BackgroundMucosal-associated invariant T (MAIT) cells are innate-like lymphocytes constituting a large proportion of peripheral blood T cells expressing αβ T-cell receptor in humans. In this study, we aimed to investigate their involvement in systemic lupus erythematosus (SLE).MethodsPeripheral blood MAIT cells from patients with SLE were assessed for their frequency, activation markers, and cell death by flow cytometry. The correlation between plasma cytokine levels and CD69 expression on MAIT cells was analyzed. The major histocompatibility complex class I-related protein MR1-restricted antigen-presenting capacity of antigen-presenting cells was investigated. Cytokine-mediated activation of MAIT cells in the absence of exogenous antigens was also examined.ResultsThe frequency of MAIT cells was markedly reduced in SLE. The reduced number of MAIT cells was not attributable to the downregulation of surface markers, but it was partially due to the enhanced cell death of MAIT cells, possibly by activation-induced cell death. The CD69 expression levels on MAIT cells in SLE correlated with disease activity. Moreover, monocytes from patients with SLE exhibited increased ability to induce MAIT cell activation. The plasma concentration of interleukin (IL)-6, IL-18, and interferon (IFN)-α positively correlated with the expression levels of CD69 on MAIT cells in SLE. MAIT cells were activated by cytokines, including IFN-α, IL-15, and IL-12 plus IL-18, in the absence of exogenous antigens.ConclusionsThese results suggest that MAIT cells reflect the pathological condition of SLE and that their activated status correlates with presence of disease.

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like lymphocytes that are restricted by major histocompatibility complex-related molecule 1 (MR1). In this study, we investigated the role of MAIT cells in the pathogenesis of lupus in FcγRIIb−/−Yaa mice, a spontaneous animal model of lupus. Using two approaches of MAIT cell deficiency, MR1 knockout animals and a newly synthesized inhibitory MR1 ligand, we demonstrate that MAIT cells augment the disease course of lupus by enhancing autoantibody production and tissue inflammation. MR1 deficiency reduced germinal center responses and T cell responses in these mice. Suppression of MAIT cell activation by the inhibitory MR1 ligand reduced autoantibody production and lupus nephritis in FcγRIIb−/−Yaa mice. MAIT cells directly enhanced autoantibody production by B cells in vitro. Our results indicate the contribution of MAIT cells to lupus pathology and the potential of these cells as novel therapeutic targets for autoimmune diseases such as lupus.

Mucosal-associated invariant T (MAIT) cells are innate T cells restricted by MHC-related molecule 1 (MR1). MAIT cells express semi-invariant T-cell receptors TRAV1-2-TRAJ33/12/20 in humans and TRAV1-TRAJ33 in mice. MAIT cells recognize vitamin B2 biosynthesis derivatives presented by MR1. Similar to other innate lymphocytes, MAIT cells are also activated by cytokines in the absence of exogenous antigens. MAIT cells have the capacity to produce cytokines, such as IFNγ, TNFα, and IL-17, and cytotoxic proteins, including perforin and granzyme B. MAIT cells were originally named after their preferential location in the mucosal tissue of the gut, but they are also abundant in other peripheral organs, including the liver and lungs. In humans, the frequency of MAIT cells is high in peripheral blood, and these cells constitute approximately 5% of circulating CD3+ cells. Their abundance in tissues and rapid activation following stimulation have led to great interest in their function in various types of immune diseases. In this review, first, we will briefly introduce key information of MAIT cell biology required for better understating their roles in immune responses, and then describe how MAIT cells are associated with autoimmune and other immune diseases in humans. Moreover, we will discuss their functions based on information from animal models of autoimmune and immunological diseases.

Objective: Peripheral helper T (T PH ) cells are a recently identified helper T cell subset that promotes B cell differentiation and antibody production in inflamed tissues. This study investigated circulating T PH cells to determine their involvement in systemic lupus erythematosus (SLE).Methods: Peripheral blood mononuclear cells collected from SLE patients and healthy individuals were analysed. T PH cells were identified as CD3 + CD4 + CD45RA -CXCR5cells with a high expression of programmed cell death protein 1 (PD-1). The frequency, activation status, and subsets of T PH cells were evaluated by flow cytometry. The production of interleukin (IL)-21 was assessed by intracellular staining and the association of T PH cells with disease activity and B cell populations was determined.Results: Circulating T PH cells, identified as CD3 + CD4 + CD45RA -PD-1 high CXCR5cells were increased in the peripheral blood of SLE patients compared with controls.Circulating T PH cells produced similar amounts of IL-21 to follicular helper T cells. The expansion and activation of T PH cells were correlated with SLE disease activity. Activated T PH cells, particularly Th1 type T PH cells, were associated with the promotion of B cell differentiation in SLE patients. 3 Conclusion: The association of T PH cells with disease activity suggests the involvement of extra-follicular T-B cell interactions in the pathogenesis of SLE. T PH cells promote autoantibody production in aberrant lymphoid organs and therefore might be a novel therapeutic target in autoantibody-producing disorders.

BackgroundInterferon-α (IFN-α) is increased and plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) are the main producer of IFN-α, but their IFN-α producing capacity has been shown to be unchanged or reduced when stimulated with a Toll-like receptor 9 (TLR9) agonist in patients with SLE compared to in healthy individuals. In this study, we investigated the IFN-α-producing capacity of lupus pDCs under different stimulation.MethodspDCs from patients with SLE and healthy controls (HC) were stimulated with TLR9 or TLR7 agonist, and their IFN-α producing capacity was examined by intracellular cytokine staining and flow cytometry. The correlation of IFN-α-producing capacity with serum IFN-α levels and disease activity was assessed. The effect of in vitro IFN-α exposure on IFN-α production by pDCs was examined. Localization of TLR7 in cellular compartments in pDCs was investigated.ResultsThe IFN-α producing capacity of pDCs was reduced after TLR9 stimulation, but increased when stimulated with a TLR7 agonist in SLE compared to in HC. IFN-α production by pDCs upon TLR9 stimulation was reduced and the percentage of IFN-α+pDC was inversely correlated with disease activity and serum IFN-α levels. However, the TLR7 agonist-induced IFN-α producing capacity of lupus pDCs was enhanced and correlated with disease activity and serum IFN-α. Exposure to IFN-α enhanced IFN-α production of TLR7-stimulated pDCs, but reduced that of pDCs activated with a TLR9 agonist. TLR7 localization was increased in late endosome/lysosome compartments in pDCs from SLE patients.ConclusionsThese findings indicate that enhanced TLR7 responses of lupus pDCs, owing to TLR7 retention in late endosome/lysosome and exposure to IFN-α, are associated with the pathogenesis of SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1441-7) contains supplementary material, which is available to authorized users.

We retrospectively analyzed the characteristics and outcomes of five patients with COVID‐19 who were received glucocorticoid (with or without pulse therapy) and therapeutic plasma exchange. The efficacy of the treatment was determined by whether the patient was able to be transferred from the COVID‐19 exclusive ICU to the general ward. In comparing patients who received prednisolone pulse therapy (three cases) with those who did not (two cases), 2/3 (66%) and 0/2 (0%) patients could be discharged from the COVID‐19 dedicated ICU, respectively. Among five patients who was performed plasma exchange, two elderly male patients who underwent plasma exchange as early as within 8 days of disease exacerbation survived and were able to be transferred to the general ward. This observational study indicates that plasma exchange in conjunction with methylprednisolone pulse therapy at the appropriate time may be an effective treatment for elderly patients with severe COVID‐19.

Long-term COVID-19 pneumonia during anti-CD20 therapy Journal Pre-proof Resolution of one-year persisting COVID-19 pneumonia and development of immune thrombocytopenia in a follicular lymphoma patient with preceding rituximab maintenance therapy: a follow-up report and literature review of cases with prolonged infections

Objective Increased IFNα is important in the pathogenesis of SLE. Plasmacytoid dendritic cells are considered the main producer of IFNα upon Toll-like receptor pathway activation. However, which cells produce IFNα following stimulation with cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) in SLE remains unknown. We investigated the IFNα producing capacity of myeloid cells under cGAS-STING pathway stimulation. Methods IFNα levels in peripheral blood mononuclear cells from SLE patients and healthy controls stimulated with 2′3′c-GAMP, a stimulator of cGAS-STING, were measured by intracellular cytokine staining and flow cytometry. STING expression and its co-localization with TBK1 were examined by flow cytometry or confocal microscopy. The effects of in vitro exposure to IFNα on IFNα production and STING expression, and in vitro rapamycin treatment on IFNα production and STING, pTBK1 and IRF3 expression were examined. Results IFNα was produced by monocytes, conventional dendritic cells and plasmacytoid dendritic cells upon cGAS-STING pathway activation. The frequency of IFNα-producing monocytes positively correlated with SLE disease activity. STING expression and its co-localization with TBK1 were increased in lupus monocytes. Prior exposure to IFNα enhanced the IFNα-producing capacity of monocytes. Inhibition of the mechanistic target of the rapamycin (mTOR) pathway suppressed IFNα production from monocytes and downregulated enhanced STING expression and its downstream molecules. Conclusion Enhanced IFNα from lupus monocytes induced by augmented STING pathway activation is associated with SLE pathogenesis. Suppression of the mTOR pathway downregulated the enhanced STING expression and the subsequent IFNα production by monocytes.