Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE.

OBJECTIVES: Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, and an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to suppress production of IL-17 and IL-21 by SLE T cells or human Th17 cells. METHODS: ROCK activity in peripheral blood mononuclear cells (PBMCs) from 29 patients with SLE, 31 patients with RA and 28 healthy controls was determined by ELISA. SLE T cells or in vitro-differentiated Th17 cells were treated with Y27632 (a pan-ROCK inhibitor), KD025 (a selective ROCK2 inhibitor) or simvastatin (which inhibits RhoA, a major ROCK activator). ROCK activity and IL-17 and IL-21 production were assessed. The transcriptional profile altered by ROCK inhibitors was evaluated by NanoString technology. RESULTS: ROCK activity levels were significantly higher in patients with SLE and RA than healthy controls. Th17 cells exhibited high ROCK activity that was inhibited by Y27632, KD025 or simvastatin; each also decreased IL-17 and IL-21 production by purified SLE T cells or Th17 cells. Immune profiling revealed both overlapping and distinct effects of the different ROCK inhibitors. CONCLUSIONS: ROCK activity is elevated in PBMCs from patients with SLE and RA. Production of IL-17 and IL-21 by SLE T cells or Th17 cells can furthermore be inhibited by targeting the RhoA-ROCK pathway via both non-selective and selective approaches.

The association between COVID-19-related stressors and mental health outcomes for survivors of past interpersonal and non-interpersonal trauma.

The mental health difficulties of trauma survivors during the COVID-19 pandemic have been under-reported. This study explored the moderating role of trauma history and trauma type (interpersonal and non-interpersonal) in the association between COVID-19-related stressors and depression, anxiety, and stress. A sample of n = 321 participants ages 19 to 71 (M = 36.63, SD = 10.36) was recruited from across the United States through MTurk. Participants reported the number of COVID-19-related stressors, trauma history and psychological symptoms. Hierarchical multiple regression analyses, controlling for age, race, ethnicity, gender, education, and income levels, were used to determine (a) whether COVID-19-related stressors are associated with adverse mental health outcomes; (b) whether trauma history and (c) trauma type moderated this association. Results revealed significant interactions; for those with a trauma history, exposure to COVID-19-related stressors was associated with higher levels of depression (ß = .21, p < .05) and anxiety (ß = .19, p < .05). For those with a history of interpersonal trauma specifically, COVID-19-related stressors were associated with depression (ß = .16, p < .05) more so than for those without a trauma history. These findings highlight the vulnerability of trauma survivors to the unprecedented COVID-19-related stress.

Quality of the sibling relationship when one sibling has autism spectrum disorder: A randomized controlled trial of a sibling support group.

LAY ABSTRACT: The sibling relationship can be negatively impacted when one child has autism spectrum disorder. One way to improve the quality of that relationship is through typically developing sibling participation in a support group in which they learn about autism spectrum disorder and coping skills, develop a peer network, and discuss their feelings. Compared to participating in a similar group without a focus on autism spectrum disorder, siblings in the support group showed improvements in the quality of the sibling relationship. Findings suggest that sibling support groups can be a valuable resource to improve sibling relationship quality when one sibling has autism spectrum disorder.