AB0164 Amyloidosis in progressive systemic sclerosis – a postmortem clinicopathologic study of 12 patients

Apáthy, Ágnes; Bély, M.

doi:10.1136/annrheumdis-2017-eular.1226

Cited by 3 publications

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“…Higher prevalence (80.0% versus 0.0%; p<0.0001) and massive AL-λ deposition in the skin (1.45 versus 0.0; p<0.0002) may be explained by qualitative differences of AL-λ and amyloid A and by a diverse affinity of circulating amyloid precursors to the qualitative changed interstitial collagen and reticulin fibers. In systemic sclerosis patients qualitative change of collagens has been demonstrated [3][4][5].…”

Section: Methodsmentioning

confidence: 99%

AB0163 Mesenchymal stem cells induce CD1C+ tolerogenic dendritic cells in human systemic lupus erythematosus via up-regulating FLT-3 ligand

Yuan

Wang

Zhang

et al. 2017

Abstracts Accepted for Publication

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BackgroundCD1c+ tolerogenic dendritic cells (DCs) play important roles in the induction of peripheral tolerance and control of adaptive immune response. Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) exhibit immunoregulation effects in systemic lupus erythematosus (SLE). However, the underlying immunosuppression mechanism of MSCs via tolerogenic DCs in SLE remains largely unknown.ObjectivesThe aim of this study was to examine tolerogenic DCs levels in SLE patients, and to further investigate the mechanism of MSCs in the regulation of tolerogenic DCs.MethodsTolerogenic DCs were isolated as Lin (CD3/19/56/14)- HLA DR+CD11c+CD1c+ from peripheral blood mononuclear cells (PBMCs). Levels of tolerogenic DCs were determined by flow cytometry, and serum concentration of Flt-3 ligand (FLT3L) were determined by ELISA from 17 healthy controls and 25 SLE patients. Eight SLE patients were given UC MSCs infusions. We compared the levels of tolerogenic DCs and serum FLT3L before and 24 hours after UC MSCs transplantation. PBMCs from 8 patients were collected and co-cultured with UC MSCs at ratios of 1:1, 10:1 and 50:1, for 24 hours, 48 hours and 72 hours, respectively, to detect the levels of tolerogenic DCs. The FLT3L in the supernatant solution were determined. FLT3L siRNA was added to the co-culture system, and the level of tolerogenic DCs were detected.ResultsThe levels of peripheral CD1c+ DCs and serum FLT3L were significantly decreased in SLE patients compared to healthy controls. After UC MSCs transplantation, the levels of CD1c+ DCs increased, along with an increase in serum FLT3L. In vitro studies showed that UC MSCs time-dependently up-regulated peripheral CD1c+ DCs, but not dose-dependently. The supernatant FLT3L level significantly increased after co-cultured with MSCs. However, the addition of FLT3L siRNA significantly abrogated the up-regulation of CD1c+ DCs by MSCs.ConclusionsUC MSCs induce CD1c+ tolerogenic DCs through up-regulating FLT3L in lupus patients.Disclosure of InterestNone declared

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Section: Methodsmentioning

confidence: 99%

AB0163 Mesenchymal stem cells induce CD1C+ tolerogenic dendritic cells in human systemic lupus erythematosus via up-regulating FLT-3 ligand

Yuan

Wang

Zhang

et al. 2017

Abstracts Accepted for Publication

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“…Rheumatoid arthritis [7,13,19,20], juvenile chronic arthritis [6,7,13], adult Still's disease, systemic lupus erythematodes [13], progressive systemic sclerosis [21], Crohn's disease [22], ulcerative colitis [23], polymyositis [13], polymyalgia rheumatica or giant-cell arteritis (GCA) [24] etc. and in association with…”

Section: Autoimmune (Inflammatory) Diseasesmentioning

confidence: 99%

β-cell Related Amyloidosis Localized to the Islets of Langerhans, Type II Diabetes Mellitus and Liponecrotic Pancreatitis in Rheumatoid Arthritis: A Postmortem Clinicopathologic Statistical Study of 234 Autopsy Patients

Bély¹,

Apáthy²

2019

IDCD

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The aim of this study was to determine the prevalence of systemic AA amyloidosis (AAa), islet amyloidosis (IA) and liponecrotic pancreatitis (LnP) including acute liponecrotic (aLnP), acute relapsing liponecrotic (aRelLnP), and chronic liponecrotic pancreatitis (chrLnP) in rheumatoid arthritis (RA), and to analyse the possible relationship between them.Patients and methods: At the National Institute of Rheumatology 11558 patients died between 1969 and 1998; among them 234 with RA, and all of them were autopsied. RA was confirmed clinically according to the criteria of the American College of Rheumatology (ACR). The diagnosis of DM was based on clinical data. Tissue samples of pancreas were available for histologic evaluation in 164 of 234 patients. AAa, IA and LnP were diagnosed histologically. Demographics of different patient cohorts were compared with the Student (Welch) t probe. The relationships between AAa and IA, furthermore between IA and DM or LnP (including aLnP, aRelLnP, chrLnP) were analyzed by Pearson’s chi-squared (c2) test.Results: AAa complicated RA in 42 (25.61%) of 164 patients. IA localized to the islets of Langerhans was observed in 16 (9.76%) of 164 pancreases. Clinically diagnosed DM was associated with RA in 31 (18.90%) of 164 patients. Pancreatitis with multiple liponecrotic foci (LnP) was found in 19 (11.58%) of 164 patients; aLnP existed in 9 (47.37%), aRelLnP in 4 (21.05%), and liponecrotic foci in combination with chronic fibrotic pancreatitis (chrLnP) in 6 (31.58%) of these 19 patients.Discussion and conclusions: There was no significant difference between female and male RA patients associated with AAa, IA, DM and LnP. The age, sex and onset of disease did not influence basically the prevalence of AAa, IA, DM and LnP except male patients with IA, whose mean age at death was significantly higher than the general RA population. IA (fibrillar amyloid IAPP deposits -AIAPP) is related to the activity of b cells and may presumably be a faulty product of b-cells (normal islets of Langerhans do not contain IA deposits). The progressive deposition of IAPP prohormon fragments inhibits the function of b-cells because of their toxic effect and/or blocking mechanically the blood supply of b-cells and they “die in their own product”. The significant correlation between IA and DM refers to a close connection between them, but not necessarily a direct cause and effect relationship; it may be an indirect result of damaged (apoptotic) b-cells. The early stage of IA is characterized by minimal IAPP deposits involving only a few islets, which represents a clinically latent DM, and the advanced stage of IA is characterized by massive IAPP deposits involving most of the islets, which correspond to clinically manifest DM. Based on the positive and significant correlation between IA and clinically not diagnosed DM, IA may be a good indicator of potential DM in the latent stage of disease. Therefore we recommend that all biopsy material and surgical specimens of pancreas to be tested for IA or IAPP deposition.

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“…Recently, CXCL4 was shown to induce type I interferon production as well as endothelial activation in SSc patients 1 . Th17 skewing has been demonstrated in SSc [5][6] , however, whether CXCL4 plays a role in the induction of IL-17 production by human CD4 T cells is currently unclear. Objectives: To investigate the effect of CXCL4 on human CD4 T cell phenotype in particular IL-17 production in the absence or presence of antigen presenting cells.…”

Section: Ab0165 Cxcl4 May Play a Key Role In Systemic Sclerosis By Drmentioning

confidence: 99%

AB0165 CXCL4 may play a key role in systemic sclerosis by driving CD4 T cells to produce IL-17

Affandi¹,

Cardoso²,

Garcia-Perez³

et al. 2017

Abstracts Accepted for Publication

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BackgroundCXCL4 regulates multiple facets of immune response and its level is highly increased in various Th17-associated rheumatic diseases, including systemic sclerosis (SSc)1–4. Recently, CXCL4 was shown to induce type I interferon production as well as endothelial activation in SSc patients1. Th17 skewing has been demonstrated in SSc5–6, however, whether CXCL4 plays a role in the induction of IL-17 production by human CD4 T cells is currently unclear.ObjectivesTo investigate the effect of CXCL4 on human CD4 T cell phenotype in particular IL-17 production in the absence or presence of antigen presenting cells.MethodsBlood was obtained from healthy donors and CD4 T cells, monocytes, dendritic cells, were isolated using magnetic-based sorting (n=20). In addition, CD4 T cells from SSc patients were isolated (n=10). CD4 T cells were activated using anti-CD3/CD28, or in co-cultures with antigen presenting cells, stimulated using superantigen Staphylococcal enterotoxin B. Exogenous recombinant human CXCL4 was added during (co-)culture in different concentrations. Cytokine production and proliferation were analyzed using Luminex immunoassays, intracellular cytokine staining, and flow cytometry.ResultsCXCL4 directly induced CD4 T cells secreting both IL-17 and IFN-γ, as well as IL-22, when costimulated with anti-CD3/CD28 (p<0.05). In many SSc patients, similar IL-17 increase upon CXCL4 treatment was observed, although this did not reach statistical significance. This might be due to the fact that CD4 T cells from SSc patients had already significant higher levels of IL-17 as compared to healthy donors (2182±722.2 vs 1053±263.6 pg/ml, mean±SEM, p<0.05). Furthermore, in co-culture system of CD4 T cells with monocytes or myeloid dendritic cells, CXCL4 treatment induced IL-17 production upon triggering by superantigen (p<0.05). Moreover, when monocyte-derived dendritic cells were differentiated in the presence of CXCL4, they orchestrated significantly increased levels of IL-17, IFN-γ, and proliferation by CD4 T cells (all p<0.05).ConclusionsAltogether, we demonstrate that CXCL4 boosts pro-inflammatory cytokine production especially IL-17 by human CD4 T cells, either by acting directly or indirectly via antigen presenting cells. This indicates that targeting CXCL4 may potentially alleviate immune responses in Th17-mediated rheumatic diseases such as systemic sclerosis.References van Bon L, Affandi AJ, Broen J, et al. N Engl J Med 2014.Tamagawa-Mineoka R, et al. Allergol Int 2008.Vettori S, et al. Clin Rheumatol 2016.Yeo L, et al. Ann Rheum Dis 2015.Radstake TRDJ, van Bon L, et al. PLoS One 2009.Yang X, et al. Arthritis Res Ther 2014. AcknowledgementsThis study was supported by the Dutch Arthritis Association (Reumafonds) to A.J.A. and T.R.D.J.R., the Netherlands Organization for Scientific Research (NWO) to A.J.A. (Mosaic grant 017.008.014) and T.R.D.J.R. (Pre-Seed grant), the Portuguese Fundação para a Ciência e a Tecnologia to S.C.S.C. (SFRH/BD/89643/2012) and the European Research Council to T.R.D.J.R. (ERC Starting gran...

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AB0164 Amyloidosis in progressive systemic sclerosis – a postmortem clinicopathologic study of 12 patients

Cited by 3 publications

References 0 publications

AB0163 Mesenchymal stem cells induce CD1C+ tolerogenic dendritic cells in human systemic lupus erythematosus via up-regulating FLT-3 ligand

AB0163 Mesenchymal stem cells induce CD1C+ tolerogenic dendritic cells in human systemic lupus erythematosus via up-regulating FLT-3 ligand

β-cell Related Amyloidosis Localized to the Islets of Langerhans, Type II Diabetes Mellitus and Liponecrotic Pancreatitis in Rheumatoid Arthritis: A Postmortem Clinicopathologic Statistical Study of 234 Autopsy Patients

AB0165 CXCL4 may play a key role in systemic sclerosis by driving CD4 T cells to produce IL-17

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