PMID- 29482663 OWN - NLM STAT- MEDLINE DCOM- 20190514 LR - 20190514 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 20 IP - 1 DP - 2018 Feb 26 TI - Impaired lymph node stromal cell function during the earliest phases of rheumatoid arthritis. PG - 35 LID - 10.1186/s13075-018-1529-8 [doi] LID - 35 AB - 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, alphaCD3/alphaCD28-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-alpha and lymphotoxin alpha(1)beta(2), 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. FAU - Hahnlein, Janine S AU - Hahnlein JS AD - Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. AD - Department of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. FAU - Nadafi, Reza AU - Nadafi R AD - Department of Molecular Cell Biology and Immunology, VU Medical Centre, Amsterdam, the Netherlands. FAU - de Jong, Tineke AU - de Jong T AD - Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. AD - Department of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. FAU - Ramwadhdoebe, Tamara H AU - Ramwadhdoebe TH AD - Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. AD - Department of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. FAU - Semmelink, Johanna F AU - Semmelink JF AD - Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. AD - Department of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. FAU - Maijer, Karen I AU - Maijer KI AD - Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. FAU - Zijlstra, IJsbrand A AU - Zijlstra IA AD - Department of Radiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. FAU - Maas, Mario AU - Maas M AD - Department of Radiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. FAU - Gerlag, Danielle M AU - Gerlag DM AD - Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. AD - Present address: Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, UK. FAU - Geijtenbeek, Teunis B H AU - Geijtenbeek TBH AD - Department of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. FAU - Tak, Paul P AU - Tak PP AD - Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. AD - Present address: Ghent University, Ghent, Belgium. AD - Present address: University of Cambridge, Cambridge, UK. AD - Present address: GlaxoSmithKline, Stevenage, UK. FAU - Mebius, Reina E AU - Mebius RE AD - Department of Molecular Cell Biology and Immunology, VU Medical Centre, Amsterdam, the Netherlands. FAU - van Baarsen, Lisa G M AU - van Baarsen LGM AD - Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. e.g.vanbaarsen@amc.uva.nl. AD - Department of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands. e.g.vanbaarsen@amc.uva.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180226 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Chemokines) RN - 0 (Vascular Cell Adhesion Molecule-1) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) SB - IM MH - Adult MH - Arthritis, Rheumatoid/genetics/*metabolism/pathology MH - Cells, Cultured MH - Chemokines/genetics/metabolism MH - Coculture Techniques MH - Female MH - Gene Expression MH - Humans MH - Intercellular Adhesion Molecule-1/genetics/metabolism MH - Leukocytes, Mononuclear/cytology/*metabolism MH - Lymph Nodes/*cytology MH - Male MH - Middle Aged MH - Stromal Cells/*metabolism MH - Vascular Cell Adhesion Molecule-1/genetics/metabolism PMC - PMC5828373 OTO - NOTNLM OT - Autoimmunity OT - Early rheumatoid arthritis OT - Immunity OT - Lymph node stromal cells OT - Tolerance COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The medical ethics committee of the Academic Medical Centre Amsterdam approved this study, and all study subjects gave written informed consent. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/02/28 06:00 MHDA- 2019/05/15 06:00 PMCR- 2018/02/26 CRDT- 2018/02/28 06:00 PHST- 2017/09/21 00:00 [received] PHST- 2018/01/29 00:00 [accepted] PHST- 2018/02/28 06:00 [entrez] PHST- 2018/02/28 06:00 [pubmed] PHST- 2019/05/15 06:00 [medline] PHST- 2018/02/26 00:00 [pmc-release] AID - 10.1186/s13075-018-1529-8 [pii] AID - 1529 [pii] AID - 10.1186/s13075-018-1529-8 [doi] PST - epublish SO - Arthritis Res Ther. 2018 Feb 26;20(1):35. doi: 10.1186/s13075-018-1529-8.