Early-onset Evans syndrome, immunodeficiency and premature immunosenescence associated with tripeptidyl-peptidase II deficiency

Polina Stepensky, Anne Rensing-Ehl, Ruth Gather, Shoshana Revel Vilk, Ute Fischer, Schafiq Nabhani, Fabian Beier, Tim H. Brümmendorf, Sebastian Fuchs, Simon Zenke, Elke Firat, Vered Molho Pessach, Arndt Borkhardt, Mirzokhid Rakhmanov, Bärbel Keller, Klaus Warnatz, Hermann Eibel, Gabriele Niedermann, Orly Elpeleg and Stephan Ehl

Key points

  • Deficiency of tripeptidyl-peptidase II is associated with Evans syndrome and viral infection susceptibility.

  • TPP2 deficiency links premature immunosenescence of T and B cells with severe autoimmunity.


Autoimmune cytopenia is a frequent manifestation of primary immunodeficiencies. Two siblings presented with Evans syndrome, viral infections and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in tripeptidyl peptidase II (TPPII) abolishing protein expression. TPPII is a serine exopeptidase involved in extralysosomal peptide degradation. Its deficiency in mice activates cell death programs and premature senescence. Similar to cells from naïve, uninfected TPPII deficient mice, patient cells showed increased MHC I expression and most CD8+ T-cells had a senescent CCR7-CD127-CD28-CD57+ phenotype with poor proliferative responses and enhanced staurosporine-induced apoptosis. T-cells showed increased expression of the effector molecules perforin and IFN-γ with high expression of the transcription factor T-bet. Age-associated B-cells with a CD21- CD11c+ phenotype expressing T-bet were increased in humans and mice, combined with antinuclear antibodies. Moreover, markers of senescence were also present in human and murine TPP2 deficient fibroblasts. Telomere length was normal in patient fibroblasts and granulocytes and low normal in lymphocytes, compatible with activation of stress-induced rather than replicative senescence programs. TPPII deficiency is the first primary immunodeficiency linking premature immunosenescence to severe autoimmunity. Determination of senescent lymphocytes should be part of the diagnostic evaluation of children with refractory multilineage cytopenias.

  • Submitted August 4, 2014.
  • Accepted November 15, 2014.