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PMID: 16861350 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Autoreactive MZ and B-1 B-cell activation by Faslpr is coincident with an increased frequency of apoptotic lymphocytes and a defect in macrophage clearance.

Blood ·Vol. 108 ·No. 3 ·2006-08-01 ·Pages 974-82

Qian Y, Conway KL, Lu X, Seitz HM, Matsushima GK, Clarke SH

Abstract

Murine autoreactive anti-Smith (Sm) B cells are negatively regulated by anergy and developmental arrest, but are also positively selected into the marginal zone (MZ) and B-1 B-cell populations. Despite positive selection, anti-Sm production occurs only in autoimmune-prone mice. To investigate autoreactive B-cell activation, an anti-Sm transgene was combined with the lpr mutation, a mutation of the proapoptotic gene Fas (Fas(lpr)), on both autoimmune (MRL) and nonautoimmune backgrounds. Fas(lpr) induces a progressive and autoantigen-specific loss of anti-Sm MZ and B-1 B cells in young adult Fas(lpr) and MRL/Fas(lpr) mice that does not require that Fas(lpr) be B-cell intrinsic. This loss is accompanied by a bypass of the early pre-plasma cell (PC) tolerance checkpoint. Although the MRL bkg does not lead to a progressive loss of anti-Sm MZ or B-1 B cells, it induces a robust bypass of the early pre-PC tolerance checkpoint. Fas(lpr) mice have a high frequency of apoptotic lymphocytes in secondary lymphoid tissues and a macrophage defect in apoptotic cell phagocytosis. Since Sm is exposed on the surface of apoptotic cells, we propose that anti-Sm MZ and B-1 B-cell activation is the result of a Fas(lpr)-induced defect in apoptotic cell clearance.

MeSH Terms
Animals Antibody Formation Apoptosis Autoimmunity B-Lymphocytes/immunology Lymph Nodes/cytology,immunology Lymphocyte Activation/immunology Lymphocytes/cytology Macrophages/immunology Mice Mice, Inbred Strains Mutation/immunology Phagocytosis fas Receptor/genetics,physiology
Chemicals
fas Receptor
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Qian Ye
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, 27599, USA.
Conway Kara L
Lu Xiangdong
Seitz Heather M
Matsushima Glenn K
Clarke Stephen H
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2005-12-006858
Published
2006-08-01
Pages
974-82
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895857
Subset
IM
Grants
NIAID NIH HHS · AI007273 · United States
NIAID NIH HHS · AI050736 · United States
NIAID NIH HHS · AI29576 · United States
NIAID NIH HHS · AI3587 · United States
External Links
PubMed source DOI: 10.1182/blood-2005-12-006858 PMC Full Text View journal details
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