Session Title: Pediatric Rheumatology - Pathogenesis and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: MAS occurs frequently in patients with active systemic juvenile idiopathic arthritis(s-JIA) and because of the similarities with Haemophagocytic Lymphohistiocytosis (HLH) is classified among secondary HLH. s-JIA is characterized by high levels of Interleukin-6 (IL-6). Impairment of natural killer (NK) cell function and decrease perforin expression have also been reported in sJIA. Aim of this study was to evaluate the effect of IL-6 on NK cell cytotoxic function.
Methods: Following in vivo treatment with poly(I:C), splenic NK cell cytotoxic activity from wild-type (WT) or IL-6 transgenic (IL-6TG) mice was evaluated using the chromium51 release assay. NK cell number, perforin, granzymeB, CD69 and CD107a expression were evaluated by flow cytometric analysis. Human polyclonal NK cells were expanded from peripheral blood mononuclear cells (PBMCs) in co-cultures with the feeder cell line RPMI8866 in the presence of tocilizumab, an IL-6 receptor blocker, or isotype control. IL-6 production in the supernatants of human polyclonal NK cells was measured by ELISA. PBMCs from healthy donors were treated with IL-6. NK cell cytotoxic activity, perforin and CD107a expression were evaluated as above.
Results: Following poly(I:C) administration, in vivo generation of splenic NK cell cytotoxicity was markedly reduced in IL6TG mice compared to WT mice. In IL6TG mice number of NK cells, number of CD69+ NK cells and degranulation were comparable to WT mice. Defective expression of both perforin and granzymeB were found in NK cells from IL6TG mice. High levels of IL-6 were found in the supernatants of human polyclonal NK cells. Neutralization of IL-6 effects with tocilizumab in co-cultures of human PBMCs increased human NK cell cytotoxicity and perforin expression. Addition of IL-6 to human PBMCs decreased perforin expression in NK cells.
Conclusion: Both in vivo in mice and in vitro in humans, IL-6 inhibits NK cytotoxicity down-regulating perforin expression. In patients with prominent inflammatory response, such as that present in s-JIA, high levels of IL-6 may contribute to the induction of MAS also by inhibiting cytotoxicity inducing a defect similar to that of primary HLH.
F. De Benedetti Sr.,
Novartis, Novimmune, Hoffmann-La Roche, SOBI, AbbVie,
AbbVie Novartis, Novimmune, Hoffmann-La Roche, SOBI ,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-natural-killer-nk-cell-cytotoxicity-by-interleukin-6-il-6-implications-for-the-pathogenesis-of-macrophage-activation-syndrome/