title: Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.
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.
authors.affiliation: Pediatric Hemato-Oncology and Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and.
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and Faculty of Biology, University of Freiburg, Freiburg, Germany;
authors.forename: Ruth
authors.initials: R
authors.lastname: Gather
authors.affiliation: Pediatric Hemato-Oncology and Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;
authors.forename: Shoshana
authors.initials: S
authors.lastname: Revel-Vilk
authors.affiliation: Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany;
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany;
authors.forename: Schafiq
authors.initials: S
authors.lastname: Nabhani
authors.affiliation: Department of Hematology, Oncology, and Stem Cell Transplantation, Rheinisch Westfälische Technische Hochschule Aachen University Medical School, Aachen, Germany;
authors.forename: Fabian
authors.initials: F
authors.lastname: Beier
authors.affiliation: Department of Hematology, Oncology, and Stem Cell Transplantation, Rheinisch Westfälische Technische Hochschule Aachen University Medical School, Aachen, Germany;
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and Faculty of Biology, University of Freiburg, Freiburg, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and.
authors.forename: Simon
authors.initials: S
authors.lastname: Zenke
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany;
authors.forename: Elke
authors.initials: E
authors.lastname: Firat
authors.affiliation: Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;
authors.forename: Vered Molho
authors.initials: VM
authors.lastname: Pessach
authors.affiliation: Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany;
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and.
authors.forename: Mirzokhid
authors.initials: M
authors.lastname: Rakhmanov
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Keller
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany;
authors.forename: Gabriele
authors.initials: G
authors.lastname: Niedermann
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and Center for Paediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
mesh_terms: D000375:Aging / Q000276:immunology*; D000626:Aminopeptidases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000744:Anemia, Hemolytic, Autoimmune / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016368:Frameshift Mutation; D015870:Gene Expression; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D054353:Perforin / Q000235:genetics / Q000276:immunology; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D035781:Siblings; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013921:Thrombocytopenia / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D054353:Perforin; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases