IL-23 Limits the Production of IL-2 and Promotes Autoimmunity in Lupus

Abstract

The IL-23/IL-17 pathway is important in multiple autoimmune diseases, but its effect on lupus pathology remains unclear with opposing trials in murine models of the disease. Herein we show a disease activity related upregulation of serum IL-23 and IL-23 receptor in patients with SLE as compared to healthy controls. IL-23 when added in SLE T cell in vitro cultures, induced IL-17 and limited IL-2 production while Tfh and DN T cells significantly expanded. To further dissect the role of IL-23 in the expression of autoimmunity and related pathology, we generated IL-23 receptor deficient MRL.lpr mice. These IL-23R−/−MRL.lpr mice displayed attenuated lupus nephritis with a striking decrease in the accumulation of double negative T (DN T) cells in the kidneys and secondary lymphoid organs. Moreover, T cells from IL-23R−/−MRL.lpr mice produced increased amounts of IL-2 and reduced amounts of IL-17 compared to T cells from wild type animals. In vitro IL-23 treatment promoted IL-17 production and downregulated IL-2 production. The IL-23R−/−MRL.lpr had fewer T follicular helper cells (Tfh), B cells and plasma cells, leading to decreased production of anti-dsDNA antibodies. Our results show that IL-23 accounts for main aspects of human and murine lupus including the expansion of DN T cells, decreased IL-2 and increased IL-17 production. We propose that blockade of IL23 should have a therapeutic value in patients with SLE.

The role of IL‐23 receptor signaling in inflammation‐mediated erosive autoimmune arthritis and bone remodeling

“…In recent years, it has become clear that the IL‐23/Th17 pathway plays a crucial role in many inflammatory autoimmune diseases including psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA) and systemic lupus erythematosus . Both RA and PsA are disorders with distinct clinical phenotypes, resulting from complex interactions between genetic and environmental factors such as smoking or infections.…”

Autoimmunity and autoimmune co‐morbidities in psoriasis

“…[139][140][141] Similar to psoriasis, IFNs, DNA-LL-37 complex and plasmacytoid DCs play a pivotal role in triggering and perpetuating systemic lupus erythematosus. [142][143][144] Interferons accelerate the formation of DNA-LL37 complex that activates plasmacytoid DCs to produce high levels of IFNs and IL-23. 142,144 Interleukin-23 induces IL-17 production, which promotes autoimmunity.…”

“…[142][143][144] Interferons accelerate the formation of DNA-LL37 complex that activates plasmacytoid DCs to produce high levels of IFNs and IL-23. 142,144 Interleukin-23 induces IL-17 production, which promotes autoimmunity. 144 Crohn's disease is also deeply linked to TNF-a/IL-23 signalling because both anti-TNF-a and anti-IL-23 biologicals are effective in this disease.…”

“…142,144 Interleukin-23 induces IL-17 production, which promotes autoimmunity. 144 Crohn's disease is also deeply linked to TNF-a/IL-23 signalling because both anti-TNF-a and anti-IL-23 biologicals are effective in this disease. 145,146 In vitiligo, IFN signature is also involved in the initiation of its immune response with the activation of plasmacytoid DCs.…”

Systemic lupus erythematosus: new horizons for diagnosis and therapy

“…Другое перспективное направление фармакотерапии СКВ связано с адаптацией широко применяемого в ревматологии лекарственного препарата устекинумаба (УСТ), представляющего собой мАТ к общей (р40) субъединице «провоспалительных» цитокинов ИЛ12 и ИЛ23 [104] и зарегистрированного для лечения псориаза, псориатического артрита (ПсА) и болезни Крона. Получены многочисленные данные, свидетельствующие об участии ИЛ12 и ИЛ23 (а также ИЛ17) в патогенезе СКВ, а именно -патологической активации Тh1-и Тh17-типов иммунного ответа и гиперодукции аутоантител В-клетками [104][105][106][107]. По данным РКИ фазы II, лечение УСТ (6 мг/кг внутривенно, затем 90 мг подкожно каждые 8 нед) ассоциировалось с достоверным снижением активности СКВ (индекс SRI-4) по сравнению с ПЛ (р=0,006) [108,109].…”