AUTHOR=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 TITLE=Natural history of type 1 diabetes on an immunodysregulatory background with genetic alteration in B-cell activating factor receptor: A case report JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.952715 DOI=10.3389/fimmu.2022.952715 ISSN=1664-3224 ABSTRACT=

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.