Enhanced mutational activity of Vκ gene rearrangements in systemic lupus erythematosus

被引:34
作者
Dörner, T
Heimbächer, C
Farner, NL
Lipsky, PE
机构
[1] Univ Texas, SW Med Ctr, Harold C Simmons Arthrit Res Ctr, Dept Internal Med, Dallas, TX 75235 USA
[2] Dept Med Charite, Berlin, Germany
关键词
D O I
10.1006/clim.1999.4740
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
To determine the differential impact of somatic hypermutation and selective influences on the light chain repertoire in systemic lupus erythematosus (SLE), the frequency and pattern of somatic hypermutations were compared between the productive and nonproductive V kappa gene repertoire manifested by individual CD19(+) B cells in a patient with SLE. The mutational frequency of nonproductive rearrangements in the SLE patient was significantly (P < 0.001) increased (3.7 x 10(-2)) compared to normals (4.8 x 10(-3)). Similarly, the mutational frequency of the productive V kappa rearrangements was also significantly increased in the SLE patient (2.8 x 10(-2) vs 1.1 x 10(-2)) (P < 0.001). There were no differences in the WS ratios of mutations in productive and nonproductive V kappa rearrangements. Moreover, a variety of mutational "hot spots" were noted, but, unexpectedly, in the FRs. As in normals, mutations were found most frequently in RGYW/ WRCY sequences accounting for 39.3% (nonproductive) and 40.1% (productive) of all mutations. Of note, nonproductive V kappa rearrangements harbored significantly more mutations than productive rearrangements (P < 0.05) indicating that there was overall selection against mutations in the expressed repertoire. This was most apparent in the CDR3. These data are most consistent with the conclusion that, in this SLE patient, the mutational machinery was markedly enhanced compared to normals, but with no subsequent positive selection of mutations. The enhanced mutational activity may play a role in the emergence of autoreactivity in this SLE patient, (C) 1999 Academic Press.
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页码:188 / 196
页数:9
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