Hematopoietic stem cell transplantation in a patient with proteasome-associated autoinflammatory syndrome (PRAAS)
| Autor: | Sandrine Florquin, Ester M. M. van Leeuwen, Jonas Johannes Papendorf, Frédéric Ebstein, Silvana van Koningsbruggen, Machiel H. Jansen, Dorit Verhoeven, Taco W. Kuijpers, Saskia M. Maas, J. Merlijn van den Berg, Mirjam van der Burg, Elke Krüger, Dieneke Schonenberg-Meinema, Paul A. Baars, Arjan C. Lankester |
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| Přispěvatelé: | Graduate School, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, Experimental Immunology, Pathology, Human Genetics, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Proteasome Endopeptidase Complex Myeloid Lipodystrophy medicine.medical_treatment Immunology autoinflammatory syndrome Hematopoietic stem cell transplantation PSMB4 inter-feron immunoproteasome medicine Humans Immunology and Allergy Child Retrospective Studies business.industry Hematopoietic Stem Cell Transplantation X-linked lymphoproliferative disease Syndrome interferon Gene signature Autoinflammatory Syndrome medicine.disease medicine.anatomical_structure surgical procedures operative proteasome PRAAS Proteasome assembly HSCT Autoinflammation Proteasome maturation protein business |
| Zdroj: | Journal of allergy and clinical immunology. Mosby Inc. Journal of Allergy and Clinical Immunology, 149(3), 1120-1127.e8. MOSBY-ELSEVIER |
| ISSN: | 0091-6749 |
| Popis: | Background: Proteasome-associated autoinflammatory syndromes (PRAASs) 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. The treatment options for these proteasome disorders consist of lifelong immunosuppressive drugs or Janus kinase inhibitors, which may have partial efficacy and noticeable side effects. Because proteasomes are ubiquitously expressed, it is unknown whether hematopoietic stem cell transplantation (HSCT) may be a sufficient treatment option. Objective: Our aim was to report the case of a young boy with a treatment-resistant cutaneous vasculitis that was initially suspected to be associated with a gene variant in SH2D1A. Methods: Whole-exome sequencing was performed to identify the genetic defect. Molecular and functional analyses were performed to assess the impact of variants on proteasomal function. The immune characterization led to the decision to perform HSCT on our patient and conduct follow-up over the 7-year period after the transplant. Because loss of myeloid chimerism after the first HSCT was associated with relapse of autoinflammation, a second HSCT was performed. Results: After the successful second HSCT, the patient developed mild symptoms of lipodystrophy, which raised the suspicion of a PRAAS. Genetic analysis revealed 2 novel heterozygous variants in PSMB4 (encoding proteasomal subunit beta 7). Retrospective analysis of patient cells stored before the first HSCT and patient cells obtained after the second HSCT demonstrated that HSCT successfully rescued proteasome function, restored protein homeostasis, and resolved the interferon-stimulated gene signature. Furthermore, successful HSCT alleviated the autoinflammatory manifestations in our patient. Conclusion: Patients with treatment-resistant PRAAS can be cured by HSCT. |
| Databáze: | OpenAIRE |
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