Interleukin (IL)-9/IL-9R axis drives γδ T cells activation in psoriatic arthritis patients

Abstract

Cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-12, interferon (IFN)-γ, IL-23 and, more recently, IL-9, have been implicated in the initiation/maintenance of inflammation in psoriasis and psoriatic arthritis (PsA). In the present study we aimed to characterize the role of γδ T cells in peripheral blood and synovial fluid of PsA patients and to investigate their response to in-vitro stimulation with antigen or cytokines (IL-9 and IL-23). γδ T cells isolated from peripheral blood mononuclear cells and synovial fluid were analysed by flow cytometry to evaluate the phenotype and cytokine production. IL-23R and IL-9R gene expression were also evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Peripheral blood mononuclear cells (PBMC), sorted γδ T cells and γδ cell lines were also stimulated in vitro with isopentenyl pyrophosphate (IPP), recombinant IL-9 or recombinant IL-23. Our results show an expansion of γδ T cells with a predominant effector memory phenotype in peripheral blood and synovium of untreated PsA patients, which reverses significantly after treatment with anti-TNF-α or anti-IL-12/IL-23R monoclonal antibodies (mAbs). Moreover, in PsA patients γδ T cells activation is driven prevalently by IL-9/IL-9R interaction, and not only by IL-23/IL-23R. Together these findings indicate γδ T cells and IL-9 as new players in the pathogenesis of PsA.

CXCL4 is a novel inducer of human Th17 cells and correlates with IL‐17 and IL‐22 in psoriatic arthritis

“…mDCs and pDCs, both capable of producing CXCL4, are increased in PsA and rheumatoid arthritis SF [35][36][37]. Furthermore, in addition to CD4 + T cells, there are other type 17 cells enriched in the PsA SF, including the type 3 innate lymphoid cells [38], CD8 T cells [39], and γδ T cells [40]. CXCL4 contribution to the IL-17 regulation in these cells still needs to be evaluated.…”

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

“…However, it remains to be elucidated whether these cells express the IL‐23R. In addition, IL‐23R + Th17 cells are detected in PsA synovial fluid and IFNy + , IL‐17 + γδ T cells are found enriched in the synovial fluid compared to peripheral blood .…”

Reply

“…In particular, in some cases, uveitis has been observed after infusion (4). Moreover, it is known that zoledronic acid might induce arrhythmias (atrial fibrillation, in particular) (5).…”

“…Zoledronic acid indeed leads to an accumulation of intracellular isopentenyl pyrophosphate (IPP) in target cells, which in turn activates human Vg91Vd21 T cells. However, only a few reports to date have described the induction of IL-17 in human Vg91Vd21 T cells, either by zoledronate (1), or directly by phosphoantigens such as IPP (2)(3)(4)(5) or the more potent microbial hydroxyl-3methyl-but-2-enyl pyrophosphate (HMBPP) (6,7) (Table 1). Collectively, these studies showed that in healthy human blood only a minor g/d T cell population produces IL-17 upon stimulation with HMBPP or IPP, whereas IL-17-producing g/d T cell numbers can increase upon stimulation with specific cytokine mixtures, during infection or autoimmune and autoinflammatory diseases (Table 1).…”

“…A patient is classified as having SS if she/he has a score of $4 from the classification criteria items. However, similar to previous SS classification criteria sets (3)(4)(5)(6), there is an inherent problem: the criteria comprise only glandular manifestations. Most patients with primary SS who need aggressive treatment (immunosuppressive or biologic agents) are those with major organ involvement, and a significant proportion of these patients do not have glandular manifestations severe enough to fulfill the classification criteria.…”