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=Volume 13 - 2022

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 check-up. Upon further evaluation, stage 2 T1D, autoimmune thrombocytopenic purpura (AITP), and common variable immunodeficiency (CVID) were diagnosed. The patient underwent low carb diet, losing >8kg, and was placed on Ig replacement therapy. Anti-CD20 monoclonal antibody (Rituximab, RTX) was administered two years after diagnosis to treat peripheral polyneuropathy, while an atypical mycobacteriosis manifested four 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 HLA DR3/DR4-DQ8. Genetic analysis identified the monoallelic mutation H159Y in TNFRSF13C, a gene encoding BAFFR. Significant reduced blood B cell numbers and BAFFR levels were observed in line with a dysregulation in BAFF-BAFFR signaling. 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.