Genetic dissection of lupus pathogenesis: Sle3/5 impacts IgH CDR3 sequences, somatic mutations, and receptor editing.
Sle3/5 is a lupus susceptibility locus identified on mouse chromosome 7 of the New Zealand Black/New Zealand White (NZB/NZW)-derived NZM2410 strain. Based on previous observations, this locus appears to contribute to lupus pathogenesis through its impact on diversification of immune responses. To understand how Sle3/5 affects somatic diversification of humoral responses, we analyzed IgH rearrangements preferentially encoding hapten-reactive IgG1 repertoires after immunization and assessed peripheral IgH VDJ recombination activities in C57BL/6 (B6) mice congenic for Sle3/5 (B6.Sle3/5). In addition to altered somatic V(H) mutation profiles, sequences from B6.Sle3/5 mice exhibited atypical IgH CDR3 structures characteristic of autoreactive B cells and consistent with peripheral B cells bearing putatively edited receptors. Significant expression of Rag genes and circular V(H)D gene excision products were detected in splenic mature B cells of B6.Sle3/5 but not B6 mice, showing that peripheral IgH rearrangements occurred beyond allelic exclusion. Taken together, on the nonautoimmune background, Sle3/5 affected V(H)DJ(H) junctional diversity and V(H) mutational diversity and led to recombinational activation of allelically excluded IgH genes in the periphery. Such impact on somatic IgH diversification may contribute to the development of autoreactive B cell repertoires. This is the first report to present evidence for significant association of a lupus susceptibility locus, which has been mapped to a chromosomal region in which no Ig genes have been identified, with somatic IgH sequence diversity and peripheral H chain receptor editing or revision without relying upon Ig transgene strategies.
Wakui
Masatoshi
M
Department of Medicine and Division of Rheumatology and Clinical Immunology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Kim
Jinho
J
Butfiloski
Edward J
EJ
Morel
Laurence
L
Sobel
Eric S
ES
D000818:Animals; D000916:Antibody Diversity / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D022801:Complementarity Determining Regions / Q000096:biosynthesis / Q000235:genetics*; D004270:DNA, Circular / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D016654:Genes, RAG-1; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D022801:Complementarity Determining Regions; D004270:DNA, Circular; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D007143:Immunoglobulin Heavy Chains; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; C064655:V(D)J recombination activating protein 2