PMID- 26432895
OWN - NLM
STAT- MEDLINE
DCOM- 20160322
LR  - 20161115
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 195
IP  - 10
DP  - 2015 Nov 15
TI  - Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1
      Diabetes-Prone Mice.
PG  - 4730-41
LID - 10.4049/jimmunol.1500438 [doi]
AB  - Autoreactive B lymphocytes that commonly arise in the developing repertoire can
      be salvaged by receptor editing, a central tolerance mechanism that alters BCR
      specificity through continued L chain rearrangement. It is unknown whether
      autoantigens with weak cross-linking potential, such as insulin, elicit receptor 
      editing, or whether this process is dysregulated in related autoimmunity. To
      resolve these issues, we developed an editing-competent model in which
      anti-insulin Vkappa125 was targeted to the Igkappa locus and paired with
      anti-insulin VH125Tg. Physiologic, circulating insulin increased RAG-2 expression
      and was associated with BCR replacement that eliminated autoantigen recognition
      in a proportion of developing anti-insulin B lymphocytes. The proportion of
      anti-insulin B cells that underwent receptor editing was reduced in the type 1
      diabetes-prone NOD strain relative to a nonautoimmune strain. Resistance to
      editing was associated with increased surface IgM expression on immature (but not
      transitional or mature) anti-insulin B cells in the NOD strain. The actions of
      mAb123 on central tolerance were also investigated, because selective targeting
      of insulin-occupied BCR by mAb123 eliminates anti-insulin B lymphocytes and
      prevents type 1 diabetes. Autoantigen targeting by mAb123 increased RAG-2
      expression and dramatically enhanced BCR replacement in newly developed B
      lymphocytes. Administering F(ab')2123 induced IgM downregulation and reduced the 
      frequency of anti-insulin B lymphocytes within the polyclonal repertoire of
      VH125Tg/NOD mice, suggesting enhanced central tolerance by direct BCR
      interaction. These findings indicate that weak or faulty checkpoints for central 
      tolerance can be overcome by autoantigen-specific immunomodulatory therapy.
CI  - Copyright (c) 2015 by The American Association of Immunologists, Inc.
FAU - Bonami, Rachel H
AU  - Bonami RH
AD  - Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt
      University, Nashville, TN 37232; and.
FAU - Thomas, James W
AU  - Thomas JW
AD  - Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt
      University, Nashville, TN 37232; and Department of Pathology, Microbiology and
      Immunology, Vanderbilt University, Nashville TN 37232
      james.w.thomas@vanderbilt.edu.
LA  - eng
SI  - GENBANK/KT250637
SI  - GENBANK/KT250638
SI  - GENBANK/KT250639
SI  - GENBANK/KT250640
SI  - GENBANK/KT250641
SI  - GENBANK/KT250642
SI  - GENBANK/KT250643
SI  - GENBANK/KT250644
SI  - GENBANK/KT250645
SI  - GENBANK/KT250646
SI  - GENBANK/KT250647
SI  - GENBANK/KT250648
SI  - GENBANK/KT250649
SI  - GENBANK/KT250650
SI  - GENBANK/KT250651
SI  - GENBANK/KT250652
SI  - GENBANK/KT250653
SI  - GENBANK/KT250654
SI  - GENBANK/KT250655
SI  - GENBANK/KT250656
SI  - GENBANK/KT250657
SI  - GENBANK/KT250658
SI  - GENBANK/KT250659
SI  - GENBANK/KT250660
SI  - GENBANK/KT250661
SI  - GENBANK/KT250662
SI  - GENBANK/KT250663
SI  - GENBANK/KT250664
SI  - GENBANK/KT250665
SI  - GENBANK/KT250666
SI  - GENBANK/KT250667
SI  - GENBANK/KT250668
SI  - GENBANK/KT250669
SI  - GENBANK/KT250670
SI  - GENBANK/KT250671
SI  - GENBANK/KT250672
SI  - GENBANK/KT250673
SI  - GENBANK/KT250674
SI  - GENBANK/KT250675
SI  - GENBANK/KT250676
SI  - GENBANK/KT250677
SI  - GENBANK/KT250678
SI  - GENBANK/KT250679
SI  - GENBANK/KT250680
SI  - GENBANK/KT250681
SI  - GENBANK/KT250682
SI  - GENBANK/KT250683
SI  - GENBANK/KT250684
SI  - GENBANK/KT250685
SI  - GENBANK/KT250686
SI  - GENBANK/KT250687
SI  - GENBANK/KT250688
SI  - GENBANK/KT250689
SI  - GENBANK/KT250690
SI  - GENBANK/KT250691
SI  - GENBANK/KT250692
SI  - GENBANK/KT250693
SI  - GENBANK/KT250694
SI  - GENBANK/KT250695
SI  - GENBANK/KT250696
SI  - GENBANK/KT250697
SI  - GENBANK/KT250698
SI  - GENBANK/KT250699
SI  - GENBANK/KT250700
SI  - GENBANK/KT250701
SI  - GENBANK/KT250702
SI  - GENBANK/KT250703
SI  - GENBANK/KT250704
SI  - GENBANK/KT250705
SI  - GENBANK/KT250706
SI  - GENBANK/KT250707
SI  - GENBANK/KT250708
SI  - GENBANK/KT250709
SI  - GENBANK/KT250710
SI  - GENBANK/KT250711
SI  - GENBANK/KT250712
SI  - GENBANK/KT250713
SI  - GENBANK/KT250714
SI  - GENBANK/KT250715
SI  - GENBANK/KT250716
SI  - GENBANK/KT250717
SI  - GENBANK/KT250718
SI  - GENBANK/KT250719
SI  - GENBANK/KT250720
SI  - GENBANK/KT250721
SI  - GENBANK/KT250722
SI  - GENBANK/KT250723
SI  - GENBANK/KT250724
SI  - GENBANK/KT250725
SI  - GENBANK/KT250726
SI  - GENBANK/KT250727
GR  - T32 GM08554/GM/NIGMS NIH HHS/United States
GR  - P30 EY08126/EY/NEI NIH HHS/United States
GR  - P30 CA68485/CA/NCI NIH HHS/United States
GR  - P30 DK058404/DK/NIDDK NIH HHS/United States
GR  - G20 RR030956/RR/NCRR NIH HHS/United States
GR  - P30 EY008126/EY/NEI NIH HHS/United States
GR  - R01 AI051448/AI/NIAID NIH HHS/United States
GR  - T32 AR059039/AR/NIAMS NIH HHS/United States
GR  - T32 HL069765/HL/NHLBI NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - T32 GM008554/GM/NIGMS NIH HHS/United States
GR  - DK058404/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151002
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Autoantigens)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Immunoglobulin M)
RN  - 0 (Immunoglobulin kappa-Chains)
RN  - 0 (Insulin)
RN  - 0 (Rag2 protein, mouse)
RN  - 0 (Receptors, Antigen, B-Cell)
SB  - AIM
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/immunology
MH  - Autoantigens/immunology
MH  - Autoimmunity/immunology
MH  - B-Lymphocytes/*immunology
MH  - DNA-Binding Proteins/biosynthesis
MH  - Diabetes Mellitus, Type 1/*therapy
MH  - Immune Tolerance/*immunology
MH  - Immunoglobulin M/biosynthesis/immunology
MH  - Immunoglobulin kappa-Chains/immunology
MH  - *Immunomodulation
MH  - Insulin/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD
MH  - Molecular Sequence Data
MH  - Receptors, Antigen, B-Cell/*immunology
PMC - PMC4637270
MID - NIHMS722873
EDAT- 2015/10/04 06:00
MHDA- 2016/03/24 06:00
CRDT- 2015/10/04 06:00
PHST- 2015/02/23 00:00 [received]
PHST- 2015/09/08 00:00 [accepted]
PHST- 2015/10/04 06:00 [entrez]
PHST- 2015/10/04 06:00 [pubmed]
PHST- 2016/03/24 06:00 [medline]
AID - jimmunol.1500438 [pii]
AID - 10.4049/jimmunol.1500438 [doi]
PST - ppublish
SO  - J Immunol. 2015 Nov 15;195(10):4730-41. doi: 10.4049/jimmunol.1500438. Epub 2015 
      Oct 2.