Impaired lymph node stromal cell function during the earliest phases of rheumatoid arthritis

Abstract

BackgroundSystemic autoimmunity can be present years before clinical onset of rheumatoid arthritis (RA). Adaptive immunity is initiated in lymphoid tissue where lymph node stromal cells (LNSCs) regulate immune responses through their intimate connection with leucocytes. We postulate that malfunctioning of LNSCs creates a microenvironment in which normal immune responses are not properly controlled, possibly leading to autoimmune disease. In this study we established an experimental model for studying the functional capacities of human LNSCs during RA development.MethodsTwenty-four patients with RA, 23 individuals positive for autoantibodies but without clinical disease (RA risk group) and 14 seronegative healthy control subjects underwent ultrasound-guided inguinal lymph node (LN) biopsy. Human LNSCs were isolated and expanded in vitro for functional analyses. In analogous co-cultures consisting of LNSCs and peripheral blood mononuclear cells, αCD3/αCD28-induced T-cell proliferation was measured using carboxyfluorescein diacetate succinimidyl ester dilution.ResultsFibroblast-like cells expanded from the LN biopsy comprised of fibroblastic reticular cells (gp38+CD31−) and double-negative (gp38−CD31−) cells. Cultured LNSCs stably expressed characteristic adhesion molecules and cytokines. Basal expression of C-X-C motif chemokine ligand 12 (CXCL12) was lower in LNSCs from RA risk individuals than in those from healthy control subjects. Key LN chemokines C-C motif chemokine ligand (CCL19), CCL21 and CXCL13 were induced in LNSCs upon stimulation with tumour necrosis factor-α and lymphotoxin α1β2, but to a lesser extent in LNSCs from patients with RA. The effect of human LNSCs on T-cell proliferation was ratio-dependent and altered in RA LNSCs.ConclusionsOverall, we developed an experimental model to facilitate research on the role of LNSCs during the earliest phases of RA. Using this innovative model, we show, for the first time to our knowledge, that the LN stromal environment is changed during the earliest phases of RA, probably contributing to deregulated immune responses early in disease pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1529-8) contains supplementary material, which is available to authorized users.

TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunity

“…The above results indicate that TLR9 inhibits peritoneal B cell recruitment via suppression of CXCL13 production; however, how TLR9 regulates peritoneal CXCL13 levels is unclear. CXCL13 is expressed in multiple cell types other than B cells (32), including DCs (33), macrophages (34), and FRCs in FALCs (9) and lymph nodes (35). We first tested to determine whether TLR9 regulated CXCL13 production from cells in the peritoneal cavity or cells from FALCs in mesenteric adipose tissues.…”

Phenotypic alterations in pancreatic lymph node stromal cells from human donors with type 1 diabetes and NOD mice

“…Similar to mice [28,30], inflammation can trigger phenotypic and transcriptional changes in human LNSCs [31], and lipopolysaccharide upregulates HLA-DR and PD-L1 in human FRCs [32]. PD-L1 is also upregulated by type I IFN during inflammation [33], and it is actually one of the mechanisms used by LNSCs (at least LECs) to control autoreactive T cells in mice [13].…”

Differential long non‑coding RNA expression profiles in the peripheral blood and CD4+ T cells of patients with active rheumatoid arthritis

“…Of these, CCL19 was an overexpressed chemokine in patients with RA. Various studies have indicated that CCL19 serves a chemotactic role in B cells, dendritic cells and naïve T cells via binding to the C-C motif chemokine receptor (CCR)7 (36)(37)(38). CCR7 is an important antigen molecule expressed on the surface of Treg cells and CCL19 may specifically bind to the receptor CCR7, which in turn exerts chemotactic activity on Treg cells (39)(40)(41).…”