SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis.

Introduction: Natural killer (NK) cells plays a pivotal role in the control of viral infections, and their function depend on the balance between their activating and inhibitory receptors. The immune dysregulation observed in COVID-19 patients was previously associated with downregulation of NK cell numbers and function, yet the mechanism of inhibition of NK cell functions and the interplay between infected cells and NK cells remain largely unknown. Methods: In this study we show that SARS-CoV-2 infection of airway epithelial cells can directly influence NK cell phenotype and functions in the infection microenvironment. NK cells were co-cultured with SARS-CoV-2 infected epithelial cells, in a direct contact with A549ACE2/TMPRSS2 cell line or in a microenvironment of the infection in a 3D ex vivo human airway epithelium (HAE) model and NK cell surface expression of a set of most important receptors (CD16, NKG2D, NKp46, DNAM-1, NKG2C, CD161, NKG2A, TIM-3, TIGIT, and PD-1) was analyzed. Results: We observed a selective, in both utilized experimental models, significant downregulation the proportion of CD161 (NKR-P1A or KLRB1) expressing NK cells, and its expression level, which was followed by a significant impairment of NK cells cytotoxicity level against K562 cells. What is more, we confirmed that SARS-CoV-2 infection upregulates the expression of the ligand for CD161 receptor, lectin-like transcript 1 (LLT1, CLEC2D or OCIL), on infected epithelial cells. LLT1 protein can be also detected not only in supernatants of SARS-CoV-2 infected A549ACE2/TMPRSS2 cells and HAE basolateral medium, but also in serum of COVID-19 patients. Finally, we proved that soluble LLT1 protein treatment of NK cells significantly reduces i) the proportion of CD161+ NK cells, ii) the ability of NK cells to control SARS-CoV-2 infection in A549ACE2/TMPRSS2 cells and iii) the production of granzyme B by NK cells and their cytotoxicity capacity, yet not degranulation level. Conclusion: We propose a novel mechanism of SARS-CoV-2 inhibition of NK cell functions via activation of the LLT1-CD161 axis.

Real-world experience of rituximab biosimilar GP2013 in rheumatoid arthritis patients naïve to or switched from reference rituximab.

Randomized controlled trials showed high comparability of biosimilar rituximab (bs-RTX) GP2013 to biologic originator RTX (bo-RTX). Data on effectiveness of switching from bo-RTX to bs-RTX, starting therapy with bs-RTX, and bs-RTX drug survival in real-world setting are sparse. To explore long-term drug effectiveness and survival of bs-RTX GP2013 in rheumatoid arthritis (RA) patients both naïve to and mandatory switched from bo-RTX, and to clarify reasons for treatment cessation. Retrospective observational cohort study including RA outpatient clinic patients treated with bs-RTX between 2018 and 2021 in Norway. Patients were examined and monitored using recommended measures for disease activity and patient-reported outcomes (PROs). For description of population medians and interquartile range were used. Difference between observation times was assessed with Signed-Rank test, drug survival with Kaplan-Meier survival analysis. Reasons for discontinuation were ascertained. Among 110 patients, at baseline, 88 were mandatory switched from bo-RTX and 22 were RTX-naïve. During 2-year follow-up, disease activity and PROs measures remained stable in switchers subgroup and improved in subgroup starting bs-RTX for the first time. Overall drug survival was 80.0% after 1 year and 57.7% after 2 years and was significantly higher in bs-RTX-switched than in bs-RTX-naïve patients (p = 0.036). Two most frequently reported reasons for drug discontinuation were remission (38.6%) and doctor's decision (27.1%). RA patients treated with bs-RTX had satisfactory treatment response and drug retention rates which supports equivalence of bs-RTX GP2013 to bo-RTX, both in patients naïve to and mandatory switched from bo-RTX.

Reactive arthritis after vaccination against SARS-CoV-2: A case series and a mini-review.

The rapid development of COVID-19 vaccines became essential for addressing the global pandemic. Reactive arthritis after vaccination has been a rare phenomenon. Here, we present a case series of three patients with joint inflammation possibly attributed to COVID-19 immunization (mRNA and live adenovirus vectored vaccine). Symptoms were alleviated using non-steroid anti-inflammatory drugs and glucocorticoids. After follow-up, the patients have not been diagnosed with any other rheumatic disease. Reactive arthritis after the COVID-19 vaccine is an unusual adverse effect and poses a negligible risk in comparison to the benefits of immunization, but it should be considered in differential diagnostics by a practicing rheumatologist who cares for patients with new-onset arthritis without apparent cause at the time of pandemic.

Chemerin as a Potential Marker of Resolution of Inflammation in COVID-19 Infection.

Chemerin is one of the specialized pro-resolving mediators that participate in the early phase of inflammation and contribute to the initiation of the pro-resolving response. There is a paucity of data regarding the time course of chemerin during acute infections. We aimed to evaluate the sequence of inflammatory responses in the acute COVID-19 phase throughout onset and resolution of inflammation. We evaluated changes in selected biomarkers in COVID-19 survivors on the 7-day and 28-day follow up. Chemerin was lower in patients with baseline moderate/severe disease at day 7 compared with asymptomatic patients and individuals with mild illness (7265 [5526-9448] vs. 8730 [6888-11,058] pg/mL; p = 0.03). Only in patients with moderate/severe disease, but not in those with mild symptoms, were chemerin concentrations decreased one week after infection onset compared with baseline (7265 [5526-9448] vs. 8866 [6383-10,690] pg/mL; p < 0.05) with a subsequent increase on the 28-day follow up (9313 [7353-11,033] pg/mL; p < 0.05). Resolution of inflammation in the group of moderate/severe SARS-CoV2 infection was associated with increasing serum concentrations of chemerin, contrary to pro-inflammatory cytokines and adipokines (pentraxin 3, TNFα, resistin, leptin). A similar pattern of angiopoietin-2 dynamics may suggest signs of enhanced vascularization as a consequence of acute SARS-CoV2 infection.

Association between cardiovascular disease, cardiovascular drug therapy, and in-hospital outcomes in patients with COVID-19: data from a large single-center registry in Poland.

BACKGROUND: The coronavirus disease 19 (COVID-19) recently became one of the leading causes of death worldwide, similar to cardiovascular disease (CVD). Coexisting CVD may influence the prognosis of patients with COVID-19. AIMS: We analyzed the impact of CVD and the use of cardiovascular drugs on the in-hospital course and mortality of patients with COVID-19. METHODS: We retrospectively studied data for consecutive patients admitted to our hospital, with COVID-19 between March 6th and October 15th, 2020. RESULTS: 1729 patients (median interquartile range age 63 [50-75] years; women 48.8%) were included. Overall, in-hospital mortality was 12.9%. The most prevalent CVD was arterial hypertension (56.1%), followed by hyperlipidemia (27.4%), diabetes mellitus (DM) (25.7%), coronary artery disease (16.8%), heart failure (HF) (10.3%), atrial fibrillation (13.5%), and stroke (8%). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) were used in 25.0% of patients, ß-blockers in 40.7%, statins in 15.6%, and antiplatelet therapy in 19.9%. Age over 65 years (odds ratio [OR], 6.4; 95% CI, 4.3-9.6), male sex (OR, 1.4; 95% CI, 1.1-2.0), pre-existing DM (OR, 1.5; 95% CI, 1.1-2.1), and HF (OR, 2.3; 95% CI, 1.5-3.5) were independent predictors of in-hospital death, whereas treatment with ACEIs/ARBs (OR, 0.4; 95% CI, 0.3-0.6), ß-blockers (OR, 0.6; 95% CI, 0.4-0.9), statins (OR, 0.5; 95% CI, 0.3-0.8), or antiplatelet therapy (OR, 0.6; 95% CI: 0.4-0.9) was associated with lower risk of death. CONCLUSIONS: Among cardiovascular risk factors and diseases, HF and DM appeared to increase in-hospital COVID-19 mortality, whereas the use of cardiovascular drugs was associated with lower mortality.