Serum interleukin‐15 is elevated in systemic lupus erythematosus

Aringer, Martin; Stummvoll, Georg; Steiner, Günter; Köller, Marcus; Steiner, Carl-Walter; Höfler, E; Hiesberger, H; Smolen, JS; Graninger, W

doi:10.1093/rheumatology/40.8.876

Cited by 103 publications

(76 citation statements)

References 41 publications

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“…In autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, both levels of IL-15 and IL-21 were concomitantly elevated, and were associated with disease activity [46][47][48][49]. Our data suggest that elevated IL-15 and IL-21 in autoimmune patients could lead to hyperactivation of B cells facilitating PC differentiation that may harbor autoreactive PCs.…”

Section: Discussionmentioning

confidence: 85%

“…Both IL-15 and IL-21 are abundant in human tonsils, and sources for these cytokines could be macrophages and Tfh cells, respectively. Several studies including ours have shown the importance of macrophages in driving PC development in vitro and in vivo [7][8][9][10] In autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, both levels of IL-15 and IL-21 were concomitantly elevated, and were associated with disease activity [46][47][48][49]. Our data suggest that elevated IL-15 and IL-21 in autoimmune patients could lead to hyperactivation of B cells facilitating PC differentiation that may harbor autoreactive PCs.…”

Section: Discussionmentioning

confidence: 99%

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Human plasma cells express granzyme B

Narayanan

Kang

et al. 2013

Eur J Immunol

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While studying the plasma cell (PC) compartment in human tonsils, we identified that immunoglobulin kappa or lambda chain-expressing PCs are the main cells expressing granzyme B (GrzB). In vitro studies revealed that activated B cells differentiated into GrzBexpressing PCs when co-cultured with macrophages and follicular helper T cells. This effect could be reproduced on combined stimulation of IL-15 (produced by macrophages) and IL-21 (produced by T follicular helper cells) in a STAT3-dependent manner. Whereas IL-21 triggers the transcription of mRNA of GrzB, IL-15 synergizes the translation of GrzB proteins. The precise role of GrzB in PC biology remains to be understood and studies in mice will not help as their PCs do not express GrzB. Keywords: B cells r Granzyme B (GrzB) r Plasma cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTo mount prompt Ab responses, B cells encounter antigens in secondary lymphoid organs, such as LNs, spleen, Peyer's patches, and tonsils [1]. B-cell activation is initiated through B-cell receptor (BCR) engagement by antigens exposed on the surface of presenting cells, including follicular dendritic cells [2], dendritic cells Correspondence: Dr. Wei Xu e-mail: wei.xu.wx6@roche.com [3][4][5][6], and macrophages [7][8][9][10]. Following BCR-mediated capture, the antigens are targeted to processing compartments that facilitate the binding of Ag-derived peptides onto MHC molecules for presentation to cognate T cells [11]. These B-T-cell interactions primarily occur in two major locations: at the follicular borders of T-and B-cell zones [12,13], and within the germinal center (GC) [14][15][16]. Thus, a typical humoral response leading to the generation of plasma cells (PCs) depends on the microarchitecture where B cells, T cells, and APCs congregate to provide niches for differentiation of PCs [17].C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 276Wei Xu et al. Eur. J. Immunol. 2014. 44: 275-284 Figure 1. Human tonsil harbors GrzB-expressing PCs. A confocal image of human tonsil section for GrzB + and Ig κ light chain + PCs. Red staining: GrzB-AF568; green staining: κ light chain-AF488; light blue staining: DAPI; dark blue staining: CD3. Scale bar: 250 or 10 μM (for 63× magnification). Similar images were obtained from >8 different tonsils from different donors.Typically, terminally differentiated PCs reside in the extrafollicular foci of peripheral lymphoid organs, and in the BM where peripheral PCs home to become long-lived PCs [18][19][20][21]. While the complexity of PC development has been extensively studied in mice, it is unclear whether the same mechanisms operate for human PC differentiation. In particular, IL-10 acts as a potent B-cell differentiation factor in humans but not in mice [22]. Furthermore, it is now appreciated that PCs may be composed of subsets [23][24][25]. It is generally accepted that the more mature PCs are associated with the lowest levels of CD19, CD20...

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Human plasma cells express granzyme B

Narayanan

Kang

et al. 2013

Eur J Immunol

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“…Elevated serum IL-15 levels have been described in patients with chronic progressive multiple sclerosis, 52 type I diabetes, 53 and systemic lupus erythematosus. 54 Elevated local amounts of IL-15 have also been observed at sites of inflammation, 55,56 including the synovium in rheumatoid arthritis, 57,58 and anti-IL-15 therapy is effective in rheumatoid arthritis patients. 59 Consistent with this, rheumatoid arthritis is also associated with elevated serum and synovial fluid NO.…”

Section: Discussionmentioning

confidence: 99%

IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3

et al. 2014

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Caspase activity is critical for both T-cell survival and death. However, little is known regarding what determines caspase activity in cycling T cells. Interleukin (IL)-2 and IL-15 confer very different susceptibilities to T-cell death. We therefore considered that IL-2 and IL-15 differentially regulate caspase activity to influence T-cell survival. We observed that IL-2-cultured primary murine effector T cells manifested elevated levels of caspase-3 activity compared with IL-15-cultured T cells. T cell receptor (TCR) restimulation further increased caspase activity and induced considerable cell death in IL-2-cultured T cells, but provoked only a minimal increase of caspase activity and cell death in IL-15-cultured T cells. IL-2 sensitization to cell death was caspase-3 mediated. Interestingly, increased active caspase-3 levels with IL-2 were independent of active initiator caspase-8 and caspase-9 that were similar with IL-2 and IL-15. Rather, caspase-3 activity was inhibited by posttranslational S-nitrosylation in IL-15-cultured T cells, but not in the presence of IL-2. This paralleled increased reactive nitrogen and oxygen species with IL-15 and reduced glycolysis. Taken together, these data suggest that the metabolic state conferred by IL-15 inhibits T-cell apoptosis in part by maintaining low levels of active caspase-3 via S-nitrosylation.

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“…Tokano, et al 3 reported that the levels of IL-12 in SLE patients were significantly higher than those in normal subjects; Aringer, et al 4 showed that IL-15 was elevated in SLE sera and was correlated significantly with Bcl-2 expression. Segal, et al 5 reported that administration of IL-12 to aging mice reversed their Th1/Th2 cytokine profile and thus rendered them vulnerable to induction of experimental SLE; and Bo, et al 6 demonstrated that elevated expression of transmembrane IL-15 in immune cells correlated with the development of murine lupus, suggesting that Th1-associated cytokines might play a crucial role in the pathogenesis and development of SLE.…”

Section: To the Editormentioning

confidence: 99%