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

Blood. 2015 Jan 29;125(5):753-61. doi: 10.1182/blood-2014-08-593202. Epub 2014 Nov 20.

Abstract

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 (TPP2) abolishing protein expression. TPP2 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 TPP2-deficient mice, patient cells showed increased major histocompatibility complex 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 interferon-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 lengths were normal in patient fibroblasts and granulocytes, and low normal in lymphocytes, which were compatible with activation of stress-induced rather than replicative senescence programs. TPP2 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / immunology*
  • Aminopeptidases / deficiency
  • Aminopeptidases / genetics
  • Aminopeptidases / immunology*
  • Anemia, Hemolytic, Autoimmune / complications
  • Anemia, Hemolytic, Autoimmune / genetics*
  • Anemia, Hemolytic, Autoimmune / immunology
  • Anemia, Hemolytic, Autoimmune / pathology
  • Animals
  • Apoptosis
  • Base Sequence
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Child
  • Child, Preschool
  • Consanguinity
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / deficiency
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / immunology*
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Frameshift Mutation*
  • Gene Expression
  • Humans
  • Immunologic Deficiency Syndromes / complications
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Deficiency Syndromes / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Perforin / genetics
  • Perforin / immunology
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / immunology*
  • Siblings
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Thrombocytopenia / complications
  • Thrombocytopenia / genetics*
  • Thrombocytopenia / immunology
  • Thrombocytopenia / pathology

Substances

  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Perforin
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 2
  • Serine Endopeptidases

Supplementary concepts

  • Evans Syndrome

Associated data

  • PIR/226400