Publications by Year: 2021

Protein phosphatase 2A (PP2A) composed of a scaffold subunit, a catalytic subunit, and multiple regulatory subunits is a ubiquitously expressed serine/threonine phosphatase. We have previously shown that the PP2A catalytic subunit is increased in T cells from patients with systemic lupus erythematosus and promotes IL-17 production by enhancing the activity of Rho-associated kinase (ROCK) in T cells. However, the molecular mechanism whereby PP2A regulates ROCK activity is unknown. In this study, we show that the PP2A regulatory subunit PPP2R2A is increased in T cells from people with systemic lupus erythematosus and binds to, dephosphorylates, and activates the guanine nucleotide exchange factor GEF-H1 at Ser(885), which in turn increases the levels of RhoA-GTP and the activity of ROCK in T cells. Genetic PPP2R2A deficiency in murine T cells reduced Th1 and Th17, but not regulatory T cell differentiation and mice with T cell-specific PPP2R2A deficiency displayed less autoimmunity when immunized with myelin oligodendrocyte glycoprotein peptide. Our studies indicate that PPP2R2A is the regulatory subunit that dictates the PP2A-directed enhanced Th1 and Th17 differentiation, and therefore, it represents a therapeutic target for pathologies linked to Th1 and Th17 cell expansion.

Human plasmacytoid dendritic cells (pDCs) play a vital role in modulating immune responses. They can produce massive amounts of type I IFNs in response to nucleic acids via TLRs, but they are also known to possess weak Ag-presenting properties inducing CD4(+) T cell activation. Previous studies showed a cross-regulation between TNF-alpha and IFN-alpha, but many questions remain about the effect of TNF-alpha in regulating human pDCs. In this study, we showed that TNF-alpha significantly inhibited the secretion of IFN-alpha and TNF-alpha of TLR-stimulated pDCs. Instead, exogenous TNF-alpha promoted pDC maturation by upregulating costimulatory molecules and chemokine receptors such as CD80, CD86, HLA-DR, and CCR7. Additionally, RNA sequencing analysis showed that TNF-alpha inhibited IFN-alpha and TNF-alpha production by downregulating IRF7 and NF-kappaB pathways, while it promoted Ag processing and presentation pathways as well as T cell activation and differentiation. Indeed, TNF-alpha-treated pDCs induced in vitro higher CD4(+) T cell proliferation and activation, enhancing the production of Th1 and Th17 cytokines. In conclusion, TNF-alpha favors pDC maturation by switching their main role as IFN-alpha-producing cells to a more conventional dendritic cell phenotype. The functional status of pDCs might therefore be strongly influenced by their overall inflammatory environment, and TNF-alpha might regulate IFN-alpha-mediated aspects of a range of autoimmune and inflammatory diseases.

Lung inflammation and damage is prominent in people infected with SARS-Cov-2 and a major determinant of morbidity and mortality. We report the deposition of complement components in the lungs of people who succumbed to COVID-19 consistent with the activation of the classical and the alternative pathways. Our study provides strong rationale for the expansion of trials involving the use of complement inhibitors to treat patients with COVID-19.

In patients with rheumatoid arthritis, a short supply of aspartate in the mitochondria can force the endoplasmic reticulum of T cells to generate transmembrane TNF, which in turn contributes to synovial inflammation.

Reactive oxygen species (ROS) are produced by immune cells in response to antigens. They are produced mostly in the mitochondria and their levels are tightly controlled by a series of metabolic processes. ROS are necessary for the development of the immune response but the role of ROS in the development of autoimmune disease needs further clarification. Early clinical information points to the beneficial role of supplementation of antioxidant agents or the reduction of ROS production. We review recent information in the field in an effort to identify areas more studies are needed.

The a disintegrin and metalloproteinase (ADAM) family of proteinases alter the extracellular environment and are involved in the development of T cells and autoimmunity. The role of ADAM family members in Th17 cell differentiation is unknown. We identified ADAM9 to be specifically expressed and to promote Th17 differentiation. Mechanistically, we found that ADAM9 cleaved the latency-associated peptide to produce bioactive transforming growth factor beta1, which promoted SMAD2/3 phosphorylation and activation. A transcription factor inducible cAMP early repressor was found to bind directly to the ADAM9 promoter and to promote its transcription. Adam9-deficient mice displayed mitigated experimental autoimmune encephalomyelitis, and transfer of Adam9-deficient myelin oligodendrocyte globulin-specific T cells into Rag1(-/-) mice failed to induce disease. At the translational level, an increased abundance of ADAM9 levels was observed in CD4(+) T cells from patients with systemic lupus erythematosus, and ADAM9 gene deletion in lupus primary CD4(+) T cells clearly attenuated their ability to differentiate into Th17 cells. These findings revealed that ADAM9 as a proteinase provides Th17 cells with an ability to activate transforming growth factor beta1 and accelerates its differentiation, resulting in aberrant autoimmunity.

The presence or absence of anti-citrullinated peptide antibodies (ACPA) and associated disparities in patients with rheumatoid arthritis (RA) implies disease heterogeneity with unknown diverse immunopathological mechanisms. Here we profile CD45(+) hematopoietic cells from peripheral blood or synovial tissues from both ACPA+ and ACPA- RA patients by single-cell RNA sequencing and identify subsets of immune cells that contribute to the pathogenesis of RA subtypes. We find several synovial immune cell abnormalities, including up-regulation of CCL13, CCL18 and MMP3 in myeloid cell subsets of ACPA- RA compared with ACPA+ RA. Also evident is a lack of HLA-DRB5 expression and lower expression of cytotoxic and exhaustion related genes in the synovial tissues of patients with ACPA- RA. Furthermore, the HLA-DR15 haplotype (DRB1/DRB5) conveys an increased risk of developing active disease in ACPA+ RA in a large cohort of patients with treatment-naive RA. Immunohistochemical staining shows increased infiltration of CCL13 and CCL18-expressing immune cells in synovial tissues of ACPA- RA. Collectively, our data provide evidence of the differential involvement of cellular and molecular pathways involved in the pathogenesis of seropositive and seronegative RA subtypes and reveal the importance of precision therapy based on ACPA status.

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.