Liam J. O’Neil's research while affiliated with University of Manitoba and other places

Publications (25)

Article
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Objectives The development of autoantibody directed towards citrullinated proteins (ACPA) are predictive of RA in at-risk individuals. The biological events that underpin loss of immune tolerance and progression into inflammatory arthritis are not known. We sought to identify serum proteomic alterations that drive autoantibody formation, persistenc...
Article
Neutrophils are the most abundant leukocytes in human blood and are essential components of innate immunity. Until recently, neutrophils were considered homogeneous and transcriptionally inactive cells, but both concepts are being challenged. Single-cell RNA sequencing (scRNA-seq) offers an unbiased view of cells along a continuum of transcriptiona...
Article
Full-text available
Background Despite immune cell dysregulation being an important event preceding the onset of rheumatoid arthritis (RA), the phenotype of T and B cells in preclinical RA is less understood. The aim of this study was to characterize T and B cell populations in RA patients and their autoantibody (aAb) negative and positive first-degree relatives (FDR)...
Article
Full-text available
Objective Rheumatoid arthritis is a chronic inflammatory autoimmune disease that can lead to synovial damage, persistent joint pain, and functional disability. Our objective was to evaluate baseline synovial transcriptome from early inflammatory arthritis patients (EIA) and identify pretreatment biomarkers that could potentially provide insights in...
Preprint
Neutrophils are the most abundant leukocytes in human blood and are essential components of innate immunity. Until recently, neutrophils were considered homogeneous and transcriptionally inactive cells, but both concepts are being challenged. To date, neutrophils have been characterized based on discrete parameters including cell-surface markers, b...
Article
Objective The events that occur prior to the onset of rheumatoid arthritis (RA) continue to be delineated. We examined the relationship between self-reported joint symptoms, functional disability, and anticitrullinated protein antibody (ACPA) status in a cohort of first-degree relatives (FDR) of RA patients who are at risk of future disease develop...
Article
Full-text available
Objectives Patients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum proteomic alterations that dictate clinically important features of stable RA, and couple broad-based...
Article
Hidradenitis suppurativa (HS), also known as acne inversa, is a debilitating inflammatory skin disorder that is characterized by nodules that lead to the development of connected tunnels and scars as it progresses from Hurley stage I to III. HS has been associated with several autoimmune diseases, including inflammatory bowel disease (IBD) and spon...
Article
Full-text available
Rheumatoid arthritis (RA) is a prevalent autoimmune disorder in which complex genetic predisposition interacts with multiple environmental factors to precipitate chronic and progressive immune-mediated joint inflammation. Currently, in most affected individuals, ongoing suppression of the inflammation is required to prevent irreversible damage and...
Article
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Objective Antibodies against carbamylated proteins (anti-CarP) are associated with poor prognosis and the development of bone erosions in rheumatoid arthritis (RA). RA neutrophils externalize modified autoantigens through the formation of neutrophil extracellular traps (NETs). Increased levels of the cathelicidin LL37 have been documented in the sy...
Article
The discovery that autoantibodies and other factors can predict the future onset of rheumatoid arthritis (RA) has encouraged the development of clinical trials looking at RA prevention. Although an exciting area of research, finding an approach that results in the successful completion of an RA prevention trial is challenging.
Article
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Background: Co-occurrence of autoantibodies specific for more than one autoimmune disease is widely prevalent in rheumatoid arthritis (RA) patients. To understand the prevalence of polyautoimmunity in preclinical RA, we performed a comprehensive autoantibody assessment in a First Nations (FN) cohort of at-risk first-degree relatives (FDR) of RA pa...
Article
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Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antigens and the mechanisms by which anti-CarP antibodies promote bone erosion in RA remain unknown. Here, we find that neutrophil extracellular traps (NETs) externalize carbamy...
Article
Objectives The pathophysiologic events that precede the onset of Rheumatoid Arthritis (RA) remain incompletely understood. We aimed to identify changes in the serum proteome that precede RA and provide new insights into the pathogenic mechanisms that lead to its development. Methods We studied a cohort of first‐degree relatives (FDR) of Indigenous...
Article
Full-text available
Significance Despite clear differences in female and male immunity that may contribute to variations in response to infections and predisposition to cancer and autoimmunity, the exact mechanisms that drive this stark contrast remain insufficiently characterized. Neutrophils play essential roles in homeostasis and disease, but little is known about...
Article
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Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immun...
Article
Neutrophil dysregulation is implicated in the pathogenesis of systemic lupus erythematosus (SLE). SLE is characterized by elevated levels of a pathogenic neutrophil subset known as low-density granulocytes (LDGs). The origin and phenotypic, functional, and pathogenic heterogeneity of LDGs remain to be systematically determined. Transcriptomics and...
Article
Full-text available
Hidradenitis suppurativa (HS), also known as acne inversa, is an incapacitating skin disorder of unknown etiology manifested as abscess-like nodules and boils resulting in fistulas and tissue scarring as it progresses. Given that neutrophils are the predominant leukocyte infiltrate in HS lesions, the role of neutrophil extracellular traps (NETs) in...
Article
Gallstone formation in adults is a common, yet incompletely understood disease process. In this issue, Muñoz et al. (2019) report a pathogenic link between neutrophil extracellular traps (NETs) and the formation of gallstones.
Article
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Systemic lupus erythematosus (SLE) is an autoimmune syndrome of unknown etiology, characterized by multi-organ inflammation and clinical heterogeneity. SLE affects mostly women and is associated with a high risk of cardiovascular disease. As the therapeutic management of SLE improved, a pattern of early atherosclerotic disease became one of the hal...
Article
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Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vascu...
Article
Rheumatoid arthritis (RA), a common autoimmune disease, is characterized by a highly coordinated inflammatory response that involves innate and adaptive immunity. One of the hallmarks of RA is an immune response directed at citrullinated peptides that are specifically targeted by anticitrullinated protein antibodies (ACPAs). Among the various mecha...
Article
Full-text available
The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in...

Citations

... There is also a lack of standard datasets to provide a reliable comparison for abnormal samples. Nonetheless, creating clinical connections using aptamer data is undergoing active progress across medical disciplines [35,[99][100][101]. The goals of aptamer-based data intersecting with AI currently focus largely on diagnosis [35,99,100] evolving into response assessment [101], with few publications exploring ML to examine management or prognosis. ...
... Autoantibody data was unavailable for 2 RA patients. Neither of the two FDR groups had clinically detectable RA, although as we previously reported, joint symptoms were prevalent in this population irrespective of their seropositivity status (16). Of note, the aAb+ FDR group was comprised of 3 individuals who were positive for ACPA only (222.5 ± 83.2 U/mL; mean ± SD), 3 individuals who were positive for RF only (27.9 ± 8.9 IU/mL; mean ± SD), and 4 individuals who were positive for both ACPA (59.6 ± 21.9 U/ mL) and RF (231.5 ± 331 IU/mL). 1 + CD4 T cells was used to calculate the ratio. ...
... However, the role of prominent B-cell and plasma cell infiltrates has not been incorporated into pathogenic understanding of the disease. In their new article in the Journal of Investigative Dermatology, Carmona-Rivera et al. (2021) present new insights regarding autoantibody-mediated macrophage activation, which bridges the link between the innate and adaptive immune responses in severe hidradenitis suppurativa. ...
... The introduction of genomic science to clinical practice and health research introduces both possibilities and challenges to address health inequities which Indigenous and racialized communities encounter in ways that are significant and institutional. Over the past decade, genomic science has produced novel tools for preventative screening particularly as it concerns chronic diseases, such as rheumatoid arthritis, gout, diabetes, a limited number of cardiac events, and adverse reactions to anesthetic (among others), many of which can be prevalent in some, but certainly not all, Indigenous and racialized communities in Canada (Fowler-Woods et al. 2021;Crowshoe et al. 2019;Nakatsuka et al. 2017). However promising these tools claim to be, the exploitation of biological and genetic data of Indigenous communities in particular since the 1980s (and continuing to the present) makes First Nations rightfully weary of participating in conventional genetic screening studies. ...
... Auto-immunity and periodontitis are connected in many ways. Patients with autoimmune conditions such as Lupus or RA are known to be more prone to developing periodontitis (55,108). Bone destruction in periodontitis shares similarities with tissue damage observed during RA and presents a TH17 cytokines overexpression that can be also found in RA, Lupus psoriasis, and many other autoimmune conditions (109,110). ...
... All this information provides a "window of opportunity" for secondary prevention. Although an exciting theory, attempts to prevent the development of RA in clinical trials have been unsuccessful so far (Deane and Holers, 2021;O'Neil and Deane, 2021). ...
... The immunological mechanisms that underlie the development of the RA autoantibodies, and the progression towards pathogenic autoimmunity in specific individuals, remain unclear. Although alterations in circulating cytokines and chemokines detected in readily accessible serum/plasma samples have provided important clues in this regard (3,10,17,18), disturbances in immune cell populations have not been defined, primarily because of the difficulty in obtaining suitable samples from atrisk individuals. In the current study, we used multiparametric flow cytometry to profile peripheral blood T and B lymphocytes in a cohort of RA autoantibody positive at-risk individuals and compared them to autoantibody negative individuals from the same population, and to RA patients with established disease. ...
... Apart from causing damage in RA joints, NETs can further provide a scaffold for the alternative pathway, increasing formation of C5a and acting as an amplification loop for C5a production, recruitment of neutrophils into the joint, NET production, and cartilage and bone damage (Figure 2). Targeting C5a or the C5aR might thus be a viable solution for modulating NET formation in RA, thus preventing the destruction of cartilage (Carmona-Rivera et al., 2020) and bone (O'Neil et al., 2020) and reducing endothelial cell damage (Schreiber et al., 2017). In agreement, both genetic ablation or pharmacological inhibition of the C5a-C5aR axis improved arthritis or prevented the disease in animal studies (Wang et al., 1995;Goodfellow et al., 2000;Ames et al., 2001;Grant et al., 2002;Ji et al., 2002;Woodruff et al., 2002;Katschke et al., 2007;Banda et al., 2012). ...
... As such, we have characterized the ACPA themselves and shown that epitope spreading (5), and a high degree of variable region glycosylation (18) were both associated with clinical disease development. Moreover, we used exploratory broad-based proteomic approaches to detect proteomic signatures that predicted RA development with a high degree of accuracy (19). These signatures were enriched for proteins associated with innate immune mechanisms. ...
... Transcriptomics analysis showed that only circulating neutrophils in females upregulated the type I interferon (IFN) pathway and were hyperresponsive to type I IFNs (Gupta S et al., 2020). Female plasmacytoid dendritic cells also produced higher level of IFN- upon TLR7/9 activation, which was attributed to the X chromosome and female sex hormones (Berghofer B et al., 2006). ...