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Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 -8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

Background: Male DNA or cells are often used to measure microchimerism in a woman. In studies of autoimmune diseases male microchimerism is most often attributed to the previous birth of a son. Objective: To determine the frequency of male microchimerism in healthy women or women with systemic sclerosis who had never given birth to a son. Methods: Real time quantitative polymerase chain reaction targeting the Y chromosome specific sequence DYS14 was employed to test DNA extracted from peripheral blood mononuclear cells of 26 women with systemic sclerosis and 23 healthy women who had never given birth to a son. Results are expressed as the genome equivalent number of male cells per million host cells (gEq/mil). Results: Male DNA was found in 15% of women with systemic sclerosis (range 0 to 23.7 gEq/mil) and in 13% of healthy women (range 0 to 5.1 gEq/mil). Although two women with male DNA had an induced abortion, most had no history of spontaneous or induced abortion (either systemic sclerosis or healthy). Conclusions: Microchimerism with male DNA can be found in the circulation of women who have never given birth to a son. Thus sources other than a male birth must be considered when male DNA is used to measure microchimerism. Although other studies are needed, there was no apparent difference in women with systemic sclerosis and healthy women. Possible sources of male DNA include unrecognised male pregnancy or unrecognised male twin, an older male sibling with transfer through the maternal circulation, or sexual intercourse alone.

Background T cell activation depends upon a calcium signaling cascade that is regulated by voltage-gated potassium channels. Effector memory T cells (T EM ), which are implicated in the immunopathogenesis of a panel of autoimmune diseases, express the potassium channel Kv1.3. Dalazatide is a potent peptide inhibitor of the Kv1.3 channel that has recently shown efficacy in a Phase 1b plaque psoriasis trial. Evidence suggests that inflammatory cytokine producing T EM cells might be involved in the immunopathology of lupus nephritis. Objectives Provide proof-of-principle ex vivo data for therapeutically targeting chronic T cell activation in systemic lupus erythematosus (SLE) by using dalazatide to block the Kv1.3 channel and to evaluate the effect of dalazatide on the in vitro inflammatory cytokine production of T EM cells from SLE patients. Methods Peripheral blood mononuclear cells from pediatric and adult SLE patients as well as healthy controls were studied. T lymphocyte subsets were assayed ex vivo for Kv1.3 expression by flow cytometry. The effect of dalazatide on phorbol myristate acetate (PMA)/ionomycin-induced inflammatory cytokine expression by T EM cells was evaluated by intracellular cytokine staining. Results Kv1.3 expression by CD8 + T EM cells was significantly higher in patients with active lupus nephritis when compared to patients with inactive SLE or healthy controls. Dalazatide inhibited IFN-γ, IL-17 and TNF-α production by both CD4 + and CD8 + T EM cells from SLE patients in a dose-dependent manner. Higher levels of dalazatide-mediated inhibition were observed in IFN-γ and TNF-α-expressing CD4 + T EM cells from patients with active SLE when compared to samples from SLE patients with inactive disease. Conclusions Ex vivo studies suggest that dalazatide inhibition of Kv1.3 may be a therapeutic target for SLE. In addition, Kv1.3 expression may be a useful biomarker of disease activity in SLE. Disclosure of Interest A. Stevens Grant/research support from: Kineta, Inc., M. Yuasa Grant/research support from: Kineta, Inc., D. Peckham Grant/research support from: Kineta, Inc., Employee of: Kineta, Inc., C. Olsen Grant/research support from: Kineta, Inc., Employee of: KPI Therapeutics, Inc, S. Iadonato Grant/research support from: Kineta, Inc., Employee of: Kineta, Inc., P. Probst Grant/research support from: Kineta, Inc., Employee of: Kineta, Inc.