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2004 ; 37
(6-7
): 431-443
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Ongoing immunoglobulin class switch DNA recombination in lupus B cells: analysis
of switch regulatory regions
#MMPMID15621569
Liu S
; Cerutti A
; Casali P
; Crow MK
Autoimmunity
2004[Sep]; 37
(6-7
): 431-443
PMID15621569
show ga
Inflammation and tissue damage in systemic lupus erythematosus (SLE) are mediated
by class-switched autoantibodies reactive with nucleic acids, nucleic
acid-binding proteins, phospholipids and other self-antigens. While some healthy
individuals produce IgM antibodies with specificities similar to those of lupus
patients, immunoglobulin class switching to mature downstream isotypes appears to
be required for the generation of pathogenic autoantibodies. To characterize the
cellular and molecular basis of pathogenic autoantibody production in SLE, we
studied the capacity of peripheral blood B cells of naive phenotype from patients
with SLE, rheumatoid arthritis (RA) or healthy control subjects to spontaneously
switch to IgG and IgA. In addition, we determined the DNA sequences of the
upstream evolutionary conserved sequence (ECS)-Igamma promoter regulatory regions
that control germline IH-CH transcription and class switch DNA recombination
(CSR) to IgG1, IgG2 and IgG4. IgM+IgD+ B cells from patients with SLE, but not
those from RA or healthy control subjects, underwent spontaneous CSR, as assessed
by expression of germline Igamma1-Cgamma1, Igamma2-Cgamma2, Igamma3-Cgamma3,
Igamma4-Cgamma4 and Ialpha1-Calpha1 transcripts, mature (switched) VHDJH-Cgamma1,
VHDJH-Cgamma2, VHDJH-Cgamma3 and VHDJH-Calpha1 transcripts and secreted IgG and
IgA. Although polymorphic DNA sequences were identified in the ECS-Igamma1,
ECS-Igamma2 and ECS-Igamma4 promoter regions, the transcription factor-binding
sites that mediate germline Igamma-Cgamma transcription were conserved in
patients and controls. However, distinct patterns of nuclear protein binding to
an ECS-Igamma promoter sequence that contains both positive and negative
regulatory elements were observed in SLE patients and controls. These results
support a role for exogenous signals, such as through CD40 ligation, rather than
altered genomic sequence, in the increased production of class switched
autoantibodies in SLE.