Person: Nigrovic, Peter
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Nigrovic
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Nigrovic, Peter
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Publication Quantifying Temporomandibular Joint Synovitis in Children With Juvenile Idiopathic Arthritis(John Wiley and Sons Inc., 2016) Resnick, Cory; Vakilian, Pouya M.; Breen, Micheal; Zurakowski, David; Caruso, Paul; Henderson, Lauren; Nigrovic, Peter; Kaban, Leonard; Peacock, ZacharyObjective: Juvenile idiopathic arthritis (JIA) frequently affects the temporomandibular joints (TMJs) and is often undetected by history, examination, and plain imaging. Qualitative assessment of gadolinium‐enhanced magnetic resonance images (MRIs) is currently the standard for diagnosis of TMJ synovitis associated with JIA. The purpose of this study is to apply a quantitative analysis of synovial enhancement to MRIs of patients with and without JIA to establish a disease threshold and sensitivity and specificity for the technique. Methods: This is a retrospective case–control study of children (age ≤16 years) who had MRIs with gadolinium including the TMJs. Subjects were divided into a JIA group and a control group. From a coronal T1‐weighted image, a ratio (enhancement ratio [ER]) of the average pixel intensity within three 0.2‐mm2 regions of interest (ROIs) in the TMJ synovium to that of a 50‐mm2 ROI of the longus capitis muscle was calculated. Receiver operating characteristic curves were used to determine the sensitivity and specificity. The inter‐ and intraexaminer reliability was evaluated with Bland‐Altman plots and 2‐way mixed, absolute agreement intraclass correlation coefficients. Results: There were 187 and 142 TMJs included in the JIA and control groups, respectively. An ER threshold of 1.55 had a sensitivity and specificity for detecting synovitis of 91% and 96%, respectively. The inter‐ and intraexaminer reliability was excellent. Conclusion: Calculating a ratio of pixel intensity between the TMJ synovium and the longus capitis muscle is a reliable way to quantify synovial enhancement. An ER of 1.55 differentiates normal TMJs from those affected by inflammatory arthritis.Publication Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis(Nature Publishing Group UK, 2018) Mizoguchi, Fumitaka; Slowikowski, Kamil; Wei, Kevin; Marshall, Jennifer L.; Rao, Deepak; Chang, Sook Kyung; Nguyen, Hung; Noss, Erika H.; Turner, Jason D.; Earp, Brandon; Blazar, Philip; Wright, John; Simmons, Barry; Donlin, Laura T.; Kalliolias, George D.; Goodman, Susan M.; Bykerk, Vivian P.; Ivashkiv, Lionel B.; Lederer, James; Hacohen, Nir; Nigrovic, Peter; Filer, Andrew; Buckley, Christopher D.; Raychaudhuri, Soumya; Brenner, MichaelFibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.Publication Detection and Quantification of Microparticles from Different Cellular Lineages Using Flow Cytometry. Evaluation of the Impact of Secreted Phospholipase A2 on Microparticle Assessment(Public Library of Science, 2015) Rousseau, Matthieu; Belleannee, Clemence; Duchez, Anne-Claire; Cloutier, Nathalie; Levesque, Tania; Jacques, Frederic; Perron, Jean; Nigrovic, Peter; Dieude, Melanie; Hebert, Marie-Josee; Gelb, Michael H.; Boilard, EricMicroparticles, also called microvesicles, are submicron extracellular vesicles produced by plasma membrane budding and shedding recognized as key actors in numerous physio(patho)logical processes. Since they can be released by virtually any cell lineages and are retrieved in biological fluids, microparticles appear as potent biomarkers. However, the small dimensions of microparticles and soluble factors present in body fluids can considerably impede their quantification. Here, flow cytometry with improved methodology for microparticle resolution was used to detect microparticles of human and mouse species generated from platelets, red blood cells, endothelial cells, apoptotic thymocytes and cells from the male reproductive tract. A family of soluble proteins, the secreted phospholipases A2 (sPLA2), comprises enzymes concomitantly expressed with microparticles in biological fluids and that catalyze the hydrolysis of membrane phospholipids. As sPLA2 can hydrolyze phosphatidylserine, a phospholipid frequently used to assess microparticles, and might even clear microparticles, we further considered the impact of relevant sPLA2 enzymes, sPLA2 group IIA, V and X, on microparticle quantification. We observed that if enriched in fluids, certain sPLA2 enzymes impair the quantification of microparticles depending on the species studied, the source of microparticles and the means of detection employed (surface phosphatidylserine or protein antigen detection). This study provides analytical considerations for appropriate interpretation of microparticle cytofluorometric measurements in biological samples containing sPLA2 enzymes.Publication Revealing the diversity of extracellular vesicles using high-dimensional flow cytometry analyses(Nature Publishing Group, 2016) Marcoux, Geneviève; Duchez, Anne-Claire; Cloutier, Nathalie; Provost, Patrick; Nigrovic, Peter; Boilard, EricExtracellular vesicles (EV) are small membrane vesicles produced by cells upon activation and apoptosis. EVs are heterogeneous according to their origin, mode of release, membrane composition, organelle and biochemical content, and other factors. Whereas it is apparent that EVs are implicated in intercellular communication, they can also be used as biomarkers. Continuous improvements in pre-analytical parameters and flow cytometry permit more efficient assessment of EVs; however, methods to more objectively distinguish EVs from cells and background, and to interpret multiple single-EV parameters are lacking. We used spanning-tree progression analysis of density-normalized events (SPADE) as a computational approach for the organization of EV subpopulations released by platelets and erythrocytes. SPADE distinguished EVs, and logically organized EVs detected by high-sensitivity flow cytofluorometry based on size estimation, granularity, mitochondrial content, and phosphatidylserine and protein receptor surface expression. Plasma EVs were organized by hierarchy, permitting appreciation of their heterogeneity. Furthermore, SPADE was used to analyze EVs present in the synovial fluid of patients with inflammatory arthritis. Its algorithm efficiently revealed subtypes of arthritic patients based on EV heterogeneity patterns. Our study reveals that computational algorithms are useful for the analysis of high-dimensional single EV data, thereby facilitating comprehension of EV functions and biomarker development.Publication Pathologically Expanded Peripheral T Helper Cell Subset Drives B Cells in Rheumatoid Arthritis(Springer Science and Business Media LLC, 2017-02-02) Rao, Deepak; Gurish, Michael F.; Marshall, Jennifer L.; Slowikowski, Kamil; Fonseka, Chamith Y.; Liu, Yanyan; Donlin, Laura T.; Henderson, Lauren; Wei, Kevin; Mizoguchi, Fumitaka; Teslovich, Nikola; Weinblatt, Michael; Massarotti, Elena; Coblyn, Jonathan; Helfgott, Simon; Lee, Yvonne C.; Todd, Derrick; Bykerk, Vivian P.; Goodman, Susan M.; Pernis, Alessandra B.; Ivashkiv, Lionel B.; Karlson, Elizabeth; Nigrovic, Peter; Filer, Andrew; Buckley, Christopher D.; Lederer, James; Raychaudhuri, Soumya; Brenner, MichaelCD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation1. Here, we used mass cytometry to evaluate activated T cells in joint tissue from patients with rheumatoid arthritis (RA), a chronic immune-mediated arthritis that affects up to 1% of the population2. This approach revealed a strikingly expanded population of PD-1hi CXCR5- CD4+ T cells in RA synovium. These cells are not exhausted. Rather, multidimensional cytometry, transcriptomics, and functional assays define a population of PD-1hi CXCR5- ‘peripheral helper’ T (Tph) cells that express factors enabling B cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hi CXCR5+ T follicular helper (Tfh) cells, Tph cells induce plasma cell differentiation in vitro via IL-21 and SLAMF5-interactions3,4. However, global transcriptomics robustly separate Tph cells from Tfh cells, with altered expression of Bcl6 and Blimp-1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in Tph cells. Tph cells appear uniquely poised to promote B cell responses and antibody production within pathologically inflamed non-lymphoid tissues.Publication Inhibition of Inflammatory Arthritis Using Fullerene Nanomaterials(Public Library of Science, 2015) Dellinger, Anthony L.; Cunin, Pierre; Lee, David; Kung, Andrew L.; Brooks, D. Bradford; Zhou, Zhiguo; Nigrovic, Peter; Kepley, Christopher L.Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis.Publication The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1(Public Library of Science, 2016) Li, Gang; Cunin, Pierre; Wu, Di; Diogo, Dorothée; Yang, Yu; Okada, Yukinori; Plenge, Robert M.; Nigrovic, PeterUnderstanding the implications of genome-wide association studies (GWAS) for disease biology requires both identification of causal variants and definition of how these variants alter gene function. The non-coding triallelic dinucleotide polymorphism CCR6DNP is associated with risk for rheumatoid arthritis, and is considered likely causal because allelic variation correlates with expression of the chemokine receptor CCR6. Using transcription activator-like effector nuclease (TALEN) gene editing, we confirmed that CCR6DNP regulates CCR6. To identify the associated transcription factor, we applied a novel assay, Flanking Restriction Enhanced Pulldown (FREP), to identify specific association of poly (ADP-ribose) polymerase 1 (PARP-1) with CCR6DNP consistent with the established allelic risk hierarchy. Correspondingly, manipulation of PARP-1 expression or activity impaired CCR6 expression in several lineages. These findings show that CCR6DNP is a causal variant through which PARP-1 regulates CCR6, and introduce a highly efficient approach to interrogate non-coding genetic polymorphisms associated with human disease.Publication The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes(WILEY-VCH Verlag, 2013) Cloutier, Nathalie; Tan, Sisareuth; Boudreau, Luc H; Cramb, Catriona; Subbaiah, Roopashree; Lahey, Lauren; Albert, Alexandra; Shnayder, Ruslan; Gobezie, Reuben; Nigrovic, Peter; Farndale, Richard W; Robinson, William H; Brisson, Alain; Lee, David Marvin; Boilard, EricImmunoglobulins, antigens and complement can assemble to form immune complexes (IC). ICs can be detrimental as they propagate inflammation in autoimmune diseases. Like ICs, submicron extracellular vesicles termed microparticles (MP) are present in the synovial fluid from patients affected with autoimmune arthritis. We examined MPs in rheumatoid arthritis (RA) using high sensitivity flow cytometry and electron microscopy. We find that the MPs in RA synovial fluid are highly heterogeneous in size. The observed larger MPs were in fact MP-containing ICs (mpICs) and account for the majority of the detectable ICs. These mpICs frequently express the integrin CD41, consistent with platelet origin. Despite expression of the Fc receptor FcγRIIa by platelet-derived MPs, we find that the mpICs form independently of this receptor. Rather, mpICs display autoantigens vimentin and fibrinogen, and recognition of these targets by anti-citrullinated peptide antibodies contributes to the production of mpICs. Functionally, platelet mpICs are highly pro-inflammatory, eliciting leukotriene production by neutrophils. Taken together, our data suggest a unique role for platelet MPs as autoantigen-expressing elements capable of perpetuating formation of inflammatory ICs.Publication Interleukin-33 Primes Mast Cells for Activation by IgG Immune Complexes(Public Library of Science, 2012) Kaieda, Shinjiro; Wang, Jun-Xia; Shnayder, Ruslan; Fishgal, Nadia; Hei, Hillary; Lee, Richard; Stevens, Richard; Nigrovic, PeterMast cells (MCs) are heterogeneous cells whose phenotype is modulated by signals received from the local microenvironment. Recent studies have identified the mesenchymal-derived cytokine IL-33 as a potent direct activator of MCs, as well as regulator of their effector phenotype, and have implicated this activity in the ability of mast cells to contribute to murine experimental arthritis. We explored the hypothesis that IL-33 enables participation of synovial MCs in murine K/BxN arthritis by promoting their activation by IgG immune complexes. Compared to wild-type (WT) control mice, transgenic animals lacking the IL-33 receptor ST2 exhibited impaired MC-dependent immune complex-induced vascular permeability (flare) and attenuated K/BxN arthritis. Whereas participation of MCs in this model is mediated by the activating IgG receptor FcγRIII, we pre-incubated bone marrow-derived MCs with IL-33 and found not only direct induction of cytokine release but also a marked increase in FcγRIII-driven production of critical arthritogenic mediators including IL-1β and CXCL2. This “priming” effect was associated with mRNA accumulation rather than altered expression of Fcγ receptors, could be mimicked by co-culture of WT but not ST2−/− MCs with synovial fibroblasts, and was blocked by antibodies against IL-33. In turn, WT but not ST2−/− MCs augmented fibroblast expression of IL-33, forming a positive feedback circuit. Together, these findings confirm a novel role for IL-33 as an amplifier of IgG immune complex-mediated inflammation and identify a potential MC-fibroblast amplification loop dependent on IL-33 and ST2.Publication PhIP-Seq Characterization of Autoantibodies From Patients With Multiple Sclerosis, Type 1 Diabetes and Rheumatoid Arthritis(Elsevier BV, 2013-06) Larman, H. Benjamin; Laserson, Uri; Querol, Luis; Verhaeghen, Katrijn; Solimini, Nicole L.; Xu, George; Klarenbeek, Paul L.; Church, George; Hafler, David A.; Plenge, Robert M.; Nigrovic, Peter; De Jager, Philip; Weets, Ilse; Martens, Geert A.; O'Connor, Kevin C.; Elledge, StephenAutoimmune disease results from a loss of tolerance to self-antigens in genetically susceptible individuals. Completely understanding this process requires that targeted antigens be identified, and so a number of techniques have been developed to determine immune receptor specificities. We previously reported the construction of a phage-displayed synthetic human peptidome and a proof-of-principle analysis of antibodies from three patients with neurological autoimmunity. Here we present data from a large-scale screen of 298 independent antibody repertoires, including those from 73 healthy sera, using phage immunoprecipitation sequencing. The resulting database of peptide-antibody interactions characterizes each individual’s unique autoantibody fingerprint, and includes specificities found to occur frequently in the general population as well as those associated with disease. Screening type 1 diabetes (T1D) patients revealed a prematurely polyautoreactive phenotype compared with their matched controls. A collection of cerebrospinal fluids and sera from 63 multiple sclerosis patients uncovered novel, as well as previously reported antibody-peptide interactions. Finally, a screen of synovial fluids and sera from 64 rheumatoid arthritis patients revealed novel disease-associated antibody specificities that were independent of seropositivity status. This work demonstrates the utility of performing PhIP-Seq screens on large numbers of individuals and is another step toward defining the full complement of autoimmunoreactivities in health and disease.