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


METHODS
Twenty-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.


RESULTS
Fibroblast-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.


CONCLUSIONS
Overall, 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.
['Hähnlein|Janine S|JS|', 'Nadafi|Reza|R|', 'de Jong|Tineke|T|', 'Ramwadhdoebe|Tamara H|TH|', 'Semmelink|Johanna F|JF|', 'Maijer|Karen I|KI|', 'Zijlstra|IJsbrand A|IA|', 'Maas|Mario|M|', 'Gerlag|Danielle M|DM|', 'Geijtenbeek|Teunis B H|TBH|', 'Tak|Paul P|PP|', 'Mebius|Reina E|RE|', 'van Baarsen|Lisa G M|LGM|']
D000328:Adult D001172:Arthritis, Rheumatoid D002478:Cells, Cultured D018925:Chemokines D018920:Coculture Techniques D005260:Female D015870:Gene Expression D006801:Humans D018799:Intercellular Adhesion Molecule-1 D007963:Leukocytes, Mononuclear D008198:Lymph Nodes D008297:Male D008875:Middle Aged D017154:Stromal Cells D019010:Vascular Cell Adhesion Molecule-1
Lymph node stromal cells Autoimmunity Immunity Early rheumatoid arthritis Tolerance