Autoimmune lymphoproliferative syndrome (ALPS)

DSAI – Educational Seminar
Autoimmune
lymphoproliferative
syndrome
(ALPS)
fabian.hauck@med.uni-muenchen.de

• Girl at 6 years with chronic lymphadenopathy and splenomegaly in 2008
• No infectious or malignant cause
• Hemolytic anemia with autoantibodies against erythrocytes
• Thrombocytopenia with autoantibodies against platelets
• IgM reduced, IgG and IgA increased
• Elevated TCRαβ + CD4 - CD8 - double-negative T cells
• sFASL and IL-10 increased
• Father at 8 years with chronic lymphadenopathy and splenomegaly in 1974
• No infectious or malignant cause
• Hemolytic anemia at the age of 8 years stopped after splenectomy
• Lymphadenopathy vanished later on
Medical history

I
II
III
III
1 2
1
3
8 9
Pedigree
10
4 5 6
1 2 3 4 5 6 7
7

Adaptive immunity

Immunity / Autoimmunity / Malignancy

FAS:FASLG central for homeostasis of the immune system

T cell proliferation and apoptosis
are carefully counterbalanced

Autoimmune
lymphoproliferative
syndrome
(ALPS)

Revised classification of ALPS
Nomenclature Gene Definition
ALPS-FAS FAS
ALPS-FAS FAS
ALPS-sFAS FAS
ALPS-FASLG FASLG
ALPS-CASP10 CASP10
Unknown Unknown
Patients fulfill ALPS diagnostic criteria and have
germline homozygous mutations in FAS
Patients fulfill ALPS diagnostic criteria and have
germline heterozygous mutations in FAS
Patients fulfill ALPS diagnostic criteria and have
somatic mutations in FAS
Patients fulfill ALPS diagnostic criteria and have
germline mutations in FASLG
Patients fulfill ALPS diagnostic criteria and have
germline mutations in CASP10
Patients meet ALPS diagnostic criteria;
however, genetic defect is undetermined
• Strongly dominant negative intracellular domain (ICD) mutations
• Weakly dominant negative extracellular domain (ECD) mutations
• FAS Haploinsufficiency ???

1.
2.
Revised diagnostic criteria for ALPS
Required
Chronic (> 6 months), nonmalignant, noninfectious
lymphadenopathy or splenomegaly or both
Elevated CD3 + TCRαβ + CD4 − CD8 − DNT cells
(≥ 1.5% of total lymphocytes or 2.5% of CD3 + lymphocytes)
Primary accessory
1. Defective lymphocyte apoptosis
2. Somatic or germline pathogenic mutation in FAS, FASLG or CASP10
1.
Secondary accessory
Elevated plasma sFASL (>200 pg/mL) OR interleukin-10 (>20 pg/mL) OR
vitamin B 12 (> 1500 ng/L) OR interleukin-18 (> 500 pg/mL) levels
2. Typical immunohistological findings
3. Autoimmune cytopenias AND elevated immunoglobulin G levels
4.
Definitive diagnosis needs 2 required plus 1 primary accessory criteria
Family history of a nonmalignant/noninfectious lymphoproliferation
with or without autoimmunity

Heterozygous germline start codon FAS c.3 G>T
in 12/19 but only 2/12 with full-blown ALPS
I
II
III
III
1 2
1
3
8 9
10
4 5 6
1 2 3 4 5 6 7
7

LOH in DNT leads to ALPS-FAS/sFAS
Control
II.6
Father
III.6
ALPS-FAS/sFAS
PBMC DNT
CCATGCTGG CCATGCTGG
CCATG/ TCTGG
CCAT G/ T CTGG
CCAT G/ TCTGG CCATTCTGG

Summary
• ALPS is caused by defective lymphocyte apoptosis
• ALPS is diagnosed with clinical, laboratory and genetic criteria
- Lymphadenopathy
- Splenomegaly
- Autoimmune cytopenias
- Elevated double-negative T cells
- Elevated biomarkers (sFASL, IL-10, vitamine B12)
- Disturbed apoptosis
- ALPS defining mutations, e.g. in FAS

Summary
• Start codon FAS c.3 G>T is impeeding expression from the
affacted allele
• No interfeering protein expressed
• MPR present sub-clinical manifestation
• Somatic LOH in DNT causes full-blown ALPS-FAS/sFAS
• In vitro apoptosis not suitable for diagnosing ALPS-sFAS
• FAS on DNT should be analyzed routinely
• FAS haploinsufficiency does not cause ALPS-FAS
• Haploinsufficient patients have to be monitored
• Without interferring FAS protein a second genetic or
environmental hit may always be necessary in the pathogenesis of
ALPS-FAS/second hit