The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints

Raja Vuyyuru, Chandra Mohan, Tim Manser, Ziaur S M Rahman

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

We have described a line of VH knock-in mice termed HKIR in which the transgenic Igh locus partially encodes "dual-reactive" antichromatin and anti-p-azophenylarsonate (Ars) BCRs. HKIR B cells termed canonical, expressing a particular Vκ L chain, evade central tolerance by down-regulating BCR levels. Canonical HKIR B cells can be recruited into the primary germinal center (GC) and Ab-forming cell (AFC) compartments via Ars immunization. However, their participation in the GC response rapidly wanes and they do not efficiently contribute to the memory compartment, indicating that they are regulated by a GC tolerance checkpoint. We analyzed the influence of the Sle1 genetic interval, shown to break tolerance of chromatin-reactive B cells, on the behavior of HKIR B cells during the anti-Ars response. Canonical B cells from congenic HKIR.Sle1 mice gave rise to elevated short and long-lived AFC responses, and the attenuated GC and memory responses characteristic of these B cells were relieved in adoptive, wild-type recipients. HKIR GC B cells containing Sle1 expressed increased levels of Bcl-2 and c-FLIP and decreased levels of Fas RNA compared with HKIR controls, suggesting direct alteration of the regulation of the GC response by Sle1. High titers of canonical and anti-dsDNA Abs spontaneously developed in many aged HKIR.Sle1 mice. Together, these data indicate that Sle1 perturbs the action of peripheral tolerance checkpoints operative on antinuclear Ag B cells in both the AFC and GC pathways in a cell autonomous fashion.

Original languageEnglish (US)
Pages (from-to)5716-5727
Number of pages12
JournalJournal of Immunology
Volume183
Issue number9
DOIs
StatePublished - Nov 1 2009

Fingerprint

Germinal Center
B-Lymphocytes
p-Azobenzenearsonate
Antibodies
Central Tolerance
Peripheral Tolerance
Chromatin
Immunization
RNA

ASJC Scopus subject areas

  • Immunology

Cite this

The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints. / Vuyyuru, Raja; Mohan, Chandra; Manser, Tim; Rahman, Ziaur S M.

In: Journal of Immunology, Vol. 183, No. 9, 01.11.2009, p. 5716-5727.

Research output: Contribution to journalArticle

Vuyyuru, Raja ; Mohan, Chandra ; Manser, Tim ; Rahman, Ziaur S M. / The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints. In: Journal of Immunology. 2009 ; Vol. 183, No. 9. pp. 5716-5727.
@article{8dce3004bf2540bd9a4d66ccbb57da9b,
title = "The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints",
abstract = "We have described a line of VH knock-in mice termed HKIR in which the transgenic Igh locus partially encodes {"}dual-reactive{"} antichromatin and anti-p-azophenylarsonate (Ars) BCRs. HKIR B cells termed canonical, expressing a particular Vκ L chain, evade central tolerance by down-regulating BCR levels. Canonical HKIR B cells can be recruited into the primary germinal center (GC) and Ab-forming cell (AFC) compartments via Ars immunization. However, their participation in the GC response rapidly wanes and they do not efficiently contribute to the memory compartment, indicating that they are regulated by a GC tolerance checkpoint. We analyzed the influence of the Sle1 genetic interval, shown to break tolerance of chromatin-reactive B cells, on the behavior of HKIR B cells during the anti-Ars response. Canonical B cells from congenic HKIR.Sle1 mice gave rise to elevated short and long-lived AFC responses, and the attenuated GC and memory responses characteristic of these B cells were relieved in adoptive, wild-type recipients. HKIR GC B cells containing Sle1 expressed increased levels of Bcl-2 and c-FLIP and decreased levels of Fas RNA compared with HKIR controls, suggesting direct alteration of the regulation of the GC response by Sle1. High titers of canonical and anti-dsDNA Abs spontaneously developed in many aged HKIR.Sle1 mice. Together, these data indicate that Sle1 perturbs the action of peripheral tolerance checkpoints operative on antinuclear Ag B cells in both the AFC and GC pathways in a cell autonomous fashion.",
author = "Raja Vuyyuru and Chandra Mohan and Tim Manser and Rahman, {Ziaur S M}",
year = "2009",
month = "11",
day = "1",
doi = "10.4049/jimmunol.0804215",
language = "English (US)",
volume = "183",
pages = "5716--5727",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "9",

}

TY - JOUR

T1 - The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints

AU - Vuyyuru, Raja

AU - Mohan, Chandra

AU - Manser, Tim

AU - Rahman, Ziaur S M

PY - 2009/11/1

Y1 - 2009/11/1

N2 - We have described a line of VH knock-in mice termed HKIR in which the transgenic Igh locus partially encodes "dual-reactive" antichromatin and anti-p-azophenylarsonate (Ars) BCRs. HKIR B cells termed canonical, expressing a particular Vκ L chain, evade central tolerance by down-regulating BCR levels. Canonical HKIR B cells can be recruited into the primary germinal center (GC) and Ab-forming cell (AFC) compartments via Ars immunization. However, their participation in the GC response rapidly wanes and they do not efficiently contribute to the memory compartment, indicating that they are regulated by a GC tolerance checkpoint. We analyzed the influence of the Sle1 genetic interval, shown to break tolerance of chromatin-reactive B cells, on the behavior of HKIR B cells during the anti-Ars response. Canonical B cells from congenic HKIR.Sle1 mice gave rise to elevated short and long-lived AFC responses, and the attenuated GC and memory responses characteristic of these B cells were relieved in adoptive, wild-type recipients. HKIR GC B cells containing Sle1 expressed increased levels of Bcl-2 and c-FLIP and decreased levels of Fas RNA compared with HKIR controls, suggesting direct alteration of the regulation of the GC response by Sle1. High titers of canonical and anti-dsDNA Abs spontaneously developed in many aged HKIR.Sle1 mice. Together, these data indicate that Sle1 perturbs the action of peripheral tolerance checkpoints operative on antinuclear Ag B cells in both the AFC and GC pathways in a cell autonomous fashion.

AB - We have described a line of VH knock-in mice termed HKIR in which the transgenic Igh locus partially encodes "dual-reactive" antichromatin and anti-p-azophenylarsonate (Ars) BCRs. HKIR B cells termed canonical, expressing a particular Vκ L chain, evade central tolerance by down-regulating BCR levels. Canonical HKIR B cells can be recruited into the primary germinal center (GC) and Ab-forming cell (AFC) compartments via Ars immunization. However, their participation in the GC response rapidly wanes and they do not efficiently contribute to the memory compartment, indicating that they are regulated by a GC tolerance checkpoint. We analyzed the influence of the Sle1 genetic interval, shown to break tolerance of chromatin-reactive B cells, on the behavior of HKIR B cells during the anti-Ars response. Canonical B cells from congenic HKIR.Sle1 mice gave rise to elevated short and long-lived AFC responses, and the attenuated GC and memory responses characteristic of these B cells were relieved in adoptive, wild-type recipients. HKIR GC B cells containing Sle1 expressed increased levels of Bcl-2 and c-FLIP and decreased levels of Fas RNA compared with HKIR controls, suggesting direct alteration of the regulation of the GC response by Sle1. High titers of canonical and anti-dsDNA Abs spontaneously developed in many aged HKIR.Sle1 mice. Together, these data indicate that Sle1 perturbs the action of peripheral tolerance checkpoints operative on antinuclear Ag B cells in both the AFC and GC pathways in a cell autonomous fashion.

UR - http://www.scopus.com/inward/record.url?scp=70749100503&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70749100503&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0804215

DO - 10.4049/jimmunol.0804215

M3 - Article

C2 - 19828626

AN - SCOPUS:70749100503

VL - 183

SP - 5716

EP - 5727

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 9

ER -