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.
Natural history of type 1 diabetes on an immunodysregulatory background with genetic alteration in B-cell activating factor receptor: A case report / Di Lorenzo, Biagio; Pacillo, Lucia; Milardi, Giulia; Jofra, Tatiana; Di Cesare, Silvia; Gerosa, Jolanda; Marzinotto, Ilaria; Zapparoli, Ettore; Rivalta, Beatrice; Cifaldi, Cristina; Barzaghi, Federica; Giancotta, Carmela; Zangari, Paola; Rapini, Novella; Deodati, Annalisa; Amodio, Giada; Passerini, Laura; Carrera, Paola; Gregori, Silvia; Palma, Paolo; Finocchi, Andrea; Lampasona, Vito; Cicalese, Maria Pia; Schiaffini, Riccardo; Di Matteo, Gigliola; Merelli, Ivan; Barcella, Matteo; Aiuti, Alessandro; Piemonti, Lorenzo; Cancrini, Caterina; Fousteri, Georgia. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - 13:(2022), p. 952715. [10.3389/fimmu.2022.952715]