Biology subjects

Scofield, R. H.

Publications and source records attributed to Scofield, R. H..

3 recordsLinked to original sources

bioRxiv2024

Mitochondrial Dysfunction and Fatigue in Sjögren's Disease

ObjectivesSjogrens disease (SjD) is a common exocrine disorder typified by chronic inflammation and dryness, but also profound fatigue, suggesting a pathological basis in cellular bioenergetics. In healthy states, damaged or dysfunctional mitochondrial components are broken down and recycled by mitophagy, a specialized form of autophagy. In many autoimmune disorders, however, evidence suggests that dysfunctional mitophagy allows poorly functioning mitochondria to persist and contribute to a cellular milieu with elevated reactive oxygen species. We hypothesized that mitophagic processes are dysregulated in SjD and that dysfunctional mitochondria contribute to overall fatigue. We sought to link fatigue with mitochondrial dysfunction directly in SjD, heretofore unexamined, and further sought to assess the pathogenic extent and implications of dysregulated mitophagy in SjD. MethodsWe isolated pan T cells via negative selection from the peripheral blood mononuclear cells of 17 SjD and 8 age-matched healthy subjects, all of whom completed fatigue questionnaires prior to phlebotomy. Isolated T cells were analyzed for mitochondrial oxygen consumption rate (OCR) and glycolysis using Seahorse, and linear correlations with fatigue measures were assessed. A mitophagy transcriptional signature in SjD was identified by reanalysis of whole-blood microarray data from 190 SjD and 32 healthy subjects. Differential expression analyses were performed by case/control and subgroup analyses comparing SjD patients by mitophagy transcriptional cluster against healthy subjects followed by bioinformatic interpretation using gene set enrichment analysis. ResultsBasal OCR, ATP-linked respiration, maximal respiration, and reserve capacity were significantly lower in SjD compared to healthy subjects with no observed differences in non-mitochondrial respiration, basal glycolysis, or glycolytic stress. SjD lymphocytic mitochondria show structural alterations compared to healthy subjects. Fatigue scores related to pain/discomfort in SjD correlated with the altered OCR. Results from subgroup analyses by mitophagic SjD clusters revealed highly variable inter-cluster differentially expressed genes (DEGs) and expanded the number of SjD-associated gene targets by tenfold within the same dataset. ConclusionMitochondrial dysfunction, associated with fatigue, is a significant problem in SjD and warrants further investigation.

immunology↗

bioRxiv2023

Increased atherosclerotic plaque and anti-oxidized low density lipoprotein in anti-Ro60 SLE autoantibody subset

ObjectivePremature atherosclerosis is associated with systemic lupus erythematosus (SLE). We previously showed an association of anti-Ro60/La/Ro52 to anti-oxidized LDL in SLE. Here, we hypothesized that atherosclerotic plaque will be associated with anti-oxidized LDL (anti-oxLDL)/anti-lipoprotein lipase (ALPL) in a specific SLE autoantibody sub-set (anti-Ro60 positive, anti-RNP positive or extractable nuclear antigen antibody negative). MethodsWe carried out a case-control study (one time-point testing) of plaque, ALPL, anti-oxLDL, anti-low density lipoprotein (ALDL) or anti-LDL in 114 SLE and 117 age/sex matched controls. Total cholesterol, LDL, HDL, triglycerides, and HDL-Trig were also measured. Students t test was used for statistical analysis ResultsInterestingly, plaque was highest in SLE subset with anti-Ro60 (23/114). Plaque and anti-oxLDL were statistically significantly elevated in the anti-Ro60 SLE subset (1.3 +/-1.66, p<0.01; 0.26 +/-0.16, p<0.002 respectively) compared to controls (0.54 +/-1.26; 0.165 +/-0.13 respectively), but not anti-LPL/anti-LDL. Plaque was significantly elevated (0.9 +/-1.71; p< 0.05) in the SLE subset without anti-ENA (63/114) compared to controls. Other antibodies in this subset were not statistically different compared to other SLE subsets or controls. Only anti-oxLDL was significantly elevated (0.29 +/-0.27; p<0.005) in SLE subset with anti-RNP (14/114) compared to controls, while none were elevated in anti-SmRNP subset (6/114). We did not find significant differences in lipids between various SLE subsets. ConclusionPlaque segregates in anti-Ro and ENA negative groups either with or without anti-oxLDL. It will be clinically important if cardiovascular events are augmented in SLE anti-Ro subset having elevated anti-oxidized LDL antibodies. Key pointsO_LIPlaque and anti-oxLDL significantly elevated in anti-Ro60 SLE subset C_LIO_LIOnly plaque significantly elevated in SLE subset without antibodies against extractable nuclear antigens C_LIO_LIIt will be clinically important to see if augmented cardiovascular events occur in SLE anti-Ro subset having elevated anti-oxidized LDL antibodies. C_LI

biochemistry↗

bioRxiv2018

Ddx3x regulates B-cell development and light chain recombination in mice

The X chromosome gene, DDX3X, is an ATP-dependent RNA helicase with roles in transcription, splicing, nuclear export, and translation. Loss of function mutations in DDX3X are linked to a variety of neoplasms, including B-cell lymphoma. We find that conditional homozygous deletion (Mb1-Cre) of Ddx3x in developing mouse B cells in female mice results in a complete absence of mature peripheral B cells associated with an absolute block at the pro-B cell stage of development in the bone marrow. In male mice with Vav1-Cre or Mb1-Cre mediated hemizygous deletion of Ddx3x, there are less severe reductions in peripheral B-cell frequencies with skewing towards the marginal zone lineage, suggesting that the Y chromosome homolog Ddx3y or other male factors may partially compensate for loss of Ddx3x. Loss of Ddx3x in male mice is associated with perturbations at developmental time points linked to cell cycle arrest and immunoglobulin chain rearrangement. Mechanistically, loss of Ddx3x in pre-B cells is associated with reduced expression of the histone reader Brwd1, failure to curtail proliferation, and defective Igk rearrangement, which skews the peripheral B cell receptor repertoire toward lambda light chain usage. These data reveal that Ddx3x plays an essential role in B-cell development by supporting proliferative and epigenetic changes necessary for rearrangement of immunoglobulin genes.

immunology↗