Cellular metabolism is important for determining cell function and shaping immune responses. Studies have shown a crucial role for stromal cells in steering proper immune responses in the lymph node microenvironment. These lymph node stromal cells (LNSCs) tightly regulate immune tolerance. We hypothesize that malfunctioning LNSCs create a microenvironment in which normal immune responses are not properly controlled, possibly leading to the development of autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we set out to determine their metabolic profile during health and systemic autoimmunity. We included autoantibody positive individuals at risk of developing RA (RA-risk individuals), RA patients and healthy volunteers. All study subjects underwent lymph node biopsy sampling. Mitochondrial function in cultured LNSCs was assessed by quantitative PCR, flow cytometry, Seahorse and oleate oxidation assays. Overall, mitochondrial respiration was lower in RA(-risk) LNSCs compared with healthy LNSCs, while metabolic potential was only lower in RA LNSCs. To maintain basal mitochondrial respiration, all LNSCs were mostly dependent on fatty acid oxidation. However, RA(-risk) LNSCs were also dependent on glutamine oxidation. Finally, we showed that RA LNSCs have impaired metabolic flexibility. Our results show that the metabolic landscape of LNSCs is not only altered during established disease, but partly already in individuals at risk of developing RA. Future studies are needed to investigate the impact of restoring metabolic capacity in LNSC-mediated immunomodulation and disease progression.

‘Treat-to-target principles’ are advised for axial spondyloarthritis (axSpA), although a clear target is not yet defined and targets do not always reflect inflammation. Treat-to-target use and motives for treatment choices in clinics are unknown. Therefore, we studied the presence of residual disease activity according physician’s opinion, patient’s opinion and composite indices and compared them to the subsequent treatment decisions. This cross-sectional multicentre study included 249 patients with a clinical diagnosis of axSpA ≥6 months. Remission and low disease activity according to the BASDAI (<1.9 and 3.5 the treatment was left unchanged, either because of low disease activity as rated by the physician [n = 15 (29%)] or because of a combination of low disease activity with non-inflammatory complaints or comorbidities [n = 11 (25%)]. Retrospective treat-to-target evaluations showed that treatments were most frequently intensified in patients with arthritis or inflammatory back pain and less often in patients with other (non-inflammatory) musculoskeletal comorbidities. This study shows that physicians do not always strictly apply treat-to-target in case of residual disease activity in axSpA. Usually, they accept low disease activity as satisfactory.

Cellular senescence, a state of proliferation arrest, is implicated in the pathogenesis of age-related diseases such as rheumatoid arthritis (RA). The pathogenesis of RA, characterized by immune dysregulation and systemic autoimmunity preceding clinical onset of disease, may involve early accumulation of senescent lymph node (LN) fibroblasts driving immune tolerance breakdown. This study aims to explore the hallmarks of senescence in LN fibroblasts during the earliest phases of RA and evaluate the effects of dasatinib. Human LN fibroblasts were isolated from inguinal LN needle biopsies from autoantibody-positive individuals at risk of developing RA (RA-risk individuals), RA patients, and seronegative healthy volunteers. Senescence hallmarks and the effects of dasatinib treatment were assessed using quantitative gene expression analysis, flow cytometry, microscopy, and live-cell imaging. Cell size, granularity, and autofluorescence were significantly greater in RA LN fibroblasts compared with controls. Altered gene expression of senescence-associated genes was observed in RA LN fibroblasts. Elevated senescence-associated β-galactosidase activity, more lipofuscin-positive granules, and DNA damage were observed in RA-risk and RA LN fibroblasts. Notably, RA(-risk) LN fibroblasts presented impaired DNA damage repair capacity. Dasatinib treatment significantly improved the size and ability of the LN fibroblast pool to repair DNA damage. We observed multiple senescence hallmarks in RA LN fibroblasts and, to a lesser extent, in RA-risk LN fibroblasts, which could be partially restored by senescent cell removal via dasatinib treatment. These findings suggest a role for senescent LN fibroblasts in RA pathogenesis and highlight the potential of dasatinib as a potential therapeutic intervention to mitigate senescence-associated defects in RA.

Interleukin (IL)-17 and tumor necrosis factor-alpha (TNF)-α are key players in psoriatic arthritis (PsA) pathogenesis. While both cytokines can be therapeutically targeted with beneficial clinical outcome, it is unclear whether inhibiting one cytokine will affect the other at sites of inflammation. If both act independently, this might provide a rationale for dual or combined inhibition of both cytokines. Here, we evaluated the effect of TNF blockade in PsA patients on IL-17 levels in both skin and synovial tissue biopsies. PsA patients with mild psoriatic skin lesions were randomized to receive either adalimumab or placebo for four weeks. Synovial and skin biopsies were obtained at weeks zero and four. Skin from healthy donors (HDs) was used for comparison. Expression of IL-17A, IL-17F, IL-17RA and IL-17RC was assessed by immunohistochemistry and analyzed with digital image analysis. We found relatively low levels of IL-17 and its receptors in the skin of PsA patients compared to HD, and only IL-17F in the dermis of lesional psoriatic skin was significantly higher compared to HD skin (p = 0.0002). Histologically IL-17A, IL-17F, IL-17RA and IL-17RC in skin and synovial tissue were not downregulated by adalimumab treatment. Thus, in this cohort of PsA patients with mild psoriasis, TNF blockade did not affect the protein levels of IL-17 cytokines and its receptors in skin and synovium, despite reduced cellular inflammation and improved clinical outcome for joint involvement.

Introduction: Murine studies have demonstrated that lymph node fibroblasts can present self-antigens via major histocompatibility complex class II molecules, inducing functional regulatory T cells and contributing to peripheral tolerance. Methods: To investigate this phenomenon in humans, we developed an in vitro system co-culturing human lymph node fibroblasts with autologous CD4+ T cells. Results: Our results reveal that lymph node fibroblasts upregulate human leukocyte antigen-DR (HLA-DR) upon contact with CD4+ T cells and maintain FoxP3 + regulatory T cells. This maintenance is lost upon blockade of HLA-DR or interleukin-2, and regulatory T cells are lost in the absence of lymph node fibroblasts. Furthermore, we demonstrate that lymph node fibroblasts directly isolated from rheumatoid arthritis patients exhibit a significant reduction in the frequency of HLA-DR + cells compared to those from individuals at risk of developing the disease. Conclusion: These findings highlight a crucial role for HLA-DR-expressing lymph node fibroblasts in maintaining peripheral tolerance within lymph nodes, a function that may be impaired in autoimmunity. Our study provides novel insights into the intricate cellular interactions within human lymph nodes and their potential implications in autoimmune disorders, opening new avenues for understanding and potentially treating these conditions.