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

• Published in: Frontiers in immunology Vol. 13; p. 952715
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 26.08.2022
• Subjects: BAFFR mutation; circulating T follicular helper cells (cTfh); common variable immunodeficiency (CVID); Immunology; islet autoimmunity; type 1 diabetes (T1D)
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.952715

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.