Publications by authors named "Elizabeth D Mellins"

114 Publications

Inflammatory Bowel Disease in Children With Systemic Juvenile Idiopathic Arthritis.

J Rheumatol 2020 Jun 15. Epub 2020 Jun 15.

This study was supported by the National Institutes of Health (NIH; grant T32AR050942-14; JM); Tashia and John Morgridge Endowed Postdoctoral Fellow Clinical Trainee Award, Stanford Maternal & Child Health Research Institute (JM); The Marcus Foundation Inc., Atlanta, Georgia (SP); Feldman Family Foundation Visiting Professors Program, Stanford University School of Medicine (DZ); Arthritis Foundation Great Western Region Center of Excellence for Arthritis (EDM); The Lucile Packard Foundation for Children's Health (EDM). The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry was supported by a grant from National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH under award Number RC2AR058934. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The CARRA Legacy Registry was also supported by CARRA, Friends of CARRA, the Arthritis Foundation, and the Duke Clinical Research Institute. J. Maller, MD, PhD, Department of Pediatrics, Division of Rheumatology, Stanford University School of Medicine, Stanford, California, USA; E. Fox, MD, Department of Pediatrics, Division of Rheumatology, Stanford University School of Medicine, Stanford, California, and Department of Pediatrics, Division of Rheumatology, Children's Mercy Hospital, University of Missouri-Kansas City, Kansas City, Missouri, USA; K.T. Park, MD, Department of Pediatrics, Division of Gastroenterology, Stanford University School of Medicine, Stanford, California, USA; S. Sertial Paul, DO, Department of Pediatrics, Goryeb Children's Hospital, Morristown, New Jersey, USA; K. Baszis, MD, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA; C. Borocco, MD, Paris University, Imagine Institute and Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital, AP-HP, Paris, France; S. Prahalad, MD, Department of Pediatrics and Department of Genetics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA; P. Quartier, MD, Paris University, Imagine Institute, RAISE Reference Centre and Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital, AP-HP, Paris, France; A. Reinhardt, MD, Department of Pediatrics, Boys Town National Research Hospital, Omaha, Nebraska, USA; D. Schonenberg-Meinema, MD, Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam Universitair Medische Centra, Amsterdam, the Netherlands; L. Shipman-Duensing, MD, Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA; M.T. Terreri, MD, Department of Pediatrics, Pediatric Rheumatology Unit, Universidade Federal de São Paulo, São Paulo, Brazil; J. Simard, ScD, Department of Health Research & Policy, Division of Epidemiology, and Department of Medicine, Division of Immunology & Rheumatology, Stanford University, Stanford, California, USA; I. Lavi, MA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel; E. Chalom, MD, Department of Pediatrics, Saint Barnabas Medical Center, Livingston, New Jersey, USA; J. Hsu, MD, Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA; D. Zisman, MD, Carmel Medical Center, Rheumatology Unit, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; E.D. Mellins, MD, Department of Pediatrics, Division of Human Gene Therapy, Program in Immunology, Stanford University School of Medicine, Stanford, California, USA. D. Zisman and E.D. Mellins are joint senior authors. EDM receives research grants from Novartis and Codexis, Inc. PQ receives consultancies or speaking fees (< US$10,000) for AbbVie, BMS, Chugai-Roche, Lilly, Novartis, Novimmune, and Swedish Orphan Biovitrum; and participates on a data safety monitoring board for Sanofi. SP is on the Novartis Macrophage Activation Syndrome Advisory Committee. Address correspondence to Dr. E.D. Mellins, Program in Immunology, Division of Human Gene Therapy, Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5164, USA. Email: Accepted for publication May 28, 2020.

Objective: The incidence of inflammatory bowel disease (IBD) in juvenile idiopathic arthritis ( JIA) is higher than in the general pediatric population. However, reports of IBD in the systemic JIA (sJIA) subtype are limited. We sought to characterize sJIA patients diagnosed with IBD and to identify potential contributing risk factors.

Methods: Using an internationally distributed survey, we identified 16 patients with sJIA who were subsequently diagnosed with IBD (sJIA-IBD cohort). Five hundred twenty-two sJIA patients without IBD were identified from the CARRA Legacy Registry and served as the sJIA-only cohort for comparison. Differences in demographic, clinical characteristics, and therapy were assessed using chi-square test, Fisher exact test, test, and univariate and multivariate logistic regression, as appropriate.

Results: Of the patients with sJIA-IBD, 75% had a persistent sJIA course and 25% had a history of macrophage activation syndrome. sJIA-IBD subjects were older at sJIA diagnosis, more often non-White, had a higher rate of IBD family history, and were more frequently treated with etanercept or canakinumab compared to sJIA-only subjects. Sixty-nine percent of sJIA-IBD patients successfully discontinued sJIA medications following IBD diagnosis, and sJIA symptoms resolved in 9 of 12 patients treated with tumor necrosis factor-α (TNF-α) inhibitors.

Conclusion: IBD in the setting of sJIA is a rare occurrence. The favorable response of sJIA symptoms to therapeutic TNF-α inhibition suggests that the sJIA-IBD cohort may represent a mechanistically distinct sJIA subgroup. Our study highlights the importance of maintaining a high level of suspicion for IBD when gastrointestinal involvement occurs in patients with sJIA and the likely broad benefit of TNF-α inhibition in those cases.
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http://dx.doi.org/10.3899/jrheum.200230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736056PMC
June 2020

Response to: 'Successful treatment of plasma exchange for refractory systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome and severe lung disease' by Sato .

Ann Rheum Dis 2020 Apr 21. Epub 2020 Apr 21.

Department of Pediatrics, Program in Immunology, Stanford University, Stanford, CA, USA

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http://dx.doi.org/10.1136/annrheumdis-2020-217426DOI Listing
April 2020

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells.

Gastroenterology 2020 Jul 1;159(1):214-226.e1. Epub 2020 Apr 1.

Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, California; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, California; Department of Microbiology and Immunology, Stanford University, Stanford, California. Electronic address:

Background & Aims: Intestinal microfold (M) cells are a unique subset of intestinal epithelial cells in the Peyer's patches that regulate mucosal immunity, serving as portals for sampling and uptake of luminal antigens. The inability to efficiently develop human M cells in cell culture has impeded studies of the intestinal immune system. We aimed to identify signaling pathways required for differentiation of human M cells and establish a robust culture system using human ileum enteroids.

Methods: We analyzed transcriptome data from mouse Peyer's patches to identify cell populations in close proximity to M cells. We used the human enteroid system to determine which cytokines were required to induce M-cell differentiation. We performed transcriptome, immunofluorescence, scanning electron microscope, and transcytosis experiments to validate the development of phenotypic and functional human M cells.

Results: A combination of retinoic acid and lymphotoxin induced differentiation of glycoprotein 2-positive human M cells, which lack apical microvilli structure. Upregulated expression of innate immune-related genes within M cells correlated with a lack of viral antigens after rotavirus infection. Human M cells, developed in the enteroid system, internalized and transported enteric viruses, such as rotavirus and reovirus, across the intestinal epithelium barrier in the enteroids.

Conclusions: We identified signaling pathways required for differentiation of intestinal M cells, and used this information to create a robust culture method to develop human M cells with capacity for internalization and transport of viruses. Studies of this model might increase our understanding of antigen presentation and the systemic entry of enteric pathogens in the human intestine.
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http://dx.doi.org/10.1053/j.gastro.2020.03.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569531PMC
July 2020

Psoriatic arthritis in childhood: A commentary on the controversy.

Clin Immunol 2020 05 27;214:108396. Epub 2020 Mar 27.

Department of Pediatrics, Program in Immunology, Stanford University, 269 Campus Drive, CCSR Rm 2105c, Stanford, CA 94305-5164, USA. Electronic address:

Approximately 5% of children with juvenile idiopathic arthritis (JIA) are diagnosed with the psoriatic form of the disease. In recent years, there has been substantial scholarship demonstrating both heterogeneity within the disease as well as similarities with other forms of JIA, culminating in a recent proposal for the categorization of JIA that excluded the psoriatic form altogether. The purpose of the review is to summarize the clinical, epidemiologic, and genetic features of psoriatic JIA (PsJIA), comparing it with other categories of JIA including spondyloarthritis. We conclude that there are sufficient unique clinical and genetic features within PsJIA as well as similarities with its adult counterpart that warrant including it within the JIA paradigm.
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http://dx.doi.org/10.1016/j.clim.2020.108396DOI Listing
May 2020

Response to: 'Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease: case report' by Bader-Meunier .

Ann Rheum Dis 2020 Feb 13. Epub 2020 Feb 13.

Department of Pediatrics, Program in Immunology, Stanford University, Stanford, California, USA

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http://dx.doi.org/10.1136/annrheumdis-2020-217000DOI Listing
February 2020

Author Correction: In vivo clonal expansion and phenotypes of hypocretin-specific CD4 T cells in narcolepsy patients and controls.

Nat Commun 2020 Jan 8;11(1):242. Epub 2020 Jan 8.

Department of Pediatrics-Human Gene Therapy, Stanford University School of medicine, Stanford, CA, 94305, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-13776-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949276PMC
January 2020

Diacylglycerol Kinase ζ Regulates Macrophage Responses in Juvenile Arthritis and Cytokine Storm Syndrome Mouse Models.

J Immunol 2020 01 4;204(1):137-146. Epub 2019 Dec 4.

Department of Orthopedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO 63110;

Dysregulation of monocyte and macrophage responses are often observed in children with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS), a potentially fatal complication of chronic rheumatic diseases. Both conditions are associated with activation of TLR signaling in monocyte and macrophage lineage cells, leading to overwhelming inflammatory responses. Despite the importance of TLR engagement in activating proinflammatory macrophages, relatively little is known about activation of intrinsic negative regulatory pathways to attenuate excessive inflammatory responses. In this study, we demonstrate that loss of diacylglycerol (DAG) kinase (Dgk) ζ, an enzyme which converts DAG into phosphatidic acid, limits inflammatory cytokine production in an arthritic mouse model dependent on TLR2 signaling and in a CSS mouse model dependent on TLR9 signaling. In vitro, deficiency results in reduced production of TNF-α, IL-6, and IL-1β and in limited M1 macrophage polarization. Mechanistically, deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgkζ levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of -DAG/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS.
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http://dx.doi.org/10.4049/jimmunol.1900721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920556PMC
January 2020

In vivo clonal expansion and phenotypes of hypocretin-specific CD4 T cells in narcolepsy patients and controls.

Nat Commun 2019 11 20;10(1):5247. Epub 2019 Nov 20.

Department of Pediatrics-Human Gene Therapy, Stanford University School of medicine, Stanford, CA, 94305, USA.

Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations of narcolepsy with the human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor α (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. Here, we present evidence of in vivo expansion of DQ6-HCRT tetramer/TRAJ24/CD4 T cells in DQ6 individuals with and without narcolepsy. We identify related TRAJ24 TCRαβ clonotypes encoded by identical α/β gene regions from two patients and two controls. TRAJ24-G allele clonotypes only expand in the two patients, whereas a TRAJ24-C allele clonotype expands in a control. A representative tetramer/G-allele TCR shows signaling reactivity to the epitope HCRT. Clonally expanded G-allele T cells exhibit an unconventional effector phenotype. Our analysis of in vivo expansion of HCRT-reactive TRAJ24 cells opens an avenue for further investigation of the autoimmune contribution to narcolepsy development.
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http://dx.doi.org/10.1038/s41467-019-13234-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868281PMC
November 2019

Combined Assay for Detecting Autoantibodies to Nucleic Acids and Apolipoprotein H in Patients with Systemic Lupus Erythematosus.

Methods Mol Biol 2020 ;2063:57-71

Department of Chemistry, Technical University of Denmark, Kgs Lyngby, Denmark.

The complicated clinical picture and biomolecular pattern of human autoimmune diseases (ADs) make knowledge on their etiology still fragmentary. The diagnostic approaches for ADs require improvement both for clinical and research effort to progress. Synthetic biomolecular antigens find growing applications for diagnosis and investigation of ADs. The main goal of this work is to detect interaction between synthetic antigens and autoantibodies in systemic lupus erythematosus within a combined, high-throughput assay. A panel of synthetic antigens has been prepared from DNA, RNA, locked nucleic acids and apolipoprotein H. The binding of synthetic antigens to autoantibodies has been confirmed in sera samples from those with active systemic lupus erythematosus (SLE) by indirect enzyme linked immunosorbent assay. Our study provides an efficient methodology for combined autoantibody profiling in SLE.
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http://dx.doi.org/10.1007/978-1-0716-0138-9_6DOI Listing
December 2020

Emergent high fatality lung disease in systemic juvenile arthritis.

Ann Rheum Dis 2019 12 27;78(12):1722-1731. Epub 2019 Sep 27.

Pediatrics, Stanford University, Stanford, California, USA

Objective: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).

Methods: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.

Results: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.

Conclusions: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.
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http://dx.doi.org/10.1136/annrheumdis-2019-216040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065839PMC
December 2019

Synergy between B cell receptor/antigen uptake and MHCII peptide editing relies on HLA-DO tuning.

Sci Rep 2019 09 25;9(1):13877. Epub 2019 Sep 25.

Department of Pediatrics - Human Gene Therapy, Stanford University School of medicine, Stanford, CA, 94305, USA.

B cell receptors and surface-displayed peptide/MHCII complexes constitute two key components of the B-cell machinery to sense signals and communicate with other cell types during antigen-triggered activation. However, critical pathways synergizing antigen-BCR interaction and antigenic peptide-MHCII presentation remain elusive. Here, we report the discovery of factors involved in establishing such synergy. We applied a single-cell measure coupled with super-resolution microscopy to investigate the integrated function of two lysosomal regulators for peptide loading, HLA-DM and HLA-DO. In model cell lines and human tonsillar B cells, we found that tunable DM/DO stoichiometry governs DM activity for exchange of placeholder CLIP peptides with high affinity MHCII ligands. Compared to their naïve counterparts, memory B cells with less DM concentrate a higher proportion of CLIP/MHCII in lysosomal compartments. Upon activation mediated by high affinity BCR, DO tuning is synchronized with antigen internalization and rapidly potentiates DM activity to optimize antigen presentation for T-cell recruitment.
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http://dx.doi.org/10.1038/s41598-019-50455-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761166PMC
September 2019

Citrullinated Peptide Epitope Targets Therapeutic Nanoparticles to Human Neutrophils.

Bioconjug Chem 2019 10 27;30(10):2584-2593. Epub 2019 Sep 27.

Department of Chemistry , Technical University of Denmark , Kongens Lyngby , Region Hovedstaden 2800 , Denmark.

Multiple drugs have been proposed for reducing harsh symptoms of human rheumatic diseases. However, a targeted therapy with mild to no side effects is still missing. In this study, we have prepared and tested a series of therapeutic nanoparticles for specific targeting of human neutrophils associated with rheumatoid arthritis. In doing this, a series of citrullinated peptide epitopes derived from human proteins, fibrinogen, vimentin, and histone 3, were screened with regard to specific recognition of neutrophils. The most potent epitope proved to be a mutated fragment of an alpha chain in human fibrinogen. Next, a straightforward synthetic strategy was developed for nanoparticles decorated with this citrullinated peptide epitope and an antisense oligonucleotide targeting disease associated microRNA miR-125b-5p. Our study shows that the nanoparticles specifically recognize neutrophils and knock down miR-125b-5p, with no apparent toxicity to human cells. In contrast to organic dendrimers, chitosan-hyaluronic acid formulations do not activate human innate immune response. Our data proves that the strategy we report herein is effective in developing peptide epitopes for decorating delivery vehicles bearing biological drugs, targeted to a specific cell type.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00518DOI Listing
October 2019

Human Intestinal Enteroids Model MHC-II in the Gut Epithelium.

Front Immunol 2019 20;10:1970. Epub 2019 Aug 20.

Program in Immunology, Department of Pediatrics, Stanford University, Stanford, CA, United States.

The role of intestinal epithelial cells (IECs) in mucosal tolerance and immunity remains poorly understood. We present a method for inducing MHC class II (MHC-II) in human enteroids, "mini-guts" derived from small intestinal crypt stem cells, and show that the intracellular MHC-II peptide-pathway is intact and functional in IECs. Our approach enables human enteroids to be used for novel studies into IEC MHC-II regulation and function during health and disease.
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http://dx.doi.org/10.3389/fimmu.2019.01970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710476PMC
October 2020

Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease: Characterization and Risk Factors.

Arthritis Rheumatol 2019 11 1;71(11):1943-1954. Epub 2019 Oct 1.

Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.

Objective: Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA-LD).

Methods: Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed.

Results: Eighteen patients with SJIA-LD were identified. Radiographic findings included diffuse ground-glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA-LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin-18 (IL-18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA-LD lacked genetic, serologic, or functional evidence of granulocyte-macrophage colony-stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA-LD rarely demonstrated proteinaceous material and had less lipid-laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA-LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA-LD contained elevated levels of IL-18 and the interferon-γ-induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA-LD identified up-regulated type II interferon and T cell activation networks. This signature was also present in SJIA-LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA-LD.

Conclusion: Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.
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http://dx.doi.org/10.1002/art.41073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817389PMC
November 2019

Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1β inhibition.

J Allergy Clin Immunol 2019 10 2;144(4):1122-1125.e6. Epub 2019 Jul 2.

Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, Calif. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.06.017DOI Listing
October 2019

Pulse-Chase Analysis for Studies of MHC Class II Biosynthesis, Maturation, and Peptide Loading.

Methods Mol Biol 2019 ;1988:315-341

Program in Immunology, Department of Pediatrics, Stanford University Medical School, Stanford, CA, USA.

Pulse-chase analysis is a commonly used technique for studying the synthesis, processing, and transport of proteins. Cultured cells expressing proteins of interest are allowed to take up radioactively labeled amino acids for a brief interval ("pulse"), during which all newly synthesized proteins incorporate the label. The cells are then returned to nonradioactive culture medium for various times ("chase"), during which proteins may undergo conformational changes, trafficking, or degradation. Proteins of interest are isolated (usually by immunoprecipitation) and resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and the fate of radiolabeled molecules is examined by autoradiography. This chapter describes a pulse-chase protocol suitable for studies of major histocompatibility complex (MHC) class II biosynthesis and maturation. We discuss how results are affected by the recognition by certain anti-class II antibodies of distinct class II conformations associated with particular biosynthetic states. Our protocol can be adapted to follow the fate of many other endogenously synthesized proteins, including viral or transfected gene products, in cultured cells.
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http://dx.doi.org/10.1007/978-1-4939-9450-2_23DOI Listing
January 2020

HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications.

Nat Rev Rheumatol 2019 06;15(6):364-381

Department of Pediatrics, Program in Immunology, Stanford University Medical Center, Stanford, CA, USA.

Our understanding of the mechanisms underlying HLA associations with inflammatory arthritis continues to evolve. Disease associations have been refined, and interactions of HLA genotype with other genes and environmental risk factors in determining disease risk have been identified. This Review provides basic information on the genetics and molecular function of HLA molecules, as well as general features of HLA associations with disease. Evidence is discussed regarding the various peptide-dependent and peptide-independent mechanisms by which HLA alleles might contribute to the pathogenesis of three types of inflammatory arthritis: rheumatoid arthritis, spondyloarthritis and systemic juvenile idiopathic arthritis. Also discussed are HLA allelic associations that shed light on the genetic heterogeneity of inflammatory arthritides and on the relationships between adult and paediatric forms of arthritis. Clinical implications range from improved diagnosis and outcome prediction to the possibility of using HLA associations in developing personalized strategies for the treatment and prevention of these diseases.
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http://dx.doi.org/10.1038/s41584-019-0219-5DOI Listing
June 2019

Tmem178 negatively regulates store-operated calcium entry in myeloid cells via association with STIM1.

J Autoimmun 2019 07 22;101:94-108. Epub 2019 Apr 22.

Department of Orthopaedics, Washington University School of Medicine, St. Louis, MO, 63110, USA; Shriners Hospitals for Children, St. Louis MO, USA. Electronic address:

Store-operated calcium entry (SOCE) modulates cytosolic calcium in multiple cells. Endoplasmic reticulum (ER)-localized STIM1 and plasma membrane (PM)-localized ORAI1 are two main components of SOCE. STIM1:ORAI1 association requires STIM1 oligomerization, its re-distribution to ER-PM junctions, and puncta formation. However, little is known about the negative regulation of these steps to prevent calcium overload. Here, we identified Tmem178 as a negative modulator of STIM1 puncta formation in myeloid cells. Using site-directed mutagenesis, co-immunoprecipitation assays and FRET imaging, we determined that Tmem178:STIM1 association occurs via their transmembrane motifs. Mutants that increase Tmem178:STIM1 association reduce STIM1 puncta formation, SOCE activation, impair inflammatory cytokine production in macrophages and osteoclastogenesis. Mutants that reduce Tmem178:STIM1 association reverse these effects. Furthermore, exposure to plasma from arthritic patients decreases Tmem178 expression, enhances SOCE activation and cytoplasmic calcium. In conclusion, Tmem178 modulates the rate-limiting step of STIM1 puncta formation and therefore controls SOCE in inflammatory conditions.
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http://dx.doi.org/10.1016/j.jaut.2019.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102427PMC
July 2019

Epitope Selection for HLA-DQ2 Presentation: Implications for Celiac Disease and Viral Defense.

J Immunol 2019 05 29;202(9):2558-2569. Epub 2019 Mar 29.

Division of Human Gene Therapy, Department of Pediatrics, Stanford University, Stanford, CA 94305;

We have reported that the major histocompatibility molecule HLA-DQ2 (DQA1*05:01/DQB1*02:01) (DQ2) is relatively resistant to HLA-DM (DM), a peptide exchange catalyst for MHC class II. In this study, we analyzed the role of DQ2/DM interaction in the generation of DQ2-restricted gliadin epitopes, relevant to celiac disease, or DQ2-restricted viral epitopes, relevant to host defense. We used paired human APC, differing in DM expression (DM versus DM) or differing by expression of wild-type DQ2, versus a DM-susceptible, DQ2 point mutant DQ2α+53G. The APC pairs were compared for their ability to stimulate human CD4 T cell clones. Despite higher DQ2 levels, DM APC attenuated T cell responses compared with DM APC after intracellular generation of four tested gliadin epitopes. DM APC expressing the DQ2α+53G mutant further suppressed these gliadin-mediated responses. The gliadin epitopes were found to have moderate affinity for DQ2, and even lower affinity for the DQ2 mutant, consistent with DM suppression of their presentation. In contrast, DM APC significantly promoted the presentation of DQ2-restricted epitopes derived intracellularly from inactivated HSV type 2, influenza hemagglutinin, and human papillomavirus E7 protein. When extracellular peptide epitopes were used as Ag, the DQ2 surface levels and peptide affinity were the major regulators of T cell responses. The differential effect of DM on stimulation of the two groups of T cell clones implies differences in DQ2 presentation pathways associated with nonpathogen- and pathogen-derived Ags in vivo.
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http://dx.doi.org/10.4049/jimmunol.1801454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494460PMC
May 2019

Plcγ2/Tmem178 dependent pathway in myeloid cells modulates the pathogenesis of cytokine storm syndrome.

J Autoimmun 2019 06 15;100:62-74. Epub 2019 Mar 15.

Department of Orthopaedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA; Shriners Hospitals for Children, St. Louis, MO, USA. Electronic address:

Cytokine storm syndrome (CSS) is a life-threatening condition characterized by excessive activation of T cells and uncontrolled inflammation, mostly described in patients with familial hemophagocytic lymphohistiocytosis and certain systemic auto-inflammatory diseases, such as systemic juvenile idiopathic arthritis (sJIA). Defects in T cell cytotoxicity as a mechanism for uncontrolled inflammation following viral infections fail to represent the whole spectrum of CSS. Evidence implicates dysregulated innate immune responses, especially activation of monocytes and macrophages, in patients with CSS. However, the direct contribution of monocytes/macrophages to CSS development and the signaling pathways involved in their activation have not been formally investigated. We find that depletion of monocytes/macrophages during early stages of CSS development, by clodronate-liposomes or neutralizing anti-CSF1 antibody, reduces mortality and inflammatory cytokine levels in two CSS mouse models, one dependent on T cells and the second induced by repeated TLR9 stimulation. We further demonstrate that activation of Plcγ2 in myeloid cells controls CSS development by driving macrophage pro-inflammatory responses. Intriguingly, the Plcγ2 downstream effector Tmem178, a negative modulator of calcium levels, acts in a negative feedback loop to restrain inflammatory cytokine production. Genetic deletion of Tmem178 leads to pro-inflammatory macrophage polarization in vitro and more severe CSS in vivo. Importantly, Tmem178 levels are reduced in macrophages from mice with CSS and after exposure to plasma from sJIA patients with active disease. Our data identify a novel Plcγ2/Tmem178 axis as a modulator of inflammatory cytokine production by monocytes/macrophages. We also find that loss of Tmem178 accentuates the pro-inflammatory responses in CSS.
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http://dx.doi.org/10.1016/j.jaut.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117784PMC
June 2019

US Adult Rheumatologists' Perspectives on the Transition Process for Young Adults With Rheumatic Conditions.

Arthritis Care Res (Hoboken) 2020 03;72(3):432-440

Stanford University, Stanford, California.

Objective: To assess the attitudes and common practices of adult rheumatologists in the US regarding health care transition (HCT) for young adults with rheumatic diseases.

Methods: An anonymous online survey was sent to US adult rheumatologist members of the American College of Rheumatology to collect demographic data and information on attitudes and common practices regarding the transition process.

Results: Of 4,064 contacted rheumatologists, 203 (5%) completed the survey. Almost half of respondents (45.1%) were never trained in transition practices, and 74.7% were not familiar with the American Academy of Pediatrics/American Academy of Family Physicians/American College of Physicians Consensus Statement About Transitions for Youth with Special Healthcare Needs. Only 56.2% felt comfortable caring for former pediatric patients. The vast majority of respondents (90.7%) did not have a multidisciplinary transition team, and 37% did not have a plan for transitioning pediatric patients into their practice. Most adult rheumatologists were unsatisfied with the current transition process (92.9%), due to insufficient resources, personnel (91.1%), and time in clinic (86.9%). They also were unsatisfied with referral data received concerning previous treatments (48.9%), hospitalization history (48%), disease activity index (45.1%), medical history summary (43.9%), comorbidities (36.4%), medication list (34.1%), and disease classification (32.6%). Three major barriers to HCT were lack of insurance reimbursement (33.7%), knowledge about community resources (30.8%), and lapses in care between primary provider and specialist (27.8%).

Conclusion: This survey identified substantial gaps in knowledge and resources regarding HCT for young adults with rheumatic diseases. These may be best addressed by further training, research, dedicated resources, adequate payment, and practice guidelines.
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http://dx.doi.org/10.1002/acr.23845DOI Listing
March 2020

Epithelial MHC Class II Expression and Its Role in Antigen Presentation in the Gastrointestinal and Respiratory Tracts.

Front Immunol 2018 25;9:2144. Epub 2018 Sep 25.

Program in Immunology, Department of Pediatrics, Stanford University, Stanford, CA, United States.

As the primary barrier between an organism and its environment, epithelial cells are well-positioned to regulate tolerance while preserving immunity against pathogens. Class II major histocompatibility complex molecules (MHC class II) are highly expressed on the surface of epithelial cells (ECs) in both the lung and intestine, although the functional consequences of this expression are not fully understood. Here, we summarize current information regarding the interactions that regulate the expression of EC MHC class II in health and disease. We then evaluate the potential role of EC as non-professional antigen presenting cells. Finally, we explore future areas of study and the potential contribution of epithelial surfaces to gut-lung crosstalk.
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http://dx.doi.org/10.3389/fimmu.2018.02144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167424PMC
October 2019

Interleukin-1 in monocyte activation phenotypes in systemic juvenile idiopathic arthritis: Observations from a clinical trial of rilonacept, an interleukin-1 inhibitor.

Clin Immunol 2018 09 19;194:9-18. Epub 2018 Jun 19.

Department of Pediatrics, Program in Immunology, Stanford University, Stanford, CA, USA. Electronic address:

Systemic juvenile idiopathic arthritis (sJIA) is a childhood rheumatic disease of unknown origin. Dysregulated innate immunity is implicated in disease pathology. We investigated if IL-1 inhibition affects circulating cytokines and monocyte gene expression. CD14+ monocytes from patients in the RAPPORT trial were analyzed by RT-PCR for expression of IL1B and transcription factors associated with monocyte activation. Serum IL-1ra decreased with treatment, and IL-18BP transiently increased. Serum levels of IL-1β, IL-6, IL-10 and IL-18 were unchanged. IRF5 and STAT6 were decreased, and PPARG was increased, independent of clinical response, and may represent a skew toward a PPARG-driven M2-like phenotype. IL1B expression was decreased in early clinical responders. A transient increase in STAT1, and a decrease in SOCS1 preceded the reduction in IL1B in early clinical responders. Changes in IL1B/STAT1/SOCS1 could be associated with crosstalk between IL-1 and IFN pathways in sJIA. These transcriptional changes might be useful as drug response biomarkers.
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http://dx.doi.org/10.1016/j.clim.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089654PMC
September 2018

Juvenile Psoriatic Arthritis: A Report from the GRAPPA 2017 Annual Meeting.

J Rheumatol Suppl 2018 Jun;94:11-16

From the Department of Rheumatology, Carmel Medical Center; The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology; Department of Pediatrics, Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel; Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama; Department of Pediatrics, Divisions of Human Gene Therapy and Allergy, Immunology and Rheumatology, Program in Immunology, Stanford University, Stanford, California, USA.

Juvenile psoriatic arthritis (JPsA), a subtype of juvenile idiopathic arthritis (JIA), constitutes 5% of JIA. The literature is inconsistent regarding features of JPsA, and physicians debate whether it is a distinct entity within JIA. A biphasic age of onset distribution has been noted. Early-onset disease is characterized by female predominance, small joint involvement, dactylitis, and positive antinuclear antibodies. Late-onset JPsA resembles adult-onset psoriatic arthritis (PsA), with male predominance, psoriasis, enthesitis, and axial disease. Recent studies report improved outcomes, likely due to the widespread use of traditional and biologic disease-modifying antirheumatic drugs. Conflicting HLA associations have been reported in JPsA, but notably both HLA class I and II allele associations are suggested. Similar to PsA cohorts, subjects with JPsA have a lower frequency of a protective interleukin 23R allele than controls or other JIA subtypes. Data in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) patient registry suggest the aggressive characteristics of JPsA: 24.6% of children have joint damage 4.6 years after symptom onset. Pediatric and adult PsA classification criteria define different JPsA cohorts within the registry and support a previous suggestion that the International League of Associations for Rheumatology criteria for JPsA may be overly stringent. Increased collaboration between pediatric and adult physicians and comparative research on these clinically related conditions are warranted.
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http://dx.doi.org/10.3899/jrheum.180131DOI Listing
June 2018

Detection of autoimmune antibodies in localized scleroderma by synthetic oligonucleotide antigens.

PLoS One 2018 11;13(4):e0195381. Epub 2018 Apr 11.

Department of Chemistry, Technical University of Denmark, Kongens Lyngby, Region Hovedstaden, Denmark.

In this study, we developed a series of synthetic oligonucleotides that allowed us to investigate the details on the antigen recognition by autoimmune antibodies in localized scleroderma subjects. Besides dramatically improved analytical specificity of the assay, our data suggests a potential linking for antibodies to DNA to the biological status of disease state in localized scleroderma. Moreover, introducing chemical modifications into short synthetic deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) molecules completely changed the binding titers of corresponding antibodies and their clinical relevance. The strongest observed effect was registered for the localized scleroderma skin damage index (LoSDI) on the IgG antibodies to TC dinucleotide-rich double-stranded antigen (p < 0.001). In addition to providing valuable tools for diagnosis of clinically relevant biomarkers, we believe that this work opens up new opportunities for research on antibodies to nucleic acids in localized scleroderma and other autoimmune diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195381PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895021PMC
July 2018

Autoantibody Profiling in Lupus Patients using Synthetic Nucleic Acids.

Sci Rep 2018 04 3;8(1):5554. Epub 2018 Apr 3.

Department of Chemistry, Technical University of Denmark, Kemitorvet 206, 2800, Kgs, Lyngby, Denmark.

Autoantibodies to nuclear components of cells (antinuclear antibodies, ANA), including DNA (a-DNA), are widely used in the diagnosis and subtyping of certain autoimmune diseases, including systemic lupus erythematosus (SLE). Despite clinical use over decades, precise, reproducible measurement of a-DNA titers remains difficult, likely due to the substantial sequence and length heterogeneity of DNA purified from natural sources. We designed and tested a panel of synthetic nucleic acid molecules composed of native deoxyribonucleotide units to measure a-DNA. ELISA assays using these antigens show specificity and reproducibility. Applying the ELISA tests to serological studies of pediatric and adult SLE, we identified novel clinical correlations. We also observed preferential recognition of a specific synthetic antigen by antibodies in SLE sera. We determined the probable basis for this finding using computational analyses, providing valuable structural information for future development of DNA antigens. Synthetic nucleic acid molecules offer the opportunity to standardize assays and to dissect antibody-antigen interactions.
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http://dx.doi.org/10.1038/s41598-018-23910-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883037PMC
April 2018

IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2018 08 28;70(8):1319-1330. Epub 2018 Jun 28.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.

Objective: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date.

Methods: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available.

Results: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]).

Conclusion: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.
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http://dx.doi.org/10.1002/art.40498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105455PMC
August 2018

Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis.

Arthritis Rheumatol 2018 06 21;70(6):957-962. Epub 2018 Apr 21.

Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.

Methods: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA.

Results: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10 ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset ≥70 years.

Conclusion: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.
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http://dx.doi.org/10.1002/art.40443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984672PMC
June 2018

Adiposity in Juvenile Psoriatic Arthritis.

J Rheumatol 2018 03 15;45(3):411-418. Epub 2017 Dec 15.

From the School of Medicine, Case Western Reserve University, Cleveland, Ohio; Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine and Department of Pediatrics, and divisions of Allergy, Immunology and Rheumatology, and Human Gene Therapy, and General Pediatrics, Stanford University, Palo Alto, California, USA; Department of Rheumatology and the Department of Community Medicine and Epidemiology, Carmel Medical Center; The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Objective: Adult patients with psoriatic arthritis are at increased risk for obesity and metabolic syndrome, but data regarding adiposity in children with juvenile psoriatic arthritis (JPsA) are limited. Our study assessed adiposity in children with JPsA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry.

Methods: Patients with JPsA in the CARRA registry were divided into nonoverweight and overweight groups using recommendations from the US Centers for Disease Control, and differences in demographic and clinical characteristics between groups at baseline and after 1-year followup were assessed using chi-square test, Fisher's exact test, T test, or Mann-Whitney U test, as appropriate. The prevalence of overweight status in the JPsA registry patients was compared to rheumatoid factor-positive and -negative polyarticular juvenile idiopathic arthritis (RF+polyJIA; RF-polyJIA) registry cohorts and the US pediatric population, using a chi-square goodness-of-fit test.

Results: Overweight children represented 36.3% of this JPsA cohort (n = 320). Compared to nonoverweight children, they were significantly older at symptom onset and rheumatologist's first assessment, and scored significantly worse on patient/physician outcome measures. At 1-year followup, changes in body mass index were not associated with changes in clinical features or outcome measures. The prevalence of overweight and obesity in patients with JPsA was significantly higher than in RF+polyJIA patients, RF-polyJIA patients, and the US pediatric population.

Conclusion: In this registry, almost 1 in 5 patients with JPsA were obese and more than one-third were overweight. This is significantly more than expected compared to the US pediatric population, and appropriate longterm followup of this JPsA subgroup is warranted.
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http://dx.doi.org/10.3899/jrheum.170598DOI Listing
March 2018

The MHC class II antigen presentation pathway in human monocytes differs by subset and is regulated by cytokines.

PLoS One 2017 23;12(8):e0183594. Epub 2017 Aug 23.

Department of Pediatrics, Program in Immunology, Stanford University, Stanford, California, United States of America.

Monocytes play a critical role in the innate and adaptive immune systems, performing phagocytosis, presenting antigen, and producing cytokines. They are a heterogeneous population that has been divided in humans into classical, intermediate, and non-classical subsets, but the roles of these subsets are incompletely understood. In this study, we investigated the expression patterns of MHC class II (MHCII) and associated molecules and find that the intermediate monocytes express the highest levels of the MHC molecules, HLA-DR (tested in n = 30 samples), HLA-DP (n = 30), and HLA-DQ (n = 10). HLA-DM (n = 30), which catalyzes the peptide exchange on the MHC molecules, is also expressed at the highest levels in intermediate monocytes. To measure HLA-DM function, we measured levels of MHCII-bound CLIP (class II invariant chain peptide, n = 23), which is exchanged for other peptides by HLA-DM. We calculated CLIP:MHCII ratios to normalize CLIP levels to MHCII levels, and found that intermediate monocytes have the lowest CLIP:MHCII ratio. We isolated the different monocyte subsets (in a total of 7 samples) and analyzed their responses to selected cytokines as model of monocyte activation: two M1-polarizing cytokines (IFNγ, GM-CSF), an M2-polarizing cytokine (IL-4) and IL-10. Classical monocytes exhibit the largest increases in class II pathway expression in response to stimulatory cytokines (IFNγ, GM-CSF, IL-4). All three subsets decrease HLA-DR levels after IL-10 exposure. Our findings argue that intermediate monocytes are the most efficient constitutive antigen presenting subset, that classical monocytes are recruited into an antigen presentation role during inflammatory responses and that IL-10 negatively regulates this function across all subsets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183594PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568224PMC
October 2017