Plasmacytoid Dendritic Cells Research Articles

Malignancies and immunoglobulin G4‐related disease

AbstractImmunoglobulin G4‐related disease (IgG4‐RD) is a systemic fibro‐inflammatory disease characterized by tumefactive lesions. Beyond the role of the disease as a cancer mimic, studies over the past decade have demonstrated that IgG4‐RD is associated with increased cancer risk. A search of articles, case reports, and reviews concerning malignancies in patients with IgG4‐RD was conducted on PubMed, Web of Science, and Google Scholar. The site of cancer development is not always affected by IgG4‐RD. The prevalence of solid cancers varies among populations. Moreover, B‐cell neoplasms constitute a proportion of the malignancies linked to this disease. The precise mechanism of oncogenesis in IgG4‐RD is ambiguous. Several mechanisms may be relevant to the increased cancer risk in patients with IgG4‐RD, including chronic inflammation, IgG4‐positive plasma cell infiltration, and the involvement of follicular helper T cells, macrophages, and plasmacytoid dendritic cells in tumor immunity. The risk factors include male sex, older age, smoking status, occupational exposure, disease recurrence, and involvement of specific organs. Malignancies in patients with IgG4‐RD are associated with a poor prognosis, underscoring the importance of cancer risk management and regular screening during follow‐up. The precise mechanisms linking IgG4‐RD to malignancy remain unclear and warrant further research. Regular cancer screening should be prioritized during follow‐up to facilitate early detection of malignancies.

Sensing of SARS-CoV-2-infected cells by plasmacytoid dendritic cells is modulated via an interplay between CD54/ICAM-1 and CD11a/LFA-1 αL integrin.

Type I interferons (IFN-I) represent an important component of the host's innate defense against initial SARS-CoV-2 infections. Plasmacytoid dendritic cells (pDCs) produce large quantities of IFN-I upon recognition of viral particles or infected cells. This study shows that pDCs sense infected cells more efficiently than viral particles, leading to a higher production of IFN-I. Physical contact between a pDC and an infected cell is critical to this process; the interaction is mediated via CD11a and ICAM-1 complex and potentially is bidirectional. SARS-CoV-2 variants of concern (VOCs) have evolved to limit the IFN response through different mechanisms. For the Alpha variant, reduced level of CD11a on infected cells is linked to less contact with pDCs and decreased IFN-I release. Overall, our study characterizes some of the early steps involved in pDC-mediated response against SARS-CoV-2 infection and shows that these processes are targeted by VOCs to likely limit IFN-I response and enhance viral spread.

A Multidisciplinary Approach to Diagnosing Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Practical Recommendations and Insights from Countries of the Gulf Cooperation Council

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive orphan hematopoietic malignancy characterized by cutaneous and systemic hematologic involvement. BPDCN is frequently misidentified, but early, accurate diagnosis is critical to extending patient survival using tagraxofusp, a first-in-class CD123-targeted therapy, and increasing their chances of receiving a potentially curative stem cell transplantation. Cases of BPDCN in countries of the Gulf Cooperation Council are lower than the extrapolated incidence from other geographic locations due to lack of awareness of key diagnostic features, lack of consensus on the minimal phenotype for diagnosis, and lack of local immunohistochemistry testing facilities, contributing to underdiagnosis in this region. Practical recommendations, a streamlined diagnostic panel, and suggested multidisciplinary approaches based on expert experience regarding diagnostic and clinical challenges specific to this region, and a review of the literature are presented here to facilitate diagnosis of BPDCN in this region by primary care physicians, dermatologists, and hematologists.

Helminth infection induces innate immune priming in plasmacytoid dendritic cells.

Heligmosomoides polygyrus co-infection is reported to have protective antiviral effects against pulmonary viral infections. To investigate a potential underlying mechanism, we infected C57BL/6 mice with H. polygyrus larvae for two weeks. Bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) were generated and stimulated with TLR agonists. We found increased expression of type 1 interferon genes (Ifnα1, Ifnα4, Ifnβ1, Mx1, Isg15), increased TNF, IL-6, IL-10 secretion, and higher expression of antigen presentation markers in BM-derived-pDCs from infected mice compared to naïve control. Our findings may partly explain the mechanism of the antiviral protection previously reported in acute helminth infections.

Integrative bioinformatics analysis reveals CGAS as a ferroptosis-related signature gene in sepsis and screens the potential natural inhibitors of CGAS.

Sepsis is a fatal organ dysfunction characterized by the simultaneous hyperinflammation and immunosuppression. Nowadays, the early precision intervention of sepsis is challenging. Ferroptosis is involved in the development of sepsis. The current study aimed to find out the signature genes of sepsis with network topology analysis and machine learning, and further provide the potential natural compounds for sepsis with virtual screening and in vitro validation. In this study, five genes namely CGAS, DPP4, MAPK14, PPARG and TXN were identified as ferroptosis-related signature genes for sepsis by network topological analysis, machine learning algorithms, and external datasets verification. The results of immune infiltration analysis confirmed these genes were significantly associated with the infiltration abundance of some immune cells including neutrophil, macrophage, plasmacytoid dendritic cell and activated dendritic cell. Moreover, coniferin, 5-O-caffeoylshikimic acid, and psoralenoside were initially identified as the natural inhibitors of CGAS by virtual screening. However, further in vitro study on macrophages revealed coniferin and psoralenoside had better inhibitory activities on CGAS. In summary, the present study pointed out the importance of CGAS in sepsis, and discovered novel natural inhibitors of CGAS.

Bioinformatics-Based Analysis and Verification of Chromatin Regulators and the Mechanism of Immune Infiltration Associated with Myocardial Infarction.

Recent studies have shown that dysfunction in chromatin regulators (CRs) may be an important mechanism of myocardial infarction (MI). They are thus expected to become a new target in the diagnosis and treatment of MI. However, the diagnostic value of CRs in MI and the mechanisms are not clear. CRs-related differentially expressed genes (DEGs) were screened between healthy controls and patients with MI via GSE48060, GSE60993, and GSE66360 datasets. DEGs were further analyzed for enrichment analysis. Hub genes were screened by least absolute shrinkage and selection operator (LASSO) regression and weighted gene co-expression network analysis (WGCNA). GSE61144 datasets were further used to validate hub genes. RT-qPCR examined peripheral blood mononuclear cells (PBMCs) to verify expressions of hub genes. In addition, a correlation between hub genes and immune cell infiltration was identified by CIBERSORT and single-sample gene set enrichment analysis (ssGSEA). Finally, we constructed a diagnostic nomogram and ceRNA network and found possible therapeutic medicines which were based on hub genes. Firstly, 16 CR-related DEGs were identified. Next, Dual-specificity phosphatase 1 (DUSP1), growth arrest and DNA damage-inducible 45 (GADD45A), and transcriptional regulator Jun dimerization protein 2 (JDP2) were selected as hub genes by LASSO and WGCNA. Receiver operating characteristic curves in the training and test data sets verified the reliability of hub genes. Results of RT-qPCR confirmed the upregulation of hub genes in MI. Subsequently, the immune infiltration analysis indicated that DUSP1, GADD45A, and JDP2 were correlated with plasmacytoid dendritic cells, natural killer cells, eosinophils, effector memory CD4 T cells, central memory CD4 T cells, activated dendritic cells, and activated CD8 T cells. Furthermore, a nomogram that included DUSP1, GADD45A, and JDP2 was created. The calibration curve, decision curve analysis, and the clinical impact curve indicated that the nomogram could predict the occurrence of MI with high efficacy. The results of the ceRNA network suggest that hub genes may be cross-regulated by various lncRNAs and miRNAs. In addition, 10 drugs, including 2H-1-benzopyran, Nifuroxazide, and Bepridil, were predicted to be potential therapeutic agents for MI. Our study identifies three promising genes associated with the progression of chromatin regulators (CRs)-related myocardial infarction (MI) and immune cell infiltration, including Dual-specificity phosphatase 1 (DUSP1), growth arrest and DNA damage-inducible 45 (GADD45A), and Jun dimerization protein 2 (JDP2), which might be worthy of further study.

Causal relationship between 731 immune cells and the risk of diabetic nephropathy: a two‑sample bidirectional Mendelian randomization study

Objective Previous observational studies have indicated associations between various immune cells and diabetic nephropathy (DN). However, the causality remains unclear. We aimed to further evaluate the causal association between immune cells and DN using bidirectional two-sample Mendelian randomization (MR) analysis. Method The DN data were retrieved from the IEU OpenGWAS Project database, while the data for 731 immune cells were sourced from GWAS summary statistics by Orru ̀ et al. The investigation into the causal relationship between immune cells and DN employed the inverse variance weighted (IVW), weighted median (WME), and MR-Egger methods. The stability and reliability of the findings underwent evaluation through Cochran’s Q test, MR-Egger intercept’s P-value, MR-PRESSO, and Leave-One-Out (LOO) method. Result The IVW estimates suggested a positive causal effect of CD25 on IgD-CD38dim B cell, CD25 on naive-mature B cell, CD127 on granulocyte, SSC-A on HLA DR + Natural Killer, HLA DR on plasmacytoid Dendritic Cell, and HLA DR on Dendritic Cell on DN. Conversely, the abundance of Myeloid Dendritic Cell, CD62L- Dendritic Cell %Dendritic Cell, CD86+ myeloid Dendritic Cell %Dendritic Cell, CD14- CD16-, CX3CR1 on CD14- CD16-, and SSC-A on CD4+ T cell had negative causal effects on DN. However, after correcting the P value for significant causality results using the FDR method, it was concluded that only Myeloid Dendritic Cells had a causal relationship with DN (FDR-p = 0.041), while the other immune cells showed no significant association with DN, so their relationship was suggestive. The results were stable with no observed horizontal pleiotropy and heterogeneity. Reverse MR analysis indicated no causal relationship between DN and the increased risk of positively identified immune cells. Conclusion This study provides an initial insight into the genetic perspective of the causal relationship between immune cells and DN. It establishes a crucial theoretical foundation for future endeavors in precision medicine and individualized treatment.

HSD11B1 overexpression in dendritic cells and stromal cells relates to endometriosis by inhibiting dendritic cell proliferation and maturation

Aims This study aims to explore the alterations of dendritic cells (DCs) subpopulations in ectopic endometrial lesions and unveil the underlying mechanisms. Materials and methods Patients with endometriosis (n = 81) and women without endometriosis (n = 19) were recruited in this study. Dendritic cells (DCs) in the endometrial samples were counted after immunohistochemistry staining. The proportion of myeloid DCs and plasmacytoid DCs was calculated by flow cytometry. Primary DCs were isolated from tissues, and the cell viability and apoptosis were examined by MTT assay and flow cytometry. Cytokines were detected by the enzyme-linked immunosorbent assay. Differentially expressed genes were filtered by analyzing two datasets that were downloaded from GEO database and detected by RT-qPCR in tissues and isolated DCs. The function of HSD11B1 was examined in an endometrial stromal cell-DCs co-culture system and in vitro cultured DCs. Results Reduced myeloid DCs and increased CD11c-CD304-DCs were found in ectopic endometrium compared to control endometrium and eutopic endometrium from endometriosis patients. Myeloid DCs isolated from ectopic endometrium expressed less CD80, CD83, CD86 and had reduced proliferation, increased apoptosis, and reduced cytokine production. The expression of HSD11B1 was significantly increased in both ectopic endometrium and isolated myeloid DCs. Overexpression of HSD11B1 in immature DCs could repress DCs maturation and cytokine production. Endometrial stromal cells overexpressing HSD11B1 secreted increased cortisol, which repressed DCs maturation. Conclusions HSD11B1 is upregulated in ectopic endometrial lesions, which may contribute to endometriosis through repressing myeloid DCs maturation.

Deletion of gE in Herpes Simplex Virus 1 Leads to Increased Extracellular Virus Production and Augmented Interferon Alpha Production by Peripheral Blood Mononuclear Cells.

Herpes simplex virus (HSV) in humans and pseudorabies virus (PRV) in pigs are both alphaherpesviruses. Plasmacytoid dendritic cells (pDCs) make part of the peripheral blood mononuclear cells (PBMCs) and are specialized in producing large amounts of antiviral type I interferon (IFN-I). IFN-I production by PBMCs in response to both HSV-1 and PRV can be virtually exclusively attributed to pDCs. Recently, we discovered that cells infected with gEnull PRV trigger increased production of IFNalpha by porcine PBMCs/pDCs compared with cells infected with wild-type (WT) PRV. This increased IFNalpha response correlates with increased extracellular virus production triggered by gEnull PRV compared with WT PRV. The gE protein and some of its currently described functions are conserved in different alphaherpesviruses, including PRV and HSV-1. In the current study, we report that cells infected with gEnull HSV-1 trigger increased IFNalpha production by human PBMCs and increased extracellular virus production compared with WT HSV-1. Hence, these recently described functions of PRV gE are conserved in HSV-1 gE. Since the increased extracellular virus production and IFNalpha response have also been reported for successful (gEnull) PRV vaccines, the current findings may have important consequences for the rational design of HSV vaccines.

Diagnostic challenges of high-grade myeloid malignancies with partial plasmacytoid dendritic cell differentiation: report of two cases with literature review

The diagnosis of myeloid neoplasms with plasmacytoid dendritic cell (pDC) differentiation can be challenging due to immunophenotypic overlap requiring detailed characterization by flow cytometry and immunohistochemistry. We describe two patients with a history of myeloproliferative neoplasm (MPN) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) who presented years later with leukocytosis, lymphadenopathy, splenomegaly, and cachexia, with rapid clinical deterioration and death. Lymph node biopsy specimens revealed involvement by myeloid sarcoma with prominent pDC differentiation. Furthermore, concomitant bone marrow aspiration and biopsy showed involvement by the underlying myeloid neoplasm but no parallel expansion of pDC, as seen in the lymph node specimens, suggesting that pDC differentiation is fostered in the lymph node microenvironment. These two cases could represent the “myeloid sarcoma” counterpart of the recently described acute myeloid leukemia with pDC differentiation (pDC-AML). Although patients with pDC-AML have an inferior outcome when treated with conventional therapies, the recognition of a pDC component in these neoplasms potentially expands the therapeutic options

Dermatoscopic features of blastic plasmacytoid dendritic cell neoplasm: a case report and review of the literature

Dermatoscopic features of blastic plasmacytoid dendritic cell neoplasm: a case report and review of the literature

BPDCN: state of the art.

The emergence of blastic plasmacytoid dendritic cell neoplasm (BPDCN) as its own distinct entity within the pantheon of hematologic malignancies is due to the growing understanding of its unique multiorgan clinical presentation and characteristic skin lesions. The occurrence of BPDCN is generally heralded by a multicompartmental presentation of violaceous cutaneous lesions, involvement by bone marrow and/or blood, lymph node invasion, and an inclination toward extramedullary organ involvement, including, most remarkably, central nervous system (CNS)/cerebrospinal fluid positivity. With a median age historically of ≥ 70 years and up to 5:1 male predominance in most of the field's earlier studies, the most notable development in the modern era is the recognition of emerging important groups with BPDCN, such as female, pediatric, and adolescent/young adult patients; CNS + BPDCN patients; and an increasing number of cases being diagnosed worldwide. These trends are in line with the increased educational and research efforts, greater international collaboration, and markedly improved diagnostic tools and clinical approaches among hematology/oncology, hematopathology, dermatology, and dermatopathology teams around the world. Now, with over 5 years since the first commercially approved targeted agent specifically dedicated for BPDCN, the CD123-targeted agent tagraxofusp, improvements have been demonstrated particularly in the frontline setting for patients with BPDCN. The field is abundant with hope, as it has experienced advancements including greater molecular characterization, expanded identification of potential targets for therapy beyond CD123, advent of combination therapies, improving parameters for stem cell transplantation, and novel clinical trials specifically available for patients with BPDCN.

FC08 Characterization of plasmacytoid dendritic cells-targeted CAR-T cells from patients with immune-mediated inflammatory diseases

Abstract Since the study by Mougiakakos et al., published in 2021 demonstrated the remission of a patient with systemic lupus erythematosus thanks to treatment with anti-CD19 CAR-T cells, (1) a growing number of studies have focused on autoimmune diseases (AID). Plasmacytoid dendritic cells (pDCs), which express highly the CD123 molecule, also play a major role in the pathophysiology of many types of AID. In psoriasis, pDCs secrete IFN-I intensively, leading to inflammation and recruitment of inflammatory cells to the skin, promoting Th17 polarization of LTs and phenotypic changes in keratinocytes. (2) Recently, our team has developed an anti-CD123 CAR-T targeting the pDCs in the context of AID. Our project aims to deeply characterize the phenotype and functional capacities of CD123 CAR-T using T cells from patients (psoriasis, hidradenitis suppurativa, systemic sclerosis and systemic lupus erythematosus) at different stages of the disease and treated with various biotherapies. T cells from patients or healthy donors (HD) were isolated from peripheral blood mononuclear cells and then activated and modified to express a third-generation CD123 CAR (CAR123). CAR-T proliferation, transduction efficiency and phenotype were assessed before (Day 0), after CAR insertion and at the end of in vivo culture (Day 10). The functionality of CAR-T was assessed through their cytotoxic activity and their ability to secrete cytokines in the presence of their target. The in vitro functional persistence of CAR-T is assessed using a model in which CAR-T are challenged with CD123+ cells every 3–4 days for 15 days. Transduction efficiency of the CAR123 is high in all patients (72.4% ± 18.9%, n = 28) and HD (70.4% ± 15.3%, n = 4) (P = ns). Patient-derived CAR123 effectively lysed autologous pDCs in vitro in a similar manner to HD (82.8% ± 14.2%, n = 28 for patients and 67.3% ± 10.7%, n = 4 for HD, P = ns). Importantly, CAR123 maintained their in vitro cytotoxic activity after 6 rechallenges with no difference with HD CAR123. Upon engagement with their target, CAR123 secreted Th1-type cytokines (IFN-γ and TNF-α) as HD CAR123. In the AID context, CAR-T are produced from potentially activated or autoreactive T cells from patients. Importantly, our preliminary results show the feasibility of the production and in vitro efficacy of CAR123 from patient T cells to a similar extend to CAR123 from HD. Further characterization of CAR-T phenotype and function is underway. In addition, in vivo experiments to demonstrate the value of CD123 CAR-T cells in these diseases are ongoing.

FC02 Immune cell signatures and T-cell receptor profiling reveal pathogenetic mechanisms in psoriasis

Abstract Psoriasis is a chronic inflammatory disease with systemic effects and currently has no cure due to an incomplete understanding of its underlying mechanisms. To gain better insights into the immune response associated with psoriasis, we conducted single-cell RNA sequencing and parallel single-cell T-cell receptor (TCR) profiling on peripheral blood mononuclear cells obtained from 11 psoriasis patients and 8 healthy controls. Additionally, we analysed two pairs of skin samples from the psoriasis cohort and performed spatial transcriptomics on two other pairs of skin samples. Our study identified specific immune signatures in myeloid and lymphocyte subsets both in blood and skin and highlighted characteristics of the immune repertoire in psoriasis. Notably, we found an increased proportion of circulating CD14+ monocytes. Furthermore, circulating plasmacytoid dendritic cells in psoriasis patients exhibited heightened expression of genes associated with skin-homing and pro-inflammatory responses. Circulating T cells in these patients showed decreased expression of activation markers. In psoriatic lesions, we observed that resting CD8+ tissue-resident memory T (TRM) cells displayed a gene expression profile similar to that of activated CD8+ TRM cells, though they had lower expression levels of cytotoxicity-related genes. Both resting and activated CD8+ TRM cells in psoriatic lesions showed enhanced interaction strength in terms of signal transmission and reception compared with non-lesions. Activated CD8+ TRM cells were densely infiltrated in the dermis of skin lesions, while resting CD8+ TRM cells were located deeper in the dermis of non-lesion areas. TCR clones that were highly expanded in skin lesions were predominantly CD8+ TRM cells. Distinct TCR clusters showed different gene expression signatures, with one CD8+ TRM cluster expressing IFNγ and another expressing IL-17. These findings provide a valuable resource for further investigation into the pathogenesis of psoriasis by offering insights into the immune cell dynamics within both circulation and local skin environments.

Venetoclax-Proteasome inhibitor-Dexamethasone for unfit patients with Blastic Plasmacytoid Dendritic Cell Neoplasm.

Venetoclax-Proteasome inhibitor-Dexamethasone for unfit patients with Blastic Plasmacytoid Dendritic Cell Neoplasm.

Mediators of Filgotinib Treatment Effects in Ulcerative Colitis: Exploring Circulating Biomarkers in the Phase 2b/3 SELECTION Study.

We utilized patient samples from the large, phase 2b/3 SELECTION trial to identify circulating biomarkers of ulcerative colitis (UC) and potential early mediators of filgotinib treatment effects. Samples were collected at baseline and during the induction phase of the SELECTION trial. Evaluated biomarkers comprised serum and stool proteins (measured by enzyme-linked immunosorbent assay), whole-blood cell counts, and whole-blood RNA-seq-derived gene-expression factors identified via exploratory factor analysis. Biomarker levels were assessed by baseline disease severity (endoscopy/bleeding/stool and Mayo Clinic Score) and biologic status (naive vs experienced). Effects of filgotinib on biomarker levels, including week 4 biomarker changes that may mediate week 10 clinical improvements, were assessed. The biomarker analysis set included 598 biologic-naive patients and 592 biologic-experienced patients. Systemic inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], serum amyloid A [SAA], and platelet cell counts) had the strongest positive correlations with baseline UC disease severity. CRP, IL-6, SAA, and neutrophil activation biomarkers (including neutrophil gelatinase-associated lipocalin [NGAL], tumor necrosis factor ɑ, and oncostatin M [OSM]), as well as platelet, neutrophil, and monocyte cell counts were increased in biologic-experienced versus biologic-naive patients. Gene-expression-derived plasmablast and cell proliferation factors were positively correlated with disease severity; B cell, T-cell activation, and plasmacytoid dendritic cell factors were negatively correlated. Filgotinib reduced nearly all proinflammatory biomarkers correlated with baseline UC disease activity; reduced SAA, CRP, IL-6, NGAL, and OSM at week 4 were identified as mediators of improved week 10 clinical scores. Filgotinib significantly impacted circulating biomarkers related to UC pathology. Several proinflammatory and neutrophil activation biomarkers may be early mediators of filgotinib treatment effects. NCT02914522.

An IFN-STAT1-CYBB Axis Defines Protective Plasmacytoid DC to Neutrophil Crosstalk During Aspergillus fumigatus Infection.

Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling the local expression of a subunit required for NADPH oxidase assembly and activity in the lung.

From Viral Infection to Skin Affliction: Unveiling Mechanisms of Cutaneous Manifestations in COVID-19 and Post-COVID Conditions.

COVID-19 skin manifestations are multifaceted, ranging from urticaria, morbilliform or papulovesicular rash, livedoid purpuric lesions, and to pseudochilblains (also called COVID toes). Recent insights into the mechanism of these manifestations have highlighted that morbilliform, papulovesicular, and livedoid/purpuric rashes are related to virus-induced endothelial cell damage and linked to moderate-to-severe disease, whereas pseudochilblains are related to an exaggerated IFN-1 production by plasmacytoid dendritic cells in protected individuals. In this paper, we will review the clinical and physiopathological features of cutaneous COVID-19 manifestations in relation to the direct viral cytopathic effects and dysregulated IFN-1 responses. We will also review the emerging insights into post-COVID conditions (also termed long COVID) and how they may be implicated in the persistence of COVID-19-associated skin diseases.

CAR-T cell therapy : recent updates and challenges in autoimmune diseases.

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies, demonstrating significant clinical efficacy and leading to FDA approval of several CAR-T cell-based products. This success has prompted exploration of CAR-T cell therapy in other disease areas, including autoimmune diseases (AIDs). CAR-T cells targeting B cells have been shown to provide clinical and biological improvements in patients with refractory AIDs. The aim of this review is to discuss promising strategies involving CAR-T cells in AIDs, such as those targeting B cells and T cells, and to explore new approaches targeting fibroblasts or plasmacytoid dendritic cells. Despite these advances, the application of CAR-T cell therapy in AIDs faces several unique challenges. The quality and functionality of T cells in patients with AIDs may be compromised due to previous treatments and the underlying inflammatory state, affecting the generation and efficacy of CAR-T cells. In addition, achieving adequate tissue biodistribution and persistence of CAR-T cells in affected tissues remains a major challenge. Finally, the high costs associated with CAR-T cell production pose economic problems, particularly in the context of chronic diseases, which are far more numerous than the hematological diseases for which CAR-Ts have been granted marketing authorization to date. If the indications for CAR-T cells increase significantly, production costs will have to drop drastically in order to obtain reliable economic models.

Potential role of bacterial extracellular vesicles in the pathophysiology of systemic lupus erythematosus

Systemic Lupus Erythematosus (SLE) is a rare autoimmune disorder influenced by various factors, including infections. Following bacterial or viral infections, there is an increase in IFN-I production, primarily by plasmacytoid dendritic cells (pDCs). Overproduction of IFN-I has been shown to drive the progression of SLE. Recent findings indicate that the gene expression signature of IFN-I in lupus nephritis patients does not co-occur with pDCs as expected; instead, it is localized in glomerular regions with anastomosing capillaries, suggesting a potential source from the blood. T cells, natural killer cells, and myeloid lineage cells may also secrete IFN in the bloodstream. Bacterial presence in the bloodstream challenges the concept of blood sterility, raising the possibility that cell-free microbial components, such as bacterial extracellular vesicles (BEVs), could trigger excessive IFN production through systemic circulation. While existing studies suggest a role for BEVs in human SLE, experimental evidence has yet to establish a direct association between the entire BEV nanoparticle and the disease. Research has primarily focused on (1) mammalian EVs and (2) purified eDNA and other specific cargoes as contributors to SLE progression. It remains unproven whether these bacterial molecules exert their effects while associated with vesicular membranes, i.e., BEVs. We hypothesize that BEVs, which carry diverse cargoes including nucleic acids, may enter systemic circulation, induce cellular responses leading to IFN overproduction, and exacerbate SLE severity. Clinical studies could investigate the association of BEVs with SLE progression by monitoring their presence and quantity in blood samples and correlating these factors with disease outcomes. Furthermore, understanding the involvement of BEVs may aid in identifying SLE biomarkers, inform infection prevention strategies, and inspire the development of BEV-neutralizing agents.