borderline DNT and mild apoptotic defect
• Defective activation of LB, LT and NK

Chun HJ, et al. Nature. 2002419(6905)395-9.
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CEDS- Caspase Eight Deficiency Syndrome

• Caspase-8 required for activation of T, B, NK and
  TLR

Su H, Bidere, N, et al. Science. 2005
4307(5714)1465-8.
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Conclusions

• ALPS Extrinsic and Intrinsic apoptosis defects
• Known defects Fas, FasL, Casp10, NRAS Lessons
  for general immunology
• CEDS hipogamma, viral infection e lymphocyte
  accumulation defective NF-Kb activation