RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares

Orange, Dana E.; Yao, Victoria; Sawicka, Kirsty; Fak, John; Frank, Mayu O.; Parveen, Salina; Blachère, Nathalie E.; Hale, Caryn; Zhang, Fan; Raychaudhuri, Soumya; Troyanskaya, Olga G.; Darnell, Robert B.

doi:10.1056/nejmoa2004114

Cited by 122 publications

(129 citation statements)

References 29 publications

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“…It is also not known whether the postpartum flare and a regular (not pregnancy-related) flare in RA share common underlying mechanisms or not. In a recent study of regular flares among 4 patients with RA [ 40 ], only few of the genes reported to have expression patterns associated with a flare overlapped with and showed expression changes in the same direction as the ones that we identified during the postpartum flare (HIC1, NRCAM, ALAS2, S100A12). The lack of commonality in the findings between this study and ours, even though Orange et al used a less stringent significance threshold ( p < 0.1) than we did, suggests that the mechanism(s) underlying the postpartum flare may indeed differ from those of a regular flare.…”

Section: Discussionmentioning

confidence: 52%

Is gene expression among women with rheumatoid arthritis dysregulated during a postpartum flare?

et al. 2021

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Background To evaluate our hypotheses that, when rheumatoid arthritis (RA) flares postpartum, gene expression patterns are altered compared to (a) healthy women, (b) RA women whose disease activity is low or in remission postpartum, and (c) pre-pregnancy expression profiles. Methods Twelve women with RA and five healthy women were included in this pilot study. RA disease activity and postpartum flare were assessed using the Clinical Disease Activity Index (CDAI). Total RNA from frozen whole blood was used for RNA sequencing. Differential gene expression within the same women (within-group) over time, i.e., postpartum vs. third trimester (T3) or pre-pregnancy (T0), were examined, using a significance threshold of q < 0.05 and fold-change ≥ 2. Results Nine of the women with RA experienced a flare postpartum (RAFlare), while three had low disease activity or were in remission (RANoFlare) during that time frame. Numerous immune-related genes were differentially expressed postpartum (vs. T3) during a flare. Fold-changes in expression from T3 to postpartum were mostly comparable between the RAFlare and healthy groups. At 3 months postpartum, compared to healthy women, several genes were significantly differentially expressed only among the RAFlare women, and not among the RANoFlare women. Some of these genes were among those whose “normal” expression was significantly modulated postpartum, and the postpartum expression patterns were significantly altered during the RA flare. There were also some genes that were significantly differentially expressed in RAFlare compared to both healthy and RANoFlare women, even though their expression was not significantly modulated postpartum. Furthermore, while postpartum expression profiles were similar to those at pre-pregnancy among healthy women, significant differences were found between those time points among the RAFlare women. Conclusions The large majority of gene expression changes between T3 and 3 months postpartum among RA women who flared postpartum reflected normal postpartum changes also seen among healthy women. Nonetheless, during a postpartum flare, a set of immune-related genes showed dysregulated expression compared to healthy women and women with RA whose disease activity was low or in remission during the same time frame, while other genes demonstrated significant differences in expression compared to RA pre-pregnancy levels.

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Section: Discussionmentioning

confidence: 52%

Is gene expression among women with rheumatoid arthritis dysregulated during a postpartum flare?

et al. 2021

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“…kidney in SLE or joints in RA). However, a recent hypothesis suggests that activated B cells act on preinflamamtory mesenchymal (PRIME) cells which then migrate to the joint in RA (111). The role of pulmonary mesenchymal cells in inflammation (112) supports the possibility of their interaction with B cells in lung TLSs.…”

Section: Discussionmentioning

confidence: 98%

Perspective: The Lung, Particles, Fibers, Nanomaterials, and Autoimmunity

Pollard

2020

Front. Immunol.

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Studies have shown that a wide range of factors including drugs, chemicals, microbes, and other environmental agents can induce pre-clinical autoimmunity. However, only a few have been confidently linked to autoimmune diseases. Among these are exposures to inhaled particulates that are known to be associated with autoimmune diseases such as lupus and rheumatoid arthritis. In this article, the potential of particle, fiber, and nanomaterial exposures to induce autoimmunity is discussed. It is hypothesized that inhalation of particulate material known to be associated with human autoimmune diseases, such as cigarette smoke and crystalline silica, results in a complex interplay of a number of pathological processes, including, toxicity, oxidative stress, cell and tissue damage, chronic inflammation, post-translational modification of self-antigens, and the formation of lymphoid follicles that provide a milieu for the accumulation of autoreactive B and T cells necessary for the development and persistence of autoimmune responses, leading to disease. Although experimental studies show nanomaterials are capable of inducing several of the above features, there is no evidence that this matures to autoimmune disease. The procession of events hypothesized here provides a foundation from which to pursue experimental studies to determine the potential of other environmental exposures to induce autoimmunity and autoimmune disease.

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“…Many RA patients suffer from periodic arthritic flares, but the mechanisms that promote and sustain bouts of joint inflammation remain poorly understood. Recent investigations suggest a contribution from circulating IgD + immature B lymphocytes and PRIME cells, as well as synovial macrophage populations (8,9). These novel observations are also consistent with our model of lymphatic dysfunction in RA flare 7, as: 1) the circulating IgD + B-cells may be the Bin cells that we observe within the lymphatic sinuses (20,21,35), 2) the circulating PDPN + PRIME cells may be lymphatic endothelial progenitors that are mobilized to repair damaged lymphatic vessels, and 3) the activated adherent macrophages in the lumen of degenerated PLVs (42) are likely from the afferent inflamed synovium (35,43).…”

Section: Discussionmentioning

confidence: 99%

“…Although autoimmune mechanisms underlie the development of RA, the pathways that trigger flare are not well understood, and alternative pathways may contribute to disease exacerbation (7). Although recent gene expression studies have identified potential roles of immature IgD + Bcells, circulating CD45 -/CD31 -/PDPN + pre-inflammatory mesenchymal (PRIME) cells, and synovial macrophages in RA flare (8,9), it is also possible that exacerbation of disease is due to the loss of protective mechanisms in the setting of chronic joint inflammation. One area of interest receiving increased attention in RA is the synovial lymphatic system and its dysfunction, based on animal models and clinical pilots, where the loss of lymphatic drainage of inflamed joints is strongly implicated in the onset of synovitis and disease progression (7,10,11).…”

Section: Introductionmentioning

confidence: 99%

Ex vivo Demonstration of Functional Deficiencies in Popliteal Lymphatic Vessels from TNF-Tg Mice with Inflammatory Arthritis

Scallan

Bouta

Rahimi

et al. 2020

Preprint

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Background: Rheumatoid arthritis (RA) is a progressive immune-mediated inflammatory disease characterized by intermittent episodes of pain and inflammation in affected joints, or flares. Recent studies demonstrated lymphangiogenesis and expansion of draining lymph nodes during chronic inflammatory arthritis, and lymphatic dysfunction associated with collapse of draining lymph nodes in RA patients and TNF-transgenic (TNF-Tg) mice experiencing arthritic flare. As the intrinsic differences between lymphatic vessels afferent to healthy, expanding, and collapsed draining lymph nodes are unknown, we characterized the ex vivo behavior of popliteal lymphatic vessels (PLVs) from WT and TNF-Tg mice. We also interrogated the mechanisms of lymphatic dysfunction through inhibition of nitric oxide synthase (NOS). Methods: Popliteal lymph nodes (PLNs) in TNF-Tg mice were phenotyped as Expanding or Collapsed by in vivo ultrasound and age-matched to WT littermate controls. The PLVs were harvested and cannulated for ex vivo functional analysis over a relatively wide range of hydrostatic pressures (0.5 to 10 cmH2O) to quantify the end diastolic diameter (EDD), tone, amplitude (AMP), ejection fraction (EF), contraction frequency (FREQ) and fractional pump flow (FPF) with or without NOS inhibitors Data was analyzed using repeated measures two-way ANOVA with Bonferroni's post hoc test. Results: Real time videos of the cannulated PLVs demonstrated the predicted phenotypes of robust versus weak contractions of the WT versus TNF-Tg PLV, respectively. Quantitative analyses confirmed that TNF-Tg PLVs had significantly decreased AMP, EF and FPF versus WT (p<0.05). EF and FPF were recovered by NOS inhibition, while the reduction in AMP was NOS independent. No differences in EDD, tone, or FREQ were observed between WT and TNF-Tg PLVs, nor between Expanding versus Collapsed PLVs. Conclusion: These findings support the concept that chronic inflammatory arthritis leads to NOS dependent and independent draining lymphatic vessel dysfunction that exacerbates disease, and may trigger arthritic flare due to decreased egress of inflammatory cells and soluble factors from affected joints.

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RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares

Cited by 122 publications

References 29 publications

Is gene expression among women with rheumatoid arthritis dysregulated during a postpartum flare?

Is gene expression among women with rheumatoid arthritis dysregulated during a postpartum flare?

Perspective: The Lung, Particles, Fibers, Nanomaterials, and Autoimmunity

Ex vivo Demonstration of Functional Deficiencies in Popliteal Lymphatic Vessels from TNF-Tg Mice with Inflammatory Arthritis

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