Systemic lupus erythematosus (SLE) treatment requires balancing rapid autoimmunity control with long-term organ repair. Mesenchymal stromal cells (MSCs) and multi-target pharmacotherapy represent fundamentally different therapeutic strategies. MSCs exert context-dependent immunomodulation, whereas the latter relies on broad immunosuppression. This contrast makes direct comparison essential to guide therapy decisions. Here, we conducted a head-to-head evaluation of these two strategies in a lupus murine model. Lupus mice received either umbilical cord-derived MSCs or TMP (tacrolimus, mycophenolate mofetil and prednisone) over an 8-week period. Both treatments significantly alleviated core lupus symptoms, including enlarged spleen/lymph nodes and excessive antibody production. However, MSCs showed greater efficacy in suppressing pathogenic autoantibodies, repairing podocyte damage, and increasing protective regulatory T cells in the kidney and peripheral tissues. TMP more effectively reduced peripheral circulating immune cells. These findings highlight the complementary therapeutic profiles of MSCs and multi-target pharmacotherapy in SLE, providing a critical rationale for personalized treatment stratification.

Micronutrient deficiency is commonly observed in patients with inflammatory bowel disease (IBD), yet the role of certain dietary trace elements in the risk of IBD development remains unclear. This study aimed to investigate the relationship between vitamin C, D, and K intake and IBD risk. This study included 3,591 participants from the 2009–2010 National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression were conducted to assess associations between vitamin C, D, and K intake and IBD risk while controlling for multiple confounders. Subgroup analyses were employed to test the robustness of the associations across participants with various characteristics. Additionally, restricted cubic spline (RCS) analysis was conducted to investigate potential nonlinear relationships. In the fully adjusted model, each 1 mcg increase in vitamin D intake was linked to an approximately 51

Chemotherapy remains a prevalent strategy in cancer therapy; however, the emergence of drug resistance poses a considerable challenge to its efficacy. Most drug resistance arises from the accumulation of genetic mutations in a minority of resistant cells. The mechanisms underlying the emergence and progression of cancer resistance from these minority-resistant cells (MRCs) remain poorly understood. This study employs force-induced remnant magnetization spectroscopy (FIRMS) alongside various biological investigations to reveal the mechanical pathways for MRCs fostering drug resistance and tumor progression. The findings show that minority Paclitaxel-resistant cancer cells have enhanced mechanical properties. These cells can transmit high-intensity forces to surrounding sensitive cells (SCs) through the force transducer, Merlin. This force transmission facilitates the assimilation of surrounding SCs, subsequently strengthening the contraction and adhesion of tumor cells. This process is termed "mechano-assimilation," which accelerates the development of drug resistance and tumor progression. Interestingly, disturbances and reductions of mechano-assimilation within tumors can restore sensitivity to Paclitaxel both in vitro and in vivo. This study provides preliminary evidence highlighting the contribution of MRCs to the development of drug resistance and malignancy, mediated through mechanical interactions. It also establishes a foundation for future research focused on integrating mechanical factors into innovative cancer therapies.

OBJECTIVES:We aimed to discriminate subpopulations of peripheral natural killer (NK) cells of patients with systemic lupus erythematosus (SLE) and evaluate their usability in monitoring disease activity.METHODS:The total number of NK cells and their subpopulations were determined by flow cytometry in 68 patients with SLE and 35 healthy controls. Clinical data were extracted from medical records, including serum anti-double-stranded-DNA (anti-dsDNA), complement C3 and C4, and urine protein. Disease activity in patients with SLE was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K).RESULTS:The percentages and absolute numbers of NK cells decreased, and the proportions of three major NK cell subsets defined by cell maturation status altered in SLE patients. The frequency of CD56brightCD16- NK (immature, Im NK) cells increased, while that of the CD57+CD56dimCD16- subset (mature, more differentiated, MD NK) decreased in patients with high-activity SLE, resulting in a significant increase in the Im NK-to-MD NK ratio as compared with that in patients with low-activity SLE. The area under the receiver operating characteristic curve indicated that the ratio was 0.722 in severe SLE and 0.773 in lupus nephritis, with optimal cut-off levels of 0.075 and 0.108, respectively. The ratio correlated positively with the SLEDAI-2K score, proteinuria, and serum anti-dsDNA antibody levels but negatively with C3 and C4 levels.CONCLUSIONS:Our data indicate that the imbalance in Im NK and MD NK cells may play a role in lupus development and serve as a predictive biomarker to assess disease activity and renal involvement in patients with SLE.

Streptococcus pneumoniae (Sp) frequently causes secondary pneumonia after influenza A virus (IAV) infection, leading to high morbidity and mortality worldwide. Concomitant pneumococcal and influenza vaccination improves protection against coinfection but does not always yield complete protection. Impaired innate and adaptive immune responses have been associated with attenuated bacterial clearance in influenza virus-infected hosts. In this study, we showed that preceding low-dose IAV infection caused persistent Sp infection and suppression of bacteria-specific T-helper type 17 (Th17) responses in mice. Prior Sp infection protected against subsequent IAV/Sp coinfection by improving bacterial clearance and rescuing bacteria-specific Th17 responses in the lungs. Furthermore, blockade of IL-17A by anti-IL-17A antibodies abrogated the protective effect of Sp preinfection. Importantly, memory Th17 responses induced by Sp preinfection overcame viral-driven Th17 inhibition and provided cross-protection against different Sp serotypes following coinfection with IAV. These results indicate that bacteria-specific Th17 memory cells play a key role in providing protection against IAV/Sp coinfection in a serotype-independent manner and suggest that a Th17-based vaccine would have excellent potential to mitigate disease caused by coinfection. IMPORTANCE Streptococcus pneumoniae (Sp) frequently causes secondary bacterial pneumonia after influenza A virus (IAV) infection, leading to increased morbidity and mortality worldwide. Current pneumococcal vaccines induce highly strain-specific antibody responses and provide limited protection against IAV/Sp coinfection. Th17 responses are broadly protective against Sp single infection, but whether the Th17 response, which is dramatically impaired by IAV infection in naïve mice, might be effective in immunization-induced protection against pneumonia caused by coinfection is not known. In this study, we have revealed that Sp-specific memory Th17 cells rescue IAV-driven inhibition and provide cross-protection against subsequent lethal coinfection with IAV and different Sp serotypes. These results indicate that a Th17-based vaccine would have excellent potential to mitigate disease caused by IAV/Sp coinfection.

Objectives Mesenchymal stromal cells (MSCs) and low-dose interleukin-2 (IL-2) both have demonstrated efficacy in treating systemic lupus erythematosus (SLE). The aim of this study is to conduct a head-to-head comparison between the 2 treatments and provide insights for clinical applications. Methods Lupus-prone mice were treated with umbilical cord-derived MSCs (UC-MSCs), IL-2, or a combination of UC-MSCs and IL-2, respectively. The lupus-like symptoms, renal pathology, and T-cell response were assessed 1 or 4 weeks later. Modulation of IL-2 production by MSCs on immune cells was investigated by the coculture assay. Disease activity and serum IL-2 of SLE patients were determined before and after receiving UC-MSCs. Results Both UC-MSCs and IL-2 improved lupus symptoms in lupus-prone mice 1 week after treatment, while the effects of UC-MSCs lasted up to 4 weeks. Moreover, the UC-MSC-treated group showed better renal pathology improvement. Importantly, UC-MSCs combined with IL-2 did not provide better efficacy than UC-MSCs alone. Consistent with this, UC-MSCs alone and UC-MSCs + IL-2 resulted in similar levels of serum IL-2 and frequencies of Tregs. Neutralization of IL-2 partly reduced the promotion of Tregs by UC-MSCs, suggesting that IL-2 was involved in the upregulation of Tregs by UC-MSCs. Lastly, an increase in serum IL-2 positively correlated with the reduction of disease activity of SLE patients by UC-MSCs. Conclusion Both the single injection of UC-MSCs and repeated IL-2 administration exerted comparable efficacy in alleviating SLE manifestations, but UC-MSCs provided sustained alleviation and showed better improvement in renal pathology.

Secondary bacterial pneumonia after influenza A virus (IAV) infection is the leading cause of hospitalization and death associated with IAV infection worldwide. Nontypeable Haemophilus influenzae (NTHi) is one of the most common causes of secondary bacterial pneumonia. Current efforts to develop vaccines against NTHi infection focus on inducing antibodies but are hindered by antigenic diversity among NTHi strains. Therefore, we investigated the contribution of the memory T helper type 17 (Th17) response in protective immunity against IAV/NTHi coinfection. We observed that even a mild IAV infection impaired the NTHi-specific Th17 response and increased morbidity and mortality compared with NTHi monoinfected mice. However, pre-existing memory NTHi-specific Th17 cells induced by a previous NTHi infection overcame IAV-driven Th17 inhibition and were cross-protective against different NTHi strains. Last, mice immunized with a NTHi protein that induced a strong Th17 memory response were broadly protected against diverse NTHi strains after challenge with coinfection. These results indicate that vaccination that limits IAV infection to mild disease may be insufficient to eliminate the risk of a lethal secondary bacterial pneumonia. However, NTHi-specific memory Th17 cells provide serotype-independent protection despite an ongoing IAV infection and demonstrate the advantage of developing broadly protective Th17-inducing vaccines against secondary bacterial pneumonia.

Objective: The mechanism by which mesenchymal stem cell (MSC) transplantation alleviates atherosclerosis in systemic lupus erythematosus (SLE) remains elusive. In this study, we aim to explore the efficacy and mechanism of MSC in ameliorating atherosclerosis in SLE. Methods: ApoE(-/-) and Fas(-/-) mice on the B6 background were cross-bred to generate SLE mice with atherosclerosis. Myeloid-derived suppressor cells (MDSCs) were sorted and quantified. The apoE(-/-)Fas(-/-) mice were either treated with anti-Gr antibody or injected with MDSCs. The lupus-like autoimmunity and atherosclerotic lesions were evaluated. Furthermore, the apoE(-/-)Fas(-/-) mice were transplanted with MSCs and lupus-like autoimmunity and atherosclerotic lesions were assessed. Results: MDSCs in peripheral blood, spleen, draining lymph nodes increased in apoE(-/-)Fas(-/-) mice compared with B6 mice. Moreover, the adoptive transfer of MDSCs aggravated both atherosclerosis and SLE pathologies, whereas depleting MDSCs ameliorated those pathologies in apoE(-/-)Fas(-/-) mice. MSC transplantation in apoE(-/-)Fas(-/-) mice decreased the percentage of MDSCs, alleviated the typical atherosclerotic lesions, including atherosclerotic lesions in aortae and liver, and reduced serum cholesterol, triglyceride and low-density lipoprotein levels. MSC transplantation also reduced SLE pathologies, including splenomegaly, glomerular lesions, anti-dsDNA antibody in serum, urine protein and serum creatinine. Moreover, MSC transplantation regulated the generation and function of MDSCs through secreting prostaglandin E 2 (PGE2). Conclusion: Taken together, these results indicated that the increased MDSCs contributed to atherosclerosis in SLE. MSC transplantation ameliorated the atherosclerosis and SLE through reducing MDSCs by secreting PGE2.

Background: Lupus nephritis (LN) is the most severe organ manifestations of systemic lupus erythematosus (SLE). Although increased knowledge of the disease pathogenesis has improved treatment options, outcomes have plateaued as current immunosuppressive therapies have failed to prevent disease relapse in more than half of treated patients. Thus, there is still an urgent need for novel therapy. Mesenchymal stem cells (MSCs) possess a potently immunosuppressive regulation on immune responses, and intravenous transplantation of MSCs ameliorates disease symptoms and has emerged as a potential beneficial therapy for LN. The objective of this review is to discuss the defective functions of MSCs in LN patients and the application of MSCs in the treatment of both LN animal models and patients. Summary: Bone marrow MSCs from SLE patients exhibit impaired capabilities of migration, differentiation, and immune regulation and display senescent phenotype. Allogeneic MSCs suppress autoimmunity and restore renal function in mouse models and patients with LN by inducing regulatory immune cells and suppressing Th1, Th17, T follicular helper cell, and B-cell responses. In addition, MSCs can home to the kidney and integrate into tubular cells and differentiate into mesangial cells. Key Messages: The efficacy of MSCs in the LN treatment remains to be confirmed, and future advances from stem cell science can be expected to pinpoint significant MSC subpopulations, as well as specific mechanisms of action, leading the way to the use of more potent stimulated or primed pretreated MSCs to treat LN.

Interleukin 27 (IL-27) plays diverse immune regulatory roles in autoimmune disorders and promotes the generation of IL-10–producing CD4+ T cells characterized by producing the immunosuppressive cytokine IL-10. However, whether IL-27 participates in pathological progress of Sjögren syndrome (SS) through regulating CD4+IL-10+ T cells remains unknown. Here we aimed to explore the potential role of IL-27 and CD4+IL-10+ T cells in the pathogenesis of SS. The IL-27 gene knockout non-obese diabetic (Il-27−/−NOD) mice were generated and injected with exogenous IL-27. Exogenous injection of IL-27 and neutralization of IL-27 with anti–IL-27 antibody in NOD mice were performed. The histopathologic changes in submandibular glands, lacrimal glands and lung, salivary flow rate, and percentages of CD4+IL-10+ T cells were determined. And, ovalbumin-immunized C57L/B6 mice were injected with IL-27 to detect the percentage of CD4+IL-10+ T cells. In vitro, splenic naive T cells from C57L/B6 mice were cultured with IL-27 for 4 days to induce the differentiation of CD4+IL-10+ T cells. In addition, IL-27, IL-10, and CD4+IL-10+ T cells were determined in health control and SS patients. The results showed that Il-27−/−NOD mice had more severe disease and lower level of CD4+IL-10+ T cells than control mice. And IL-27 promoted the generation and differentiation of CD4+IL-10+ T cells in vivo and in vitro significantly. In agreement with the findings in the SS-like mice, patients with SS showed lower levels of IL-27, IL-10, and CD4+IL-10+ T cells. Our findings indicated that IL-27 deficiency aggravated SS by regulating CD4+IL-10+ T cells. Targeting IL-27 and CD4+IL-10+ T cells may be a novel therapy for patients with SS.

Background . Immunosuppressants such as cyclophosphamide (CTX) have been employed to treat a wide array of autoimmune diseases. The most unfavourable side effects of these drugs are their suppression on the antimicrobial immunity and increasing the risk of infection. As a promising substitution/adjunct, mesenchymal stem cells (MSCs) are currently being tested in several clinical trials. However, their influence on the recipients’ antimicrobial immunity remains unclear. Methods . In this study, C57BL/6 mice were treated with either CTX or MSCs, and then both the innate and adaptive immunity of the lung were determined. To investigate the influence of CTX and MSCs on the immune defence against infection, the treated mice were intranasally infected with opportunistic pathogen Haemophilus influenzae (Hi) . Bacterial clearance and antibacterial immune responses were analysed. Results . Our data showed that CTX strongly inhibited the proliferation of lung immune cells, including alveolar macrophages (AMs) and T cells, whereas MSCs increased the numbers of these cells. CTX suppressed the phagocytic activity of AMs; on the contrary, MSCs enhanced it. Notably, infusion of MSCs led to a remarkable increase of regulatory T cells and Th1 cells in the lung. When infected by Hi, CTX did not significantly impair the elimination of invaded bacteria. However, MSC-treated mice exhibited accelerated bacterial clearance and moderate inflammation and tissue damage. Conclusion . Our study reported that unlike traditional immunosuppressants, modulation of MSCs on the recipient’s immune response is more elegant. It could preserve and even enhance the antimicrobial defence, suggesting that MSCs are better choice for patients with high risk of infection or those who need long-term immunosuppressive regimen.

Background Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN) and plays a pivotal role in immune responses, but it is not known if its effect on LN pathogenesis derives from regulating the immune imbalance of T lymphocyte subsets. Methods The expression of LCN2 in T cells and kidneys was assessed in renal biopsies from patients with LN. We investigated the relationship between LCN2 levels and development of LN and systemic illness by injecting anti-LCN2 antibodies into MRL/lprmice and analyzing pristane-treatedLCN2(-/-)mice. Results LCN2 is highly expressed in CD4(+)T cells and in renal tissues, and is associated with severe renal damage in patients with LN and in mice with experimental lupus. LCN2 promotes IFN-gamma overexpression in CD4(+)T cells through the IL-12/STAT4 pathway in an autocrine or paracrine manner. Both neutralization of LCN2 in MRL/lprmice and genetic depletion of LCN2 in pristane-induced lupus mice greatly ameliorate nephritis. The frequency and number of splenic and renal Th1 cells decrease in proportion to LN disease activity. Conversely, administration of LCN2 exacerbates the disease with significantly higher renal activity scores and increased numbers of Th1 cells. Conclusions LCN2 plays a crucial role in Th1 cell differentiation, and may present a potential therapeutic target for LN. Significance Statement Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN), but its exact role and the underlying mechanism of its association with the condition remain unclear. LCN2 is a key regulator of T helper type 1 (Th1) cell differentiation in the pathogenesis of LN, acting through the IL-12/signal transducer and activator of transcription 4 pathway in an autocrine or paracrine manner. Amelioration of nephritis in MRL/lprmice given LCN2-neutralizing antibodies and in pristane-treatedLCN2(-/-)mice, provides the first proof of concept that decreasing LCN2 protects against renal injury through dampening the Th1 response. LCN2 blockade may present a promising new strategy to attenuate LN.

Abstract Background Mesenchymal stem cells (MSCs) can regulate innate and adaptive immune systems through interacting with immune cells directly and secreting multiple soluble factors. Due to their immunosuppressive properties, MSC transplantation has been applied to treat many clinical and experimental autoimmune diseases. However, the therapeutic effects and mechanisms by which MSCs regulate myeloid cells in Sjögren’s syndrome (SS) still remain elusive. Methods The number and immune-suppressive activity of myeloid-derived suppressor cells (MDSCs), polymorphonuclear MDSCs (PMN-MDSCs), and monocytic MDSCs (M-MDSCs) were determined in non-obese diabetic (NOD) mice with sialadenitis and in NOD mice with human umbilical cord-derived MSC (UC-MSC) transplantation. Bone marrow cells were cultured with MSC-conditioned medium (MSC-CM) for 4 days. The number and immune-suppressive gene of MDSCs were detected by flow cytometry or qRT-PCR. Results The results showed that the number of MDSCs and PMN-MDSCs was higher and M-MDSCs were lower in NOD mice with sialadenitis. UC-MSCs ameliorated SS-like syndrome by reducing MDSCs, PMN-MDSCs, and M-MDSCs and promoting the suppressive ability of MDSCs significantly in NOD mice. UC-MSCs inhibited the differentiation of MDSCs. In addition, UC-MSCs enhanced the suppressive ability of MDSCs in vitro. Mechanistically, MSCs inhibited the differentiation of MDSCs and PMN-MDSCs via secreting prostaglandin E2 (PGE2) and inhibited the differentiation of M-MDSCs through secreting interferon-β (IFN-β). Conclusions Our findings suggested that MSCs alleviated SS-like symptoms by suppressing the aberrant accumulation and improving the suppressive function of MDSCs in NOD mice with sialadenitis.

OBJECTIVES:Mesenchymal stem cells (MSCs) have shown great potential in treating autoimmune diseases (ADs). Unlike the traditional immunosuppressants, which inadvertently impair patients' antimicrobial immunity, MSCs reduce the incidence and duration of respiratory infection. However, the underlying mechanisms are unknown. METHODS:To investigate how MSCs regulate the lung immunity and improve the defence against respiratory infection, we infected MSC-treated wild-type and lupus-prone mice with Haemophilus influenzae intranasally and determined the clearance of bacteria. Tissue damage and inflammatory cytokines were measured by H&E staining and ELISA separately. Immune cell subsets in the tissues were analysed by flow cytometry. RESULTS:MSC pretreatment prevented overwhelming inflammation and accelerated bacterial clearance in both wild-type and lupus-prone mice. Tregs increased dramatically in the lung after MSC treatment. Adoptive transfer of Tregs isolated from MSC-treated mice offered similar protection, while deletion of Tregs abrogated the protective effects of MSCs. The majority of the intravenously injected MSCs were engulfed by lung phagocytes, which in turn produced CXCL9 and CXCL10 and recruited tremendous CXCR3+ Tregs into the lung. Compared with their CXCR3- counterparts, CXCR3+ Tregs displayed enhanced proliferation and stronger inhibitory functions. Neutralisation of CXCL9 and CXCL10 significantly downregulated the migration of CXCR3+ Tregs and eliminated the benefits of MSC pretreatment. CONCLUSION:Here, we showed that by recruiting CXCR3+ Tregs, MSC treatment restricted the overactivation of inflammatory responses and prevented severe symptoms caused by infection. By discovering this novel property of MSCs, our study sheds light on optimising long-term immunosuppressive regimen for autoimmune diseases and other immune disorders.

Background: Defective clearance of apoptotic cells (ACs) has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on SLE, but whether MSCs phagocytose ACs and contributes to the underlying mechanism in the treatment of SLE remain unknown. Methods: Human umbilical cord (UC) MSCs were co-cultured with ACs, and the engulfment of ACs by MSCs was either detected by flow cytometry or observed under confocal laser scanning microscope. Peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) were cultured in MSC conditioned medium (MCM) or MSC exposed to ACs (AC-MSC) conditioned medium(ACMCM), and then CD4(+) T cell proliferation was detected. Soluble factors including prostaglandin (PG) E2 in the supernatants ofMSCs and AC-MSCs, aswell as in the mouse peritoneal lavage fluids (PLF) were determined by enzyme-linked immunosorbent assay (ELISA). Cyclooxygenase (COX) 2 inhibitors and siRNA transfection were utilized to determine the function of COX2/PGE2 in AC-MSC-mediated immunosuppression. PGE2 metabolites (PGEM) in the plasma of SLE patients were measured before and 24 h after MSC transplantation respectively. Findings: Human UCMSCs possessed the ability to engulf ACs. AC-MSCs increased MSC-mediated suppression of CD4(+) T cell proliferation compared to MSCs alone. Mechanistically, ACs stimulated MSCs to express COX2 and consequently produced PGE2 that inhibited T cell responses. NF-kappa B signalling pathway mediated the activation of COX2/PGE2 in AC-MSCs. Importantly, in patients with SLE, the plasma PGEM levels increased significantly in those with reduced apoptotic mononuclear cells in peripheral blood after MSC transplantation. Interpretation: Clearance of ACs byMSCs contributes to immunosuppressive function via increasing PGE2 production. These findings reveal a previously unrecognized role of MSC-mediated phagocytosis of ACs in MSC-based immunotherapy.

Objective To investigate the expression of transcription factor AT-rich interaction domain 3a (ARID3a) in peripheral blood B cells of patients with systemic lupus erythematosus (SLE) and its clinical significance. Methods Peripheral blood mononuclear cells were isolated from 17 SLE patients and 13 healthy controls. Then, the expression of ARID3a by B cells was determined by flow cytometry. Data was analyzed with independent sample t test. The correlations between the frequencies of ARID3a+ B cells and clinical indicators of SLE patients were assessed by Pearson cor relation analysis. The expression of ARID3a in kidney was detected by immunohistochemistry in 14 cases of lupus nephritis (LN). Results The percentages of ARID3a+ B cells in SLE patients [(51.6±3.2)%] were significantly higher than those in healthy controls [(32.6±3.4)%](t=4.0, P<0.01). There was a positive correlation between the percentages of ARID3a+ B cells in SLE patients and their 24-hour urinary protein (r=0.68, P<0.05). Furthermore, the percentages of ARID3a+ B cells in peripheral blood from patients with active LN[(62.3±4.3)%] were remarkably higher than that from patients without LN or with inactive LN [(43.3±2.8)%] (t=3.8, P<0.01). The expression of ARID3a in glomerula and tubules of LN patients markedly increased. Conclusion Elevated expression of transcription factor ARID3a in B cells may participate in the pathogenesis of LN. Key words: Lupus erythematosus, systemic; Lupus nephritis; B cells; AT-rich interaction domain 3a

Rationale: Although mesenchymal stem cell (MSC) transplantation has been proved to be an effective therapeutic approach to treat experimental Sjögren's syndrome (SS), the detailed underlying mechanisms remains unknown. IL-27 has diverse influences on the regulation of T cell differentiation and was involved in SS through modulating immune response. Here we aimed to explore whether IL-27-mediated regulation of immune cells was responsible for the beneficial effects of MSC transplantation on SS. Methods: The SS-like symptoms were evaluated in IL-27 deficient and recombinant IL-27-treated NOD mice. The MSCs were infused into NOD mice via the tail vein. The histological features of submandibular glands, saliva flow rate and serum IL-27 were examined. The effects of MSCs on the IL-27 production and Th17/Treg cell in SS patients and mice in vitro and in vivo were determined for the mechanistic study. Results: This study showed that SS patients had decreased IL-27 level and increased ratio of Th17/Treg cells. Consistently, exacerbated SS-like symptoms were observed in IL-27 deficient NOD mice, along with increased ratio of Th17/Treg cells. Importantly, MSC transplantation alleviated SS-like symptoms by elevating the level of IL-27 to restore Th17/Treg balance in NOD mice. Mechanistically, MSC-secreted interferon-β (IFN-β) promote dendritic cells to produce IL-27. Conclusions: Thus, we have revealed a previously unrecognized function of MSC-mediated IL-27 production by DCs in suppressing SS-like syndrome, which provided evidences for clinical application of MSC in patients with SS.

Infection is a common cause of hospitalization and mortality in patients with systemic lupus erythematosus (SLE). How the underlying immune dysfunctions affect the antimicrobial immunity remains largely unknown. In the present study, employing the pulmonary infection model, we determined the antimicrobial defence of lupus-prone mice. After infecting with opportunistic bacterium Haemophilus influenzae (Hi), lupus-prone mice (B6/lpr) exhibited inefficient bacterial elimination and recovered slowly. They generated severer inflammation at the early stage of infection, as excessive accumulation of neutrophils and enhanced production of proinflammatory cytokines were observed in the lung. In addition, a large number of apoptotic cells were detected in the lungs of B6/lpr mice. For adaptive immune responses, B6/lpr mice were capable to generate enough protective Hi-specific Th17 cells. They evoked stronger Hi-specific γδ T17 response in both lungs and spleens. Unexpectedly, both CD4 and γδ T cells from lupus-prone mice showed deficiency in IFN-γ production. For humoral immune responses, compared with those of WT mice, the concentrations of Hi-specific IgA, IgM, and IgG, especially IgG, were significantly higher in the B6/lpr mice. Our findings suggest that lupus mice are capable to generate antibacterial immune responses; however, the overwhelming inflammation and overactivated immune responses increase the severity of infection.