Systemic Lupus Erythematosus Disease Pathogenesis Research Articles

Blockade of TLR9 signaling in B cells impaired anti-dsDNA antibody production in mice induced by activated syngenic lymphocyte-derived DNA immunization

We previously established a systemic lupus erythematosus (SLE) animal model in non-susceptible BALB/c mice by immunizing with activated syngeneic lymphocyte-derived DNA (ALD-DNA), manifested by high level of anti-double-stranded DNA (dsDNA) antibodies (Abs), proteinuria, glomerular deposition of immune complex and glomerulonephritis. The production of anti-dsDNA Abs is closely related with the renal inflammation and damage in this model. However, recognition of ALD-DNA and its signaling pathway within antigen-presenting cells (APC) remains not fully clarified. Herein, in this study, Toll-like receptor 9 (TLR9), a well-known pattern-recognition receptor for dsDNA with CpG motif, was found to be dynamically up-regulated in B cells during the process of the SLE disease. Knockdown of TLR9 by short interfering RNA (siRNA) in B cells in vitro and in vivo reduced the production of anti-dsDNA antibody and consequently ameliorated the SLE syndrome in mice while the affinity and isotype of the antibody remained the same. Our results implied that TLR9 signaling of B cells might play an important role in the production of anti-dsDNA Abs triggered by auto dsDNA, which would extend our understanding of TLR9 immune recognition in the pathogenesis of SLE disease.

The Unexplained Female Predominance of Systemic Lupus Erythematosus: Clues from Genetic and Cytokine Studies

Despite recent progress in the understanding of systemic lupus erythematosus (SLE), the striking 9:1 female to male ratio of disease incidence remains largely unexplained. In addition, peak SLE incidence rates occur during the early reproductive years in women. Studies which illuminate potential causes underlying this sex difference and characteristic onset during the reproductive years have the potential to fundamentally advance our understanding of disease pathogenesis in SLE. Similarly, progress in this area will likely inform human reproductive immunology. Studies of sex hormone function in the immune system are of obvious importance; however, it seems likely that many other types of sex-related genetic and immunological differences will contribute to SLE. In this review, we will focus on recent work in sex-related differences in cytokine pathways and genetics of these pathways as they relate to SLE pathogenesis. It seems quite possible that many of these sex-related differences could be important to reproductive fitness, which may explain the conservation of these immune system features and the observed female predominance of SLE.

The influence of interferon-gamma, interleukin-2, prostaglandin E2, and cyclosporine on the polyclonal and anti-DNA antibody secretion in lymphocyte cultures derived from patients with systemic lupus erythematosus

The influence of various immunoregulatory substances was studied in lymphocyte cultures derived from patients suffering from systemic lupus erythematosus (SLE) by using the model of spontaneous secretion of polyclonal immunoglobulin G (IgG)/immunoglobulin M (IgM) and anti-DNA autoantibodies. Compared with healthy donors, lymphocytes derived from patients with active SLE disease showed an elevated secretion of total IgG as well as anti-DNA-IgG in vitro, which was associated with an increase in the proportion of activated (HLA-class II +) T cells in their peripheral blood. Recombinant interferon-gamma increases the total IgG/IgM as well as anti-DNA-IgG/IgM secretion, which suggests that it has a possible role in the pathogenesis of SLE disease. Recombinant interleukin-2 and prostaglandin E2 normalize the high, spontaneous total IgG secretion, but elevate anti-DNA-IgG/IgM secretion. These results suggest that autoreactive B-cell clones are regulated differently in SLE patients. Cyclosporine inhibits total IgG/IgM secretion in all patients and anti-DNA-IgG/IgM secretion in six of eight patients. The possible therapeutic use of such immunomodulatory substances in SLE disease is discussed.