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Autoantibody-Positive Healthy Individuals with Lower Lupus Risk Display a Unique Immune Endotype

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Autoantibody-Positive Healthy Individuals with Lower Lupus Risk Display a Unique Immune Endotype Autoantibody-positive healthy individuals with lower lupus risk display a unique immune endotype Samantha Slight-Webb, PhD,a Miles Smith, PhD,a Aleksandra Bylinska, MS,a Susan Macwana, MS,a Carla Guthridge, PhD,a Rufei Lu, MD, PhD,a,c Joan T. Merrill, MD,a Eliza Chakravarty, MD,a Cristina Arriens, MD,a,b,c Melissa E. Munroe, MD, PhD,a Holden T. Maecker, PhD,d Paul J. Utz, MD,e Joel M. Guthridge, PhD,a,c* and Judith A. James, MD, PhDa,b,c* Oklahoma City, Okla, and Stanford, Calif GRAPHICAL ABSTRACT From athe Department of Arthritis and Clinical Immunology, Oklahoma Medical by the Oklahoma Medical Research Foundation J. Donald and Patricia Capra Fellow- Research Foundation, and bthe Department of Internal Medicine and cthe Department ship Support to R.L. and the Oklahoma Medical Research Foundation Lou C. Kerr of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City; dthe Chair in Biomedical Research to J.A.J. Institute for Immunity, Transplantation, and Infection and ethe Division of Immu- Disclosure of potential conflict of interest: Oklahoma Medical Research Foundation has nology and Rheumatology, Stanford University School of Medicine. licensed intellectual property of J.A. James and M.E. Munroe to Progentec Bio- *These authors contributed equally to this work. sciences. M.E. Munroe has subsequently obtained part-time employment with This work was supported by the National Institute of Allergy and Infectious Diseases, the Progentec Biosciences. The rest of the authors declare that they have no relevant National Institute of Arthritis and Musculoskeletal and Skin Diseases, and an Institu- conflicts of interest. tional Development Award from the National Institute of General Medical Sciences Received for publication December 19, 2019; revised April 1, 2020; accepted for publi- through the National Institutes of Health (U19AI082714, U19AI082719, cation April 15, 2020. U54GM104938, U01AI101934, P30AR073750, R01AR072401, UM1AI44292 Corresponding author: Judith A. James, MD, PhD, Arthritis and Clinical Immunology, T32AI007633 [S.S.W.], and S10RR026735) and was conceived through interactions Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK of the National Institute of Allergy and Infectious Diseases Autoimmunity Centers 73104. E-mail: [email protected]. of Excellence and National Institute of Allergy and Infectious Diseases Cooperative 0091-6749/$36.00 Ó Working Group on Autoimmune Disease Prevention programs. The contents are solely 2020 American Academy of Allergy, Asthma & Immunology the responsibility of the authors and do not necessarily represent the official views of https://doi.org/10.1016/j.jaci.2020.04.047 the National Institutes of Health or one of its institutes. This work was also supported 1 2 SLIGHT-WEBB ET AL J ALLERGY CLIN IMMUNOL nnn 2020 Background: Autoimmune diseases comprise a spectrum of illnesses and are on the rise worldwide. Although antinuclear Abbreviations used antibodies (ANAs) are detected in many autoimmune diseases, AA: African American up to 20% of healthy women are ANA-positive (ANA1) and ANA: Antinuclear antibody 2 most will never develop clinical symptoms. Furthermore, ANA : ANA-negative 1 disease transition is higher among ANA1 African Americans ANA : ANA-positive BCR: B-cell receptor compared with ANA1 European Americans. BLyS: B lymphocytes stimulator Objective: We sought to determine the immune features that CMV: Cytomegalovirus might define and prevent transition to clinical autoimmunity in CyTOF: Cytometry by time-of-flight ANA1 healthy individuals. DC: Dendritic cell Methods: We comprehensively phenotyped immune profiles of ds: Double-stranded African Americans and European Americans who are ANA- EA: European American negative (ANA2) healthy, ANA1 healthy, or have SLE using HSV: Herpes simplex virus single cell mass cytometry, next-generation RNA-sequencing, NK: Natural killer pDC: Plasmacytoid DC multiplex cytokine profiling, and phospho-signaling analyses. RNP: Ribonucleoprotein 2 1 Results: We found that, compared with both ANA and ANA SCF: Stem cell factor healthy individuals, patients with SLE of both races displayed TCR: T-cell receptor T-cell expansion and elevated expression of type I and II tSNE: t-Distributed stochastic neighboring embedding interferon pathways. We discovered a unique immune signature that suggests a suppressive immune phenotype and reduced CD11C1 autoimmunity-associated B cells in healthy ANA1 European Americans that is absent in their SLE or even healthy to ANA-positivity, including IL-5, IL-6, and IFN-g.6 Other innate ANA2 counterparts, or among African American cohorts. In cytokines, interferon-associated chemokines (such as monokine contrast, ANA1 healthy African Americans exhibited elevated induced by IFN-g/C-X-C motif ligand 9), and BLyS increase expression of T-cell activation markers and higher plasma levels ;10 months before SLE classification.6 Nevertheless, we lack a of IL-6 than did healthy ANA1 European Americans. comprehensive evaluation of immunophenotypes and immune Conclusions: We propose that this novel immune signature 1 1 function for healthy ANA individuals versus patients with identified in ANA healthy European Americans may protect SLE and for ANA1 versus ANA2 subjects. As a result, it is them from T-cell expansion, heightened activation of interferon not fully understood why only a subset of ANA1 healthy individ- pathways, and disease transition. (J Allergy Clin Immunol nnn nnn nnn uals will transition to disease. 2020; : - .) In addition to ANA-positivity and elevated soluble mediators, Key words: ANA1 healthy, SLE, Autoantibodies, immune suppres- race and ethnicity contribute to the risk for developing autoim- sion, T cells, race, cytokines mune disease. For instance, systemic autoimmune rheumatic diseases often show a later onset and milder clinical presentation Autoimmune diseases, such as SLE, are driven by both in those with European American (EA) versus African American environmental and genetic factors. Approximately 8% of the (AA) ancestry.9 Genetic, environmental, and socioeconomic fac- population has a classified autoimmune disease, often associated tors likely influence the diverse biological mechanisms that with the presence of antinuclear antibodies (ANAs).1,2 ANAs and contribute to autoimmunity. Autoantibody-dependent inter- other autoantibodies can be detected up to 10 years before auto- feron-activation pathways, BLyS serum cytokine levels, and 1 immune disease onset. Indeed, ANAs are detected in about 20% DNA methylation in naive CD4 T cells differ between AA of healthy people, particularly females, the elderly, and non- and EA patients with SLE.10-15 Although ancestral backgrounds whites;1,3 however, the presence of autoantibodies alone does display distinct genetic factors and gene signatures,15 no studies not predict the development of clinical symptoms.4-6 Whether a have examined ANA1 healthy individuals by race. This analysis subset of ANA-positive (ANA1) individuals possess protective is needed to identify potentially clinically relevant, but unknown, cellular factors and mechanisms that prevent disease transition mechanisms that regulate the transition from an ANA1 healthy is unknown. status to SLE. Significant effort has focused on understanding the mecha- Here, we used an in-depth immune screening platform to nisms that drive autoimmune disease. Compared with patients identify regulatory and inflammatory immune features that are with SLE, ANA1 healthy individuals have lower levels of stem critical for the development of clinical autoimmunity. We cell factor (SCF), B lymphocyte stimulator (BLyS), and type I examined populations that are at higher risk (AA) and lower interferons (IFN-a and IFN-b), as well as higher levels of the risk (EA) for transitioning to SLE, and compared ANA1 healthy regulatory cytokine, IL-1 receptor antagonist .7 However, we individuals with ANA2 controls and patients with SLE to recently found that immune pathways are already dysregulated discover putative regulatory mechanisms. Unexpectedly, EA in ANA1 versus ANA-negative (ANA2) healthy individuals; ANA1 healthy subjects exhibited a unique immune suppression ANA1 healthy subjects show a modest elevation of signature in T cells that was not present in EA ANA2 controls or proinflammatory cytokines in serum.7 The frequencies of patients with SLE or the AA cohorts. Our results identify the first monocytes, B cells, and TH follicular cells were also elevated in protective immune profile displayed during development of ANA1 versus ANA2 healthy individuals.7,8 In addition, we clinical autoimmune disease and thus point to potential thera- discovered that some soluble mediators are elevated in serum peutic avenues to activate a pathway that could delay or prevent approximately 3.5 years before SLE classification and even prior disease transition. J ALLERGY CLIN IMMUNOL SLIGHT-WEBB ET AL 3 VOLUME nnn, NUMBER nn METHODS CyTOF immunophenotyping Study population and autoantibody screening Assays were performed in the Human Immune Monitoring Center at All experiments were performed in accordance with the Helsinki Stanford University. Antibody clones, staining protocols, and gating strategies 22 Declaration and approved by the Institutional Review Board of the Oklahoma were previously described. Briefly, PBMCs were thawed, washed, and Medical Research Foundation. Healthy individuals were recruited through 15 resuspended in cell sorting buffer (PBS supplemented with 2% BSA, 2 health fairs, and screened initially
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