Publications by authors named "Iannis E Adamopoulos"

57 Publications

IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation.

J Clin Invest 2021 Jun;131(12)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Interstitial kidney inflammation is present in various nephritides in which serum interleukin 23 (IL-23) is elevated. Here we showed that murine and human renal tubular epithelial cells (TECs) expressing the IL-23 receptor (IL-23R) responded to IL-23 by inducing intracellular calcium flux, enhancing glycolysis, and upregulating calcium/calmodulin kinase IV (CaMK4), which resulted in suppression of the expression of the arginine-degrading enzyme arginase 1 (ARG1), thus increasing in situ levels of free L-arginine. Limited availability of arginine suppressed the ability of infiltrating T cells to proliferate and produce inflammatory cytokines. TECs from humans and mice with nephritis expressed increased levels of IL-23R and CaMK4 but reduced levels of ARG1. TEC-specific deletion of Il23r or Camk4 suppressed inflammation, whereas deletion of Arg1 exacerbated inflammation in different murine disease models. Finally, TEC-specific delivery of a CaMK4 inhibitor specifically curbed renal inflammation in lupus-prone mice without affecting systemic inflammation. Our data offer the first evidence to our knowledge of the immunosuppressive capacity of TECs through a mechanism that involves competitive uptake of arginine and signify the importance of modulation of an inflammatory cytokine in the function of nonlymphoid cells, which leads to the establishment of an inflammatory microenvironment. New approaches to treat kidney inflammation should consider restoring the immunosuppressive capacity of TECs.
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http://dx.doi.org/10.1172/JCI142428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203450PMC
June 2021

IL-23 Inhibition in Ankylosing Spondylitis: Where Did It Go Wrong?

Front Immunol 2020 18;11:623874. Epub 2021 Feb 18.

Department of Medicine, Division of Rheumatology and Clinical Immunology, Beth Israel Medical Deaconess Center, Boston, MA, United States.

Axial spondyloarthritis is a prevalent form of chronic arthritis which is related to psoriatic arthritis and skin psoriasis. TNF and IL-17A as well as IL-17F are key cytokines contributing to the pathobiology of this disease, as evidence by the therapeutic efficacy of inhibition of these factors. Despite the evidence that IL-23 acts as an upstream driver of Th17 cells, the T lymphocytes producing IL-17, and that IL-23 inhibition shows profound efficacy in psoriasis, blocking IL-23 failed to show any evidence of clinical efficacy in axial spondyloarthritis. In this viewpoint article, we revisit the reasons-to-believe in a role of IL-23 in the pathobiology of axial spondyloarthritis, discuss what we have learned on the pathobiology of this disease in general and on the function of the IL-23/IL-17 axis in particular, and share a handful of lessons learned that are of relevance for the translation of emerging biological insights into clinical therapeutics.
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http://dx.doi.org/10.3389/fimmu.2020.623874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935519PMC
February 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Interleukin-17 and Interleukin-23: A Narrative Review of Mechanisms of Action in Psoriasis and Associated Comorbidities.

Dermatol Ther (Heidelb) 2021 Apr 29;11(2):385-400. Epub 2021 Jan 29.

Dalhousie University, Halifax, NS, Canada.

Psoriasis is an immune-mediated inflammatory skin disease associated with numerous inflammatory comorbidities, including increased cardiovascular risk. The interleukin (IL)-23/IL-17 axis plays a central role in the immunopathogenesis of psoriasis and related comorbidities by acting to stimulate keratinocyte hyperproliferation and feed-forwarding circuits of perpetual T cell-mediated inflammation. IL-17 plays an important role in the downstream portion of the psoriatic inflammatory cascade. This review discusses the distinct mechanisms of action of IL-17 and IL-23 in the immunopathogenesis of psoriasis and related comorbidities plus the significant therapeutic benefits of selectively inhibiting these cytokines in patients with moderate to severe plaque psoriasis.
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http://dx.doi.org/10.1007/s13555-021-00483-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019008PMC
April 2021

Axial spondyloarthritis: new advances in diagnosis and management.

BMJ 2021 01 4;372:m4447. Epub 2021 Jan 4.

Rheumatology, Allergy & Clinical Immunology Division, University of California, Davis, Shriners Hospital, Sacramento, California, USA.

Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing spondylitis required advanced changes on plain radiographs of the sacroiliac joints. Classification criteria released in 2009, however, identified a subset of patients, under the age of 45, with back pain for more than three months in the absence of radiographic sacroiliitis who were classified as axSpA based on a positive magnetic resonance imaging or HLAB27 positivity and specific clinical features. This subgroup was labeled non-radiographic (nr)-axSpA. These patients, compared with those identified by the older New York criteria, contained a larger percentage of women and demonstrated less structural damage. However, their clinical manifestations and response to biologics were similar to radiographic axSpA. The discovery of the interleukin (IL) IL-23/IL-17 pathway revealed key molecules involved in the pathophysiology of axSpA. This discovery propelled the generation of antibodies directed toward IL-17A, which are highly effective and demonstrate treatment responses in axSpA that are similar to those observed with anti-TNF agents. The finding that agents that block IL-23 were not effective in axSpA came as a surprise and the potential underlying mechanisms underlying this lack of response are discussed. New agents with dual inhibition of the IL-17A and F isoforms and some oral small molecule agents that target the Jak-STAT pathway, have also shown efficacy in axSpA.
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http://dx.doi.org/10.1136/bmj.m4447DOI Listing
January 2021

A site-specific map of the human plasma glycome and its age and gender-associated alterations.

Sci Rep 2020 10 15;10(1):17505. Epub 2020 Oct 15.

Department of Dermatology, University of California Davis School of Medicine, 3301 C Street Suite 1400, Sacramento, CA, 95816, USA.

Alterations in the human glycome have been associated with cancer and autoimmunity. Thus, constructing a site-specific map of the human glycome for biomarker research and discovery has been a highly sought-after objective. However, due to analytical barriers, comprehensive site-specific glycoprofiling is difficult to perform. To develop a platform to detect easily quantifiable, site-specific, disease-associated glycan alterations for clinical applications, we have adapted the multiple reaction monitoring mass spectrometry method for use in glycan biomarker research. The adaptations allow for highly precise site-specific glycan monitoring with minimum sample prep. Using this technique, we successfully mapped out the relative abundances of the most common 159 glycopeptides in the plasma of 97 healthy volunteers. This plasma glycome map revealed 796 significant (FDR < 0.05) site-specific inter-protein and intra-protein glycan associations, of which the vast majority were previously unknown. Since age and gender are relevant covariants in biomarker research, these variables were also characterized. 13 glycopeptides were found to be associated with gender and 41 to be associated with age. Using just five age-associated glycopeptides, a highly accurate age prediction model was constructed and validated (r = 0.62 ± 0.12). The human plasma site-specific glycan map described herein has utility in applications ranging from glycan biomarker research and discovery to the development of novel glycan-altering interventions.
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http://dx.doi.org/10.1038/s41598-020-73588-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567094PMC
October 2020

Psoriatic arthritis; overcoming the challenges by creating opportunities.

Clin Immunol 2020 09 2;218:108519. Epub 2020 Jul 2.

Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Sacramento, CA 95616, USA. Electronic address:

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http://dx.doi.org/10.1016/j.clim.2020.108519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595648PMC
September 2020

Psoriatic arthritis under the influence of IFNγ.

Clin Immunol 2020 09 20;218:108513. Epub 2020 Jun 20.

Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, USA. Electronic address:

Psoriasis is a common multifactorial autoimmune disease of the skin, and in a large percentage of patients, immune responses involve nail and joint pathology, which develop psoriatic arthritis (PsA). Historically, T helper 1 (Th1)-derived-IFN-γ was abundantly detected in psoriatic skin and its correlation with development and severity of PsO, led to an early classification of psoriasis as a Th1-mediated disease. Investigations of the cellular and molecular mechanisms of PsO pathogenesis in recent years, together with impressive results of biologics against interleukin 17A (IL-17) have shifted focus on IL-17A. However, the contributions of IFN-γ in IL-17 induced pathology and its involvement in the development of PsA have been largely overshadowed. This review summarizes the current knowledge on IFN-γ and provides new insights on the contribution of IFN-γ to PsO and PsA disease pathogenesis and development.
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http://dx.doi.org/10.1016/j.clim.2020.108513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595649PMC
September 2020

Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells.

Nat Commun 2020 06 5;11(1):2859. Epub 2020 Jun 5.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Mature double negative (DN) T cells are a population of αβ T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8 T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.
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http://dx.doi.org/10.1038/s41467-020-16636-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275084PMC
June 2020

Go with the flow-hidden vascular passages in bone.

Nat Metab 2019 Feb 21;1(2):173-174. Epub 2019 Jan 21.

Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.

The circulatory system in long bones is incompletely understood. A new study published in unveils the presence of dense vascular networks in long bones that facilitate the egress of bone marrow cells and potentially the exchange of nutrients between the bone marrow and the systemic circulation.
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http://dx.doi.org/10.1038/s42255-018-0024-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831092PMC
February 2019

γδ T cells in rheumatic diseases: from fundamental mechanisms to autoimmunity.

Semin Immunopathol 2019 09 10;41(5):595-605. Epub 2019 Sep 10.

Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA.

The innate and adaptive arms of the immune system tightly regulate immune responses in order to maintain homeostasis and host defense. The interaction between those two systems is critical in the activation and suppression of immune responses which if unchecked may lead to chronic inflammation and autoimmunity. γδ T cells are non-conventional lymphocytes, which express T cell receptor (TCR) γδ chains on their surface and straddle between innate and adaptive immunity. Recent advances in of γδ T cell biology have allowed us to expand our understanding of γδ T cell in the dysregulation of immune responses and the development of autoimmune diseases. In this review, we summarize current knowledge on γδ T cells and their roles in skin and joint inflammation as commonly observed in rheumatic diseases.
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http://dx.doi.org/10.1007/s00281-019-00752-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815259PMC
September 2019

2D Visualization of the Psoriasis Transcriptome Fails to Support the Existence of Dual-Secreting IL-17A/IL-22 Th17 T Cells.

Front Immunol 2019 4;10:589. Epub 2019 Apr 4.

Department of Dermatology, University of California, Davis, Sacramento, CA, United States.

The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of and . This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of , and were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between and . These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations.
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http://dx.doi.org/10.3389/fimmu.2019.00589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458264PMC
July 2020

Compendium of synovial signatures identifies pathologic characteristics for predicting treatment response in rheumatoid arthritis patients.

Clin Immunol 2019 05 1;202:1-10. Epub 2019 Mar 1.

Department of Computer Science, University of California at Davis, California, United States; Genome Center, University of California at Davis, California, United States. Electronic address:

Rheumatoid arthritis (RA) is therapeutically challenging due to patient heterogeneity and variability. Herein we describe a novel integration of RA synovial genome-scale transcriptomic profiling of different patient cohorts that can be used to provide predictive insights on drug responses. A normalized compendium consisting of 256 RA synovial samples that cover an intersection of 11,769 genes from 11 datasets was build and compared with similar datasets derived from OA patients and healthy controls. Differentially expression genes (DEGs) that were identified in three independent methods were fed into functional network analysis, with subsequent grouping of the samples based on a non-negative matrix factorization method. RA-relevant pathway activation scores and four machine learning classification techniques supported the generation of a predictive model of patient treatment response. We identified 876 up-regulated DEGs including 24 known genetic risk factors and 8 drug targets. DEG-based subgrouping revealed 3 distinct RA patient clusters with distinct activity signatures for RA-relevant pathways. In the case of infliximab, we constructed a classifier of drug response that was highly accurate with an AUC/AUPR of 0.92/0.86. The most informative pathways in achieving this performance were the NFκB-, FcεRI- TCR-, and TNF signaling pathways. Similarly, the expression of the HMMR, PRPF4B, EVI2A, RAB27A, MALT1, SNX6, and IFIH1 genes contributed in predicting the patient outcome. Construction and analysis of normalized synovial transcriptomic compendia can provide useful insights for understanding RA-related pathway involvement and drug responses for individual patients.
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http://dx.doi.org/10.1016/j.clim.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605311PMC
May 2019

Interleukin-17A and Pathologic New Bone Formation: The Myth of Prometheus Revisited.

Arthritis Rheumatol 2019 04 18;71(4):483-485. Epub 2019 Feb 18.

University of California at Davis, Shriners Hospitals for Children Northern California, Sacramento.

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http://dx.doi.org/10.1002/art.40817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438746PMC
April 2019

Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight.

Clin Immunol 2019 09 6;206:15-22. Epub 2018 Sep 6.

Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, CA, USA; Shriners Hospitals for Children Northern California, Institute for Pediatric Regenerative Medicine, CA, USA. Electronic address:

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis of unknown etiology, and currently the cellular and molecular interactions that dictate its pathogenesis remain elusive. A role of the interleukin-23 (IL-23)/IL-23R (IL-23 receptor) interaction in the development of psoriasis and PsA is well established. As IL-23 regulates the differentiation and activation of innate and adaptive immunity, it pertains to a very complex pathophysiology involving a plethora of effectors and transducers. In this review, we will discuss recent advances on the cellular and molecular pathophysiological mechanisms that regulate the initiation and progression of PsA as well as new therapeutic approaches for IL-23/IL-23R targeted therapeutics.
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http://dx.doi.org/10.1016/j.clim.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401348PMC
September 2019

Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A.

JCI Insight 2018 07 12;3(13). Epub 2018 Jul 12.

Department of Dermatology, School of Medicine, UCD, Sacramento, California, USA.

Numerous studies of relatively few patients have linked T cell receptor (TCR) genes to psoriasis but have yielded dramatically conflicting results. To resolve these discrepancies, we have chosen to mine RNA-Seq datasets for patterns of TCR gene segment usage in psoriasis. A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A. TRGV5, a TCR-γ segment, was also associated with psoriasis but correlated instead with IL-36A, other IL-36 family members, and IL-17C (not IL-17A). In contrast, TRAJ39 was strongly associated with healthy skin. T cell diversity measurements and analysis of CDR3 sequences were also conducted, revealing no psoriasis-associated public CDR3 sequences. Finally, in comparison with the expression of TCR-αβ genes, the expression of TCR-γδ genes was relatively low but mildly elevated in psoriatic skin. These results have implications for the development of targeted therapies for psoriasis and other autoimmune diseases. Also, the techniques employed in this study have applications in other fields, such as cancer immunology and infectious disease.
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http://dx.doi.org/10.1172/jci.insight.120682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124526PMC
July 2018

γδTCR regulates production of interleukin-27 by neutrophils and attenuates inflammatory arthritis.

Sci Rep 2018 05 15;8(1):7590. Epub 2018 May 15.

Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, USA.

γδ T cells have been implicated in inflammatory diseases as an important link between the innate and adaptive immune responses, however, their role in inflammatory arthritis remain unclear. To define the contribution of γδ T cells in the pathogenesis of inflammatory arthritis, we performed gene transfer of IL-23 in B10.RIII mice to establish joint inflammation in the presence or absence of γδ T cells. We demonstrated that γδ T cell blockade has a protective effect on arthritis incidence and severity by preventing neutrophil accumulation in the blood, spleen and bone marrow as well as by reducing neutrophil infiltration into the joints. Furthermore, our data demonstrate that absence of γδ T cells was associated with an increase of IL-27 levels produced by neutrophils and dendritic cells, and systemic IL-27 expression also prevents IL-23-induced inflammatory arthritis and limits neutrophil expansion. Collectively our findings reveal an immunomodulatory effect of γδ T cells on neutrophils associated with IL-27 synthesis and secretion and indicate a novel link between IL-27 and the modulation of γδ T cells and neutrophils that can be targeted in the treatment of inflammatory arthritis.
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http://dx.doi.org/10.1038/s41598-018-25988-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954154PMC
May 2018

Targeting IL-17 in psoriatic arthritis.

Eur J Rheumatol 2017 Dec 10;4(4):272-277. Epub 2017 Nov 10.

Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, CA, USA.

Psoriatic arthritis (PsA) is a chronic and progressive inflammatory arthritis intimately associated with psoriasis, and can be an impairing disease that leads to reduced quality of life and significant morbidity. Treatment often requires TNF antagonists, yet many patients with PsA are not responsive to the standard anti-TNF therapies. The interleukin-17 (IL-17)/IL-17 receptor (IL-17R) family has recently been implicated in the pathogenesis of PsA and psoriasis. Much enthusiasm has been generated for the development of biologics that target the IL-17 signaling pathway directly or indirectly, many of which have produced striking results in the setting of psoriasis and PsA. Herein, we review the role of IL-17 and the IL-17 receptor (IL-17R) in the pathogenesis of PsA, as well as the clinical evidence for IL-17 and IL-17R targeted therapeutics.
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http://dx.doi.org/10.5152/eurjrheum.2017.17037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741341PMC
December 2017

Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.

Immunity 2018 01 26;48(1):45-58.e6. Epub 2017 Dec 26.

Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium; VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium. Electronic address:

Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.
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http://dx.doi.org/10.1016/j.immuni.2017.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773378PMC
January 2018

Ca-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis.

J Immunol 2018 01 15;200(2):749-757. Epub 2017 Dec 15.

Division of Rheumatology, Allergy, and Clinical Immunology, Department of Internal Medicine, University of California Davis, Davis, CA 95616;

In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca-dependent mechanisms causing pathological bone loss. Ca-dependent CREB/c-fos activation via Ca-calmodulin kinase IV (CaMKIV) induces transcriptional regulation of osteoclast-specific genes via NFATc1, which facilitate bone resorption. In leukocytes, Ca regulation of NFAT-dependent gene expression oftentimes involves the activity of the Ca-activated K channel KCa3.1. In this study, we evaluate KCa3.1 as a modulator of Ca-induced NFAT-dependent osteoclast differentiation in inflammatory bone loss. Microarray analysis of receptor activator of NF-κB ligand (RANKL)-activated murine bone marrow macrophage (BMM) cultures revealed unique upregulation of KCa3.1 during osteoclastogenesis. The expression of KCa3.1 in vivo was confirmed by immunofluorescence staining on multinucleated cells at the bone surface of inflamed mouse joints. Experiments on in vitro BMM cultures revealed that KCa3.1 and TRAM-34 treatment significantly reduced the expression of osteoclast-specific genes ( < 0.05) alongside decreased osteoclast formation ( < 0.0001) in inflammatory (RANKL+TNF) and noninflammatory (RANKL) conditions. In particular, live cell Ca imaging and Western blot analysis showed that TRAM-34 pretreatment decreased transient RANKL-induced Ca amplitudes in BMMs by ∼50% ( < 0.0001) and prevented phosphorylation of CaMKIV. KCa3.1 reduced RANKL+/-TNF-stimulated phosphorylation of CREB and expression of in BMMs ( < 0.01), culminating in decreased NFATc1 protein expression and transcriptional activity ( < 0.01). These data indicate that KCa3.1 regulates Ca-dependent NFATc1 expression via CaMKIV/CREB during inflammatory osteoclastogenesis in the presence of TNF, corroborating its role as a target candidate for the treatment of bone erosion in inflammatory arthritis.
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http://dx.doi.org/10.4049/jimmunol.1701170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815326PMC
January 2018

Inflammation in bone physiology and pathology.

Curr Opin Rheumatol 2018 Jan;30(1):59-64

Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis.

Purpose Of Review: Bone is constantly being remodeled throughout adult life through constant anabolic and catabolic actions that maintain tissue homeostasis. A number of hormones, cytokines growth factors, and the proximity of various cells to bone surfaces influence this process. Inflammatory changes at the bone microenvironment result in alterations leading to both excessive bone loss and bone formation. Detailed understanding of the physiological and pathological mechanisms that dictate these changes will allow us to harness inflammatory signals in bone regeneration.

Recent Findings: Recent reports have suggested that inflammatory signals are able to stimulate transcription factors that regulate osteoblast differentiation from their precursors.

Summary: In this review, we summarized current understanding of the roles of inflammation in bone resorption and bone formation, which give rise to different disorders and discuss the huge potential of harnessing these inflammatory signals to achieve bone regeneration.
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http://dx.doi.org/10.1097/BOR.0000000000000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963529PMC
January 2018

Corrigendum to "Autophagy-linked FYVE containing protein WDFY3 interacts with TRAF6 and modulates RANKL-induced osteoclastogenesis" [J. Autoimmun. 73C (2016) 73-84].

J Autoimmun 2017 11 27;84:132. Epub 2017 Jul 27.

Graduate Group in Immunology, University of California at Davis, United States; Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, United States; Department of Pathology and Laboratory Medicine, University of California at Davis, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jaut.2017.06.011DOI Listing
November 2017

Loss of WDFY3 ameliorates severity of serum transfer-induced arthritis independently of autophagy.

Cell Immunol 2017 06 22;316:61-69. Epub 2017 Apr 22.

Graduate Group in Immunology, University of California at Davis, USA; Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Northern California, USA. Electronic address:

WDFY3 is a master regulator of selective autophagy that we recently showed to interact with TRAF6 and augment RANKL-induced osteoclastogenesis in vitro and in vivo via the NF-κB pathway. Since the NF-κB pathway plays a major role in inflammation herein, we investigate the role of WDFY3 in an arthritis animal model. Our data show that WDFY3 conditional knockout mice (Wdfy3-LysM-Cre+) were protected in the K/BxN serum transfer-induced arthritis animal model. These effects were independent of alterations in starvation-induced autophagy as evidenced by Western blot analysis of the autophagy marker LC3, autophagosome formation in osteoclast precursors and lysosome formation in osteoclasts derived from WDFY3-cKO mice compared to controls. Moreover, we demonstrate by immunofluorescence and co-immunoprecipitation that WDFY3 interacts with SQSTM1 in macrophages and osteoclasts. Collectively, our data suggest that loss of WDFY3 in myeloid cells leads to reduced severity of inflammatory arthritis independently of WDFY3 function in starvation-induced autophagy.
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http://dx.doi.org/10.1016/j.cellimm.2017.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515728PMC
June 2017

Concise Review: Stem Cells in Osteoimmunology.

Stem Cells 2017 06 2;35(6):1461-1467. Epub 2017 May 2.

Institute for Pediatric Regenerative Medicine, University of California at Davis, Sacramento, California, USA.

Bone remodeling is a lifelong process in which mature bone tissue is removed from the skeleton by bone resorption and is replenished by new during ossification or bone formation. The remodeling cycle requires both the differentiation and activation of two cell types with opposing functions; the osteoclast, which orchestrates bone resorption, and the osteoblast, which orchestrates bone formation. The differentiation of these cells from their respective precursors is a process which has been overshadowed by enigma, particularly because the precise osteoclast precursor has not been identified and because the identification of skeletal stem cells, which give rise to osteoblasts, is very recent. Latest advances in the area of stem cell biology have enabled us to gain a better understanding of how these differentiation processes occur in physiological and pathological conditions. In this review we postulate that modulation of stem cells during inflammatory conditions is a necessary prerequisite of bone remodeling and therefore an essential new component to the field of osteoimmunology. In this context, we highlight the role of transcription factor nuclear factor of activated T cells cytoplasmic 1 (NFATc1), because it directly links inflammation with differentiation of osteoclasts and osteoblasts. Stem Cells 2017;35:1461-1467.
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http://dx.doi.org/10.1002/stem.2625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047890PMC
June 2017

Autophagy and autoimmunity.

Clin Immunol 2017 03 15;176:55-62. Epub 2017 Jan 15.

Graduate Group in Immunology, University of California at Davis, USA; Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, USA. Electronic address:

Autophagy is a highly conserved protein degradation pathway from yeasts to humans that is essential for removing protein aggregates and misfolded proteins in healthy cells. Recently, autophagy-related genes polymorphisms have been implicated in several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and multiple sclerosis. Numerous studies reveal autophagy and autophagy-related proteins also participate in immune regulation. Conditional deletions of autophagy-related proteins in mice have rendered protection from experimental autoimmune encephalomyelitis, and TNF-mediated joint destruction in animal models of multiple sclerosis and experimental arthritis respectively. As autophagy is strongly implicated in immune functions such as removal of intracellular bacteria, inflammatory cytokine secretion, antigen presentation, and lymphocyte development, in this review we summarized current understanding of the roles of autophagy and autophagy proteins in autoimmune diseases.
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http://dx.doi.org/10.1016/j.clim.2017.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346336PMC
March 2017

Critical Role of LTB4/BLT1 in IL-23-Induced Synovial Inflammation and Osteoclastogenesis via NF-κB.

J Immunol 2017 01 28;198(1):452-460. Epub 2016 Nov 28.

Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA 95616; and

IL-23 activates the synthesis and production of leukotriene B (LTB) in myeloid cells, which modulate inflammatory arthritis. In this study we investigated the role of LTB and its receptor LTBR1 (BLT1) in synovial inflammation and osteoclast differentiation. Specifically, we used IL-23 in vivo gene transfer to induce arthritis in mice and showed that elevated serum LTB and synovial expression of 5-lipoxygenase correlated with increased disease severity by histological evaluation and paw swelling compared with GFP gene transfer controls. To further investigate the effect of the LTB pathway in bone loss, we performed osteoclast differentiation assays by stimulating with M-CSF and receptor activator of NF-κB ligand bone marrow cells derived from BLT1 and/or BLT1 mice and used quantitative PCR for gene expression analysis in terminally differentiated osteoclasts. Deficiency in BLT1 resulted in the upregulation of osteoclast-related genes and an increase in the formation of giant, multinucleated TRAP cells capable of F-actin ring formation. Additionally, BLT1 deficiency showed an increase of phosphorylated NF-κB and phosphorylated IκB levels in osteoclasts. We also performed real-time calcium imaging to study the effect of BLT1 deficiency in receptor activator of NF-κ-B ligand-induced activation of intracellular calcium flux in vitro. Our data show that LTB and its receptor BLT1 exacerbate synovial inflammation in vivo and bone resorption in vitro, suggesting that LTB and BLT1 could be effectively targeted for the treatment of musculoskeletal diseases.
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http://dx.doi.org/10.4049/jimmunol.1601346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173389PMC
January 2017

CD4 virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.

J Autoimmun 2017 02 25;77:76-88. Epub 2016 Nov 25.

Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States. Electronic address:

It is widely accepted that central and effector memory CD4 T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. Here we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts. CD4 T cell repertoire analysis of highly purified T cell populations from naive animals revealed that the HEL-specific clones displayed effector and central "memory" cell surface phenotypes even prior to having encountered their cognate antigen. Furthermore, HEL-inexperienced CD4 T cells were found to reside within the naïve, regulatory, central memory, and effector memory T cell populations at similar frequencies and the majority of the CD4 T cells within the regulatory and memory populations were unexpanded. These findings support a new paradigm for CD4 T cell maturation in which a specific clone can undergo a differentiation process to exhibit a "memory" or regulatory phenotype without having undergone a clonal expansion event. It also demonstrates that a foreign-specific T cell is just as likely to reside within the regulatory T cell compartment as it would the naïve compartment, arguing against the specificity of the regulatory T cell compartment being skewed towards self-reactive T cell clones. Finally, we demonstrate that the same set of foreign and autoreactive CD4 T cell clones are repetitively generated throughout adulthood. The latter observation argues against T cell-depleting strategies or autologous stem cell transplantation as therapies for autoimmunity-as the immune system has the ability to regenerate pathogenic clones.
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http://dx.doi.org/10.1016/j.jaut.2016.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066671PMC
February 2017

T Cell-Independent Mechanisms Associated with Neutrophil Extracellular Trap Formation and Selective Autophagy in IL-17A-Mediated Epidermal Hyperplasia.

J Immunol 2016 12 24;197(11):4403-4412. Epub 2016 Oct 24.

Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California at Davis, Davis, CA 95616;

IL-17A has been strongly associated with epidermal hyperplasia in many cutaneous disorders. However, because IL-17A is mainly produced by αβ and γδT cells in response to IL-23, the role of T cells and IL-23 has overshadowed any IL-17A-independent actions. In this article, we report that IL-17A gene transfer induces epidermal hyperplasia in Il23rRag1- and Tcrδ-deficient mice, which can be prevented by neutrophil depletion. Moreover, adoptive transfer of CD11bGr-1 cells, after IL-17A gene transfer, was sufficient to phenocopy the disease. We further show that the IL-17A-induced pathology was prevented in transgenic mice with impaired neutrophil extracellular trap formation and/or neutrophils with conditional deletion of the master regulator of selective autophagy, Wdfy3. Our data demonstrate a novel T cell-independent mechanism that is associated with neutrophil extracellular trap formation and selective autophagy in IL-17A-mediated epidermal hyperplasia.
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http://dx.doi.org/10.4049/jimmunol.1600383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123839PMC
December 2016

Autophagy-linked FYVE containing protein WDFY3 interacts with TRAF6 and modulates RANKL-induced osteoclastogenesis.

J Autoimmun 2016 09 18;73:73-84. Epub 2016 Jun 18.

Graduate Group in Immunology, University of California at Davis, United States; Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, United States; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Northern California, United States. Electronic address:

Recently, autophagy-related proteins were shown to regulate osteoclast mediated bone resorption, a critical process in autoimmune diseases such as rheumatoid arthritis. However, the role of autophagy-linked FYVE containing protein, WDFY3, in osteoclast biology remains elusive. WDFY3 is a master regulator in selective autophagy for clearing ubiquitinated protein aggregates and has been linked with rheumatoid arthritis. Herein, we used a series of WDFY3 transgenic mice (Wdfy3(lacZ) and Wdfy3(loxP)) to investigate the function of WDFY3 in osteoclast development and function. Our data demonstrate that WDFY3 is highly expressed at the growth plate of neonatal mice and is expressed in osteoclasts in vitro cultures. Osteoclasts derived from WDFY3 conditional knockout mice (Wdfy3(loxP/loxP)-LysM-Cre(+)) demonstrated increased osteoclast differentiation as evidenced by higher number and enlarged size of TRAP(+) multinucleated cells. Western blot analysis also revealed up-regulation of TRAF6 and an increase in RANKL-induced NF-κB signaling in WDFY3-deficient bone marrow-derived macrophages compared to wild type cultures. Consistent with these observations WDFY3-deficient cells also demonstrated an increase in osteoclast-related genes Ctsk, Acp5, Mmp9 and an increase of dentine resorption in in vitro assays. Importantly, in vivo RANKL gene transfer exacerbated bone loss in WDFY3 conditional knockout mice, as evidenced by elevated serum TRAP, CTX-I and micro-CT analysis of distal femurs compared to wild type littermates. Taken together, our data highlight a novel role for WDFY3 in osteoclast development and function, which can be exploited for the treatment of musculoskeletal diseases.
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http://dx.doi.org/10.1016/j.jaut.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003737PMC
September 2016

Interactions of the Immune System with Skin and Bone Tissue in Psoriatic Arthritis: A Comprehensive Review.

Clin Rev Allergy Immunol 2016 Aug;51(1):87-99

Department of Dermatology, University of California, Davis, 3301 C St. Suite 1400, Sacramento, CA, 95816, USA.

Cutaneous psoriasis (e.g., psoriasis vulgaris (PsV)) and psoriatic arthritis (PsA) are complex heterogeneous diseases thought to have similar pathophysiology. The soluble and cellular mediators of these closely related diseases are being elucidated through genetic approaches such as genome-wide association studies (GWAS), as well as animal and molecular models. Novel therapeutics targeting these mediators (IL-12, IL-23, IL-17, IL-17 receptor, TNF) are effective in treating both the skin and joint manifestations of psoriasis, reaffirming the shared pathophysiology of PsV and PsA. However, the molecular and cellular interactions between skin and joint disease have not been well characterized. Clearly, PsV and PsA are highly variable in terms of their clinical manifestations, and this heterogeneity can partially be explained by differences in HLA-associations (HLA-Cw*0602 versus HLA-B*27, for example). In addition, there are numerous other genetic susceptibility loci (LCE3, CARD14, NOS2, NFKBIA, PSMA6, ERAP1, TRAF3IP2, IL12RB2, IL23R, IL12B, TNIP1, TNFAIP3, TYK2) and geoepidemiologic factors that contribute to the wide variability seen in psoriasis. Herein, we review the complex interplay between the genetic, cellular, ethnic, and geographic mediators of psoriasis, focusing on the shared mechanisms of PsV and PsA.
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http://dx.doi.org/10.1007/s12016-016-8529-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080719PMC
August 2016