Enhanced mutational activity of Vkappa gene rearrangements in systemic lupus erythematosus.
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 Vkappa 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 Vkappa 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 R/S ratios of mutations in productive and nonproductive Vkappa 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 Vkappa 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.
Dörner
T
T
Department of Internal Medicine and Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, 75235, USA.
Heimbächer
C
C
Farner
N L
NL
Lipsky
P E
PE
D020029:Base Pairing; D003062:Codon; D004252:DNA Mutational Analysis; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D017354:Point Mutation
D003062:Codon; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains