TY - JOUR
T1 - Genetic dissection of lupus pathogenesis
T2 - Sle3/5 impacts IgH CDR3 sequences, somatic mutations, and receptor editing
AU - Wakui, Masatoshi
AU - Kim, Jinho
AU - Butfiloski, Edward J.
AU - Morel, Laurence
AU - Sobel, Eric S.
PY - 2004/12/15
Y1 - 2004/12/15
N2 - 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 coagenic for Sle3/5 (B6.Sle3/5). In addition to altered somatic VH 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 VHD 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 HDJH junctional diversity and VH 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.
AB - 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 coagenic for Sle3/5 (B6.Sle3/5). In addition to altered somatic VH 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 VHD 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 HDJH junctional diversity and VH 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.
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U2 - 10.4049/jimmunol.173.12.7368
DO - 10.4049/jimmunol.173.12.7368
M3 - Article
C2 - 15585861
AN - SCOPUS:10344265955
SN - 0022-1767
VL - 173
SP - 7368
EP - 7376
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -