T-cell receptor signaling in Schimke immuno-osseous dysplasia is SMARCAL1-independent

Autores de IIS La Fe

• Elena Román Ortiz

  Autor

Participantes ajenos a IIS La Fe

• Marin A.V.
• Jiménez-Reinoso A.
• Mazariegos M.S.
• Regueiro J.R.

Abstract

Schimke immuno-osseous dysplasia (SIOD) caused by mutations in SMARCAL1 is an ultra-rare disease characterized by specific facial features, skeletal dysplasia, and steroid-resistant nephrotic syndrome, which often leads to kidney failure and requires transplantation. Cellular (T-cell) deficiency, lymphopenia, and infections have been frequently reported, but whether they are due to T-cell-intrinsic defects in T-cell receptor (TCR) signaling associated with SMARCAL1 deficiency or to T-cell-extrinsic effects such as the impaired proliferation of hematopoietic precursors or T-cell-specific immunosuppression after renal transplantation remains unknown. We have explored the effects of SMARCAL1 deficiency on T-cell receptor signaling in primary and immortalized T cells from a 9-year-old SIOD patient under immunosuppression treatment when compared to healthy donors. Immortalized T cells recapitulated the SMARCAL1 deficiency of the patient, as judged by their impaired response to gamma irradiation. The results indicated that TCR-mediated signaling was normal in SIOD-derived immortalized T cells but strongly impaired in the primary T cells of the patient, although rescued with TCR-independent stimuli such as PMA + ionomycin, suggesting that SIOD-associated T-cell signaling is not intrinsically defective but rather the result of the impaired proliferation of hematopoietic precursors or of T-cell-specific immunosuppression. The lack of early thymic emigrants in our patients may support the former hypothesis. Copyright © 2022 Marin, Jiménez-Reinoso, Mazariegos, Román-Ortiz and Regueiro.

Keywords

• Child; DNA Helicases; Humans; Immunologic Deficiency Syndromes; Nephrotic Syndrome; Receptors, Antigen, T-Cell; Signal Transduction; everolimus; prednisone; tacrolimus; DNA helicase; lymphocyte antigen receptor; SMARCAL1 protein, human; Article; cardiopulmonary insufficiency; case report; child; chronic kidney failure; clinical article; DNA repair; dysplasia; empty sella syndrome; female; flow cytometry; focal glomerulosclerosis; genetic disorder; human; hypertension; hypothyroidism; kidney transplantation; male; nephrotic syndrome; Schimke immuno osseous dysplasia; Schimke immuno osseous dysplasia; spondyloepiphyseal dysplasia; TCR signaling; complication; genetics; immune deficiency; metabolism; nephrotic syndrome; signal transduction