PMID- 36090979
OWN - NLM
STAT- MEDLINE
DCOM- 20220913
LR  - 20220914
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - Natural history of type 1 diabetes on an immunodysregulatory background with 
      genetic alteration in B-cell activating factor receptor: A case report.
PG  - 952715
LID - 10.3389/fimmu.2022.952715 [doi]
LID - 952715
AB  - 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.
CI  - Copyright (c) 2022 Di Lorenzo, Pacillo, Milardi, Jofra, Di Cesare, Gerosa, 
      Marzinotto, Zapparoli, Rivalta, Cifaldi, Barzaghi, Giancotta, Zangari, Rapini, 
      Deodati, Amodio, Passerini, Carrera, Gregori, Palma, Finocchi, Lampasona, 
      Cicalese, Schiaffini, Di Matteo, Merelli, Barcella, Aiuti, Piemonti, Cancrini and 
      Fousteri.
FAU - Di Lorenzo, Biagio
AU  - Di Lorenzo B
AD  - Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milan, Italy.
FAU - Pacillo, Lucia
AU  - Pacillo L
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
AD  - Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology 
      and Vaccinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a 
      Carattere Scientifico, Rome, Italy.
FAU - Milardi, Giulia
AU  - Milardi G
AD  - Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milan, Italy.
FAU - Jofra, Tatiana
AU  - Jofra T
AD  - Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milan, Italy.
FAU - Di Cesare, Silvia
AU  - Di Cesare S
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
FAU - Gerosa, Jolanda
AU  - Gerosa J
AD  - Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milan, Italy.
FAU - Marzinotto, Ilaria
AU  - Marzinotto I
AD  - Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milan, Italy.
FAU - Zapparoli, Ettore
AU  - Zapparoli E
AD  - Center for Omics Sciences, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milano, Italy.
FAU - Rivalta, Beatrice
AU  - Rivalta B
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
AD  - Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology 
      and Vaccinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a 
      Carattere Scientifico, Rome, Italy.
FAU - Cifaldi, Cristina
AU  - Cifaldi C
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
AD  - Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology 
      and Vaccinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a 
      Carattere Scientifico, Rome, Italy.
FAU - Barzaghi, Federica
AU  - Barzaghi F
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Istituto di Ricovero 
      e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
AD  - Pediatric Immunohematology and Bone Marrow Transplantation Unit, Istituto di 
      Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, 
      Italy.
FAU - Giancotta, Carmela
AU  - Giancotta C
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
AD  - Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology 
      and Vaccinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a 
      Carattere Scientifico, Rome, Italy.
FAU - Zangari, Paola
AU  - Zangari P
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
AD  - Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology 
      and Vaccinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a 
      Carattere Scientifico, Rome, Italy.
FAU - Rapini, Novella
AU  - Rapini N
AD  - Unit of Endocrinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e 
      Cura a Carattere Scientifico, Rome, Italy.
FAU - Deodati, Annalisa
AU  - Deodati A
AD  - Unit of Endocrinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e 
      Cura a Carattere Scientifico, Rome, Italy.
FAU - Amodio, Giada
AU  - Amodio G
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Istituto di Ricovero 
      e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
FAU - Passerini, Laura
AU  - Passerini L
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Istituto di Ricovero 
      e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
FAU - Carrera, Paola
AU  - Carrera P
AD  - Unit of Genomics for Human Disease Diagnosis and Laboratory of Clinical Molecular 
      Biology, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San 
      Raffaele, Milan, Italy.
FAU - Gregori, Silvia
AU  - Gregori S
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Istituto di Ricovero 
      e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
FAU - Palma, Paolo
AU  - Palma P
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
AD  - Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology 
      and Vaccinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a 
      Carattere Scientifico, Rome, Italy.
FAU - Finocchi, Andrea
AU  - Finocchi A
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
AD  - Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology 
      and Vaccinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a 
      Carattere Scientifico, Rome, Italy.
FAU - Lampasona, Vito
AU  - Lampasona V
AD  - Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milan, Italy.
FAU - Cicalese, Maria Pia
AU  - Cicalese MP
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Istituto di Ricovero 
      e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
AD  - Pediatric Immunohematology and Bone Marrow Transplantation Unit, Istituto di 
      Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, 
      Italy.
AD  - Faculty of Medicine, University Vita-Salute San Raffaele, Milan, Italy.
FAU - Schiaffini, Riccardo
AU  - Schiaffini R
AD  - Unit of Endocrinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e 
      Cura a Carattere Scientifico, Rome, Italy.
FAU - Di Matteo, Gigliola
AU  - Di Matteo G
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
FAU - Merelli, Ivan
AU  - Merelli I
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Istituto di Ricovero 
      e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
AD  - Department of Bioinformatics, Institute for Biomedical Technologies National 
      Research Council, Segrate, Italy.
FAU - Barcella, Matteo
AU  - Barcella M
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Istituto di Ricovero 
      e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
AD  - Department of Bioinformatics, Institute for Biomedical Technologies National 
      Research Council, Segrate, Italy.
FAU - Aiuti, Alessandro
AU  - Aiuti A
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Istituto di Ricovero 
      e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
AD  - Pediatric Immunohematology and Bone Marrow Transplantation Unit, Istituto di 
      Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, 
      Italy.
AD  - Faculty of Medicine, University Vita-Salute San Raffaele, Milan, Italy.
FAU - Piemonti, Lorenzo
AU  - Piemonti L
AD  - Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milan, Italy.
FAU - Cancrini, Caterina
AU  - Cancrini C
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
AD  - Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology 
      and Vaccinology, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a 
      Carattere Scientifico, Rome, Italy.
FAU - Fousteri, Georgia
AU  - Fousteri G
AD  - Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico 
      Ospedale San Raffaele, Milan, Italy.
LA  - eng
PT  - Case Reports
PT  - Research Support, Non-U.S. Gov't
DEP - 20220826
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Autoantibodies)
RN  - 0 (B-Cell Activating Factor)
RN  - 0 (Insulin)
SB  - IM
MH  - Adolescent
MH  - Autoantibodies
MH  - B-Cell Activating Factor/genetics
MH  - *Diabetes Mellitus, Type 1
MH  - Humans
MH  - Insulin/genetics
MH  - Mutation
PMC - PMC9459137
OTO - NOTNLM
OT  - BAFFR mutation
OT  - circulating T follicular helper cells (cTfh)
OT  - common variable immunodeficiency (CVID)
OT  - islet autoimmunity
OT  - type 1 diabetes (T1D)
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/09/13 06:00
MHDA- 2022/09/14 06:00
PMCR- 2022/01/01
CRDT- 2022/09/12 03:53
PHST- 2022/05/25 00:00 [received]
PHST- 2022/08/02 00:00 [accepted]
PHST- 2022/09/12 03:53 [entrez]
PHST- 2022/09/13 06:00 [pubmed]
PHST- 2022/09/14 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.952715 [doi]
PST - epublish
SO  - Front Immunol. 2022 Aug 26;13:952715. doi: 10.3389/fimmu.2022.952715. eCollection 
      2022.