517 results on '"Judith A James"'
Search Results
2. 1012 Deep peripheral blood immunophenotyping identifies a subgroup of lupus nephritis patients characterized by high type 1 interferon signaling, persistent activated immune cells and poor renal response to standard of care at 1 year
- Author
-
Richard Furie, Judith A James, Maria Dall’Era, Michelle A Petri, Chaim Putterman, Peter Izmirly, Jill P Buyon, Diane L Kamen, Betty Diamond, David Wofsy, Soumya Raychaudhuri, Jennifer Grossman, Fan Zhang, Jun Inamo, Nir Hacohen, Alice Horisberger, Kenneth C Kalunian, Michael B Brenner, Mariko Ishimori, David Hildeman, Robert Clancy, ANNE DAVIDSON, Matthias Kretzler, Michael Weisman, Celine C Berthier, Andrea Fava, Takanori Sasaki, Jennifer L Barnas, Jennifer H Anolik, Paul J Hoover, Deepak A Rao, Joshua Keegan, James A Lederer, Joel Guthridge, Michael Belmont, Arnon Arazi, William Apruzzese, Fernanda Payan-Schober, Jeffrey Hodgin, Thomas M Eisenhaure, Steve Woodle, Maureen A McMahon, Ekaterina Murzin, Katie Preisinger, Alec Griffith, Kaitlyn Howard, Tusharkanti Ghosh, Rebecca Beuschel, John Pulford, Brandon Hancock, and Maria Gutierrez-Arcelus
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2024
- Full Text
- View/download PDF
3. 1009 In-depth analysis of myeloid cell subsets in lupus nephritis kidneys provides insights into disease mechanisms: lessons from the accelerating medicines partnership (AMP) in RA/SLE consortium
- Author
-
Richard Furie, Joel M Guthridge, Judith A James, Maria Dall’Era, Michelle A Petri, Chaim Putterman, Jill P Buyon, Diane L Kamen, Betty Diamond, David Wofsy, Soumya Raychaudhuri, Thomas Tuschl, Jennifer Grossman, Peter M Izmirly, Qian Xiao, Nir Hacohen, Kenneth C Kalunian, Michael B Brenner, Mariko Ishimori, H Michael Belmont, Robert Clancy, ANNE DAVIDSON, Matthias Kretzler, Michael Weisman, Celine C Berthier, Andrea Fava, Jennifer L Barnas, Jennifer H Anolik, Paul J Hoover, Deepak A Rao, Arnon Arazi, William Apruzzese, Fernanda Payan-Schober, Joseph Mears, Saori Sakaue, James Lederer, Michael Peters, Tony Jones, Thomas M Eisenhaure, Siddarth Gurajala, Derek Fine, David A Hildeman, Steve Woodle, Maureen A McMahon, and Jeffery Hodgin
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2024
- Full Text
- View/download PDF
4. LO-006 Change in urinary biomarkers at three months predicts 1-year treatment response of lupus nephritis better than proteinuria
- Author
-
Richard Furie, Michelle Petri, Judith A James, Kenneth Kalunian, Maria Dall’Era, Jill Buyon, Chaim Putterman, Peter Izmirly, Betty Diamond, David Wofsy, Soumya Raychaudhuri, Daniel Goldman, Nir Hacohen, Jennifer Anolik, H Michael Belmont, Laurence Magder, Robert Clancy, ANNE DAVIDSON, Deepak Rao, Andrea Fava, Diane Kamen, Joel Guthridge, Celine Berthier, Arnon Arazi, Jose Monroy-Trujillo, Mohamed G Atta, William Apruzzese, Jennifer Barnas, Paul Hoover, Jeffrey Hodgin, Derek Fine, Alessandra Ida Celia, Avi Rosenberg, and Dawit Demeke
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2023
- Full Text
- View/download PDF
5. Genetic load in incomplete lupus erythematosus
- Author
-
Joseph M Kheir, Joel M Guthridge, Judith A James, Teresa Aberle, Catriona A Wagner, Miles Smith, Susan Macwana, Wade DeJager, Matt Slief, and Colin Mowery
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Abstract
Objective Patients with incomplete lupus erythematosus (ILE) have lupus features but insufficient criteria for SLE classification. Some patients with ILE transition to SLE, but most avoid major organ involvement. This study tested whether the milder disease course in ILE is influenced by reduced SLE risk allele genetic load.Methods We calculated the genetic load based on 99 SLE-associated risk alleles in European American patients with SLE (≥4 American College of Rheumatology (ACR) 1997 criteria, n=170), patients with ILE (3 ACR 1997 criteria, n=169), a subset of patients with ILE not meeting Systemic Lupus International Collaborating Clinics (SLICC) classification (ILESLICC, n=119) and healthy controls (n=133). Unweighted genetic loads were calculated as the total sum of risk alleles for each individual, while weighted genetic loads were defined as the sum of risk alleles multiplied by the natural logarithm of the previously published OR of each risk allele for SLE susceptibility.Results The median unweighted and weighted SLE risk allele genetic load was significantly greater in patients with ILE (unweighted: 81, p value=0.01; weighted: 16.3, p value=0.001) and patients with SLE (80, p value=0.02; 16.29, p value=0.0006) compared with healthy controls (78, 15.76). Patients with ILESLICC trended towards an increased genetic load, although not statistically significant (unweighted: 80, p value=0.14; weighted: 16.05, p value=0.07). However, the median genetic load did not significantly differ between ILE and SLE, and genetic load did not differentiate patients with ILE and SLE (area under the curve=0.51, p=0.78) by receiver operator characteristic analysis.Conclusions Patients with ILE and SLE have comparable genetic loads of SLE risk loci, suggesting similar genetic predispositions between these conditions. Phenotypical differences between SLE and ILE may instead be influenced by ILE-specific variants and gene–environment interactions.
- Published
- 2023
- Full Text
- View/download PDF
6. Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.
- Author
-
Leora I Horwitz, Tanayott Thaweethai, Shari B Brosnahan, Mine S Cicek, Megan L Fitzgerald, Jason D Goldman, Rachel Hess, S L Hodder, Vanessa L Jacoby, Michael R Jordan, Jerry A Krishnan, Adeyinka O Laiyemo, Torri D Metz, Lauren Nichols, Rachel E Patzer, Anisha Sekar, Nora G Singer, Lauren E Stiles, Barbara S Taylor, Shifa Ahmed, Heather A Algren, Khamal Anglin, Lisa Aponte-Soto, Hassan Ashktorab, Ingrid V Bassett, Brahmchetna Bedi, Nahid Bhadelia, Christian Bime, Marie-Abele C Bind, Lora J Black, Andra L Blomkalns, Hassan Brim, Mario Castro, James Chan, Alexander W Charney, Benjamin K Chen, Li Qing Chen, Peter Chen, David Chestek, Lori B Chibnik, Dominic C Chow, Helen Y Chu, Rebecca G Clifton, Shelby Collins, Maged M Costantine, Sushma K Cribbs, Steven G Deeks, John D Dickinson, Sarah E Donohue, Matthew S Durstenfeld, Ivette F Emery, Kristine M Erlandson, Julio C Facelli, Rachael Farah-Abraham, Aloke V Finn, Melinda S Fischer, Valerie J Flaherman, Judes Fleurimont, Vivian Fonseca, Emily J Gallagher, Jennifer C Gander, Maria Laura Gennaro, Kelly S Gibson, Minjoung Go, Steven N Goodman, Joey P Granger, Frank L Greenway, John W Hafner, Jenny E Han, Michelle S Harkins, Kristine S P Hauser, James R Heath, Carla R Hernandez, On Ho, Matthew K Hoffman, Susan E Hoover, Carol R Horowitz, Harvey Hsu, Priscilla Y Hsue, Brenna L Hughes, Prasanna Jagannathan, Judith A James, Janice John, Sarah Jolley, S E Judd, Joy J Juskowich, Diane G Kanjilal, Elizabeth W Karlson, Stuart D Katz, J Daniel Kelly, Sara W Kelly, Arthur Y Kim, John P Kirwan, Kenneth S Knox, Andre Kumar, Michelle F Lamendola-Essel, Margaret Lanca, Joyce K Lee-Lannotti, R Craig Lefebvre, Bruce D Levy, Janet Y Lin, Brian P Logarbo, Jennifer K Logue, Michele T Longo, Carlos A Luciano, Karen Lutrick, Shahdi K Malakooti, Gail Mallett, Gabrielle Maranga, Jai G Marathe, Vincent C Marconi, Gailen D Marshall, Christopher F Martin, Jeffrey N Martin, Heidi T May, Grace A McComsey, Dylan McDonald, Hector Mendez-Figueroa, Lucio Miele, Murray A Mittleman, Sindhu Mohandas, Christian Mouchati, Janet M Mullington, Girish N Nadkarni, Erica R Nahin, Robert B Neuman, Lisa T Newman, Amber Nguyen, Janko Z Nikolich, Igho Ofotokun, Princess U Ogbogu, Anna Palatnik, Kristy T S Palomares, Tanyalak Parimon, Samuel Parry, Sairam Parthasarathy, Thomas F Patterson, Ann Pearman, Michael J Peluso, Priscilla Pemu, Christian M Pettker, Beth A Plunkett, Kristen Pogreba-Brown, Athena Poppas, J Zachary Porterfield, John G Quigley, Davin K Quinn, Hengameh Raissy, Candida J Rebello, Uma M Reddy, Rebecca Reece, Harrison T Reeder, Franz P Rischard, Johana M Rosas, Clifford J Rosen, Nadine G Rouphael, Dwight J Rouse, Adam M Ruff, Christina Saint Jean, Grecio J Sandoval, Jorge L Santana, Shannon M Schlater, Frank C Sciurba, Caitlin Selvaggi, Sudha Seshadri, Howard D Sesso, Dimpy P Shah, Eyal Shemesh, Zaki A Sherif, Daniel J Shinnick, Hyagriv N Simhan, Upinder Singh, Amber Sowles, Vignesh Subbian, Jun Sun, Mehul S Suthar, Larissa J Teunis, John M Thorp, Amberly Ticotsky, Alan T N Tita, Robin Tragus, Katherine R Tuttle, Alfredo E Urdaneta, P J Utz, Timothy M VanWagoner, Andrew Vasey, Suzanne D Vernon, Crystal Vidal, Tiffany Walker, Honorine D Ward, David E Warren, Ryan M Weeks, Steven J Weiner, Jordan C Weyer, Jennifer L Wheeler, Sidney W Whiteheart, Zanthia Wiley, Natasha J Williams, Juan P Wisnivesky, John C Wood, Lynn M Yee, Natalie M Young, Sokratis N Zisis, and Andrea S Foulkes
- Subjects
Medicine ,Science - Abstract
ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.
- Published
- 2023
- Full Text
- View/download PDF
7. 902 Loss-of-function variants in SAT1 cause X-linked Childhood-onset Systemic Lupus Erythematosus
- Author
-
Jim C Oates, Qing Sun, Joel M Guthridge, Judith A James, Lei Wang, Diane L Kamen, Fang Wang, Miaojia Zhang, Gary S Gilkeson, Deborah K McCurdy, Lingxiao Xu, Wenfeng Tan, Jian Zhao, Ting Liu, Bevra H Hahn, Betty P Tsao, R Hal Scofield, Yun Deng, Prithvi Raj, Edward K Wakeland, Linyu Geng, Xue Xu, Yunjuan Wu, Jingfeng Zhu, and Alexander Awgulewitsch
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2022
- Full Text
- View/download PDF
8. 1107 Immune cell heterogeneity in lupus nephritis kidneys and its relation to histopathological features: lessons from the accelerating medicines partnership (AMP) in SLE Consortium
- Author
-
Richard Furie, Joel M Guthridge, Judith A James, Maria Dall’Era, Michelle A Petri, Chaim Putterman, Jill P Buyon, Diane L Kamen, Betty Diamond, David Wofsy, Soumya Raychaudhuri, Thomas Tuschl, Jennifer Grossman, Peter M Izmirly, Qian Xiao, Nir Hacohen, Kenneth C Kalunian, Michael B Brenner, Mariko Ishimori, H Michael Belmont, Robert Clancy, ANNE DAVIDSON, Matthias Kretzler, Michael Weisman, Celine C Berthier, Andrea Fava, Jennifer L Barnas, Jennifer H Anolik, Paul J Hoover, Deepak A Rao, Arnon Arazi, William Apruzzese, Fernanda Payan-Schober, Saori Sakaue, James Lederer, Michael Peters, Tony Jones, Jospeh Mears, Thomas M Eisenhaure, Siddarth Gurajala, Derek Fine, David A Hildeman, Steve Woodle, Maureen A McMahon, and Jeffery Hodgin
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2022
- Full Text
- View/download PDF
9. 1112 Change in urinary biomarkers at three months predicts 1-year treatment response of lupus nephritisbetter than proteinuria
- Author
-
Judith A James, Maria Dall’Era, Jill Buyon, Peter Izmirly, Betty Diamond, Soumya Raychaudhuri, Nir Hacohen, Daniel W Goldman, H Michael Belmont, Laurence Magder, ANNE DAVIDSON, Deepak Rao, Andrea Fava, Arnon Arazi, Mohamed G Atta, William Apruzzese, Derek Fine, Joel Guthdridge, and Jose Monroy Trujillo
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2022
- Full Text
- View/download PDF
10. 1702 Patients enrolled in the accelerating medicines partnership (AMP) RA/SLE network with isolated renal disease report minimal quality of life impairment on PROMIS-29 compared to patients with extrarenal symptoms
- Author
-
Richard Furie, Michelle Petri, Judith A James, Kenneth Kalunian, Maria Dall’Era, Jill Buyon, Chaim Putterman, Peter Izmirly, Betty Diamond, Jessica Li, Jennifer Anolik, H Michael Belmont, Philip Carlucci, Deepak Rao, Andrea Fava, Diane Kamen, Celine Berthier, Jose Monroy-Trujillo, Kristin Haag, William Apruzzese, Sean Connery, Fernanda Payan-Schober, Kerry Cho, Kristina Deonaraine, Derek Fine, Heather T Gold, and Susana Serrate-Sztein
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2022
- Full Text
- View/download PDF
11. Dysregulated long non-coding RNA in Sjögren’s disease impacts both interferon and adaptive immune responses
- Author
-
Astrid Rasmussen, Kathy L Sivils, Joel M Guthridge, Judith A James, Jennifer A Kelly, Patrick M Gaffney, Jonathan D Wren, Stuart B Glenn, R Hal Scofield, Christopher J Lessard, Donald U Stone, David M Lewis, Lida Radfar, A Darise Farris, John A Ice, Courtney G Montgomery, Michelle L Joachims, Bhuwan Khatri, Chuang Li, Kandice L Tessneer, Anna M Stolarczyk, Nicolas Means, Kiely M Grundahl, Graham B Wiley, and Indra Adrianto
- Subjects
Medicine - Abstract
Objective Sjögren’s disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjDRo+) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised.Methods Whole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjDRo−); n=27 Ro/SSA positive (SjDRo+) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log2 fold change ≥2 or ≤0.5; padj
- Published
- 2022
- Full Text
- View/download PDF
12. Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network
- Author
-
Andrew Filer, Michael H Weisman, Judith A James, Kenneth Kalunian, Michelle A Petri, Chaim Putterman, H Michael Belmont, Ilfita Sahbudin, Karim Raza, Maria Dall'Era, Jill P Buyon, Diane L Kamen, Karen Salomon-Escoto, Kazuyoshi Ishigaki, Patrick Dunn, David Wofsy, Michele Bombardieri, Vivian Bykerk, Myles Lewis, Ming Wu, Soumya Raychaudhuri, Hemant Suryawanshi, Thomas Tuschl, Christopher Ritchlin, Maureen McMahon, Jennifer Grossman, Philip M Carlucci, Alessandra Nerviani, Peter M Izmirly, Fan Zhang, Felice Rivellese, Joan Bathon, Zhu Zhu, Qian Xiao, Jessica Li, Holden Maecker, Nir Hacohen, Rong Mao, Jennifer Anolik, Javier Rangel-Moreno, Nida Meednu, Susan Goodman, Lindsy Forbess, Mariko Ishimori, Kevin Deane, David Hildeman, Yuhong Li, Laura Hughes, Robert Clancy, ANNE DAVIDSON, Matthias Kretzler, Larry Moreland, Harris Perlman, Peter Gregersen, Celine C Berthier, Andrea Fava, David Boyle, Derek M Fine, Ami Ben-Artzi, P J Utz, Melanie Smith, Beatrice Goilav, Carla Cuda, Andrew McDavid, Deepak A Rao, Joshua Keegan, Ilya Korsunsky, Joel Guthridge, Kevin Wei, Arnon Arazi, Thomas Eisenhaure, Michael Brenner, Susan Macwana, Pavel Morozov, Manjunath Kustagi, Gerald Watts, Kristina K Deonaraine, Jose Monroy-Trujillo, Mohamed G Atta, Kristin Haag, William Apruzzese, Sean Connery, Fernanda Payan-Schober, Kerry Cho, Jennifer Goff, Aparna Nathan, Joseph Mears, Nghia Millard, Kathryn Weinand, Saori Sakaue, Bill Robinson, Wade DeJager, Louis Bridges, Laura Donlin, Edward DiCarlo, Amit Lakhanpal, Heather Sherman, Anvita Singaraju, Lorien Shakib, Brendan Boyce, Darren Tabechian, Jen Albrecht, James Lederer, A Helena Jonsson, Daimon Simmons, Gregory Keras, Adam Chicoine, Zhihan Jian Li, Mandy McGeachy, Gary Firestein, Arnold Ceponis, Diane Horowitz, Salina Dominguez, Arthur Mandelin, Anjali Thakrar, Mike Holers, Jennifer Seifert, Constanino Pitzalis, Ellen Gravallese, Jennifer Barnas, Raymond Hsu, Steven Woodle, Paul Hoover, Michael Peters, Tony Jones, David Lieb, Jeffrey Hodgin, and Raji Menon
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Abstract
Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.
- Published
- 2021
- Full Text
- View/download PDF
13. Increased cognitive workload evokes greater neurovascular coupling responses in healthy young adults.
- Author
-
Tamas Csipo, Agnes Lipecz, Peter Mukli, Dhay Bahadli, Osamah Abdulhussein, Cameron D Owens, Stefano Tarantini, Rachel A Hand, Valeriya Yabluchanska, J Mikhail Kellawan, Farzaneh Sorond, Judith A James, Anna Csiszar, Zoltan I Ungvari, and Andriy Yabluchanskiy
- Subjects
Medicine ,Science - Abstract
Understanding how the brain allocates resources to match the demands of active neurons under physiological conditions is critically important. Increased metabolic demands of active brain regions are matched with hemodynamic responses known as neurovascular coupling (NVC). Several methods that allow noninvasive assessment of brain activity in humans detect NVC and early detection of NVC impairment may serve as an early marker of cognitive impairment. Therefore, non-invasive NVC assessments may serve as a valuable tool to detect early signs of cognitive impairment and dementia. Working memory tasks are routinely employed in the evaluation of cognitive task-evoked NVC responses. However, recent attempts that utilized functional near-infrared spectroscopy (fNIRS) or transcranial Doppler sonography (TCD) while using a similar working memory paradigm did not provide convincing evidence for the correlation of the hemodynamic variables measured by these two methods. In the current study, we aimed to compare fNIRS and TCD in their performance of differentiating NVC responses evoked by different levels of working memory workload during the same working memory task used as cognitive stimulation. Fourteen healthy young individuals were recruited for this study and performed an n-back cognitive test during TCD and fNIRS monitoring. During TCD monitoring, the middle cerebral artery (MCA) flow was bilaterally increased during the task associated with greater cognitive effort. fNIRS also detected significantly increased activation during a more challenging task in the left dorsolateral prefrontal cortex (DLPFC), and in addition, widespread activation of the medial prefrontal cortex (mPFC) was also revealed. Robust changes in prefrontal cortex hemodynamics may explain the profound change in MCA blood flow during the same cognitive task. Overall, our data support our hypothesis that both TCD and fNIRS methods can discriminate NVC evoked by higher demand tasks compared to baseline or lower demand tasks.
- Published
- 2021
- Full Text
- View/download PDF
14. Cell-bound complement activation products associate with lupus severity in SLE
- Author
-
Richard A Furie, Daniel J Wallace, Judith A James, Susan Manzi, Amit Saxena, Rosalind Ramsey-Goldman, Chaim Putterman, John Conklin, Thierry Dervieux, Jill P Buyon, Tyler O'Malley, Elena Massarotti, Roberta Vezza Alexander, Sonali Narain, Arthur Weinstein, Cristina Arriens, Kenneth C Kalunian, Christopher E Collins, Ghalib A Bello, and Joseph Ahearn
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Abstract
Objectives To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4.Methods All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons.Results Abnormal CB-CAPs were more prevalent than low complement values irrespective of LSI levels (62% vs 38%, respectively, p
- Published
- 2020
- Full Text
- View/download PDF
15. Toxin-neutralizing antibodies elicited by naturally acquired cutaneous anthrax are elevated following severe disease and appear to target conformational epitopes.
- Author
-
Eric K Dumas, Hayati Demiraslan, Rebecca J Ingram, Rebecca M Sparks, Emily Muns, Adriana Zamora, Jason Larabee, Lori Garman, Jimmy D Ballard, Geert-Jan Boons, Judith A James, Uner Kayabas, Mehmet Doganay, and A Darise Farris
- Subjects
Medicine ,Science - Abstract
Understanding immune responses to native antigens in response to natural infections can lead to improved approaches to vaccination. This study sought to characterize the humoral immune response to anthrax toxin components, capsule and spore antigens in individuals (n = 46) from the Kayseri and Malatya regions of Turkey who had recovered from mild or severe forms of cutaneous anthrax infection, compared to regional healthy controls (n = 20). IgG antibodies to each toxin component, the poly-γ-D-glutamic acid capsule, the Bacillus collagen-like protein of anthracis (BclA) spore antigen, and the spore carbohydrate anthrose, were detected in the cases, with anthrax toxin neutralization and responses to Protective Antigen (PA) and Lethal Factor (LF) being higher following severe forms of the disease. Significant correlative relationships among responses to PA, LF, Edema Factor (EF) and capsule were observed among the cases. Though some regional control sera exhibited binding to a subset of the tested antigens, these samples did not neutralize anthrax toxins and lacked correlative relationships among antigen binding specificities observed in the cases. Comparison of serum binding to overlapping decapeptides covering the entire length of PA, LF and EF proteins in 26 cases compared to 8 regional controls revealed that anthrax toxin-neutralizing antibody responses elicited following natural cutaneous anthrax infection are directed to conformational epitopes. These studies support the concept of vaccination approaches that preserve conformational epitopes.
- Published
- 2020
- Full Text
- View/download PDF
16. Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.
- Author
-
He Li, Tove Ragna Reksten, John A Ice, Jennifer A Kelly, Indra Adrianto, Astrid Rasmussen, Shaofeng Wang, Bo He, Kiely M Grundahl, Stuart B Glenn, Corinne Miceli-Richard, Simon Bowman, Sue Lester, Per Eriksson, Maija-Leena Eloranta, Johan G Brun, Lasse G Gøransson, Erna Harboe, Joel M Guthridge, Kenneth M Kaufman, Marika Kvarnström, Deborah S Cunninghame Graham, Ketan Patel, Adam J Adler, A Darise Farris, Michael T Brennan, James Chodosh, Rajaram Gopalakrishnan, Michael H Weisman, Swamy Venuturupalli, Daniel J Wallace, Kimberly S Hefner, Glen D Houston, Andrew J W Huang, Pamela J Hughes, David M Lewis, Lida Radfar, Evan S Vista, Contessa E Edgar, Michael D Rohrer, Donald U Stone, Timothy J Vyse, John B Harley, Patrick M Gaffney, Judith A James, Sean Turner, Ilias Alevizos, Juan-Manuel Anaya, Nelson L Rhodus, Barbara M Segal, Courtney G Montgomery, R Hal Scofield, Susan Kovats, Xavier Mariette, Lars Rönnblom, Torsten Witte, Maureen Rischmueller, Marie Wahren-Herlenius, Roald Omdal, Roland Jonsson, Wan-Fai Ng, for UK Primary Sjögren's Syndrome Registry, Gunnel Nordmark, Christopher J Lessard, and Kathy L Sivils
- Subjects
Genetics ,QH426-470 - Abstract
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
- Published
- 2017
- Full Text
- View/download PDF
17. Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis.
- Author
-
Melissa E Munroe, Nathan Pezant, Michael A Brown, Dustin A Fife, Joel M Guthridge, Jennifer A Kelly, Graham Wiley, Patrick M Gaffney, Judith A James, and Courtney G Montgomery
- Subjects
Medicine ,Science - Abstract
Antiviral defenses are inappropriately activated in systemic lupus erythematosus (SLE) and association between SLE and the antiviral helicase gene, IFIH1, is well established. We sought to extend the previously reported association of pathogenic soluble mediators and autoantibodies with mouse Mda5 to its human ortholog, IFIH1. To better understand the role this gene plays in human lupus, we assessed association of IFIH1 variants with soluble mediators and autoantibodies in 357 European-American SLE patients, first-degree relatives, and unrelated, unaffected healthy controls. Association between each of 135 genotyped SNPs in IFIH1 and four lupus-associated plasma mediators, IL-6, TNF-α, IFN-β, and IP-10, were investigated via linear regression. No significant associations were found to SNPs orthologous to those identified in exon 13 of the mouse. However, outside of this region there were significant associations between IL-6 and rs76162067 (p = 0.008), as well as IP-10 and rs79711023 (p = 0.003), located in a region of IFIH1 previously shown to directly influence MDA-5 mediated IP-10 and IL-6 secretion. SLE patients and FDRs carrying the minor allele for rs79711023 demonstrated lower levels of IP-10, while only FDRs carrying the minor allele for rs76162067 demonstrated an increased level of IL-6. This would suggest that the change in IP-10 is genotypically driven, while the change in IL-6 may be reflective of SLE transition status. These data suggest that IFIH1 may contribute to SLE pathogenesis via altered inflammatory mechanisms.
- Published
- 2017
- Full Text
- View/download PDF
18. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity
- Author
-
Prithvi Raj, Ekta Rai, Ran Song, Shaheen Khan, Benjamin E Wakeland, Kasthuribai Viswanathan, Carlos Arana, Chaoying Liang, Bo Zhang, Igor Dozmorov, Ferdicia Carr-Johnson, Mitja Mitrovic, Graham B Wiley, Jennifer A Kelly, Bernard R Lauwerys, Nancy J Olsen, Chris Cotsapas, Christine K Garcia, Carol A Wise, John B Harley, Swapan K Nath, Judith A James, Chaim O Jacob, Betty P Tsao, Chandrashekhar Pasare, David R Karp, Quan Zhen Li, Patrick M Gaffney, and Edward K Wakeland
- Subjects
targeted sequencing ,HLA ,SLE risk ,haplotype ,risk allele ,LD ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.
- Published
- 2016
- Full Text
- View/download PDF
19. High Affinity Antibodies against Influenza Characterize the Plasmablast Response in SLE Patients After Vaccination.
- Author
-
Kaval Kaur, Nai-Ying Zheng, Kenneth Smith, Min Huang, Lie Li, Noel T Pauli, Carole J Henry Dunand, Jane-Hwei Lee, Michael Morrissey, Yixuan Wu, Michelle L Joachims, Melissa E Munroe, Denise Lau, Xinyan Qu, Florian Krammer, Jens Wrammert, Peter Palese, Rafi Ahmed, Judith A James, and Patrick C Wilson
- Subjects
Medicine ,Science - Abstract
Breakdown of B cell tolerance is a cardinal feature of systemic lupus erythematosus (SLE). Increased numbers of autoreactive mature naïve B cells have been described in SLE patients and autoantibodies have been shown to arise from autoreactive and non-autoreactive precursors. How these defects, in the regulation of B cell tolerance and selection, influence germinal center (GC) reactions that are directed towards foreign antigens has yet to be investigated. Here, we examined the characteristics of post-GC foreign antigen-specific B cells from SLE patients and healthy controls by analyzing monoclonal antibodies generated from plasmablasts induced specifically by influenza vaccination. We report that many of the SLE patients had anti-influenza antibodies with higher binding affinity and neutralization capacity than those from controls. Although overall frequencies of autoreactivity in the influenza-specific plasmablasts were similar for SLE patients and controls, the variable gene repertoire of influenza-specific plasmablasts from SLE patients was altered, with increased usage of JH6 and long heavy chain CDR3 segments. We found that high affinity anti-influenza antibodies generally characterize the plasmablast responses of SLE patients with low levels of autoreactivity; however, certain exceptions were noted. The high-avidity antibody responses in SLE patients may also be correlated with cytokines that are abnormally expressed in lupus. These findings provide insights into the effects of dysregulated immunity on the quality of antibody responses following influenza vaccination and further our understanding of the underlying abnormalities of lupus.
- Published
- 2015
- Full Text
- View/download PDF
20. Ribosomal and immune transcripts associate with relapse in acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura.
- Author
-
Contessa E Edgar, Deirdra R Terrell, Sara K Vesely, Jonathan D Wren, Igor M Dozmorov, Timothy B Niewold, Michael Brown, Fang Zhou, Mark Barton Frank, Joan T Merrill, Johanna A Kremer Hovinga, Bernhard Lämmle, Judith A James, James N George, and A Darise Farris
- Subjects
Medicine ,Science - Abstract
Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe acquired ADAMTS13 deficiency experience one or more relapses. Risk factors for relapse other than severe ADAMTS13 deficiency and ADAMTS13 autoantibodies are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This cross-sectional study asked whether autoantibodies against RNA-binding proteins or peripheral blood gene expression profiles measured during remission are associated with history of prior relapse in acquired ADAMTS13-deficient TTP. Peripheral blood from 38 well-characterized patients with autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies and global gene expression. A subset of TTP patients (9 patients, 24%) exhibited a peripheral blood gene signature composed of elevated ribosomal transcripts that associated with prior relapse. A non-overlapping subset of TTP patients (9 patients, 24%) displayed a peripheral blood type I interferon gene signature that associated with autoantibodies to RNA-binding proteins but not with history of relapse. Patients who had relapsed bimodally expressed higher HLA transcript levels independently of ribosomal transcripts. Presence of any one potential risk factor (ribosomal gene signature, elevated HLA-DRB1, elevated HLA-DRB5) associated with relapse (OR = 38.4; p = 0.0002) more closely than any factor alone or all factors together. Levels of immune transcripts typical of natural killer (NK) and T lymphocytes positively correlated with ribosomal gene expression and number of prior episodes but not with time since the most recent episode. Flow cytometry confirmed elevated expression of cell surface markers encoded by these transcripts on T and/or NK cell subsets of patients who had relapsed. These data associate elevated ribosomal and immune transcripts with relapse history in acquired, ADAMTS13-deficient TTP.
- Published
- 2015
- Full Text
- View/download PDF
21. Vitamin d deficiency in a multiethnic healthy control cohort and altered immune response in vitamin D deficient European-American healthy controls.
- Author
-
Lauren L Ritterhouse, Rufei Lu, Hemangi B Shah, Julie M Robertson, Dustin A Fife, Holden T Maecker, Hongwu Du, Charles G Fathman, Eliza F Chakravarty, R Hal Scofield, Diane L Kamen, Joel M Guthridge, and Judith A James
- Subjects
Medicine ,Science - Abstract
In recent years, vitamin D has been shown to possess a wide range of immunomodulatory effects. Although there is extensive amount of research on vitamin D, we lack a comprehensive understanding of the prevalence of vitamin D deficiency or the mechanism by which vitamin D regulates the human immune system. This study examined the prevalence and correlates of vitamin D deficiency and the relationship between vitamin D and the immune system in healthy individuals.Healthy individuals (n = 774) comprised of European-Americans (EA, n = 470), African-Americans (AA, n = 125), and Native Americans (NA, n = 179) were screened for 25-hydroxyvitamin D [25(OH)D] levels by ELISA. To identify the most noticeable effects of vitamin D on the immune system, 20 EA individuals with severely deficient (24.8 ng/mL) vitamin D levels were matched and selected for further analysis. Serum cytokine level measurement, immune cell phenotyping, and phosphoflow cytometry were performed.Vitamin D sufficiency was observed in 37.5% of the study cohort. By multivariate analysis, AA, NA, and females with a high body mass index (BMI, >30) demonstrate higher rates of vitamin D deficiency (p
- Published
- 2014
- Full Text
- View/download PDF
22. PTPN22 association in systemic lupus erythematosus (SLE) with respect to individual ancestry and clinical sub-phenotypes.
- Author
-
Bahram Namjou, Xana Kim-Howard, Celi Sun, Adam Adler, Sharon A Chung, Kenneth M Kaufman, Jennifer A Kelly, Stuart B Glenn, Joel M Guthridge, Robert H Scofield, Robert P Kimberly, Elizabeth E Brown, Graciela S Alarcón, Jeffrey C Edberg, Jae-Hoon Kim, Jiyoung Choi, Rosalind Ramsey-Goldman, Michelle A Petri, John D Reveille, Luis M Vilá, Susan A Boackle, Barry I Freedman, Betty P Tsao, Carl D Langefeld, Timothy J Vyse, Chaim O Jacob, Bernardo Pons-Estel, Argentine Collaborative Group, Timothy B Niewold, Kathy L Moser Sivils, Joan T Merrill, Juan-Manuel Anaya, Gary S Gilkeson, Patrick M Gaffney, Sang-Cheol Bae, Marta E Alarcón-Riquelme, BIOLUPUS and GENLES Networks, John B Harley, Lindsey A Criswell, Judith A James, and Swapan K Nath
- Subjects
Medicine ,Science - Abstract
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7 × 10(-9), OR = 1.40 (95% CI = 1.25-1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67-0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7 × 10(-5), OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.
- Published
- 2013
- Full Text
- View/download PDF
23. Clostridium difficile 027/BI/NAP1 encodes a hypertoxic and antigenically variable form of TcdB.
- Author
-
Jordi M Lanis, Latisha D Heinlen, Judith A James, and Jimmy D Ballard
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
The Clostridium difficile exotoxin, TcdB, which is a major virulence factor, varies between strains of this pathogen. Herein, we show that TcdB from the epidemic BI/NAP1/027 strain of C. difficile is more lethal, causes more extensive brain hemorrhage, and is antigenically variable from TcdB produced by previously studied strains of this pathogen (TcdB003). In mouse intoxication assays, TcdB from a ribotype 027 strain (TcdB027) was at least four fold more lethal than TcdB003. TcdB027 caused a previously undescribed brain hemorrhage in mice and this correlated with a heightened sensitivity of brain microvascular endothelial cells to the toxin. TcdB003 and TcdB027 also differed in their antigenic profiles and did not share cross-neutralizing epitopes in a major immunogenic region of the protein. Solid phase humoral mapping of epitopes in the carboxy-terminal domains (CTD) of TcdB027 and TcdB003 identified 11 reactive epitopes that varied between the two forms of TcdB, and 13 epitopes that were shared or overlapping. Despite the epitope differences and absence of neutralizing epitopes in the CTD of TcdB027, a toxoid form of this toxin primed a strong protective response. These findings indicate TcdB027 is a more potent toxin than TcdB003 as measured by lethality assays and pathology, moreover the sequence differences between the two forms of TcdB alter antigenic epitopes and reduce cross-neutralization by antibodies targeting the CTD.
- Published
- 2013
- Full Text
- View/download PDF
24. Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.
- Author
-
Julio E Molineros, Amit K Maiti, Celi Sun, Loren L Looger, Shizhong Han, Xana Kim-Howard, Stuart Glenn, Adam Adler, Jennifer A Kelly, Timothy B Niewold, Gary S Gilkeson, Elizabeth E Brown, Graciela S Alarcón, Jeffrey C Edberg, Michelle Petri, Rosalind Ramsey-Goldman, John D Reveille, Luis M Vilá, Barry I Freedman, Betty P Tsao, Lindsey A Criswell, Chaim O Jacob, Jason H Moore, Timothy J Vyse, Carl L Langefeld, Joel M Guthridge, Patrick M Gaffney, Kathy L Moser, R Hal Scofield, Marta E Alarcón-Riquelme, BIOLUPUS Network, Scott M Williams, Joan T Merrill, Judith A James, Kenneth M Kaufman, Robert P Kimberly, John B Harley, and Swapan K Nath
- Subjects
Genetics ,QH426-470 - Abstract
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
- Published
- 2013
- Full Text
- View/download PDF
25. MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus.
- Author
-
Yun Deng, Jian Zhao, Daisuke Sakurai, Kenneth M Kaufman, Jeffrey C Edberg, Robert P Kimberly, Diane L Kamen, Gary S Gilkeson, Chaim O Jacob, R Hal Scofield, Carl D Langefeld, Jennifer A Kelly, Rosalind Ramsey-Goldman, Michelle A Petri, John D Reveille, Luis M Vilá, Graciela S Alarcón, Timothy J Vyse, Bernardo A Pons-Estel, Argentine Collaborative Group, Barry I Freedman, Patrick M Gaffney, Kathy Moser Sivils, Judith A James, Peter K Gregersen, Juan-Manuel Anaya, Timothy B Niewold, Joan T Merrill, Lindsey A Criswell, Anne M Stevens, Susan A Boackle, Rita M Cantor, Weiling Chen, Jeniffer M Grossman, Bevra H Hahn, John B Harley, Marta E Alarcόn-Riquelme, BIOLUPUS and GENLES networks, Elizabeth E Brown, and Betty P Tsao
- Subjects
Genetics ,QH426-470 - Abstract
We previously reported that the G allele of rs3853839 at 3'untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10(-10), odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10(-11), OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3'UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R(2) = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3'UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10(-19), OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
- Published
- 2013
- Full Text
- View/download PDF
26. Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4.
- Author
-
Harinder Manku, Carl D Langefeld, Sandra G Guerra, Talat H Malik, Marta Alarcon-Riquelme, Juan-Manuel Anaya, Sang-Cheol Bae, Susan A Boackle, Elizabeth E Brown, Lindsey A Criswell, Barry I Freedman, Patrick M Gaffney, Peter A Gregersen, Joel M Guthridge, Sang-Hoon Han, John B Harley, Chaim O Jacob, Judith A James, Diane L Kamen, Kenneth M Kaufman, Jennifer A Kelly, Javier Martin, Joan T Merrill, Kathy L Moser, Timothy B Niewold, So-Yeon Park, Bernardo A Pons-Estel, Amr H Sawalha, R Hal Scofield, Nan Shen, Anne M Stevens, Celi Sun, Gary S Gilkeson, Jeff C Edberg, Robert P Kimberly, Swapan K Nath, Betty P Tsao, and Tim J Vyse
- Subjects
Genetics ,QH426-470 - Abstract
We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P=1.71 × 10(-34) , OR=1.43[1.26-1.60]) and rs1234317-T (P=1.16 × 10(-28) , OR=1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5' region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5' risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.
- Published
- 2013
- Full Text
- View/download PDF
27. Evidence of dynamically dysregulated gene expression pathways in hyperresponsive B cells from African American lupus patients.
- Author
-
Igor Dozmorov, Nicolas Dominguez, Andrea L Sestak, Julie M Robertson, John B Harley, Judith A James, and Joel M Guthridge
- Subjects
Medicine ,Science - Abstract
Recent application of gene expression profiling to the immune system has shown a great potential for characterization of complex regulatory processes. It is becoming increasingly important to characterize functional systems through multigene interactions to provide valuable insights into differences between healthy controls and autoimmune patients. Here we apply an original systematic approach to the analysis of changes in regulatory gene interconnections between in Epstein-Barr virus transformed hyperresponsive B cells from SLE patients and normal control B cells. Both traditional analysis of differential gene expression and analysis of the dynamics of gene expression variations were performed in combination to establish model networks of functional gene expression. This Pathway Dysregulation Analysis identified known transcription factors and transcriptional regulators activated uniquely in stimulated B cells from SLE patients.
- Published
- 2013
- Full Text
- View/download PDF
28. Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression.
- Author
-
Daisuke Sakurai, Jian Zhao, Yun Deng, Jennifer A Kelly, Elizabeth E Brown, John B Harley, Sang-Cheol Bae, Marta E Alarcόn-Riquelme, BIOLUPUS and GENLES networks, Jeffrey C Edberg, Robert P Kimberly, Rosalind Ramsey-Goldman, Michelle A Petri, John D Reveille, Luis M Vilá, Graciela S Alarcón, Kenneth M Kaufman, Timothy J Vyse, Chaim O Jacob, Patrick M Gaffney, Kathy Moser Sivils, Judith A James, Diane L Kamen, Gary S Gilkeson, Timothy B Niewold, Joan T Merrill, R Hal Scofield, Lindsey A Criswell, Anne M Stevens, Susan A Boackle, Jae-Hoon Kim, Jiyoung Choi, Bernardo A Pons-Estel, Argentine Collaborative Group, Barry I Freedman, Juan-Manuel Anaya, Javier Martin, C Yung Yu, Deh-Ming Chang, Yeong Wook Song, Carl D Langefeld, Weiling Chen, Jennifer M Grossman, Rita M Cantor, Bevra H Hahn, and Betty P Tsao
- Subjects
Genetics ,QH426-470 - Abstract
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10⁻⁸, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
- Published
- 2013
- Full Text
- View/download PDF
29. Immunodominance of antigenic site B over site A of hemagglutinin of recent H3N2 influenza viruses.
- Author
-
Lyubov Popova, Kenneth Smith, Ann H West, Patrick C Wilson, Judith A James, Linda F Thompson, and Gillian M Air
- Subjects
Medicine ,Science - Abstract
H3N2 influenza viruses have now circulated in the human population for 43 years since the pandemic of 1968, accumulating sequence changes in the hemagglutinin (HA) and neuraminidase (NA) that are believed to be predominantly due to selection for escape from antibodies. Examination of mutations that persist and accumulate led to identification of antigenically significant mutations that are contained in five antigenic sites (A-E) mapped on to the H3 HA. In early H3N2 isolates, antigenic site A appeared to be dominant while in the 1990s site B seemed more important. To obtain experimental evidence for dominance of antigenic sites on modern H3 HAs, we have measured antibodies in plasma of human subjects who received the 2006-07 trivalent subunit influenza vaccine (H3 component A/Wisconsin/67/05) or the 2008-09 formulation (H3 component A/Uruguay/716/07). Plasmas were tested against expressed HA of Wisconsin-like influenza A/Oklahoma/309/06 and site-directed mutants in antigenic site A (NNES121-124ITEG, N126T, N133D, TSSS135-138GSNA, K140I, RSNNS142-146PGSG), and antigenic site B (HL156-157KS, KFK158-160GST, NDQI189-192QEQT, A196V). "Native ELISA" analysis and escape mutant selection with two human monoclonal antibodies demonstrated that antibody E05 binds to antigenic site A and 1_C02 binds to site B. We find that most individuals, after vaccination in seasons 2006-07 and/or 2008-09, showed dominance of antigenic site B recognition over antigenic site A. A minority showed dominance of site A in 2006 but these were reduced in 2008 when the vaccine virus had a site A mutation. A better understanding of immunodominance may allow prediction of future antigenic drift and assist in vaccine strain selection.
- Published
- 2012
- Full Text
- View/download PDF
30. The University at Buffalo Robert Creeley Lectures in Poetry and Poetics: Poetry's Embodiments
- Author
-
Judith Goldman, James Maynard and Judith Goldman, James Maynard
- Published
- 2024
31. Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.
- Author
-
Jian Zhao, Hui Wu, Melanie Khosravi, Huijuan Cui, Xiaoxia Qian, Jennifer A Kelly, Kenneth M Kaufman, Carl D Langefeld, Adrienne H Williams, Mary E Comeau, Julie T Ziegler, Miranda C Marion, Adam Adler, Stuart B Glenn, Marta E Alarcón-Riquelme, BIOLUPUS Network, GENLES Network, Bernardo A Pons-Estel, John B Harley, Sang-Cheol Bae, So-Young Bang, Soo-Kyung Cho, Chaim O Jacob, Timothy J Vyse, Timothy B Niewold, Patrick M Gaffney, Kathy L Moser, Robert P Kimberly, Jeffrey C Edberg, Elizabeth E Brown, Graciela S Alarcon, Michelle A Petri, Rosalind Ramsey-Goldman, Luis M Vilá, John D Reveille, Judith A James, Gary S Gilkeson, Diane L Kamen, Barry I Freedman, Juan-Manuel Anaya, Joan T Merrill, Lindsey A Criswell, R Hal Scofield, Anne M Stevens, Joel M Guthridge, Deh-Ming Chang, Yeong Wook Song, Ji Ah Park, Eun Young Lee, Susan A Boackle, Jennifer M Grossman, Bevra H Hahn, Timothy H J Goodship, Rita M Cantor, Chack-Yung Yu, Nan Shen, and Betty P Tsao
- Subjects
Genetics ,QH426-470 - Abstract
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6×10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9×10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta) = 3.2×10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5×10(-4), OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.
- Published
- 2011
- Full Text
- View/download PDF
32. 60 kD Ro and nRNP A frequently initiate human lupus autoimmunity.
- Author
-
Latisha D Heinlen, Micah T McClain, Lauren L Ritterhouse, Benjamin F Bruner, Colin C Edgerton, Michael P Keith, Judith A James, and John B Harley
- Subjects
Medicine ,Science - Abstract
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, humoral autoimmune disorder. The unifying feature among SLE patients is the production of large quantities of autoantibodies. Serum samples from 129 patients collected before the onset of SLE and while in the United States military were evaluated for early pre-clinical serologic events. The first available positive serum sample frequently already contained multiple autoantibody specificities (65%). However, in 34 SLE patients the earliest pre-clinical serum sample positive for any detectable common autoantibody bound only a single autoantigen, most commonly 60 kD Ro (29%), nRNP A (24%), anti-phospholipids (18%) or rheumatoid factor (15%). We identified several recurrent patterns of autoantibody onset using these pre-diagnostic samples. In the serum samples available, anti-nRNP A appeared before or simultaneously with anti-nRNP 70 K in 96% of the patients who had both autoantibodies at diagnosis. Anti-60 kD Ro antibodies appeared before or simultaneously with anti-La (98%) or anti-52 kD Ro (95%). The autoantibody response in SLE patients begins simply, often binding a single specific autoantigen years before disease onset, followed by epitope spreading to additional autoantigenic specificities that are accrued in recurring patterns.
- Published
- 2010
- Full Text
- View/download PDF
33. Osteopontin and systemic lupus erythematosus association: a probable gene-gender interaction.
- Author
-
Shizhong Han, Joel M Guthridge, Isaac T W Harley, Andrea L Sestak, Xana Kim-Howard, Kenneth M Kaufman, Bahram Namjou, Harshal Deshmukh, Gail Bruner, Luis R Espinoza, Gary S Gilkeson, John B Harley, Judith A James, and Swapan K Nath
- Subjects
Medicine ,Science - Abstract
Osteopontin (SPP1) is an important bone matrix mediator found to have key roles in inflammation and immunity. SPP1 genetic polymorphisms and increased osteopontin protein levels have been reported to be associated with SLE in small patient collections. The present study evaluates association between SPP1 polymorphisms and SLE in a large cohort of 1141 unrelated SLE patients [707 European-American (EA) and 434 African-American (AA)], and 2009 unrelated controls (1309 EA and 700 AA). Population-based case-control association analyses were performed. To control for potential population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT), and principal components analysis (PCA) were applied. Combined analysis of 2 ethnic groups, showed the minor allele of 2 SNPs (rs1126616T and rs9138C) significantly associated with higher risk of SLE in males (P = 0.0005, OR = 1.73, 95% CI = 1.28-2.33), but not in females. Indeed, significant gene-gender interactions in the 2 SNPs, rs1126772 and rs9138, were detected (P = 0.001 and P = 0.0006, respectively). Further, haplotype analysis identified rs1126616T-rs1126772A-rs9138C which demonstrated significant association with SLE in general (P = 0.02, OR = 1.30, 95%CI 1.08-1.57), especially in males (P = 0.0003, OR = 2.42, 95%CI 1.51-3.89). Subgroup analysis with single SNPs and haplotypes also identified a similar pattern of gender-specific association in AA and EA. GC, STRAT, and PCA results within each group showed consistent associations. Our data suggest SPP1 is associated with SLE, and this association is especially stronger in males. To our knowledge, this report serves as the first association of a specific autosomal gene with human male lupus.
- Published
- 2008
- Full Text
- View/download PDF
34. Common variants within MECP2 confer risk of systemic lupus erythematosus.
- Author
-
Amr H Sawalha, Ryan Webb, Shizhong Han, Jennifer A Kelly, Kenneth M Kaufman, Robert P Kimberly, Marta E Alarcón-Riquelme, Judith A James, Timothy J Vyse, Gary S Gilkeson, Chan-Bum Choi, R Hal Scofield, Sang-Cheol Bae, Swapan K Nath, and John B Harley
- Subjects
Medicine ,Science - Abstract
Systemic lupus erythematosus (SLE) is a predominantly female autoimmune disease that affects multiple organ systems. Herein, we report on an X-chromosome gene association with SLE. Methyl-CpG-binding protein 2 (MECP2) is located on chromosome Xq28 and encodes for a protein that plays a critical role in epigenetic transcriptional regulation of methylation-sensitive genes. Utilizing a candidate gene association approach, we genotyped 21 SNPs within and around MECP2 in SLE patients and controls. We identify and replicate association between SLE and the genomic element containing MECP2 in two independent SLE cohorts from two ethnically divergent populations. These findings are potentially related to the overexpression of methylation-sensitive genes in SLE.
- Published
- 2008
- Full Text
- View/download PDF
35. A Flare Risk Index Informed by Select Immune Mediators in Systemic Lupus Erythematosus
- Author
-
Melissa E. Munroe, Derek Blankenship, Daniele DeFreese, Mohan Purushothaman, Wade DeJager, Susan Macwana, Joel M. Guthridge, Stan Kamp, Nancy Redinger, Teresa Aberle, Eliza F. Chakravarty, Cristina Arriens, Yanfeng Li, Hu Zeng, Kathleen A. McCarthy‐Fruin, Shirley‐Ann Osei‐Onomahm, Uma Thanarajasingam, Judith A. James, and Eldon Jupe
- Subjects
Rheumatology ,Immunology ,Immunology and Allergy - Abstract
SLE is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study seeks to identify optimal immune mediators informing an empirically refined Flare Risk Index (FRI) reflecting altered immunity prior to clinical disease flare.SLE-associated plasma mediators (n=37) were evaluated by microfluidic immunoassay in 46 Pre-Flare and 53 Pre-Nonflare samples selected from a unique longitudinal cohort of 106 patients with classified SLE (meeting ACR and SLICC criteria). Autoantibody specificities, hybrid SLEDAI (hSLEDAI) scores, clinical features, and medication usage were also compared at Pre-Flare (111±47 days prior to Flare) vs. Pre-Nonflare (99±21 days prior to Nonflare) time points. Variable importance was determined by random forest with logistic regression subsequently applied to determine the optimal number and type of analytes informing a refined FRI.Pre-Flare vs. Pre-Nonflare differences were not associated with demographics, autoantibody specificities, hSLEDAI scores, clinical features, nor medication usage. Forward selection and backward elimination of mediators ranked by variable importance drew up to 17 candidates differentiating Pre-Flare from Pre-Nonflare. A final combination of 11 mediators best informed a newly refined FRI, achieving a maximum of 97% sensitivity and 98% specificity after applying decision curve analysis to define low, medium, and high FRI scores.We verified altered immune mediators associated with imminent disease flare; a subset improved the FRI to identify SLE patients at risk of imminent flare. This molecularly-informed proactive management approach could be critical in prospective clinical trials and the clinical management of lupus.
- Published
- 2023
36. A Theatre for Spenserians: Papers of the International Spencer Colloquium Fredericton, New Brunswick October 1969
- Author
-
Judith Kennedy, James Reither and Judith Kennedy, James Reither
- Published
- 2019
37. Unique Serum Immune Phenotypes and Stratification of Oklahoma Native American Rheumatic Disease Patients
- Author
-
Samantha Slight-Webb, Tim Gross, Ly Thi-Hai Tran, Joel M. Guthridge, Bobby Saunkeah, Sohail Khan, Virginia C. Roberts, Hua Chen, Joseph M Kheir, Carla J. Guthridge, Michael T. Peercy, and Judith A. James
- Subjects
Systemic disease ,business.industry ,Autoantibody ,Undifferentiated connective tissue disease ,Arthritis ,Disease ,medicine.disease ,Immune system ,Rheumatology ,Rheumatoid arthritis ,Immunology ,medicine ,Polyarthritis ,business - Abstract
Native American (NA) populations have higher rates of rheumatic disease and present with overlapping disease symptoms and nontraditional serologic features, thus presenting an urgent need for better biomarkers in NA diagnostics. This study used a machine learning approach to identify immune signatures that more effectively stratify NA patients with rheumatic disease.Adult NA patients with autoantibody-positive (AAB+) rheumatoid arthritis (RA; n = 28), autoantibody negative (AAB-) RA (n = 18), systemic autoimmune rheumatic disease (n = 28), arthralgia/osteoarthritis (n = 28), or polyarthritis/undifferentiated connective tissue disease (n = 28), and control patients (n = 28) provided serum samples for cytokine, chemokine, and AAB assessment. Random forest clustering and soluble mediator groups were used to identify patients and control patients with similar biologic signatures. The American College of Rheumatology criteria specific for systemic disease and RA identified differences in disease manifestations across clusters.Serum soluble mediators were not homogenous between different NA rheumatic disease diagnostic groups, reflecting the heterogeneity of autoimmune diseases. Clustering by serum biomarkers created 5 analogous immune phenotypes. Soluble mediators and pathways associated with chronic inflammation and involvement of the innate, B cell, T follicular helper cell, and interferon-associated pathways, along with regulatory signatures, distinguished the 5 immune signatures among patients. Select clinical features were associated with individual immune profiles. Patients with low inflammatory and higher regulatory signatures were more likely to have few clinical manifestations, whereas those with T cell pathway involvement had more arthritis.Serum protein signatures distinguished NA patients with rheumatic disease into distinct immune subsets. Following these immune profiles over time may assist with earlier diagnoses and help guide more personalized treatment approaches.
- Published
- 2022
38. Loss-of-function variants inSAT1cause X-linked childhood-onset systemic lupus erythematosus
- Author
-
Lingxiao Xu, Jian Zhao, Qing Sun, Xue Xu, Lei Wang, Ting Liu, Yunjuan Wu, Jingfeng Zhu, Linyu Geng, Yun Deng, Alexander Awgulewitsch, Diane L Kamen, Jim C Oates, Prithvi Raj, Edward K Wakeland, R Hal Scofield, Joel M Guthridge, Judith A James, Bevra H Hahn, Deborah K McCurdy, Fang Wang, Miaojia Zhang, Wenfeng Tan, Gary S Gilkeson, and Betty P Tsao
- Subjects
Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
ObjectivesFamilies that contain multiple siblings affected with childhood onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus.MethodsSanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional patients with SLE. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively.ResultsThe two familial ultra-rare, predicted loss-of-function (LOF)SAT1variants exhibited X-linked recessive Mendelian inheritance in two unrelated African–American families. Each LOF variant was transmitted from the heterozygous unaffected mother to her two sons with childhood-onset SLE. The p.Asp40Tyr variant affected a splice donor site causing deleterious transcripts. The young hemizygous male and homozygous femaleSat1p.Glu92Leufs*6KI mice spontaneously developed splenomegaly, enlarged glomeruli with leucocyte infiltration, proteinuria and elevated expression of type I interferon-inducible genes.SAT1is highly expressed in neutrophils and encodes spermidine/spermine-N1-acetyltransferase 1 (SSAT1), a rate-limiting enzyme in polyamine catabolism. Young male KI mice exhibited neutrophil defects and decreased proportions of Foxp3 +CD4+ T-cell subsets. Circulating neutrophil counts and proportions of Foxp3 +CD4+ T cells correlated with decreased plasma levels of spermine in treatment-naive, incipient SLE patients.ConclusionsWe identified two novelSAT1LOF variants, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism and identifiedSAT1LOF variants as new monogenic causes for SLE.
- Published
- 2022
39. The promise of precision medicine in rheumatology
- Author
-
Joel M. Guthridge, Catriona A. Wagner, and Judith A. James
- Subjects
Rheumatology ,Rheumatic Diseases ,Humans ,General Medicine ,Precision Medicine ,Article ,General Biochemistry, Genetics and Molecular Biology ,Autoantibodies ,Autoimmune Diseases - Abstract
Systemic autoimmune rheumatic diseases (SARDs) exhibit extensive heterogeneity in clinical presentation, disease course, and treatment response. Therefore, precision medicine – whereby treatment is tailored according to the underlying pathogenic mechanisms of an individual patient at a specific time – represents the ‘holy grail’ in SARD clinical care. Current strategies include treat-to-target therapies and autoantibody testing for patient stratification; however, these are far from optimal. Recent innovations in high-throughput “omic” technologies are now enabling comprehensive profiling at multiple levels, helping to identify subgroups of patients who may taper off potentially toxic medications or better respond to current molecular targeted therapies. Such advances may help to optimize outcomes and identify new pathways for treatment, but there are many challenges along the path towards clinical translation. In this review, we discuss recent efforts to dissect cellular and molecular heterogeneity across multiple SARDs and future directions for implementing stratification approaches for SARD treatment in the clinic.
- Published
- 2022
40. Peptidoglycan fromBacillus anthracisInhibits Human Macrophage Efferocytosis in Part by Reducing Cell Surface Expression of MERTK and TIM-3
- Author
-
Joshua S Mytych, Zijian Pan, Charmaine Lopez-Davis, Nancy Redinger, Christina Lawrence, Jadith Ziegler, Narcis Popescu, Judith A. James, and A. Darise Farris
- Abstract
Bacillus anthracispeptidoglycan (PGN) is a major component of the bacterial cell wall and a key pathogen-associated molecular pattern (PAMP) contributing to anthrax pathology, including organ dysfunction and coagulopathy. Increases in apoptotic lymphocytes are a late-stage feature of anthrax and sepsis, suggesting there is a defect in apoptotic clearance. Here, we tested the hypothesis thatB. anthracisPGN inhibits the capacity of human monocyte-derived, tissue-like macrophages (MΦ) to efferocytose apoptotic cells. Exposure of CD206+CD163+MΦ to PGN for 24h impaired efferocytosis in a manner dependent on human serum opsonins but independent of complement component C3. PGN treatment reduced cell surface expression of the pro-efferocytic signaling receptors MERTK, TYRO3, AXL, integrin αVβ5, CD36 and TIM-3, whereas TIM-1, αVβ5, CD300b, CD300f, STABILIN-1 and STABILIN-2 were unaffected. Soluble forms of MERTK, TYRO3, AXL, CD36, and TIM-3 were increased in PGN-treated supernatants, suggesting involvement of proteases. ADAM17 is a major membrane-bound protease implicated in mediating efferocytotic receptor cleavage. ADAM17 inhibitors TAPI-0 and Marimastat abolished TNF release, indicating effective protease inhibition, modestly increased cell-surface levels of MerTK and TIM-3 but only partially restored efferocytic capacity by PGN-treated MΦ. We conclude that human serum factors are required for optimal recognition of PGN by human MΦ and thatB. anthracisPGN inhibits efferocytosis in part by reducing cell surface expression of efferocytic receptors.
- Published
- 2023
41. Urine Proteomics and Renal <scp>Single‐Cell</scp> Transcriptomics Implicate Interleukin‐16 in Lupus Nephritis
- Author
-
Avi Z. Rosenberg, H. Michael Belmont, Paride Fenaroli, Nir Hacohen, Arnon Arazi, William Apruzzese, Chandra Mohan, Accelerating Medicines Partnership Ra, Jose Monroy Trujillo, Jill Buyon, Robert R. Clancy, Michelle Petri, Deepak A. Rao, Derek M. Fine, Peter M. Izmirly, David Wofsy, Anne Davidson, Andrea Fava, Betty Diamond, Celine C. Berthier, Judith A. James, Soumya Raychaudhuri, and Ting Zhang
- Subjects
medicine.diagnostic_test ,business.industry ,Urinary system ,Immunology ,Lupus nephritis ,medicine.disease ,Immune system ,Rheumatology ,Platelet degranulation ,medicine ,Immunology and Allergy ,Biomarker (medicine) ,Renal biopsy ,business ,Nephritis ,Extracellular matrix organization - Abstract
Objectives Current treatments are effective only in 30% of lupus nephritis patients emphasizing the need for novel therapeutic strategies. To develop mechanistic hypotheses and explore novel biomarkers, we analyzed the longitudinal urinary proteomic profiles in patients with lupus nephritis undergoing treatment. Methods We quantified 1,000 urinary proteins in 30 patients with lupus nephritis at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single cell transcriptomics of renal biopsies from lupus nephritis patients. Results Our analysis revealed multiple biological pathways including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization that could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with lupus nephritis as compared to controls without SLE. IL-16, CD163, and TGF-β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction of urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in lupus nephritis kidneys. IL-16 producing cells were found at key sites of kidney injury. Conclusion Urine proteomics may profoundly change the diagnosis and management of lupus nephritis by noninvasively monitor active intrarenal biological pathways. These findings implicate IL-16 in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker.
- Published
- 2022
42. Antibody Responses to <scp>Epstein‐Barr</scp> Virus in the Preclinical Period of Rheumatoid Arthritis Suggest the Presence of Increased Viral Reactivation Cycles
- Author
-
William H. Robinson, Jill A Norris, V. Michael Holers, Carla J Guthridge, Kevin D. Deane, Nichole E. Carlson, M. Kristen Demoruelle, Heather M. Berens, Jess D. Edison, Rachel L. Johnson, Elizabeth A. Bemis, Sabrina Fechtner, John B. Harley, and Judith A. James
- Subjects
Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,medicine.medical_treatment ,Immunology ,Antibodies, Viral ,medicine.disease_cause ,Anti-Citrullinated Protein Antibodies ,Article ,Virus ,Autoimmunity ,Arthritis, Rheumatoid ,Immune system ,Rheumatology ,Rheumatoid Factor ,Humans ,Immunology and Allergy ,Medicine ,biology ,business.industry ,Autoantibody ,medicine.disease ,Epstein–Barr virus ,Immunoglobulin A ,Cytokine ,Immunoglobulin M ,Immunoglobulin G ,Rheumatoid arthritis ,Antibody Formation ,Cytomegalovirus Infections ,biology.protein ,Antibody ,business - Abstract
Patients with established rheumatoid arthritis (RA) demonstrate altered immune responses to Epstein-Barr virus (EBV), but the presence and roles of EBV have not been fully explored during the pre-clinical disease period. This study was undertaken to determine if EBV infection, as evidenced by an altered anti-EBV antibody response, either plays an important role in driving the development of RA or is a result of expanded RA-related autoimmunity.A total of 83 subjects with RA according to the 1987 American College of Rheumatology (ACR) criteria and 83 age-, sex-, and race-matched control subjects without RA were included in our study. We collected sera from RA subjects and matched controls during the pre-RA and post-RA diagnosis periods and tested the sera for the presence of 5 anti-EBV antibodies (anti-EBV nuclear antigen 1 IgG isotype, anti-viral capsid antigen [anti-VCA] isotypes IgG and IgA, and anti-early antigen [EA] isotypes IgG and IgA), 7 RA-related autoantibodies (rheumatoid factor measured by nephelometry [RF-Neph] as well as isotype-specific IgA-RF, IgM-RF, and IgG-RF, and anti-cyclic citrullinated peptide [anti-CCP] antibodies, including anti-CCP2, anti-CCP3, and anti-CCP3.1), 22 cytokines/chemokines, 36 individual anti-citrullinated protein antibodies, and IgG-cytomegalovirus (CMV) antibodies. Random forest classification, mixed modeling, and joint mixed modeling were used to determine differences in anti-EBV antibody levels between RA subjects and controls.Random forest analysis identified the presence of preclinical EBV antibodies in the serum that differentiated RA subjects from controls without RA. Specifically, IgG-EA antibody levels were higher in RA subjects (mean ± SD 0.82 ± 0.72 international standardized ratio [ISR]) compared to controls (mean ± SD 0.49 ± 0.28 ISR). In subjects with RA, elevated serum IgG-EA levels in the preclinical period before seroconversion were significantly correlated with increased serum IgM-RF levels (P = 0.007), whereas this correlation was not seen in control subjects without RA (P = 0.15). IgG-CMV antibody levels did not differ between groups.Subjects whose serum IgG-EA antibody levels are elevated in the preclinical period will eventually develop RA, which suggests that EBV reactivation cycles are increased during the preclinical period of RA. A combination of RF and EBV reactivation may play an important role in the development of RA.
- Published
- 2022
43. 1401 A Genome Wide Association Scan of SLE genetic risk in a cohort of African-American persons
- Author
-
Isaac TW Harley, Celi Sun, Adrienne H Williams, Julie T Ziegler, Mary E Comeau, Miranda C Marion, Stuart B Glenn, Adam Adler, Summer G Frank-Pearce, Nan Shen, Jennifer A Kelly, Bahram Namjou-Khales, Michelle Petri, Marta Alarcon-Riquelme, W Joseph McCune, Patrick Gaffney, Kathy Sivils, Jane E Salmon, Michael H Weisman, Jeffrey C Edberg, Elizabeth E Brown, Tammy Utset, Lindsey A Criswell, Chaim O Jacob, Betty Tsao, Timothy J Vyse, Judith A James, Gary S Gilkeson, Diane L Kamen, Courtney Montgomery, Joan T Merrill, Swapan K Nath, Viktoryia Laurynenka, Iouri Chepelev, Valerie Harris-Lewis, R Hal Scofield, Robert P Kimberly, Carl D Langefeld, John B Harley, and Kenneth M Kaufman
- Published
- 2022
44. 902 Loss-of-function variants inSAT1cause X-linked Childhood-onset Systemic Lupus Erythematosus
- Author
-
Lingxiao Xu, Jian Zhao, Qing Sun, Xue Xu, Lei Wang, Ting Liu, Yunjuan Wu, Jingfeng Zhu, Linyu Geng, Yun Deng, Alexander Awgulewitsch, Diane L Kamen, Jim C Oates, Prithvi Raj, Edward K Wakeland, R Hal Scofield, Joel M Guthridge, Judith A James, Bevra H Hahn, Deborah K McCurdy, Fang Wang, Miaojia Zhang, Wenfeng Tan, Gary S Gilkeson, and Betty P Tsao
- Published
- 2022
45. The modifying influence of HLA class II DQB1∗06:02 on the Streptococcus and clinical phenotype correlation among anti-Ro+ mothers of children with neonatal lupus
- Author
-
Robert M. Clancy, Carla J. Guthridge, Miranda C. Marion, Joel Guthridge, Timothy D. Howard, Peter M. Izmirly, Mala Masson, Jill P. Buyon, Judith A. James, and Carl D. Langefeld
- Subjects
Cell Biology ,Molecular Biology ,Biochemistry ,Genetics (clinical) - Published
- 2022
46. Lupus Susceptibility Region Containing CDKN1B rs34330 Mechanistically Influences Expression and Function of Multiple Target Genes, Also Linked to Proliferation and Apoptosis
- Author
-
Xu-jie Zhou, Yuta Kochi, Guru P. Maiti, Joel M. Guthridge, Sang Cheol Bae, Mehdi Fazel-Najafabadi, Kek Heng Chua, Judith A. James, Loren L. Looger, Yukinori Okada, Swapan K. Nath, Chikashi Terao, Bhupinder Singh, Celi Sun, Hong Zhang, Matthew T. Weirauch, John B. Harley, and Gaurav K. Varshney
- Subjects
1.1 Normal biological development and functioning ,Immunology ,Lupus ,Apoptosis ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Autoimmune Disease ,Article ,Promoter Regions ,Genetic ,Rheumatology ,Underpinning research ,Genetics ,Lupus Erythematosus, Systemic ,Humans ,2.1 Biological and endogenous factors ,Immunology and Allergy ,Genetic Predisposition to Disease ,Epigenetics ,Polymorphism ,Aetiology ,Promoter Regions, Genetic ,Enhancer ,Transcription factor ,Alleles ,Cell Proliferation ,Lupus Erythematosus ,Inflammatory and immune system ,Systemic ,Human Genome ,Computational Biology ,Promoter ,Single Nucleotide ,Chromatin ,CTCF ,H3K4me3 ,Generic health relevance ,Cyclin-Dependent Kinase Inhibitor p27 ,Genome-Wide Association Study ,Biotechnology - Abstract
ObjectiveIn a recent genome-wide association study, a significant genetic association between rs34330 of CDKN1B and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant.MethodsWe performed an allelic association analysis in patients with SLE, followed by a meta-analysis assessing genome-wide association data across 11 independent cohorts (n = 28,872). In silico bioinformatics analysis and experimental validation in SLE-relevant cell lines were applied to determine the functional consequences of rs34330.ResultsWe replicated a genetic association between SLE and rs34330 (meta-analysis P = 5.29 × 10-22 , odds ratio 0.84 [95% confidence interval 0.81-0.87]). Follow-up bioinformatics and expression quantitative trait locus analysis suggested that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and chromatin immunoprecipitation-real-time quantitative polymerase chain reaction, we demonstrated substantial allele-specific promoter and enhancer activity, and allele-specific binding of 3 histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), CCCTC-binding factor, and a critical immune transcription factor (interferon regulatory factor 1 [IRF-1]). Chromosome conformation capture revealed long-range chromatin interactions between rs34330 and the promoters of neighboring genes APOLD1 and DDX47, and effects on CDKN1B and the other target genes were directly validated by clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. Finally, CRISPR/dead CRISPR-associated protein 9-based epigenetic activation/silencing confirmed these results. Gene-edited cell lines also showed higher levels of proliferation and apoptosis.ConclusionCollectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA Pol II, and IRF-1 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis. This process could potentially underlie the association of rs34330 with SLE.
- Published
- 2021
47. Associations Between Smoking and Systemic Lupus Erythematosus–Related Cytokines and Chemokines Among US Female Nurses
- Author
-
Jill Hahn, Bing Lu, Judith A. James, Laura D. Kubzansky, Xinyi Liu, Candace H. Feldman, Melissa E. Munroe, Elizabeth W. Karlson, Andrea L. Roberts, Susan Malspeis, Cianna Leatherwood, Karen H. Costenbader, and Jeffrey A. Sparks
- Subjects
Time Factors ,Anti-nuclear antibody ,medicine.medical_treatment ,Nurses ,Risk Assessment ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Risk Factors ,B-Cell Activating Factor ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Prospective Studies ,Risk factor ,B-cell activating factor ,Aged ,Autoantibodies ,030203 arthritis & rheumatology ,Smokers ,Systemic lupus erythematosus ,biology ,business.industry ,Smoking ,Autoantibody ,Non-Smokers ,Middle Aged ,medicine.disease ,United States ,Interleukin-10 ,Cross-Sectional Studies ,Cytokine ,Immunology ,biology.protein ,Women's Health ,Female ,Antibody ,Ex-Smokers ,business ,Biomarkers - Abstract
OBJECTIVE Smoking has been associated with increased systemic lupus erythematosus (SLE) risk, but the biologic basis for this association is unknown. Our objective was to investigate whether women's smoking was positively associated with SLE-associated proinflammatory chemokines/cytokines (stem cell factor [SCF], B lymphocyte stimulator [BLyS], interferon-γ-inducible 10-kd protein [IP-10], and interferon-α); or negatively associated with antiinflammatory cytokine interleukin-10 (IL-10); and whether associations were modified by SLE-related autoantibody status. METHODS The Nurses' Health Study (NHS, n = 121,700) and NHSII (n = 116,429) cohorts were begun in 1976 and 1989. In 1988-1990 (NHS) and 1996-1999 (NHSII), ~25% of participants donated blood samples. We identified 1,177 women without SLE with banked samples, and we tested by enzyme-linked immunoassay (ELISA) for chemokines/cytokines as well as anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP. Antinuclear antibodies (ANAs) were detected by HEp-2 cell indirect immunofluorescence, and anti-double-stranded DNA antibodies and were assayed by ELISA. Smoking was assessed until blood draw. Separate tobit and linear regression analyses, adjusted for potential confounders, modeled associations between smoking and log-transformed chemokine/cytokine concentrations. Analyses were stratified by autoantibody status. Effect estimates were calculated as ratios of geometric means expressed as percentage differences. RESULTS Among the 15% of current/recent versus 85% of past/never smokers, BLyS levels were 8.7% higher (P < 0.01) and were 24% higher (P < 0.0001) among those who were ANA positive. Current/recent smokers had IL-10 concentrations 46% lower (P < 0.01) than past/never smokers; each 10 pack-years of smoking was associated with a 17% decrease in IL-10 level (P < 0.001). Smoking was not associated with IP-10 or SCF. CONCLUSION Elevated BLyS and lower IL-10 levels among current smokers, particularly among ANA-positive women, may be involved in SLE pathogenesis.
- Published
- 2021
48. Genetic load in incomplete lupus erythematosus
- Author
-
Matt Slief, Joseph Kheir, Miles Smith, Colin Mowery, Susan Macwana, Wade DeJager, Catriona A. Wagner, Teresa Aberle, Judith A. James, and Joel M. Guthridge
- Subjects
Rheumatology ,immune system diseases ,General Medicine ,skin and connective tissue diseases - Abstract
ObjectivePatients with incomplete lupus erythematosus (ILE) have lupus features but insufficient criteria for SLE classification. Some patients with ILE transition to SLE, but most avoid major organ involvement. This study tested whether the milder disease course in ILE is influenced by reduced SLE risk allele genetic load.MethodsWe calculated the genetic load based on 99 SLE-associated risk alleles in European American patients with SLE (≥4 American College of Rheumatology (ACR) 1997 criteria, n=170), patients with ILE (3 ACR 1997 criteria, n=169), a subset of patients with ILE not meeting Systemic Lupus International Collaborating Clinics (SLICC) classification (ILESLICC, n=119) and healthy controls (n=133). Unweighted genetic loads were calculated as the total sum of risk alleles for each individual, while weighted genetic loads were defined as the sum of risk alleles multiplied by the natural logarithm of the previously published OR of each risk allele for SLE susceptibility.ResultsThe median unweighted and weighted SLE risk allele genetic load was significantly greater in patients with ILE (unweighted: 81, p value=0.01; weighted: 16.3, p value=0.001) and patients with SLE (80, p value=0.02; 16.29, p value=0.0006) compared with healthy controls (78, 15.76). Patients with ILESLICCtrended towards an increased genetic load, although not statistically significant (unweighted: 80, p value=0.14; weighted: 16.05, p value=0.07). However, the median genetic load did not significantly differ between ILE and SLE, and genetic load did not differentiate patients with ILE and SLE (area under the curve=0.51, p=0.78) by receiver operator characteristic analysis.ConclusionsPatients with ILE and SLE have comparable genetic loads of SLE risk loci, suggesting similar genetic predispositions between these conditions. Phenotypical differences between SLE and ILE may instead be influenced by ILE-specific variants and gene–environment interactions.
- Published
- 2022
49. Dysregulated long non-coding RNA in Sjögren's disease impacts both interferon and adaptive immune responses
- Author
-
Michelle L Joachims, Bhuwan Khatri, Chuang Li, Kandice L Tessneer, John A Ice, Anna M Stolarczyk, Nicolas Means, Kiely M Grundahl, Stuart B Glenn, Jennifer A Kelly, David M Lewis, Lida Radfar, Donald U Stone, Joel M Guthridge, Judith A James, R Hal Scofield, Graham B Wiley, Jonathan D Wren, Patrick M Gaffney, Courtney G Montgomery, Kathy L Sivils, Astrid Rasmussen, A Darise Farris, Indra Adrianto, and Christopher J Lessard
- Subjects
Sjogren's Syndrome ,Rheumatology ,Calcineurin ,Immunology ,Immunity ,Receptors, Antigen, T-Cell ,Immunology and Allergy ,Humans ,RNA, Long Noncoding ,Interferons ,Antiviral Agents ,Autoimmune Diseases ,Autoantibodies - Abstract
ObjectiveSjögren’s disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjDRo+) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised.MethodsWhole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjDRo−); n=27 Ro/SSA positive (SjDRo+) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log2fold change ≥2 or ≤0.5; padjLINC01871was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targetedLINC01871deletion (LINC01871−/−) and in vitro stimulation assays.ResultsWhole blood RNA-seq revealed autoantibody-specific transcription profiles and disproportionate downregulation of DE transcripts in SjD cases relative to HCs. Sixteen DE lncRNAs exhibited correlated expression with the interferon (IFN)-regulated gene,RSAD2, in SjDRo+(r≥0.65 or ≤−0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines.LINC01871was upregulated in all SjD cases. RNA-seq and pathway analyses ofLINC01871−/−cells implicated roles in cytotoxic function, differentiation and IFNγ induction.LINC01871was induced by IFNγ in a myeloid cell line and regulated by calcineurin/NFAT pathway and T cell receptor (TCR) signalling in primary human T cells.ConclusionLINC01871influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. AlteredLINC01871expression may influence the dysregulated T cell inflammatory pathways implicated in SjD.
- Published
- 2022
50. Autoantibodies identify primary Sjögren’s syndrome in patients lacking serum IgG specific for Ro/SS-A and La/SS-B
- Author
-
Sherri Longobardi, Charmaine Lopez-Davis, Bhuwan Khatri, Constantin Georgescu, Cherilyn Pritchett-Frazee, Christina Lawrence, Astrid Rasmussen, Lida Radfar, Robert Hal Scofield, Alan N Baer, Susan A Robinson, Erika Darrah, Robert C Axtell, Gabriel Pardo, Jonathan D Wren, Kristi A Koelsch, Joel M Guthridge, Judith A James, Christopher J Lessard, and Amy Darise Farris
- Subjects
Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
ObjectiveIdentify autoantibodies in anti-Ro/SS-A negative primary Sjögren’s syndrome (SS).MethodsThis is a proof-of-concept, case-control study of SS, healthy (HC) and other disease (OD) controls. A discovery dataset of plasma samples (n=30 SS, n=15 HC) was tested on human proteome arrays containing 19 500 proteins. A validation dataset of plasma and stimulated parotid saliva from additional SS cases (n=46 anti-Ro+, n=50 anti-Ro–), HC (n=42) and OD (n=54) was tested on custom arrays containing 74 proteins. For each protein, the mean+3 SD of the HC value defined the positivity threshold. Differences from HC were determined by Fisher’s exact test and random forest machine learning using 2/3 of the validation dataset for training and 1/3 for testing. Applicability of the results was explored in an independent rheumatology practice cohort (n=38 Ro+, n=36 Ro–, n=10 HC). Relationships among antigens were explored using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) interactome analysis.ResultsRo+SS parotid saliva contained autoantibodies binding to Ro60, Ro52, La/SS-B and muscarinic receptor 5. SS plasma contained 12 novel autoantibody specificities, 11 of which were detected in both the discovery and validation datasets. Binding to ≥1 of the novel antigens identified 54% of Ro–SS and 37% of Ro+SS cases, with 100% specificity in both groups. Machine learning identified 30 novel specificities showing receiver operating characteristic area under the curve of 0.79 (95% CI 0.64 to 0.93) for identifying Ro–SS. Sera from Ro–cases of an independent cohort bound 17 of the non-canonical antigens. Antigenic targets in both Ro+and Ro–SS were part of leukaemia cell, ubiquitin conjugation and antiviral defence pathways.ConclusionWe identified antigenic targets of the autoantibody response in SS that may be useful for identifying up to half of Ro seronegative SS cases.
- Published
- 2023
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.