Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process.
OBJECTIVE
Toll-like receptors (TLRs) are pattern-associated receptors in innate immunity that may be involved in the recognition of self antigens and the production of pathogenic autoantibodies. This study was undertaken to examine the expression and function of various TLRs in subpopulations of peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE).


METHODS
The expression of TLRs in PBMCs from 50 SLE patients with active disease (SLE Disease Activity Index [SLEDAI] score >or=8; n = 26) or inactive disease (SLEDAI score <8; n = 24) and 20 healthy controls was studied by flow cytometry. TLR expression was assessed on various subpopulations of PBMCs (TLR-2 and TLR-4 by membrane staining; TLR-3 and TLR-9 by intracellular staining). TLR function was accessed by stimulating PBMCs with specific ligands.


RESULTS
The proportion of B cells and monocytes expressing TLR-9 was higher among patients with active SLE (mean +/- SD 49.5 +/- 24.4% and 30.7 +/- 24.1%, respectively) than among patients with inactive disease (22.8 +/- 19.6% and 14.3 +/- 8.4%, respectively; P = 0.02 and P = 0.03). Among B cells, the proportion of plasma cells and memory B cells expressing TLR-9 was increased in patients with active SLE. Increased percentages of TLR-9-expressing B cells correlated with the presence of anti-double-stranded DNA antibodies (P = 0.007). Treatment with serum from patients with active disease increased the percentage of TLR-9-expressing plasma cells in serum from healthy controls. Enhanced induction of HLA-DR after TLR-9 stimulation was documented in B cells from patients with active disease.


CONCLUSIONS
In patients with active SLE, the proportion of peripheral blood memory B cells and plasma cells expressing TLR-9 is increased. Endogenous nucleic acids released during apoptotic cell death may stimulate B cells via TLR-9 and contribute to SLE pathogenesis.
Papadimitraki
Eva D
ED
University of Crete Medical School, Heraklion, Greece.
Choulaki
Christianna
C
Koutala
Eleni
E
Bertsias
George
G
Tsatsanis
Christos
C
Gergianaki
Irini
I
Raptopoulou
Amalia
A
Kritikos
Heraklis D
HD
Mamalaki
Clio
C
Sidiropoulos
Prodromos
P
Boumpas
Dimitrios T
DT
D000328:Adult; D017209:Apoptosis / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D001798:Blood Proteins / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism*
D001798:Blood Proteins; C513533:CpG ODN 2006; D009838:Oligodeoxyribonucleotides; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9