Abstract
Defects in Fas function correlate with susceptibility to systemic autoimmune diseases like autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosus (SLE). C57BL/6 lpr (B6/lpr) mice are used as an animal model of ALPS and develop a mild SLE phenotype. Involvement of interleukin-17A (IL-17A) has been suggested in both phenotypes. Since IL-17 receptor A is part of the signaling pathway of many IL-17 family members we investigated the role of IL-17 receptor signaling in disease development in mice with a B6/lpr background. B6/lpr mice were crossed with IL-17 receptor A deficient (IL-17RA KO) mice and followed over time for disease development. IL-17RA KO/lpr mice presented with significantly enhanced lymphoproliferation compared with B6/lpr mice, which was characterized by dramatic lymphadenomegaly/splenomegaly and increased lymphocyte numbers, expansion of double-negative (DN) T-cells and enhanced plasma cell formation. However, the SLE phenotype was not enhanced, as anti-nuclear antibody (ANA) titers and induction of glomerulonephritis were not different. In contrast, levels of High Mobility Group Box 1 (HMGB1) and anti-HMGB1 autoantibodies were significantly increased in IL-17RA KO/lpr mice compared to B6/lpr mice. These data show that lack of IL-17RA signaling aggravates the lymphoproliferative phenotype in B6/lpr mice but does not affect the SLE phenotype.
Highlights
Defects in Fas function correlate with susceptibility to several systemic autoimmune diseases such as autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosus (SLE)[1]
This study demonstrates that deletion of IL-17 receptor A (IL-17RA) signaling markedly aggravates the lymphoproliferation in between C57BL/6 (B6)/ lpr mice, but does not affect SLE pathology
The greatly increased spleen and lymph node size in IL-17RA KO/lpr mice, characterized by expansion of CD4+ T cells, CD8+ T cells, DN T cells and B cells indicates an important role for IL-17RA signaling in limiting the lymphoproliferative phenotype in B6/lpr mice
Summary
Defects in Fas function correlate with susceptibility to several systemic autoimmune diseases such as autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosus (SLE)[1]. It was demonstrated that HMGB1 levels are increased in serum and urine of SLE patients and are related to disease activity[9,10] Both ALPS and SLE phenotypes can spontaneously develop in lpr mouse models, carrying mutations in the Tnfrsf[6] gene, encoding the Tumor Necrosis factor (TNF)-family receptor protein FAS or CD95 that has the capacity to induce apoptosis. These lpr mice are often referred to as lupus mice and display lymphoproliferation, expansion of DN T cells and autoimmune nephritis, including anti-dsDNA autoantibodies[11]. C57BL/6-lpr (B6/lpr) mice are used as an animal model of ALPS and present a milder SLE phenotype[13]
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