A B S T R A C TBackground: The clinical and pathologic diversity of systemic lupus erythematosus (SLE) hinders diagnosis, management, and treatment development. This study addresses heterogeneity in SLE through comprehensive molecular phenotyping and machine learning clustering. Methods: Adult SLE patients (n = 198) provided plasma, serum, and RNA. Disease activity was scored by modified SELENA-SLEDAI. Twenty-nine co-expression module scores were calculated from microarray geneexpression data. Plasma soluble mediators (n = 23) and autoantibodies (n = 13) were assessed by multiplex bead-based assays and ELISAs. Patient clusters were identified by machine learning combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators. Findings: SLEDAI scores correlated with interferon, plasma cell, and select cell cycle modules, and with circulating IFN-a, IP10, and IL-1a levels. Co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated in Clusters 1 (moderately) and 4 (strongly), with decreased T cell modules in Cluster 4. Monocyte, neutrophil, plasmablast, B cell, and T cell modules distinguished the remaining clusters. Active clinical features were similar across clusters. Clinical SLEDAI trended highest in Clusters 3 and 4, though Cluster 3 lacked strong interferon and inflammation signatures. Renal activity was more frequent in Cluster 4, and rare in Clusters 2, 5, and 7. Serology findings were lowest in Clusters 2 and 5. Musculoskeletal and mucocutaneous activity were common in all clusters. Interpretation: Molecular profiles distinguish SLE subsets that are not apparent from clinical information. Prospective longitudinal studies of these profiles may help improve prognostic evaluation, clinical trial design, and precision medicine approaches.
Expanded trinucleotide repeat sequences are the cause of several inherited neurodegenerative diseases. Disease pathogenesis is correlated with several features of somatic instability of these sequences, including further large expansions in postmitotic tissues. The presence of somatic expansions in postmitotic tissues is consistent with DNA repair being a major determinant of somatic instability. Indeed, proteins in the mismatch repair (MMR) pathway are required for instability of the expanded (CAG·CTG)n sequence, likely via recognition of intrastrand hairpins by MutSβ. It is not clear if or how MMR would affect instability of disease-causing expanded trinucleotide repeat sequences that adopt secondary structures other than hairpins, such as the triplex/R-loop forming (GAA·TTC)n sequence that causes Friedreich ataxia. We analyzed somatic instability in transgenic mice that carry an expanded (GAA·TTC)n sequence in the context of the human FXN locus and lack the individual MMR proteins Msh2, Msh6 or Pms2. The absence of Msh2 or Msh6 resulted in a dramatic reduction in somatic mutations, indicating that mammalian MMR promotes instability of the (GAA·TTC)n sequence via MutSα. The absence of Pms2 resulted in increased accumulation of large expansions in the nervous system (cerebellum, cerebrum, and dorsal root ganglia) but not in non-neuronal tissues (heart and kidney), without affecting the prevalence of contractions. Pms2 suppressed large expansions specifically in tissues showing MutSα-dependent somatic instability, suggesting that they may act on the same lesion or structure associated with the expanded (GAA·TTC)n sequence. We conclude that Pms2 specifically suppresses large expansions of a pathogenic trinucleotide repeat sequence in neuronal tissues, possibly acting independently of the canonical MMR pathway.
Objective
Incomplete lupus erythematosus (ILE) involves clinical and/or serologic manifestations consistent with but insufficient for SLE classification. Because the nature of ILE is poorly understood and no treatment recommendations exist, we examined clinical manifestations, medication history, and immunologic features in a diverse collection of ILE and SLE patients.
Methods
Medical records of subjects enrolled to the Lupus Family Registry and Repository were reviewed for medication history and American College of Rheumatology (ACR) classification criteria to identify ILE patients (3 ACR criteria; n=440) and SLE patients (≥4 ACR criteria; n=3,397). Participants completed the connective tissue disease screening questionnaire (CSQ). Anti-cardiolipin and plasma BLyS were measured by ELISA, anti-nuclear antibodies by indirect immunofluorescence, and 13 autoantibodies by bead-based assays.
Results
ILE patients were older than SLE patients (46.2 vs. 42.0 y, P<0.0001), and fewer ILE patients were African American (23.9% vs. 32.2%, P<0.001). ILE patients exhibited fewer autoantibody specificities (1.3 vs. 2.6, P<0.0001) than SLE patients and were less likely to have ANA titers ≥1:1080 (10.5% vs. 19.5%,P<0.0001). BLyS levels were intermediate in ILE patients (controls
ObjectivesEpstein-Barr virus (EBV) is considered an important environmental factor in SLE aetiology, but the relationship between SLE and EBV in the Filipino population is unknown. We tested associations between SLE, lupus-associated autoantibodies and seropositivity for EBV and other herpes viruses in the Filipino population.MethodsSera from Filipino patients with SLE (n=233), unaffected first-degree relatives (FDRs, n=543) and unrelated controls (n=221) were tested for antibodies against EBV, cytomegalovirus (CMV) and herpes simplex viruses (HSV-1 and HSV-2) by standardised ELISAs. Humoral specificity against EBV nuclear antigen (EBNA)-1 was compared by solid-phase epitope mapping. Autoantibodies were detected by a bead-based multiplex assay. Results were analysed by Fisher's exact test, Student's t-test, χ2 test and one-way analysis of variance, as appropriate for the question.ResultsFilipino patients with SLE had increased seroprevalence and elevated antibody concentrations against EBV viral capsid antigen (EBV-VCA), CMV, HSV-1 and HSV-2 compared with unrelated controls (p<0.05). Seropositivity for anti-EBV early antigen (EA), a marker of EBV reactivation, was dramatically increased in patients with SLE compared with unrelated controls (92.3% vs 40.4%; OR 17.15(95% CI 10.10, 30.66), p<0.0001) or unaffected FDRs (49.4%; OR 12.04(7.42, 20.74), p<0.0001), despite similar seroprevalence of EBV-VCA in patients and FDRs. In patients with SLE, EBV-EA seropositivity correlated with lupus-associated autoantibodies (p<0.001), most notably with autoantibodies against dsDNA, chromatin, Sm, SmRNP and RNP A (p<0.01). Patient and unrelated control sera reacted to the highly repetitive glycine and alanine domain of EBNA-1. An epitope spanning EBNA-1410-420 was identified in sera of patients with SLE and showed limited binding by FDR and control sera.ConclusionsFilipino patients with SLE have elevated prevalence and concentrations of antibodies against EBV, CMV, HSV-1 and HSV-2 antigens, along with altered anti-EBNA-1 specificities. EBV reactivation is more common among Filipino patients with SLE compared with healthy Filipinos and may contribute to SLE pathogenesis in this population.
Objective To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. Methods pSS patients met American–European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. Results Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell–attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. Conclusion Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.