TY - JOUR
T1 - Hematopoietic stem cell transplantation in a patient with proteasome-associated autoinflammatory syndrome (PRAAS)
AU - Verhoeven, Dorit
AU - Schonenberg-Meinema, Dieneke
AU - Ebstein, Frédéric
AU - Papendorf, Jonas J.
AU - Baars, Paul A.
AU - van Leeuwen, Ester M. M.
AU - Jansen, Machiel H.
AU - Lankester, Arjan C.
AU - van der Burg, Mirjam
AU - Florquin, Sandrine
AU - Maas, Saskia M.
AU - van Koningsbruggen, Silvana
AU - Krüger, Elke
AU - van den Berg, J. Merlijn
AU - Kuijpers, Taco W.
N1 - Funding Information: Supported by the German Research Foundation (grant SFB-TR167 A04 [to E.K.]). Publisher Copyright: © 2021 The Authors
PY - 2021
Y1 - 2021
N2 - 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 β7). 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.
AB - 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 β7). 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.
KW - Autoinflammation
KW - HSCT
KW - PRAAS
KW - PSMB4
KW - autoinflammatory syndrome
KW - immunoproteasome
KW - interferon
KW - proteasome
UR - http://www.scopus.com/inward/record.url?scp=85115020015&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jaci.2021.07.039
DO - https://doi.org/10.1016/j.jaci.2021.07.039
M3 - Article
C2 - 34416217
SN - 0091-6749
JO - Journal of allergy and clinical immunology
JF - Journal of allergy and clinical immunology
ER -