Dysfunction of CD27+IgD+ B cells correlates with aggravated systemic lupus erythematosus.

OBJECTIVE: The apoptotic signaling pathway is obviously disordered in systemic lupus erythematosus (SLE). Natural IgM (nIgM) is important in clearing apoptotic cells and preventing them from triggering deleterious autoimmunity. B-1 and innate-like B (ILBs) cells are the main nIgM producers. Human CD27+IgD+ B cells (un-switched memory B cells) are considered ILBs. However, their functional properties in SLE remain undefined. METHODS: Peripheral blood sample of 50 SLE patients and 50 healthy controls were collected, and twelve SLE patients were assessed in a follow-up study. The amount of CD27+IgD+ B cell in each population was analyzed by flow cytometry. The IgM and IL-10 levels of CD27+IgD+ B cell were assessed by ELISPOT and qRT-PCR, respectively. SPSS 17.0 (SPSS, USA) was employed for data analysis. P < 0.05 indicated statistical significance. RESULT: The amounts of CD27+IgD+ B cell were significantly decreased in SLE patients than healthy control (P < 0.01). CD27+IgD+ B cell amounts were positively correlated with WBC (r = 0.337, P = 0.017), platelet count (r = 0.396, P = 0.004), and serum C3 levels (r = 0.415, P = 0.003) and negatively correlated with serum creatinine levels (r = - 0.285, P = 0.045), SLEDAI(r = - 0.724, P = 0.000), and anti-dsDNA(r = - 0.477, P = 0.000). The IgM and IL-10 levels of CD27+IgD+ B in active SLE were decreased than healthy control (P < 0.001). Moreover, CD27+IgD+ B cells are increased in SLE cases after treatment than before treatment (P < 0.001). CONCLUSION: The amounts of CD27+IgD+ B cell were significantly decreased in SLE patients compared with the healthy population, and CD27+IgD+ B cell was verified to be correlated with clinical and immunological features in SLE patients. CD27+IgD+ B cells had impaired function associated with IgM and IL-10 production in active SLE. Moreover, the amounts of CD27+IgD+ B cells were recovered to the normal level in SLE cases with treatment-related disease remission. Key Points • CD27+IgD+ B cell amounts are significantly decreased in SLE patients than healthy control. • CD27+IgD+ B cells are functionally impaired in producing natural antibody-like IgM and IL-10 in SLE patients. • CD27+IgD+ B cell amounts are correlated with clinical and immunological features in SLE.

Efficacy and safety of HLX01 in patients with moderate-to-severe rheumatoid arthritis despite methotrexate therapy: a phase 3 study.

BACKGROUND: To evaluate the efficacy and safety of HLX01, a rituximab biosimilar, as combination therapy with methotrexate in Chinese patients with active rheumatoid arthritis who had inadequate responses to methotrexate. METHODS: In this double-blind, placebo-controlled phase 3 trial, biologic-naïve patients with moderate-to-severe active rheumatoid arthritis and inadequate responses to methotrexate were randomized 2:1 to receive 1000 mg HLX01 or placebo intravenously on days 1 and 15. On the first day of weeks 24 and 26, patients in both groups received 1000 mg HLX01 via intravenous infusion. The primary endpoint was the American College of Rheumatology (ACR) 20 response rate at week 24. Secondary endpoints including efficacy, safety, immunogenicity, pharmacokinetics and pharmacodynamics were assessed up to week 48. RESULTS: Between 28 May 2018 and 11 September 2020, 275 patients were randomized to the HLX01 group (n = 183) or the placebo group (n = 92). At week 24, the proportion of patients achieving ACR20 response was significantly greater in the HLX01 group compared with the placebo group in the intention-to-treat population (60.7% vs 35.9%; P < 0.001) and per-protocol set (60.3% vs 37.1%; P < 0.001). Most secondary efficacy endpoints favoured HLX01 when assessed at weeks 12, 24, 36 and 48. Incidences of treatment-emergent adverse events were similar between groups. Infusion-related reactions occurred more frequently following the initial two doses of HLX01 than the subsequent doses. CONCLUSIONS: HLX01 plus methotrexate improved clinical outcomes compared with placebo in Chinese patients with rheumatoid arthritis who had inadequate responses to methotrexate. This treatment regimen was well tolerated, showing comparable safety profiles to placebo. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03522415 . Registered on 11 May 2018.

Long non­coding RNA NEAT1 promotes pulmonary fibrosis by regulating the microRNA­455­3p/SMAD3 axis.

Pulmonary fibrosis is an excessive repair response to tissue damage, triggering hyperplasia of fibrotic connective tissues; however, there is no effective treatment in a clinical setting. The purpose of the present study was to investigate the roles of long non­coding RNA nuclear enriched abundant transcript 1 (NEAT1) and microRNA­455­3p (miR­455­3p) were investigated in pulmonary fibrosis. In this study, the mRNA expression levels of NEAT1, miR­455­3p and SMAD3 in the HPAEpiC alveolar and BEAS­2B bronchial epithelial cell lines were determined using reverse transcription­quantitative PCR, while the markers of epithelial­mesenchymal transformation (EMT) and collagen production were determined using western blot analysis. A wound healing assay was performed to evaluate the migratory ability of the HPAEpiC and BEAS­2B cell lines. The interactions between NEAT1 and miR­455­3p or SMAD3 and miR­455­3p were validated using a luciferase reporter gene assay. The results showed that the mRNA expression levels of NEAT1 and SMAD3 were upregulated in the TGF­ß1­treated HPAEpiC and BEAS­2B cell lines, while the mRNA expression level of miR­455­3p was significantly decreased. In addition, silencing NEAT1 effectively alleviated the migratory ability, EMT and collagen generation of the epithelial cells. Following these experiments, NEAT1 was identified as a sponge for miR­455­3p, and SMAD3 was a target gene of miR­455­3p. NEAT1 downregulation or miR­455­3p mimic inhibited the migratory ability, EMT and collagen production of the epithelial cells; however, the effects were reversed by the overexpression of SMAD3. Furthermore, NEAT1 knockdown reduced the expression level of SMAD3 by increasing the expression level of miR­455­3p to further inhibit the migratory ability, EMT and collagen production of epithelial cells.