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

Abstract

Key Points• Deficiency of TPP2 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 (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 1 T-cells had a senescent CCR7-CD127 2 CD28 2 CD57 1 phenotype with poor proliferative responses and enhanced staurosporine-induced apoptosis. T-cells showed increased expression of the effector molecules perforin and interferon-g with high expression of the transcription factor T-bet. Age-associated B-cells with a CD212 CD11c 1 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. (Blood. 2015;125(5):753-761)

From Primary Immunodeficiency to Autoimmunity: How Extreme Situations Highlight the Main Genetic Factors Involved in Autoimmune Disease

“…However patients with loss of function mutations in TPP2 have been reported with a phenotype of variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, susceptibility to infections, B and T cells immunosensecence including other major phenotypic alterations associated to defects in apoptosis, proliferation and lymphocyte functions [58]. It has been theorized that the defective TPP2 is unable to control senescence leading to this clinical and immunological features, akin to those that happen gradually in the normal aging of the immune system, but in a more "acute" process [59].…”

There’s no such fool like an immunosenescent fool

“…This is also observed in other cell types, including fibroblasts, as well as in TPPII-deficient mice. 1 Together with a reduction of the antigen receptor diversity, loss of naive lymphocytes, reduced lymphocyte proliferative capacity, and deregulated apoptosis, this leads to an accumulation of autoreactive cells causing autoimmunity that largely resembles other newly described PIDs with cytopenia, such as LRBA deficiency, CTLA4 deficiency, PI(3)K hyperactivity, and loss of STK4, 4-7 as indicated. Of note, an immunosenescence-like abnormal differentiation of T cells has also been identified recently in one of the examples par excellence of autoimmune cytopenias, namely, ALPS-Fas.…”

“…1 Senescence of T and B lymphocytes is a striking finding, which has recently come into the limelight because it can be linked to primary immunodeficiency syndromes with autoimmunity.…”

“…However, shared features include an increased proportion of terminally differentiated effector memory T cells, loss of naivety, a contracted antigen receptor repertoire, deregulated apoptosis, and impaired lymphocyte proliferation. 1 Physiologic induction of cell-cycle arrest, senescence, or apoptosis is an evolutionarily conserved cell fate decision. This is executed in response to various stresses in a manner dependent on the tissue type as well as the kind and degree of stress.…”

“…In this issue of Blood, Stepensky et al characterize the immune phenotype underlying a novel PID with early-onset Evans syndrome due to loss of a central cytoplasmic peptidase, TPPII. 1 Stepensky et al show that a stress-induced immunosenescence program is induced in T and B lymphocytes of human subjects with TPPII deficiency. This is also observed in other cell types, including fibroblasts, as well as in TPPII-deficient mice.…”