Frontiers in Immunology (Aug 2022)

Natural history of type 1 diabetes on an immunodysregulatory background with genetic alteration in B-cell activating factor receptor: A case report

  • Biagio Di Lorenzo,
  • Lucia Pacillo,
  • Lucia Pacillo,
  • Giulia Milardi,
  • Tatiana Jofra,
  • Silvia Di Cesare,
  • Jolanda Gerosa,
  • Ilaria Marzinotto,
  • Ettore Zapparoli,
  • Beatrice Rivalta,
  • Beatrice Rivalta,
  • Cristina Cifaldi,
  • Cristina Cifaldi,
  • Federica Barzaghi,
  • Federica Barzaghi,
  • Carmela Giancotta,
  • Carmela Giancotta,
  • Paola Zangari,
  • Paola Zangari,
  • Novella Rapini,
  • Annalisa Deodati,
  • Giada Amodio,
  • Laura Passerini,
  • Paola Carrera,
  • Silvia Gregori,
  • Paolo Palma,
  • Paolo Palma,
  • Andrea Finocchi,
  • Andrea Finocchi,
  • Vito Lampasona,
  • Maria Pia Cicalese,
  • Maria Pia Cicalese,
  • Maria Pia Cicalese,
  • Riccardo Schiaffini,
  • Gigliola Di Matteo,
  • Ivan Merelli,
  • Ivan Merelli,
  • Matteo Barcella,
  • Matteo Barcella,
  • Alessandro Aiuti,
  • Alessandro Aiuti,
  • Alessandro Aiuti,
  • Lorenzo Piemonti,
  • Caterina Cancrini,
  • Caterina Cancrini,
  • Georgia Fousteri

DOI
https://doi.org/10.3389/fimmu.2022.952715
Journal volume & issue
Vol. 13

Abstract

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The immunological events leading to type 1 diabetes (T1D) are complex and heterogeneous, underscoring the necessity to study rare cases to improve our understanding. Here, we report the case of a 16-year-old patient who showed glycosuria during a regular checkup. Upon further evaluation, stage 2 T1D, autoimmune thrombocytopenic purpura (AITP), and common variable immunodeficiency (CVID) were diagnosed. The patient underwent low carb diet, losing > 8 kg, and was placed on Ig replacement therapy. Anti-CD20 monoclonal antibody (Rituximab, RTX) was administered 2 years after diagnosis to treat peripheral polyneuropathy, whereas an atypical mycobacteriosis manifested 4 years after diagnosis and was managed with prolonged antibiotic treatment. In the fifth year of monitoring, the patient progressed to insulin dependency despite ZnT8A autoantibody resolution and IA-2A and GADA autoantibody decline. The patient had low T1D genetic risk score (GRS = 0.22817) and absence of human leukocyte antigen (HLA) DR3/DR4-DQ8. Genetic analysis identified the monoallelic mutation H159Y in TNFRSF13C, a gene encoding B-cell activating factor receptor (BAFFR). Significant reduced blood B-cell numbers and BAFFR levels were observed in line with a dysregulation in BAFF–BAFFR signaling. The elevated frequency of PD-1+ dysfunctional Tfh cells composed predominantly by Th1 phenotype was observed at disease onset and during follow-up. This case report describes a patient progressing to T1D on a BAFFR-mediated immunodysregulatory background, suggesting a role of BAFF–BAFFR signaling in islet-specific tolerance and T1D progression.

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