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• 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
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Pedigree
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 Patients fulfill ALPS diagnostic criteria and have germline homozygous mutations in FAS
ALPS-FAS FAS Patients fulfill ALPS diagnostic criteria and have germline heterozygous mutations in FAS
ALPS-sFAS FAS Patients fulfill ALPS diagnostic criteria and have somatic mutations in FAS
ALPS-FASLG FASLG Patients fulfill ALPS diagnostic criteria and have germline mutations in FASLG
ALPS-CASP10 CASP10 Patients fulfill ALPS diagnostic criteria and have germline mutations in CASP10
Unknown Unknown 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 ???
Revised diagnostic criteria for ALPS
Required
1. Chronic (> 6 months), nonmalignant, noninfectious lymphadenopathy or splenomegaly or both
2. 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
Secondary accessory
1. Elevated plasma sFASL (>200 pg/mL) OR interleukin-10 (>20 pg/mL) OR vitamin B12 (> 1500 ng/L) OR interleukin-18 (> 500 pg/mL) levels
2. Typical immunohistological findings 3. Autoimmune cytopenias AND elevated immunoglobulin G levels
4. Family history of a nonmalignant/noninfectious lymphoproliferation with or without autoimmunity
Definitive diagnosis needs 2 required plus 1 primary accessory criteria
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Heterozygous germline start codon FAS c.3 G>T in 12/19 but only 2/12 with full-blown ALPS
II.6 Father
Control
III.6 ALPS-FAS/sFAS
PBMC DNT
CCATGCTGG CCATGCTGG
CCATG/TCTGG CCATG/
TCTGG
CCATG/TCTGG CCATTCTGG
LOH in DNT leads to ALPS-FAS/sFAS
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
