Publications

BACKGROUND: Infections are one of the most common causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). SLE patients have a higher risk of tuberculosis (TB) infection due to impaired immune defence. OBJECTIVES: To investigate the demographics, clinical characteristics and outcomes of patients with SLE and concomitant TB. METHODS: Medical records of SLE patients with TB who were admitted to Peking Union Medical College (PUMC) Hospital in 1983-2019 were retrospectively reviewed. Age- and sex-matched SLE inpatients without TB were randomly selected as controls. Clinical and laboratory features and treatment were analysed and compared, and subjects were followed up to assess their outcome. RESULTS: Of the 10 469 SLE inpatients, 249 (2.4%) were diagnosed with TB. Compared with controls, SLE/TB + patients exhibited higher frequency of prior haematologic, mucocutaneous and musculoskeletal system involvement, and prior treatment with potent glucocorticoid/immunosuppressive agents (GC/ISA). Arthritis and alopecia, positive T-SPOT.TB test and lymphocytopenia were more common in SLE/TB + patients. SLE/TB + patients with lupus before TB (SLE –> TB) had higher risk of miliary TB (22.8%) and intracranial TB (16.5%) than SLE/TB + patients with lupus after TB (TB –> SLE). SLE/TB + patients exhibited shorter long-term survival than SLE/TB- patients; those with poorer in-hospital outcomes had more severe lymphocytopenia and had received less treatment with ISAs. CONCLUSION: Systemic lupus erythematosus patients treated vigorously with GC/ISA should be alerted of increased risk of TB infection, especially miliary and intracranial TB. Positive T-SPOT.TB and lymphocytopenia served as discriminatory variables between SLE/TB + and SLE/TB- patients. Lymphocytopenia was associated with poorer outcomes in SLE/TB + patients.

The preferential activation of regulatory T (T(reg)) cells by interleukin-2 (IL-2), which selectively binds to the trimeric IL-2 receptor (IL-2R) on T(reg) cells, makes this cytokine a promising therapeutic for the treatment of autoimmune diseases. However, IL-2 has a narrow therapeutic window and a short half-life. Here, we show that the pharmacokinetics and half-life of IL-2 can be substantially improved by orthogonally conjugating the cytokine to poly(ethylene glycol) (PEG) moieties via a copper-free click reaction through the incorporation of azide-bearing amino acids at defined sites. Subcutaneous injection of a PEGylated IL-2 that optimally induced sustained T(reg)-cell activation and expansion over a wide range of doses through highly selective binding to trimeric IL-2R led to enhanced therapeutic efficacy in mouse models of lupus, collagen-induced arthritis and graft-versus-host disease without compromising the immune defences of the host against viral infection. Site-specific PEGylation could be used more generally to engineer cytokines with improved therapeutic performance for the treatment of autoimmune diseases.

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo , Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro , SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical success attained in patients with cancer treated with checkpoint inhibitors has renewed the interest in the immune system and in particular in T cells as a therapeutic tool to eliminate tumors. Here, we discuss recent studies that evaluate the anti-tumor role of CD8 T cells and the mechanisms that interfere with this function. In particular, we review recent literature that has reported on the phenotype and transcriptome of tumor-infiltrating CD8 T cells and deciphered the mechanisms associated with failed tumor rejection.

Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38(high) T cell subset in a subgroup of patients with increased rates of infections. CD8CD38(high) T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38(high) T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

PURPOSE OF REVIEW: Th1, Th17, and Treg cells play distinct roles in autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. During the last 5 years we have learned that T-cell metabolism affects cell survival, differentiation and fate of T cells. RECENT FINDINGS: We highlight recent studies which have reported on T-cell metabolism in autoimmune diseases, differences in cellular metabolisms in T-cell subsets among various diseases and transcription factors which control the expression and function of central metabolic enzymes. SUMMARY: Distinct metabolic processes control the function of T-cell subsets in autoimmune disease and known transcription factors control the activity of metabolic enzymes. The revealed insights into the metabolic events of immune cells offer opportunities for new therapeutic approaches.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune cell abnormalities which lead to the production of autoantibodies and the deposition of immune complexes. Interleukin (IL)-17-producing cells play an important role in the pathogenesis of the disease, making them an attractive therapeutic target. Studies in lupus-prone mice and of ex vivo cells from patients with SLE humans have shown that IL-17 represents a promising therapeutic target. Here we review molecular mechanisms involved in IL-17 production and Th17 cell differentiation and function and an update on the role of IL-17 in autoimmune diseases and the expected usefulness for targeting IL-17 therapeutically.

Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI.

Mature double negative (DN) T cells are a population of alphabeta T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8(+) T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.