Expansion of toll-like receptor 9–expressing B cells in active systemic lupus erythematosus: Implications for the induction and maintenance of the autoimmune process (original) (raw)

Toll-like receptors (TLRs) are patternassociated 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 >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. Conclusion. 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. Toll-like receptors (TLRs) have recently emerged as key components of the innate immune system that activate multiple pathways of inflammation and coordinate systemic defense against pathogens. At least 11 TLRs have been identified in mammals, with each one of them recognizing unique molecular patterns associated with different classes of pathogens. Of interest, TLR-2 and TLR-4 also recognize a number of self proteins, predominantly members of the heat-shock protein and fibronectin families, while TLR-3 and TLR-9 are capable of recognizing nucleic acids (RNA and DNA, respectively) that may not always be unique to microorganisms (1). Normally, there is a constant interplay between the innate and adaptive immune systems, which leads to protective immune responses against pathogens and contributes effectively to self-nonself discrimination. However, inappropriate activation of TLR pathways