Lupus Serum IgG Induces Skin Inflammation through the TNFR1 Signaling Pathway

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by high autoantibody levels and multiorgan tissue damage, including kidney and skin. Cutaneous manifestations are frequent in patients with SLE, yet the etiology and pathogenesis of skin injury in SLE remains unclear. We reasoned that lupus serum containing high levels of autoreactive Ig contributes to skin injury. In this article, we report that serum from SLE patients and lupus-prone mice induces skin inflammation following intradermal injection into normal mice. Lupus serum depleted of IgG failed to cause skin inflammation. Monocytes, but not lymphocytes, were found to be crucial in the development of lupus serum-induced skin inflammation, and lupus serum IgG induced monocyte differentiation into dendritic cells (DCs). TNF-α and TNFR1, but not TNFR2, were required for the development of lupus serum-induced skin inflammation. TNFR1, not TNFR2, represented the main molecule expressed in the skin lesions caused by injected lupus serum. Our studies demonstrated that lupus serum IgG causes skin injury by involving the TNFR1 signaling pathway and monocyte differentiation to DCs. Accordingly, disruption of the TNFR1-mediated signaling pathway and blockade of DC generation may prove to be of therapeutic value in patients with cutaneous lupus erythematosus.

Apolipoprotein A-I Modulates Regulatory T Cells in Autoimmune LDLr−/−, ApoA-I−/− Mice

“…4, panel C). These results strongly suggest that IgG or IgG-containing complexes represent a major contributor to skin inflammation in diet-fed DKO mice, because tissue damage in autoimmune disorders have been associated with the presence of autoantibody (27).…”

“…Because tissue damage in certain autoimmune disorders has been associated with the presence of autoantibodies (27), we examined skin sections from each of the diet-fed groups for the presence of IgG. The supplemental Fig.…”

Selective Inhibition of BTK Prevents Murine Lupus and Antibody-Mediated Glomerulonephritis

“…In brief, 500 ml whole blood and 1 ml compound or vehicle were added to a deep well plate and incubated at 37˚C for 1 h. Twenty-five microliters of each sample was then stimulated with 20 mg/ml goat anti-hIgD F(ab9) 2 and incubated at 37˚C for 3 h (Southern Biotech, Birmingham, AL). Cells were then washed and stained with anti-CD19 APC and anti-CD69 PE Abs (BD Biosciences).…”

“…IC deposition in SLE patients is often observed in tissues such as kidney and skin. Importantly, IgG containing ICs can activate the complement cascade and directly mediate tissue damage, as well as promote inflammation via recruitment of granulocytes (2)(3)(4)(5). ICs also directly activate cells such as macrophage and dendritic cells by signaling through FcRs, which are critical for the development of glomerulonephritis in multiple animal models (6)(7)(8).…”

Generation and Characterization of Small Single Domain Antibodies Inhibiting Human Tumor Necrosis Factor Receptor 1

“…Furthermore, TNFR1 neutralization may indirectly stimulate TNF/TNFR2 signaling in the experimental autoimmune encephalomyelitis lesions, which subsequently promotes remyelination in chemically induced demyelination (83). In addition, type I diabetes and systemic lupus erythematosus might also depend on the immunomodulating TNF/TNFR2 signaling for protection or recovery (52,84). Other diseases that can benefit from exclusive TNFR1 inhibition have been reviewed (3).…”