PMID- 28628673
OWN - NLM
STAT- MEDLINE
DCOM- 20170921
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 6
DP  - 2017
TI  - Multiple tolerance defects contribute to the breach of B cell tolerance in New 
      Zealand Black chromosome 1 congenic mice.
PG  - e0179506
LID - 10.1371/journal.pone.0179506 [doi]
LID - e0179506
AB  - Lupus is characterized by a loss of B cell tolerance leading to autoantibody 
      production. In this study, we explored the mechanisms underlying this loss of 
      tolerance using B6 congenic mice with an interval from New Zealand Black 
      chromosome 1 (denoted c1(96-100)) sufficient for anti-nuclear antibody 
      production. Transgenes for soluble hen egg white lysozyme (sHEL) and anti-HEL 
      immunoglobulin were crossed onto this background and various tolerance mechanisms 
      examined. We found that c1(96-100) mice produced increased levels of IgM and IgG 
      anti-HEL antibodies compared to B6 mice and had higher proportions of germinal 
      center B cells and long-lived plasma cells, suggesting a germinal 
      center-dependent breach of B cell anergy. Consistent with impaired anergy 
      induction, c1(96-100) double transgenic B cells showed enhanced survival and CD86 
      upregulation. Hematopoietic chimeric sHEL mice with a mixture of B6 and 
      c1(96-100) HEL transgenic B cells recapitulated these results, suggesting the 
      presence of a B cell autonomous defect. Surprisingly, however, there was 
      equivalent recruitment of B6 and c1(96-100) B cells into germinal centers and 
      differentiation to splenic plasmablasts in these mice. In contrast, there were 
      increased proportions of c1(96-100) T follicular helper cells and long-lived 
      plasma cells as compared to their B6 counterparts, suggesting that both B and T 
      cell defects are required to breach germinal center tolerance in this model. This 
      possibility was further supported by experiments showing an enhanced breach of 
      anergy in double transgenic mice with a longer chromosome 1 interval with 
      additional T cell defects.
FAU - Chang, Nan-Hua
AU  - Chang NH
AD  - Arthritis Centre of Excellence, Division of Genetics and Development, Krembil 
      Research Institute, Toronto, Ontario, Canada.
FAU - Manion, Kieran P
AU  - Manion KP
AD  - Arthritis Centre of Excellence, Division of Genetics and Development, Krembil 
      Research Institute, Toronto, Ontario, Canada.
AD  - Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
FAU - Loh, Christina
AU  - Loh C
AD  - Arthritis Centre of Excellence, Division of Genetics and Development, Krembil 
      Research Institute, Toronto, Ontario, Canada.
AD  - Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
FAU - Pau, Evelyn
AU  - Pau E
AD  - Arthritis Centre of Excellence, Division of Genetics and Development, Krembil 
      Research Institute, Toronto, Ontario, Canada.
AD  - Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
FAU - Baglaenko, Yuriy
AU  - Baglaenko Y
AD  - Arthritis Centre of Excellence, Division of Genetics and Development, Krembil 
      Research Institute, Toronto, Ontario, Canada.
AD  - Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
FAU - Wither, Joan E
AU  - Wither JE
AUID- ORCID: 0000-0001-5961-9228
AD  - Arthritis Centre of Excellence, Division of Genetics and Development, Krembil 
      Research Institute, Toronto, Ontario, Canada.
AD  - Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
AD  - Division of Rheumatology, University Health Network, Toronto, Ontario, Canada.
LA  - eng
PT  - Journal Article
DEP - 20170619
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (B7-2 Antigen)
RN  - 0 (Immunoglobulins)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 3.2.1.- (hen egg lysozyme)
RN  - EC 3.2.1.17 (Muramidase)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - B-Lymphocytes/cytology/immunology/*metabolism
MH  - B7-2 Antigen/metabolism
MH  - CD4-Positive T-Lymphocytes/cytology/metabolism
MH  - Cell Differentiation
MH  - Chickens
MH  - Chromosomes/*genetics/metabolism
MH  - *Immune Tolerance
MH  - Immunoglobulins/genetics/metabolism
MH  - Mice
MH  - Mice, Congenic
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microscopy, Fluorescence
MH  - Muramidase/genetics/metabolism
MH  - New Zealand
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Spleen/metabolism/pathology
MH  - Up-Regulation
PMC - PMC5476272
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2017/06/20 06:00
MHDA- 2017/09/22 06:00
PMCR- 2017/06/19
CRDT- 2017/06/20 06:00
PHST- 2016/09/07 00:00 [received]
PHST- 2017/05/31 00:00 [accepted]
PHST- 2017/06/20 06:00 [entrez]
PHST- 2017/06/20 06:00 [pubmed]
PHST- 2017/09/22 06:00 [medline]
PHST- 2017/06/19 00:00 [pmc-release]
AID - PONE-D-16-36019 [pii]
AID - 10.1371/journal.pone.0179506 [doi]
PST - epublish
SO  - PLoS One. 2017 Jun 19;12(6):e0179506. doi: 10.1371/journal.pone.0179506. 
      eCollection 2017.