Publications by authors named "Mariana J Kaplan"

179 Publications

Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients with VEXAS Syndrome.

Arthritis Rheumatol 2021 Mar 28. Epub 2021 Mar 28.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.

Objective: Somatic mutations in ubiquitin activating enzyme 1 (UBA1) cause a newly defined syndrome known as VEXAS. More than fifty percent of patients currently identified with VEXAS meet diagnostic criteria for relapsing polychondritis (RP). Clinical features that characterize VEXAS within a cohort of RP have not been defined.

Methods: Exome and targeted sequencing of the UBA1 gene was performed in a prospective observational cohort of patients with RP. Clinical and immunological characteristics of patients with RP were compared based on presence or absence of UBA1 mutations. Random forest was used to derive a clinical algorithm to identify patients with UBA1 mutations.

Results: Seven out of 92 patients with RP (7.6%) had UBA1 mutations (VEXAS-RP). Patients with VEXAS-RP were male, ≥ 45 years at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than RP (27% vs 2%, p=0.01). Elevated acute phase reactants and hematologic abnormalities (e.g. macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, MCV>100fL, and platelet count<200k/uL classified between VEXAS-RP and RP with 100% sensitivity and 96% specificity.

Conclusion: Mutations in UBA1 are causal for disease in a subset of patients with RP. These patients are defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.
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http://dx.doi.org/10.1002/art.41743DOI Listing
March 2021

Linking clotting and autoimmunity.

Authors:
Mariana J Kaplan

Science 2021 03;371(6534):1100-1101

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA.

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http://dx.doi.org/10.1126/science.abg6449DOI Listing
March 2021

Bite of the wolf: innate immune responses propagate autoimmunity in lupus.

J Clin Invest 2021 Feb;131(3)

The etiopathogenesis of systemic lupus erythematosus (SLE), a clinically heterogeneous multisystemic syndrome that derives its name from the initial characterization of facial lesions that resemble the bite of a wolf, is considered a complex, multifactorial interplay between underlying genetic susceptibility factors and the environment. Prominent pathogenic factors include the induction of aberrant cell death pathways coupled with defective cell death clearance mechanisms that promote excessive externalization of modified cellular and nuclear debris with subsequent loss of tolerance to a wide variety of autoantigens and innate and adaptive immune dysregulation. While abnormalities in adaptive immunity are well recognized and are key to the pathogenesis of SLE, recent findings have emphasized fundamental roles of the innate immune system in the initiation and propagation of autoimmunity and the development of organ damage in this disease. This Review focuses on recent discoveries regarding the role of components of the innate immune system, specifically neutrophils and interferons, in promoting various aspects of lupus pathogenesis, with potential implications for novel therapeutic strategies.
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http://dx.doi.org/10.1172/JCI144918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843222PMC
February 2021

Correspondence on 'Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine'.

Ann Rheum Dis 2021 Jan 15. Epub 2021 Jan 15.

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1136/annrheumdis-2020-219648DOI Listing
January 2021

Association between anti-interferon-alpha autoantibodies and COVID-19 in systemic lupus erythematosus.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda MD, 20892, USA.

Objectives: Anti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE). Recently, an association of these autoantibodies with severe COVID-19 was reported in the general population. We assessed whether having pre-existing anti-IFNα autoantibodies was associated with COVID-19 infection in SLE patients.

Methods: Patients with SLE who developed COVID-19 between April 1 to October 1, 2020 were studied. Biobanked pre-COVID-19 plasma from these SLE subjects and healthy controls were tested for anti-IFNα IgG autoantibodies by ELISA. The ability of plasma anti-IFNα autoantibodies to block signal transducer and activator of transcription 1 (STAT1) phosphorylation by recombinant human IFNα in vitro was assessed by flow cytometry.

Results: Ten SLE subjects with COVID-19 were identified. A 40% of these subjects had stable autoantibodies against IFNα for up to three years preceding COVID-19 diagnosis. A 50% of the subjects with these autoantibodies neutralized IFNα induced STAT1 phosphorylation. None of the other SLE samples blocked IFNα signaling.

Conclusions: We noted an increased prevalence of pre-existing anti-IFNα autoantibodies in SLE patients with COVID-19 compared to the reported prevalence in lupus patients and the general population with severe COVID-19. Autoantibodies against IFNα in SLE patients may be pathogenic and patients with them maybe at-risk of developing COVID-19.
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http://dx.doi.org/10.1101/2020.10.29.20222000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658959PMC
November 2020

Neutrophils in the Pathogenesis of Rheumatic Diseases: Fueling the Fire.

Clin Rev Allergy Immunol 2021 Feb 5;60(1):1-16. Epub 2020 Nov 5.

Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, 12N248C, Bethesda, MD, USA.

Systemic rheumatic diseases are a heterogeneous group of disorders characterized by profound immune dysregulation. Recent discoveries have led to a significant resurgence of interest in neutrophils as shapers of immune dysregulation and as triggers of organ damage in rheumatic diseases. Neutrophils contribute to the initiation, promotion, and perpetuation of immune dysregulation through a variety of mechanisms including synthesis of proinflammatory cytokines, direct tissue damage through degranulation and synthesis of reactive oxygen species, and the formation of neutrophil extracellular traps (NETs). The identification of a subset of proinflammatory neutrophils, the low-density granulocytes (LDGs), which promote Th1 responses and cause endothelial dysfunction, has further strengthened the pathogenic role of neutrophils in various rheumatic diseases. The presence of autoantibodies targeting molecules commonly expressed in neutrophils suggests that neutrophils, particularly NETs, may be a source of autoantigens. An imbalance between NET formation and degradation, which leads to increased NET levels in the circulation and tissues, could enhance the exposure of the immune system to modified autoantigens, promote vascular disease, and increase tissue damage. This review will present an overview of recent advances in our understanding of how neutrophil dysregulation modulates the innate and adaptive immune responses in systemic rheumatic diseases and their putative contributions to pathogenicity. Understanding the potential pathogenic role of neutrophil dysregulation may provide better molecular candidates for therapeutic targeting, and ultimately promote improvements in the clinical outcomes in rheumatic diseases.
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http://dx.doi.org/10.1007/s12016-020-08816-3DOI Listing
February 2021

Neutrophil-mediated carbamylation promotes articular damage in rheumatoid arthritis.

Sci Adv 2020 Oct 28;6(44). Epub 2020 Oct 28.

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antigens and the mechanisms by which anti-CarP antibodies promote bone erosion in RA remain unknown. Here, we find that neutrophil extracellular traps (NETs) externalize carbamylated proteins and that RA subjects develop autoantibodies against carbamylated NET (cNET) antigens that, in turn, correlate with levels of anti-CarP. Transgenic mice expressing the human RA shared epitope (HLADRB1* 04:01) immunized with cNETs develop antibodies to citrullinated and carbamylated proteins. Furthermore, anti-carbamylated histone antibodies correlate with radiographic bone erosion in RA subjects. Moreover, anti-carbamylated histone-immunoglobulin G immune complexes promote osteoclast differentiation and potentiate osteoclast-mediated matrix resorption. These results demonstrate that carbamylated proteins present in NETs enhance pathogenic immune responses and bone destruction, which may explain the association between anti-CarP and erosive arthritis in RA.
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http://dx.doi.org/10.1126/sciadv.abd2688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608797PMC
October 2020

Somatic Mutations in and Severe Adult-Onset Autoinflammatory Disease.

N Engl J Med 2020 12 27;383(27):2628-2638. Epub 2020 Oct 27.

From the National Human Genome Research Institute (D.B.B., A.K.O., W.P., N.B., D.L.R., D.O.C., K.M., P.H., S.R., L.X., H.O., M.N., A.J., R.S.L., N.D., J.J.C., M.C.V.M., D.N., B.D.S., W.A.G., S.M.B., I.A., D.L.K.), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (M.A.F., K.A.S., S.N., W.L.T., S.G., C.C.-R., W.G., E.R., K.V.W., G.W., S.B., S.D., Z.D., R.A.C., M.J.K., M.G., P.C.G.), the National Institute of Dental and Craniofacial Research (J.C.C., A.J.A., A.W.), the Undiagnosed Diseases Program, Common Fund, Office of the Director (N.B., D.L.R., M.C.V.M., D.N., W.A.G.), the Hematology Branch, National Heart, Lung, and Blood Institute (Z.W., B.P., E.M.G., F.G.-R., L.W.D., C.S.H., N.S.Y.), the National Institute of Allergy and Infectious Diseases (K.S.B.), the Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (C.-C.R.L.), the National Institutes of Health (NIH) Intramural Sequencing Center, National Human Genome Research Institute (J.M.), the Department of Laboratory Medicine (W.W., M.T., A.D.-F., K.R.C.), and the National Eye Institute (M.A.-A.), NIH, Bethesda, and GeneDx, Gaithersburg (K.R.) - both in Maryland; and the National Amyloidosis Centre, Royal Free Hospital London NHS Foundation Trust and University College London, London (D.R., H.J.L.), and the National Institute for Health Research-Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds (S.S.) - both in the United Kingdom.

Background: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.

Methods: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.

Results: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.

Conclusions: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
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http://dx.doi.org/10.1056/NEJMoa2026834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847551PMC
December 2020

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model.

Front Immunol 2020 24;11:554725. Epub 2020 Sep 24.

Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2'-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. mice showed increased influx of Ly6C monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of mice had significantly higher expression of type I IFN genes (, and ). In keeping with loss of resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent expression was observed in BMDMs from mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced expression in monocytes associated with skin involvement in SLE patients and the expression of was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.
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http://dx.doi.org/10.3389/fimmu.2020.554725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541920PMC
September 2020

Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus.

Ann Rheum Dis 2021 02 28;80(2):209-218. Epub 2020 Sep 28.

NIAMS, National Institutes of Health, Bethesda, Maryland, USA

Objectives: Low-density granulocytes (LDGs) are a distinct subset of proinflammatory and vasculopathic neutrophils expanded in systemic lupus erythematosus (SLE). Neutrophil trafficking and immune function are intimately linked to cellular biophysical properties. This study used proteomic, biomechanical and functional analyses to further define neutrophil heterogeneity in the context of SLE.

Methods: Proteomic/phosphoproteomic analyses were performed in healthy control (HC) normal density neutrophils (NDNs), SLE NDNs and autologous SLE LDGs. The biophysical properties of these neutrophil subsets were analysed by real-time deformability cytometry and lattice light-sheet microscopy. A two-dimensional endothelial flow system and a three-dimensional microfluidic microvasculature mimetic (MMM) were used to decouple the contributions of cell surface mediators and biophysical properties to neutrophil trafficking, respectively.

Results: Proteomic and phosphoproteomic differences were detected between HC and SLE neutrophils and between SLE NDNs and LDGs. Increased abundance of type 1 interferon-regulated proteins and differential phosphorylation of proteins associated with cytoskeletal organisation were identified in SLE LDGs relative to SLE NDNs. The cell surface of SLE LDGs was rougher than in SLE and HC NDNs, suggesting membrane perturbances. While SLE LDGs did not display increased binding to endothelial cells in the two-dimensional assay, they were increasingly retained/trapped in the narrow channels of the lung MMM.

Conclusions: Modulation of the neutrophil proteome and distinct changes in biophysical properties are observed alongside differences in neutrophil trafficking. SLE LDGs may be increasingly retained in microvasculature networks, which has important pathogenic implications in the context of lupus organ damage and small vessel vasculopathy.
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http://dx.doi.org/10.1136/annrheumdis-2020-218338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855438PMC
February 2021

Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus.

Arthritis Rheumatol 2021 03 15;73(3):459-471. Epub 2021 Feb 15.

AstraZeneca, Gaithersburg, Maryland.

Objective: Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo.

Methods: Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma.

Results: Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05).

Conclusion: These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.
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http://dx.doi.org/10.1002/art.41518DOI Listing
March 2021

Immunometabolism in the pathogenesis of systemic lupus erythematosus: an update.

Curr Opin Rheumatol 2020 11;32(6):562-571

Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Purpose Of Review: To provide an update on state-of-the-art evidence on the role of immunometabolism reprogramming in the pathogenesis of systemic lupus erythematosus (SLE).

Recent Findings: Mitochondrial dysfunction and enhanced oxidative stress, along with specific defects in other metabolic pathways, can promote dysregulation of innate and adaptive immune responses in SLE. These abnormalities appear to be driven by genetic and epigenetic factors, modulated by stochastic events. In addition to extensive descriptions of abnormalities in immunometabolism of lupus lymphocytes, recent studies support the critical role of dysregulation of metabolic pathways in innate immune cells including neutrophils, macrophages and dendritic cells, in SLE pathogenesis. Recent abnormalities described in lipid metabolism have been associated with SLE disease activity and related damage. Promising therapeutic strategies that target these metabolic abnormalities have recently been described in SLE.

Summary: Fundamental new insights regarding the role of mitochondrial dysfunction in innate immune dysregulation in SLE pathogenesis have recently emerged. Defects in specific molecular pathways pertinent to immunometabolism in SLE have been described. New insights in translational medicine and promising therapeutic targets have been proposed based on these recent findings.
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http://dx.doi.org/10.1097/BOR.0000000000000738DOI Listing
November 2020

Lupus-like autoimmunity and increased interferon response in patients with STAT3-deficient hyper-IgE syndrome.

J Allergy Clin Immunol 2021 Feb 5;147(2):746-749.e9. Epub 2020 Aug 5.

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862417PMC
February 2021

The "Infodemic" of COVID-19.

Arthritis Rheumatol 2020 11 22;72(11):1806-1808. Epub 2020 Sep 22.

Brigham and Women's Hospital and Boston Children's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1002/art.41468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435516PMC
November 2020

Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage.

Arthritis Rheumatol 2020 12 17;72(12):2118-2129. Epub 2020 Oct 17.

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

Objective: Gasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as pyroptosis. Recent reports have also implicated GSDMD in other mechanisms of cell death, including apoptosis, necroptosis, and NETosis. Given the role of dysregulated cell death in autoimmune syndromes such as systemic lupus erythematosus (SLE), this study was undertaken in a murine lupus model to investigate whether GSDMD plays a pathogenic role in systemic autoimmunity by promoting inflammatory cell death, leading to increased generation of nuclear autoantigens and autoantibodies.

Methods: An imiquimod-induced model of SLE was tested in GSDMD mice (n = 30), with wild-type (WT) mice as controls (n = 34), on a C57BL/6 background. At the time of euthanasia, the mice were examined for serum autoantibodies, immune complex deposition, organ inflammation, immune dysregulation, and type I interferon responses. A model of pristane-induced lung injury in GSDMD mice (n = 7), with WT mice as controls (n = 10), was used to confirm the pulmonary phenotype. Regulation of various mechanisms of cell death by GSDMD was investigated in the mice.

Results: Unexpectedly, GSDMD mice developed enhanced mortality, more severe renal and pulmonary inflammation, and exacerbated autoantibody production in response to imiquimod. Pulmonary involvement was also more severe in the absence of GSDMD in mice with pristane-induced lung injury. Compared to WT mice, lack of GSDMD was associated with increased levels of circulating nuclear autoantigens (P < 0.01), anti-double-stranded DNA autoantibodies (P < 0.01), tissue immune complex deposition (P < 0.05), expansion of myeloid cell subsets (P < 0.05), and enhanced B cell activation and plasma cell differentiation (P = 0.001). Moreover, in the absence of GSDMD, enhanced autoantigen generation was associated with increased local induction of cell death in vivo.

Conclusion: GSDMD negatively regulates autoantigen generation and immune dysregulation in response to tissue injury and may play previously unappreciated protective roles in systemic autoimmunity.
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http://dx.doi.org/10.1002/art.41444DOI Listing
December 2020

Immunity to commensal skin fungi promotes psoriasiform skin inflammation.

Proc Natl Acad Sci U S A 2020 07 29;117(28):16465-16474. Epub 2020 Jun 29.

Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892;

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.
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http://dx.doi.org/10.1073/pnas.2003022117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368261PMC
July 2020

Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism.

Proc Natl Acad Sci U S A 2020 07 29;117(28):16481-16491. Epub 2020 Jun 29.

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892;

Differences between female and male immunity may contribute to variations in response to infections and predisposition to autoimmunity. We previously reported that neutrophils from reproductive-age males are more immature and less activated than their female counterparts. To further characterize the mechanisms that drive differential neutrophil phenotypes, we performed RNA sequencing on circulating neutrophils from healthy adult females and males. Female neutrophils displayed significant up-regulation of type I IFN (IFN)-stimulated genes (ISGs). Single-cell RNA-sequencing analysis indicated that these differences are neutrophil specific, driven by a distinct neutrophil subset and related to maturation status. Neutrophil hyperresponsiveness to type I IFNs promoted enhanced responses to Toll-like receptor agonists. Neutrophils from young adult males had significantly increased mitochondrial metabolism compared to those from females and this was modulated by estradiol. Assessment of ISGs and neutrophil maturation genes in Klinefelter syndrome (47, XXY) males and in prepubescent children supported that differences in neutrophil phenotype between adult male and female neutrophils are hormonally driven and not explained by X chromosome gene dosage. Our results indicate that there are distinct sex differences in neutrophil biology related to responses to type I IFNs, immunometabolism, and maturation status that may have prominent functional and pathogenic implications.
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http://dx.doi.org/10.1073/pnas.2003603117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368314PMC
July 2020

Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis.

Proc Natl Acad Sci U S A 2020 06 15;117(26):15160-15171. Epub 2020 Jun 15.

Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge CB2 0QH, United Kingdom;

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.
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http://dx.doi.org/10.1073/pnas.2000943117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334513PMC
June 2020

Arthritis & Rheumatology: Evolving to Meet the Challenges of Rheumatology.

Arthritis Rheumatol 2020 08 8;72(8):1254-1255. Epub 2020 Jun 8.

Brigham and Women's Hospital and Boston Children's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1002/art.41303DOI Listing
August 2020

Neutrophil extracellular traps mediate articular cartilage damage and enhance cartilage component immunogenicity in rheumatoid arthritis.

JCI Insight 2020 07 9;5(13). Epub 2020 Jul 9.

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.

Rheumatoid arthritis (RA) is characterized by synovial joint inflammation, cartilage damage, and dysregulation of the adaptive immune system. While neutrophil extracellular traps (NETs) have been proposed to play a role in the generation of modified autoantigens and in the activation of synovial fibroblasts, it remains unknown whether NETs are directly involved in cartilage damage. Here, we report a new mechanism by which NET-derived elastase disrupts cartilage matrix and induces release of membrane-bound peptidylarginine deiminase-2 by fibroblast-like synoviocytes (FLSs). Cartilage fragments are subsequently citrullinated, internalized by FLSs, and then presented to antigen-specific CD4+ T cells. Furthermore, immune complexes containing citrullinated cartilage components can activate macrophages to release proinflammatory cytokines. HLA-DRB1*04:01 transgenic mice immunized with NETs develop autoantibodies against citrullinated cartilage proteins and display enhanced cartilage damage. Inhibition of NET-derived elastase rescues NET-mediated cartilage damage. These results show that NETs and neutrophil elastase externalized in these structures play fundamental pathogenic roles in promoting cartilage damage and synovial inflammation. Strategies targeting neutrophil elastase and NETs could have a therapeutic role in RA and in other inflammatory diseases associated with inflammatory joint damage.
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http://dx.doi.org/10.1172/jci.insight.139388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406272PMC
July 2020

Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL- mice.

Lupus Sci Med 2020 04 16;7(1). Epub 2020 Apr 16.

Vermont Center for Immunology and Infectious Diseases, Department of Medicine, University of Vermont Larner College of Medicine, Burlington, VT, USA

Objectives: Recent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants.

Methods: Lupus-prone MRL- mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function.

Results: MitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody .

Conclusions: These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.
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http://dx.doi.org/10.1136/lupus-2020-000387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199895PMC
April 2020

Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells.

Immunity 2020 03;52(3):513-527.e8

Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK; Institute for Systemic Inflammation Research, University of Lübeck, Lübeck 23562, Germany. Electronic address:

Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.
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http://dx.doi.org/10.1016/j.immuni.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111494PMC
March 2020

Using the circulating proteome to assess type I interferon activity in systemic lupus erythematosus.

Sci Rep 2020 03 10;10(1):4462. Epub 2020 Mar 10.

AstraZeneca, Gaithersburg, MD, USA.

Type I interferon (IFN) drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts in blood. Here, we examined whether measurement of circulating proteins, which enter the bloodstream from inflamed tissues, also offers insight into global IFN activity. Using a novel protocol we generated 1,132 aptamer-based protein measurements from anti-dsDNA SLE blood samples and derived an IFN protein signature (IFNPS) that approximates the IFN 21-gene signature (IFNGS). Of 82 patients with SLE, IFNPS was elevated for 89% of IFNGS-high patients (49/55) and 26% of IFNGS-low patients (7/27). IFNGS-high/IFNPS-high patients exhibited activated NK, CD4, and CD8 T cells, while IFNPS-high only patients did not. IFNPS correlated with global disease activity in lymphopenic and non-lymphopenic patients and decreased following type I IFN neutralisation with anifrolumab in the SLE phase IIb study, MUSE. In summary, we developed a protein signature that reflects IFNGS and identifies a new subset of patients with SLE who have IFN activity.
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http://dx.doi.org/10.1038/s41598-020-60563-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064569PMC
March 2020

Use of Magnetic Resonance Imaging to Identify Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis.

JAMA Netw Open 2020 02 5;3(2):e200032. Epub 2020 Feb 5.

Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.

Importance: Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for an ever-increasing number of cancers. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis. A reproducible, reliable, and accessible modality is needed to assess and distinguish early ICI-induced inflammatory arthritis and help in management. Magnetic resonance imaging (MRI) of joints may be helpful for early diagnosis, guiding therapeutic decision-making, and identifying patients at high risk for erosive disease.

Objective: To assess the role of MRI of joints in patients with ICI-induced inflammatory arthritis.

Design, Setting, And Participants: This retrospective case series included patients enrolled at the National Institutes of Health Clinical Center in Bethesda, Maryland. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. A retrospective health record review was performed to determine demographic characteristics, clinical characteristics of inflammatory arthritis and malignant tumors, and imaging findings. Inclusion criteria were patients who were enrolled on various institutional review board-approved protocols of ICIs, developed joint-related symptoms, and had MRI data for at least 1 joint. Data were analyzed from June 1, 2019, to September 1, 2019.

Exposures: Undergoing MRI of at least 1 joint.

Main Outcomes And Measures: All MRIs were reviewed for synovitis, tenosynovitis, bone marrow edema, and soft tissue conditions.

Results: A total of 8 patients (mean [SD] age, 58.8 [5.2] years; 6 women and 2 men) between the ages of 50 and 65 years who were undergoing ICI therapy for a variety of malignant tumors were included in this study. Only 1 patient was receiving combined ICI therapy. The results of 13 separate MRI examinations were reviewed. The most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs). Tenosynovitis and synovitis were frequently seen in the hands and wrists. Bone marrow edema and erosions were also found in 3 patients, suggesting early damage. In larger joints (ie, knees and ankles), joint effusions and synovial thickening were characteristic. Most patients (5 patients) were treated with corticosteroids and had good responses. In patients with high-risk features on MRI imaging (eg, bone marrow edema, erosions), disease-modifying antirheumatic drug therapy was also discussed as a treatment option.

Conclusions And Relevance: These findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137682PMC
February 2020

Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus.

Proc Natl Acad Sci U S A 2020 03 24;117(10):5409-5419. Epub 2020 Feb 24.

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;

Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.
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http://dx.doi.org/10.1073/pnas.1916897117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071891PMC
March 2020

Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA.

Idiopathic inflammatory myopathies (IIM) are characterized by muscle inflammation and weakness, myositis-specific autoantibodies (MSAs), and extramuscular organ damage. The role of neutrophil dysregulation and neutrophil extracellular traps (NETs) in IIM is unclear. We assessed whether pathogenic neutrophil subsets (low-density granulocytes [LDGs]) and NETs were elevated in IIM, associated with clinical presentation and MSAs, and their effect on skeletal myoblasts and myotubes. Circulating NETs and LDGs were quantified and correlated with clinical measures. Specific MSAs were tested for their ability to induce NETs. NETs and neutrophil gene expression were measured in IIM biopsies. Whether NETs damage skeletal myoblasts and myotubes was tested. Circulating LDGs and NETs were increased in IIM. IIM LDGs had an enhanced ability to form NETs. LDGs and NETs correlated with IIM disease activity and muscle damage. The serum MSA anti-MDA5 correlated with circulating and tissue NETs and directly enhanced NET formation. An enhanced neutrophil gene signature was present in IIM muscle and associated with muscle injury and tissue IFN gene signatures. IIM NETs decreased the viability of myotubes in a citrullinated histone-dependent manner. Dysregulated neutrophil pathways may play pathogenic roles in IIM through their ability to directly injure muscle cells and other affected tissues.
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http://dx.doi.org/10.1172/jci.insight.134189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098779PMC
February 2020

Of larks and owls.

Authors:
Mariana J Kaplan

Nat Immunol 2020 02;21(2):104-105

Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41590-019-0579-7DOI Listing
February 2020

The mechanics of myeloid cells.

Biol Cell 2020 Apr 20;112(4):103-112. Epub 2020 Jan 20.

National Heart and Lung Institute, Imperial College London.

The effects of cell size, shape and deformability on cellular function have long been a topic of interest. Recently, mechanical phenotyping technologies capable of analysing large numbers of cells in real time have become available. This has important implications for biology and medicine, especially haemato-oncology and immunology, as immune cell mechanical phenotyping, immunologic function, and malignant cell transformation are closely linked and potentially exploitable to develop new diagnostics and therapeutics. In this review, we introduce the technologies used to analyse cellular mechanical properties and review emerging findings following the advent of high throughput deformability cytometry. We largely focus on cells from the myeloid lineage, which are derived from the bone marrow and include macrophages, granulocytes and erythrocytes. We highlight advances in mechanical phenotyping of cells in suspension that are revealing novel signatures of human blood diseases and providing new insights into pathogenesis of these diseases. The contributions of mechanical phenotyping of cells in suspension to our understanding of drug mechanisms, identification of novel therapeutics and monitoring of treatment efficacy particularly in instances of haematologic diseases are reviewed, and we suggest emerging topics of study to explore as high throughput deformability cytometers become prevalent in laboratories across the globe.
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http://dx.doi.org/10.1111/boc.201900084DOI Listing
April 2020

VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease.

Science 2019 12 19;366(6472):1531-1536. Epub 2019 Dec 19.

Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USA.

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type Ι interferon (IFN) response. Mitochondrial outer membrane permeabilization, which is required for mtDNA release, has been extensively studied in apoptotic cells, but little is known about its role in live cells. We found that oxidatively stressed mitochondria release short mtDNA fragments via pores formed by the voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane. Furthermore, the positively charged residues in the N-terminal domain of VDAC1 interact with mtDNA, promoting VDAC1 oligomerization. The VDAC oligomerization inhibitor VBIT-4 decreases mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. Thus, inhibiting VDAC oligomerization is a potential therapeutic approach for diseases associated with mtDNA release.
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http://dx.doi.org/10.1126/science.aav4011DOI Listing
December 2019

NETs spread ever wider in rheumatic diseases.

Nat Rev Rheumatol 2020 Feb;16(2):73-74

Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41584-019-0352-1DOI Listing
February 2020