Selection of anti-double-stranded DNA B cells in autoimmune MRL-lpr/lpr mice.
Abs to DNA and nucleoproteins are expressed in systemic autoimmune diseases, whereas B cells producing such Abs are edited, deleted, or inactivated in healthy individuals. Why autoimmune individuals fail to regulate is not well understood. In this study, we investigate the sources of anti-dsDNA B cells in autoimmune transgenic MRL-lpr/lpr mice. These mice are particularly susceptible to lupus because they carry a site-directed transgene, H76R that codes for an anti-DNA H chain. Over 90% of the B cells are eliminated in the bone marrow of these mice, and the few surviving B cells are associated with one of two Vkappa editors, Vkappa38c and Vkappa21D. Thus, it appears that negative selection by deletion and editing are intact in MRL-lpr/lpr mice. However, a population of splenic B cells in the H76R MRL-lpr/lpr mice produces IgG anti-nuclear Abs, and these mice have severe autoimmune organ damage. These IgG Abs are not associated with editors but instead use a unique Vkappa gene, Vkappa23. The H76R/Vkappa23 combination has a relatively high affinity for dsDNA and an anti-nuclear Ab pattern characteristic of lupus. Therefore, this Vkappa gene may confer a selective advantage to anti-DNA Abs in diseased mice.
Chen
Ching
C
Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA. chenq@ohsu.edu
Li
Hui
H
Tian
Qi
Q
Beardall
Michael
M
Xu
Yang
Y
Casanova
Nina
N
Weigert
Martin
M
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D001853:Bone Marrow / Q000276:immunology; D006825:Hybridomas; D050440:Immunoglobulin Subunits / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D050440:Immunoglobulin Subunits