IL-17 in Systemic Lupus Erythematosus

IL-17 is a cytokine with powerful proinflammatory activity. Production of IL-17 is abnormally increased in patients with systemic lupus erythematosus (SLE), a multiorgan chronic autoimmune disease. In patients with SLE, CD3+CD4−CD8− (double negative) T cells are an important source of IL-17. IL-17 produced by double negative and CD4 T cells participates in the pathogenesis of the disease. IL-17-producing T cells are present in the kidneys of patients with lupus nephritis. IL-17 increased production in patients with SLE can amplify the immune response by increasing target organ inflammation and damage and by augmenting the production of antibodies by B cells

Lupus-Prone Mice Fail to Raise Antigen-Specific T Cell Responses to Intracellular Infection

Systemic lupus erythematosus (SLE) is characterized by multiple cellular abnormalities culminating in the production of autoantibodies and immune complexes, resulting in tissue inflammation and organ damage. Besides active disease, the main cause of morbidity and mortality in SLE patients is infections, including those from opportunistic pathogens. To understand the failure of the immune system to fend off infections in systemic autoimmunity, we infected the lupus-prone murine strains B6.lpr and BXSB with the intracellular parasite Toxoplasma gondii and survival was monitored. Furthermore, mice were sacrificed days post infection and parasite burden and cellular immune responses such as cytokine production and cell activation were assessed. Mice from both strains succumbed to infection acutely and we observed greater susceptibility to infection in older mice. Increased parasite burden and a defective antigen-specific IFN-gamma response were observed in the lupus-prone mice. Furthermore, T cell:dendritic cell co-cultures established the presence of an intrinsic T cell defect responsible for the decreased antigen-specific response. An antigen-specific defect in IFN- gamma production prevents lupus-prone mice from clearing infection effectively. This study reveals the first cellular insight into the origin of increased susceptibility to infections in SLE disease and may guide therapeutic approaches

Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases

Spleen tyrosine kinase (Syk) is involved in the development of the adaptive immune system and has been recognized as being important in the function of additional cell types, including platelets, phagocytes, fibroblasts, and osteoclasts, and in the generation of the inflammasome. Preclinical studies presented compelling evidence that Syk inhibition may have therapeutic value in the treatment of rheumatoid arthritis and other forms of arthritis, systemic lupus erythematosus, autoimmune cytopenias, and allergic and autoinflammatory diseases. In addition, Syk inhibition may have a place in limiting tissue injury associated with organ transplant and revascularization procedures. Clinical trials have documented exciting success in the treatment of patients with rheumatoid arthritis, autoimmune cytopenias, and allergic rhinitis. While the extent and severity of side effects appear to be limited so far, larger studies will unravel the risk involved with the clinical benefit

The IL-2 Defect in Systemic Lupus Erythematosus Disease Has an Expansive Effect on Host Immunity

IL-2 production is decreased in systemic lupus erythematosus (SLE) patients and affects T cell function and other aspects of host immunity. Transcription factors regulating IL-2 production behave aberrantly in SLE T cells. In addition to IL-2 dysregulation, other IL-2 family members (IL-15 and IL-21) are abnormally expressed in SLE. Decreased IL-2 production in SLE patients leads to many immune defects such as decreased Treg production, decreased activation-induced cell death (AICD), and decreased cytotoxicity. IL-2 deficiency results in systemic dysregulation of host immune responses in patients suffering from SLE disease

Treatment with Anti-Interleukin 23 Antibody Ameliorates Disease in Lupus-Prone Mice

Interleukin 23 receptor expressing IL-17 producing T cells have been shown to be important in the development of murine lupus. The usefulness of IL-23 inhibition in ameliorating lupus nephritis is unknown. We hypothesized that inhibition of IL-23 will ameliorate nephritis in lupus-prone mice. To this end, we treated MRL/lpr lupus-prone mice for 6 weeks with a rat anti-IL-23p19 antibody, which resulted in delaying the onset of nephritis without affecting the production of anti-dsDNA antibodies. The effect of the treatment was hampered by the production of murine anti-rat IgG antibodies. The amelioration of murine lupus by IL-23 inhibition strengthens the rationale for targeting IL-23 in patients with systemic lupus erythematosus

SLE serum deposits C4d on red blood cells, decreases red blood cell membrane deformability, and promotes nitric oxide production

Objective Systemic lupus erythematosus (SLE) is characterized by intravascular activation of the complement system and deposition of complement fragments (C3 and C4) on plasma membranes of circulating cells, including red blood cells (RBC). The aim of this study was to address whether this process affects the biophysical properties of RBC. Methods Serum and red blood cells were isolated from patients with SLE, and healthy controls. RBC from healthy O Rh negative individuals were incubated with SLE or control serum. We used flow cytometry to assess complement fragment deposition on RBC. RBC membrane deformability was measured using 2D microchannel arrays. Protein phosphorylation levels were quantified by western blot. Results Incubation of healthy donor RBC with sera from patients with SLE but not control sera led to deposition of C4 fragments on the RBC. Complement decorated RBC exhibited significant decrease in both membrane deformability and flickering. Sera from SLE patients triggered a transitory Ca++ influx in RBC that was associated with decreased phosphorylation of ?-spectrin, and increased phosphorylation of band 3, two key proteins of RBC cytoskeleton. Finally, SLE but not control sera led to the production of nitric oxide (NO) by RBC. Conclusion Our data suggest that complement activation in patients with SLE leads to calcium dependent cytosketeletal changes in RBC that render them less deformable, likely impairing their flow through capillaries. This phenomenon may negatively impact the delivery of oxygen to the tissues