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THE MICROBIOME OF NEW-ONSET RHEUMATOID ARTHRITIS (NORA) PATIENTS DRIVES TLR4-DEPENDENT TH17 RESPONSES [Meeting Abstract]

Koenders, M.; Evans-Marin, H.; Aarts, J.; Girija, P.; Rogier, R.; Koralov, S.; Manasson, J.; Van der Kraan, P.; Abdollahi-Roodsaz, S.; Scher, J.
ISI:000555905000417
ISSN: 0003-4967
CID: 4562862

Involvement of T helper 17 cells in inflammatory arthritis depends on the host intestinal microbiota

Evans-Marin, Heather; Rogier, Rebecca; Koralov, Sergei B; Manasson, Julia; Roeleveld, Debbie; van der Kraan, Peter M; Scher, Jose U; Koenders, Marije I; Abdollahi-Roodsaz, Shahla
OBJECTIVE:The intestinal microbiota has been associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine the requirement of Th17 cells, beyond the cytokine interleukin-17 (IL-17), for arthritis development. We further examined whether the involvement of Th17 cells in arthritis depends on the host microbiota. METHODS:) mice, and assessed the impact of microbiota on the Th17-dependence of CIA. RESULTS: mice showed a specific reduction of mucosal Th17 and partially reduced IL-17-producing CD8 T cells. However, total levels of IL-17A, mostly produced by γδ T cells and neutrophils, were unaffected. Arthritis was significantly reduced in Th17-deficient mice, suggesting additional IL-17A-independent roles for Th17 cells. Accordingly, antigen-stimulated T cells from Th17-deficient mice produced less IL-17A, IL-17F and GM-CSF. Importantly, Th17-dependence of arthritis was lost upon substitution of intestinal microbiota. CONCLUSION/CONCLUSIONS:These data suggest that activation of mucosal immunity precedes arthritis development, and support a microbiota-dependent role for Th17 cells in arthritis. Therefore, a microbiome-guided stratification of patients might improve the efficacy of Th17-targeted therapies.
PMID: 29975009
ISSN: 2326-5205
CID: 3186152

The involvement of Toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis

Fischer, Anita; Abdollahi-Roodsaz, Shahla; Böhm, Christina; Niederreiter, Birgit; Meyer, Brigitte; Yau, Anthony C Y; Lönnblom, Erik; Joosten, Leo A B; Koenders, Marije; Lehmann, Christian H K; Dudziak, Diana; Krönke, Gerhard; Holmdahl, Rikard; Steiner, Günter
Endogenous nucleic acids and their receptors may be involved in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). As the role of the DNA sensing Toll-like receptor (TLR) 9 in RA is unclear, we aimed to investigate its involvement in the pathogenesis of autoimmune arthritis using three different experimental models of RA. The data obtained revealed involvement of TLR9 in the T cell-dependent phase of inflammatory arthritis. In rats with pristane-induced arthritis (PIA), TLR9 inhibition before disease onset reduced arthritis significantly and almost completely abolished bone erosion. Accordingly, serum levels of IL-6, α-1-acid-glycoprotein and rheumatoid factor were reduced. Moreover, in TLR9-/- mice, streptococcal cell wall (SCW)-induced arthritis was reduced in the T cell-dependent phase, whereas T cell-independent serum-transfer arthritis was not affected. Remarkably, while TLR7 expression did not change during in vitro osteoclastogenesis, TLR9 expression was higher in precursor cells than in mature osteoclasts and partial inhibition of osteoclastogenesis was achieved only by the TLR9 antagonist. These results demonstrate a pivotal role for TLR9 in the T cell-dependent phases of inflammatory arthritis and additionally suggest some role during osteoclastogenesis. Hence, endogenous DNA seems to be crucially involved in the pathophysiology of inflammatory autoimmune arthritis.
PMCID:6111819
PMID: 29992753
ISSN: 1582-4934
CID: 3192562

Augmented Th17 Differentiation Leads to Cutaneous and Synovio-Entheseal Inflammation in a Novel Model of Psoriatic Arthritis

Yang, Lu; Fanok, Melania H; Mediero-Munoz, Aranzazu; Fogli, Laura K; Corciulo, Carmen; Abdollahi, Shahla; Cronstein, Bruce N; Scher, Jose U; Koralov, Sergei B
OBJECTIVE:CD4Cre mice, and investigate the role of Th17 cytokines in the disease pathogenesis. METHODS:CD4Cre mice onto an IL-22 knockout background or treating them with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines contribute to disease pathogenesis. RESULTS:CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP numbers and RANKL expression on stromal cells. CONCLUSION/CONCLUSIONS:CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation, and bone pathology highly reminiscent of psoriatic arthritis. Both IL-17A and IL-22 produced by Th17 cells play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes psoriatic arthritis..
PMCID:5984671
PMID: 29439292
ISSN: 2326-5205
CID: 2958282

Alteration of the intestinal microbiome characterizes preclinical inflammatory arthritis in mice and its modulation attenuates established arthritis

Rogier, Rebecca; Evans-Marin, Heather; Manasson, Julia; van der Kraan, Peter M; Walgreen, Birgitte; Helsen, Monique M; van den Bersselaar, Liduine A; van de Loo, Fons A; van Lent, Peter L; Abramson, Steven B; van den Berg, Wim B; Koenders, Marije I; Scher, Jose U; Abdollahi-Roodsaz, Shahla
Perturbations of the intestinal microbiome have been observed in patients with new-onset and chronic autoimmune inflammatory arthritis. However, it is currently unknown whether these alterations precede the development of arthritis or are rather a consequence of disease. Modulation of intestinal microbiota by oral antibiotics or germ-free condition can prevent arthritis in mice. Yet, the therapeutic potential of modulation of the microbiota after the onset of arthritis is not well characterized. We here show that the intestinal microbial community undergoes marked changes in the preclinical phase of collagen induced arthritis (CIA). The abundance of the phylum Bacteroidetes, specifically families S24-7 and Bacteroidaceae was reduced, whereas Firmicutes and Proteobacteria, such as Ruminococcaceae, Lachnospiraceae and Desulfovibrinocaceae, were expanded during the immune-priming phase of arthritis. In addition, we found that the abundance of lamina propria Th17, but not Th1, cells is highly correlated with the severity of arthritis. Elimination of the intestinal microbiota during established arthritis specifically reduced intestinal Th17 cells and attenuated arthritis. These effects were associated with reduced serum amyloid A expression in ileum and synovial tissue. Our observations suggest that intestinal microbiota perturbations precede arthritis, and that modulation of the intestinal microbiota after the onset of arthritis may offer therapeutic opportunities.
PMCID:5688157
PMID: 29142301
ISSN: 2045-2322
CID: 2784592

Alteration of the Intestinal Microbiome in the Preclinical Phase of Experimental Arthritis and the Efficacy of Microbiota Modulation in Established Arthritis in Mice [Meeting Abstract]

Rogier, Rebecca; Evans-Marin, Heather; Manasson, Julia; van der Kraan, Peter M; van den Berg, Wim B; Koenders, Marije I; Scher, Jose U; Abdollahi-Roodsaz, Shahla
ISI:000411824100401
ISSN: 2326-5205
CID: 2766922

Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis

Rogier, Rebecca; Ederveen, Thomas H A; Boekhorst, Jos; Wopereis, Harm; Scher, Jose U; Manasson, Julia; Frambach, Sanne J C M; Knol, Jan; Garssen, Johan; van der Kraan, Peter M; Koenders, Marije I; van den Berg, Wim B; van Hijum, Sacha A F T; Abdollahi-Roodsaz, Shahla
BACKGROUND: Perturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. Mice deficient in interleukin-1 receptor antagonist (Il1rn -/- mice) spontaneously develop autoimmune arthritis and are susceptible to other autoimmune diseases such as psoriasis, diabetes, and encephalomyelitis; however, the mechanisms of increased susceptibility to these autoimmune phenotypes are poorly understood. We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of commensal intestinal microbiota, and assessed the involvement of microbiota subsets and innate and adaptive mucosal immune responses that underlie the development of spontaneous arthritis in Il1rn -/- mice. RESULTS: Using high-throughput 16S rRNA gene sequencing, we show that IL-1Ra critically maintains the diversity and regulates the composition of intestinal microbiota in mice. IL-1Ra deficiency reduced the intestinal microbial diversity and richness, and caused specific taxonomic alterations characterized by overrepresented Helicobacter and underrepresented Ruminococcus and Prevotella. Notably, the aberrant intestinal microbiota in IL1rn -/- mice specifically potentiated IL-17 production by intestinal lamina propria (LP) lymphocytes and skewed the LP T cell balance in favor of T helper 17 (Th17) cells, an effect transferable to WT mice by fecal microbiota. Importantly, LP Th17 cell expansion and the development of spontaneous autoimmune arthritis in IL1rn -/- mice were attenuated under germ-free condition. Selective antibiotic treatment revealed that tobramycin-induced alterations of commensal intestinal microbiota, i.e., reduced Helicobacter, Flexispira, Clostridium, and Dehalobacterium, suppressed arthritis in IL1rn -/- mice. The arthritis phenotype in IL1rn -/- mice was previously shown to depend on Toll-like receptor 4 (TLR4). Using the ablation of both IL-1Ra and TLR4, we here show that the aberrations in the IL1rn -/- microbiota are partly TLR4-dependent. We further identify a role for TLR4 activation in the intestinal lamina propria production of IL-17 and cytokines involved in Th17 differentiation preceding the onset of arthritis. CONCLUSIONS: These findings identify a critical role for IL1Ra in maintaining the natural diversity and composition of intestinal microbiota, and suggest a role for TLR4 in mucosal Th17 cell induction associated with the development of autoimmune disease in mice.
PMCID:5481968
PMID: 28645307
ISSN: 2049-2618
CID: 2604562

INVOLVEMENT OF T HELPER 17 CELLS IN INFLAMMATORY ARTHRITIS DEPENDS ON THE HOST INTESTINAL MICROBIOTA [Meeting Abstract]

Evans-Marin, H; Rogier, R; Scher, J; Roeleveld, D; Koenders, M; Abdollahi-Roodsaz, S
ISI:000413181400518
ISSN: 1468-2060
CID: 2790242

ALTERATION OF THE INTESTINAL MICROBIOME IN THE PRECLINICAL PHASE OF EXPERIMENTAL ARTHRITIS AND THE EFFICACY OF MICROBIOTA MODULATION IN ESTABLISHED ARTHRITIS IN MICE [Meeting Abstract]

Rogier, R; Evans-Marin, H; van der Kraan, P; van den Berg, W; Koenders, M; Scher, J; Abdollahi-Roodsaz, S
ISI:000413181401472
ISSN: 1468-2060
CID: 2790202

PARTIAL ELIMINATION OF INTESTINAL MICROBIOTA DAMPENS T HELPER 17 CELL DIFFERENTIATION AND ESTABLISHED COLLAGEN-INDUCED ARTHRITIS IN MICE [Meeting Abstract]

Rogier, Rebecca; Evans-Marin, Heather; Walgreen, Birgitte; Helsen, Monique M; van den Bersselaar, Liduine A; van der Kraan, Peter M; de Loo, Fons AJvan; van Lent, Peter LEM; Scher, Jose U; van den Berg, Wim B; Koenders, Marije I; Abdollahi-Roodsaz, Shahla
ISI:000411783100106
ISSN: 1468-2060
CID: 2738472