The Journal of allergy and clinical immunology | 2021
Hematopoietic stem cell transplantation in a patient with proteasome-associated auto-inflammatory syndrome (PRAAS).
Abstract
BACKGROUND\nProteasome associated auto-inflammatory syndromes (PRAAS) form a family of recently described rare autosomal recessive disorders of disturbed proteasome assembly and proteolytic activity caused by mutations in genes coding for proteasome subunits. Treatment options for these proteasome disorders consist of life-long immunosuppressive drugs or JAK inhibitors, which may have partial efficacy and noticeable side effects. Since proteasomes are ubiquitously expressed, it is unknown whether hematopoietic stem cell transplantation (HSCT) may be a sufficient treatment option.\n\n\nOBJECTIVE\nThis study reports a young boy with a treatment-resistant cutaneous vasculitis initially suspected to be associated with a gene variant in SH2D1A. We describe the immune characterization that led to the decision of HSCT in our patient and follow-up during seven years post-transplant. Loss of myeloid chimerism after the first HSCT was associated with relapse of auto-inflammation. After a second successful HSCT, he developed mild symptoms of lipodystrophy which raised the suspicion of a PRAAS.\n\n\nMETHODS\nWhole-exome sequencing was performed to identify the genetic defect. Molecular and functional analyses were performed to assess the variant impact on proteasomal function.\n\n\nRESULTS\nGenetic analysis revealed two novel heterozygous variants in PSMB4 (encoding proteasomal subunit β7). Retrospective analysis of stored patient cells prior to the first HSCT and patient cells after the second HSCT demonstrated that HSCT successfully rescued proteasome function, restored protein homeostasis and resolved the interferon stimulated gene (ISG) signature. Furthermore, successful HSCT alleviated the auto-inflammatory manifestations in our patient.\n\n\nCONCLUSION\nTreatment-resistant PRAAS patients can be cured by HSCT.