IL-12 and IL-23/Th17 axis in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a very complex disease where multiple immunological pathways can concur in inducing tissue damage. Cytokines are key mediators in this process and among them the role of interleukin (IL)-12 and the IL-23/Th17 axis has recently emerged. IL-12 and IL-23 have a heterodimeric structure with a common subunit, named p40. Although they share a partially common structure, their functions appear slightly different. Indeed, IL-12 is a key cytokine in inducing an efficient T helper 1 (Th1) response and in Th differentiation, while IL-23 plays a crucial role in chronic inflammation and Th17 cell activation, which results in IL-17 secretion. The increasing knowledge on the interaction between IL-12 and IL-23/Th17 axis in the development of autoimmune diseases has led to the identification of new therapeutic strategies targeting these immunological pathways. IL-23/Th17 axis has recently been suggested to be essential in developing lupus nephritis, both in mice and in humans. In keeping with these observations, ustekinumab, a fully human IgG1κ monoclonal antibody (mAb) directed towards p40 subunit, has been investigated in SLE. Promising data from a phase II randomized controlled trial in SLE patients suggest that this mAb might be a potential novel therapeutic strategy in SLE. In this review, we summarize the complex interaction between IL-12 and IL-23/Th17 axis in SLE with a special focus on drugs which affect this immune pathway. Impact statement Our article is focused on emerging pathogenetic pathways in systemic lupus erythematosus (SLE). Notably, IL-12 and IL-23 have been described as emerging cytokines in SLE pathogenesis. We know that IL-23 stimulates Th17 cells to produce IL-17. We try to point out the importance of IL-23/Th17 axis in SLE and to focus on the interaction between this axis and IL-12. Ustekinumab, a fully human IgG1κ monoclonal antibody directed towards the p40 shared subunit of IL-12 and IL-23, has been recently investigated in SLE, suggesting a potential novel therapeutic strategy in SLE. To our knowledge, there are no reviews which simultaneously focus on IL-12 an IL-23/Th17 axis in SLE. Thus, we believe our work will be of interest to the readers.

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

“…The role of IL17A in regulating granulopoiesis and neutrophil recruitment via induction of G-CSF is well recognized under homeostatic conditions 34,70 and a few studies have identified IL17-A as important for neutrophil recruitment to the sites of sterile inflammation 71,72 . In lupus, elevated IL-17A expression is found in cutaneous lesions 73,74 and increased circulating IL-17A levels have been associated with worse disease manifestations 75,76 , although the specific relationship to neutrophils, a pathogenic population in this disease, 11,[15][16][17] remains unexplored. Besides its direct effects on G-CSF-mediated mobilization of neutrophils from the bone marrow, IL-17A may also contribute to neutrophil homing to the kidney by stimulating expression of adhesion molecules (e.g.…”

Baricitinib: New Pharmacotherapy Options for Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Rheumatic Diseases

“…Вызывают интерес предварительные данные об эффективности БАРИ у пациентов с ювенильным дерматомиозитом [118], на фоне лечения которым отмечена положительная динамика большинства клинических показателей, входящих в стандарты оценки эффективности терапии (ACR/EULAR) этого заболевания, а также счета 28 IRG (interferon-regulated gene) и сывороточной концентрации IP-10 (Interferon gamma-induced protein 10) -хемокина, играющего важную роль в иммунопатогенезе ИВРЗ [119]. Следует обратить внимание и на другой потенциально важный механизм, определяющий эффективность БАРИ при СКВ и других ИВРЗ, связанный с ингибицией ИЛ12 и ИЛ23 (JAK2/TYK2-зависимые цитокины), которые вызывают патологическую активацию Тh1и Тh2-типов иммунного ответа и гиперпродукции аутоантител В-клетками [120]. В настоящее время проводится серия РКИ, касающихся изучения эффективности терапии БАРИ при СКВ (фаза II -NCT02708095, фаза III: NCN03843125, NCT03616964), гигантоклеточном артериите (фаза II -NCT03026504), ревматической полимиалгии (фаза II -NCT04027101).…”

Efficacy and Safety of Tofacitinib for Immunemediated Inflammatory Rheumatic Diseases (Part Ii)

“…Отмечена связь между развитием СКВ и полиморфизмом генов, участвующих в сигнализации JAK-STAT (JAK2, TYK2 и STAT4) [48], и гиперпродукцией широкого спектра JAK-STATзависимых цитокинов, в первую очередь ИФН типа I (ИФНα/β), ИФНγ, а также ИЛ2, ИЛ6, ИЛ21, ИЛ17, ИЛ12, ИЛ23 и др. [49,50]. Все это вместе взятое привлекло внимание к возможности использования ингибиторов JAK в лечении СКВ [50,51].…”