IL-15, IL-17
Il-15 activating receptors
NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically Involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, the shedding of soluble NKG2D ligand MICA (SMICA) decreased upon potentially diminishing inflammation inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naïve CD8 + T cells into highly activated, cytotoxic CD8 + T cells demonstrating high NKG2D NKG2D-dependent lysis of myoblasts in vitro. CD8 + T cell NKG2D high frequencies were increased in the peripheral blood of polymyositis (PM) and correlated patients with serum creatinine kinase concentrations, while serum levels SMICA significantly were not changed. The NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues. (1)
Expression
IL-15 expression correlated negatively with improvement in muscle function. IL-15 expression in macrophages in muscle biopsies from patients with myositis is consistent with observations in synovial tissues from patients with rheumatoid arthritis. IL-15 may mediate its functions via trans-presentation—that is, IL-15Rα-producing cells bind IL-15 and then present it to cells expressing IL-2Rβ and γc subunits. This trans-presentation is anticipated to be relevant for T cells as they express IL-2Rβ and γc subunits on their cell membrane. T cell infiltration in skeletal muscle is a characteristic histopathological feature of PM/DM. (2)
Il-17 and connective tissue
IL-17A–null mice have been shown to develop significantly attenuated forms of collagen-induced arthritis (CIA) , experimental autoimmune encephalopathy (EAE) , and experimental autoimmune uveoretinitis . IL-17A neutralization had therapeutic effects on these autoimmune diseases as well as on experimental autoimmune myocarditis . Of note, the activity of most of these diseases was attenuated in IL-6–null mice and by blockade of the IL-6 signaling pathway . Since the presence of IL-6 in addition to transforming growth factor β (TGFβ) is essential for Th17 cell differentiation , it is reasonable to assume that IL-6 blockade exerted its effects by suppressing Th17 cell development.(3)
IL-15 induces the expression of chemokine receptors and adhesion molecules on CD4+CD28− T cells. IL-15 amplify the pathogenic potential of CD4+CD28− T cells, thus contributing to tissue damage.(4) such as the Il-17.
Similar to the muscles of patients with PM, the muscles of mice with CIM in several studies had infiltration of mononuclear cells expressing IL-6. Hosts defective in IL-6 were resistant to CIM induction, while those defective in IL-17A were fully susceptible. Anti–IL-6R monoclonal antibody administration ameliorated myositis not only in a preventive protocol but, more importantly, in a therapeutic one. The antibody should inhibit pathologic pathways evoked by IL-6 production that could be triggered by adjuvants in CIM and might be triggered by another pathologic process in PM. (4)
Relevance
Experimental autoimmune myocarditis is a mouse model of postinfectious myositis of the heart and is mediated by CD4 T cells . Anti–IL-17A antibody treatment of T-bet–null mutant mice showed that the disease processes depend on IL-17A. As noted above, myosin-induced EAM is a myositis model likely driven by CD4 T cells . Scuderi et al reported that myosin-induced EAM , to which B6 mice had been shown to be resistant , was not inducible in IL-6–null mutant B6 mice. It should be noted that EAM can be transferred to naive mice by serum transfer . Since IL-6 is crucial for antibody production, IL-6 dependence of EAM could be well predicted. Alternatively, it might be another instance of an IL-17A–dependent autoimmune disease model.(5)
Il 17 and Il 15 Correlation
In Several Studies serum levels of IL-15, IL-17, MCP-1, and MIP-1β were significantly higher in IIM patients than in HC. IL-17 serum levels were directly correlated (r = 0.39, p = 0.02) with disease duration while a significant inverse correlation was detected between IL-17 levels and MMT scores (r = –0.4, p = 0.02). The highest IL-15 levels were present in autoimmune patients (p = 0.02 vs. PM). The most striking finding was the strong correlation between IL-15 and IL-17 levels (r = 0.60, p = 0.0001), and this correlation was even stronger in autoimmune disease patients (r = 0.82, p = 0.006). (6)
What’s Next
Targeting IL-15 and IL-17 might therefore be a possible novel treatment for PM and DM, at least in a subgroup of patients with high IL-15 expression in muscle tissue after conventional IS treatment. (1)
Footnotes:
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Yang, C.CRH knockout inhibits the murine innate immune responses in association with endoplasmic reticulum stress after thermal injury.July 2015Volume 158, Issue 1, Pages 255–265. http://europepmc.org/abstract/med/26646698
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Zong,M.Effects of immunosuppressive treatment on interleukin-15 and interleukin-15 receptor α expression in muscle tissue of patients with polymyositis or dermatomyositis Ann Rheum Dis doi:10.1136/annrheumdis-2011-200495 .Clinical and epidemiological research. http://ard.bmj.com/content/early/2012/01/20/annrheumdis-2011-200495.abstract
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Bieke ,B. IL-15 Amplifies the Pathogenic Properties of CD4+CD28− T Cells in Multiple Sclerosis .Published online before print January 23, 2015, doi: 10.4049/jimmunol.1401547. http://www.jimmunol.org/content/194/5/2099.short
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Notarnicola A. Correlation between serum levels of IL-15 and IL-17 in patients with idiopathic inflammatory myopathies. Scandinavian Journal of Rheumatology .Volume 44, Issue 3, 2015 . view
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Ingrid L. Decreased expression of interleukin-1α, interleukin-1β, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis. Arthritis & Rheumatism Volume 43, Issue 2, pages 336–348, February 2000. view
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Tomoko S. Increased IL‐15 production of muscle cells in polymyositis and dermatomyositis. Int. Immunol. (2002) 14 (8): 917-924. doi: 10.1093/intimm/dxf062. view
