The lupus susceptibility locus Sle1 facilitates the peripheral development and selection of anti-DNA B cells through impaired receptor editing.
Systemic lupus erythematosus is characterized by the spontaneous production of IgG autoantibodies in patients and lupus-prone mice. In this study, we investigated the effect of the Sle1 lupus susceptibility locus on the peripheral development of 56R(+) anti-DNA transgenic B cells by tracking 56R(+) B cells in mice without (B6.56R) or with (B6.Sle1.56R) the Sle1 locus. Compared with B6.56R mice, B6.Sle1.56R mice exhibited increased class-switched IgG2a anti-DNA Abs in their serum, encoded by the transgene. Interestingly, within the spleen, Sle1 facilitated the development of these cells into clusters of IgG2a class-switched B cells juxtaposed to CD4(+) T cells within extrafollicular sites. Through sequence analysis of B cell hybridomas, we also found that B cells from B6.Sle1.56R mice are inefficient at Ig H and L chain editing. Thus, the Ig H chains in Sle1.56R(+) B cells are partnered more often with cationic L chains that facilitate DNA binding. Taken together, these findings indicate that the Sle1 lupus-susceptibility locus may facilitate the emergence of anti-DNA B cells by subduing BCR revision and possibly by shaping the extrafollicular development of effector B cells, although the precise molecular mechanisms await further study.
Department of Anatomy and Biomedical Sciences, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea; Department of Microbiology and Immunology, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seocho-Gu, Seoul, 137-040, Republic of Korea;
Soog-Hee
SH
Chang
Department of Anatomy and Biomedical Sciences, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea; Department of Microbiology and Immunology, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seocho-Gu, Seoul, 137-040, Republic of Korea;
Tae-Joo
TJ
Kim
Department of Anatomy and Biomedical Sciences, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea; Department of Microbiology and Immunology, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seocho-Gu, Seoul, 137-040, Republic of Korea;
Young-Joo
YJ
Kim
Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
Yang
Y
Liu
Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
So-Youn
SY
Min
Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seocho-Gu, Seoul, 137-040, Republic of Korea;
Min-Jung
MJ
Park
Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seocho-Gu, Seoul, 137-040, Republic of Korea;
Hyun-Sil
HS
Park
Department of Anatomy and Biomedical Sciences, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea;
Sun-Kyung
SK
Lee
Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongwon-gun, Chungbuk 363-883, Republic of Korea.
Ki-Hoan
KH
Nam
Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seocho-Gu, Seoul, 137-040, Republic of Korea; hangrae2@snu.ac.kr chandra.mohan@utsouthwestern.edu ho0919@catholic.ac.kr.
Ho-Youn
HY
Kim
Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; and hangrae2@snu.ac.kr chandra.mohan@utsouthwestern.edu ho0919@catholic.ac.kr.
Chandra
C
Mohan
Department of Anatomy and Biomedical Sciences, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea; hangrae2@snu.ac.kr chandra.mohan@utsouthwestern.edu ho0919@catholic.ac.kr.
Hang-Rae
HR
Kim
D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D056426:Genetic Loci / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell