Inflammation In Systemic Lupus Erythematosus Research Articles

The Therapeutic Effects of Probiotic on Systemic Lupus Erythematosus in Lupus Mice Models: A Systematic Review.

Increasing evidence suggests the beneficial immunomodulatory effects of probiotics can reduce inflammation in systemic lupus erythematosus (SLE). However, there is no summary of the existing evidence available. This study aims to investigate the therapeutic effects of probiotics on SLE in a lupus mouse model by examining various markers, including inflammatory cytokines, Treg cells, disease activity, and gut microbiota. A systematic search was conducted using three databases (Web of Science, PubMed, and Scopus) to identify animal studies that reported the therapeutic benefits of probiotics against SLE. Data extracted from the selected articles were qualitatively synthesized. The SYRCLE risk of bias tool was used to evaluate the risk of bias. Out of a total of 3205 articles, 12 met the inclusion criteria. Probiotic strains, quantities, and routes of administration varied among the studies. The treatment ranged from 8 to 47weeks. Probiotic strains such as L. fermentum CECT5716, L. casei B255, L. reuteri DSM 17509, L. plantarum LP299v, and L. acidophilus can significantly reduce pro-inflammatory cytokines (TNF-α, IL-12, IL-6, IL-1β, IL-17, and IFN-γ) levels while increasing anti-inflammatory IL-10 and Treg cells. Probiotics also delay the production of autoantibodies, thus prolonging the remission period, decreasing flare frequency, and delaying disease progression. Furthermore, probiotic administration prevents gut dysbiosis, increases intestinal stability, and prevents pathogen colonization. In conclusion, probiotics can be considered a new alternative therapeutic approach for the management of SLE. Further clinical studies are required to investigate and validate the safety and effectiveness of probiotics in humans.

Platelet-to-lymphocyte ratio as a biomarker of systemic inflammation in systemic lupus erythematosus: A meta-analysis and systematic review.

The objective of this study was to evaluate the relationship between the platelet-to-lymphocyte ratio (PLR) and systemic lupus erythematosus (SLE). Additionally, the study aimed to establish an association between PLR and SLE disease activity, specifically lupus nephritis (LN). We conducted a comprehensive search across Medline, Embase, and Cochrane databases to identify relevant articles. Subsequently, we performed meta-analyses to compare PLR between SLE patients and controls, as well as active and inactive SLE cases, along with LN and non-LN groups. Furthermore, a meta-analysis was conducted on correlation coefficients between PLR and various parameters in SLE patients, including the SLE Disease Activity Index (SLEDAI), C3, C4, anti-dsDNA, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). In total, fifteen studies comprising 1,522 SLE patients and 1,424 controls were eligible for inclusion. The meta-analysis demonstrated a significant elevation of PLR in the SLE group compared to the control group (Standardized Mean Difference [SMD] = 0.604, 95% Confidence Interval [CI] = 0.299-0.909, p < 0.001). Upon stratification by ethnicity, an elevated PLR was observed in the SLE group among both Asian and Arab populations. Subgroup analysis based on sample size revealed consistently higher PLR in both small (n < 200) and large sample (n ≥ 200) SLE groups. Moreover, when considering disease activity, there was a noteworthy trend of increased PLR in the active disease group compared to the inactive group (SMD = 0.553, 95% CI = 0.000-1.106, p = 0.050). However, the meta-analysis did not demonstrate a significant distinction in PLR between the LN and non-LN groups. Notably, a positive association was established between PLR and SLEDAI (correlation coefficient = 0.325, 95% CI = 0.176-0.459, p < 0.001). Furthermore, PLR exhibited positive correlations with ESR, CRP, proteinuria, C3, and anti-dsDNA antibody levels. The outcomes of this meta-analysis underscored the elevated PLR in SLE patients, suggesting its potential as a biomarker for gauging systemic inflammation in SLE. Additionally, PLR exhibited correlations with SLEDAI, as well as with key indicators such as ESR, CRP, proteinuria, C3, and anti-dsDNA antibody levels.

P162 Dimethyl fumarate modulates T cell metabolism and function in systemic lupus erythematosus patient samples

Abstract Background/Aims Activated CD4+T cells make a significant contribution to inflammation in systemic lupus erythematosus (SLE) through secretion of proinflammatory cytokines such as IFN-γ and TNF-α. CD4+T cells can also express activating NK receptors such as NKG2D that can engage with stress-induced ligands such as MICA, as noted in lupus nephritis, and mediate nonspecific tissue injury. We know that cellular metabolism regulates the activation of T cells. Evidence from patients with multiple sclerosis indicates that dimethyl fumarate (DMF), an electrophile, targets cellular metabolism to modulate CD4+T cell activation and function. Here, we investigated whether DMF modulates T cell metabolism and function in samples from patients with SLE in a series of in vitro experiments. Methods All experiments were performed using isolated T cells from freshly drawn whole blood samples from patients with SLE. T cells were isolated using negative selection using stem cell or Miltenyei magnetic bead separation kit. Isolated T cells were activated with anti-CD3 and IL-2 and incubated with either DMF at 25μM concentration or DMSO alone for three or seven days at 37 °C and 5% CO2 before harvesting. Results In Seahorse experiments, after three days of incubation, dimethyl fumarate (DMF) inhibited Figure A-i) the oxygen consumption rate (OCR) and A-ii) extra cellular acidification rate (ECAR) in isolated T cells when compared with samples incubated with vehicle, dimethyl sulfoxide (DMSO). Our results revealed that DMF significantly inhibited: 1) aerobic glycolysis and oxidative phosphorylation in activated T cells from patients with SLE (n = 4) (Figure A- i and ii) in vitro; 2) T cell activation and proliferation as assessed by a reduction in the frequency of CD69 (n = 4) and D) Ki67 (n = 2) positivity, respectively (Figure B-E); 3) Collectively, these results suggest that DMF inhibits T cell activation and proliferation in samples from patients with SLE. After 7 days of incubation, DMF significantly inhibited the expression of activating NK receptors CD158a and NKG2D on T cells whereas there was a trend toward enhancing the expression of inhibitory NK receptors NKG2A and CD158b (Figure F-I). After 7 days of incubation, DMF significantly reduced intracellular expression of IFN-γ, TNF-α, IL-17 and secretion of pro-inflammatory cytokines IFN-γ and TNF-α in supernatants (Figure J - N). Conclusion Our preliminary data indicated that, in SLE patient samples, DMF modulates metabolic programming of CD4+ T cells and inhibits glycolysis and oxidative phosphorylation of activated CD4+ T cells. In vitro, DMF inhibited: T cell activation; proliferation; the expression of activating NK receptors; and secretion of proinflammatory cytokines from T cells patients with SLE. Taken together with the existing safety data in humans, these data provide mechanistic rationale for investigating the potential of dimethyl fumarate, with a distinct mechanism of action, as a novel therapy for SLE. Disclosure L. Kell: None. K. Shah: None. S. Taylor: None. R. De Maeyer: None. D.A. Isenberg: None. D. Sen: None. M. Castelino: None. M. Leandro: None. A. Akbar: None. V. Reddy: Grants/research support; UCLH Biomedical research centre funded this work, Dr.Reddy's work was supported through MR/T024968/1 MRC-CARP Fellowship.

Transcobalamin 2 orchestrates monocyte proliferation and TLR4-driven inflammation in systemic lupus erythematosus via folate one-carbon metabolism.

SLE is a complex autoimmune disease with deleterious effects on various organs. Accumulating evidence has shown abnormal vitamin B12 and one-carbon flux contribute to immune dysfunction. Transcobalamin II (TCN2) belongs to the vitamin B12-binding protein family responsible for the cellular uptake of vitamin B12. The role of TCN2 in SLE is still unclear. We collected clinical information and blood from 51 patients with SLE and 28 healthy controls. RNA sequencing analysis, qPCR, and western blot confirmed the alteration of TCN2 in disease monocytes. The correlation between TCN2 expression and clinical features and serological abnormalities was analyzed. TCN2 heterozygous knockout THP1 cells were used to explore the effects of TCN2 dysfunction on monocytes. CCK-8 assay and EdU staining were used to detect cell proliferation. ELISA was conducted to assess vitamin B12, glutathione, and cytokines changes. UHPLC-MRM-MS/MS was used to detect changes in the intermediates of the one-carbon cycle. Flow cytometry is used to detect cell cycle, ROS, mitoROS, and CD14 changes. Elevated TCN2 in monocytes was correlated positively with disease progression and specific tissue injuries. Using CD14+ monocytes and TCN2 genetically modified THP1 cell lines, we found that the TCN2 was induced by LPS in serum from SLE patients. TCN2 heterozygous knockout inhibited cellular vitamin B12 uptake and one-carbon metabolism, leading to cell proliferation arrest and decreased Toll-like receptor 4 (TLR4)-mediated CCL2 release. Methionine cycle metabolites, s-adenosylmethionine and homocysteine, rescued these effects, whereas folate treatment proved to be ineffective. Folate deficiency also failed to replicate the impact of TCN2 downregulation on THP1 inflammatory response. Our study elucidated the unique involvement of TCN2-driven one-carbon flux on SLE-associated monocyte behavior. Increased TCN2 may promote disease progression and tissue damage by enhancing one-carbon flux, fostering monocyte proliferation, and exacerbating TLR4 mediated inflammatory responses. The inhibition of TCN2 may be a promising therapeutic approach to ameliorate SLE.

Toll-like receptor expression and functional behavior in platelets from patients with systemic lupus erythematosus

BackgroundMultiple blood cell abnormalities participate in the development of inflammation in systemic lupus erythematosus (SLE). Although platelets have been suggested as one of these contributors through the release of their content during activation, there are limited specific data about their role as immune players in SLE. Materials and MethodsThirteen SLE patients were included. Flow cytometry was used to measure Toll-like receptors (TLR) 2, 4, and 9 in resting platelets, platelet-activation markers (PAC-1 binding, P-selectin, CD63, and CD40 ligand -L) and platelet-leukocyte aggregates before and after specific TLR stimulation. Soluble CD40L and von Willebrand factor (vWf) release from stimulated platelets was measured using ELISA. ResultsIn resting conditions, SLE platelets showed normal expression levels of TLR 2, 4 and 9. Platelet surface activation markers, soluble CD40L, and vWf release were normal at baseline and after TLR stimulation. Platelet-monocyte aggregates were elevated in resting conditions in SLE samples and showed only a marginal increase after TLR stimulation, while baseline and stimulated platelet-neutrophil and platelet-lymphocyte aggregates were normal. C-reactive protein levels positively correlated with platelet-monocyte aggregates both at baseline and after stimulation with the TLR-2 agonist PAM3CSK4, suggesting these complexes could reflect the inflammatory activity in SLE. In our cohort, 12 of 13 patients received treatment with hydroxychloroquine (HCQ), a known inhibitor of endosomal activity and a potential inhibitor of platelet activation. The fact that SLE platelets showed an adequate response to TLR agonists suggests that, despite this treatment, they retain the ability to respond to the increased levels of damage-associated molecular patterns (DAMPs), which represent known TLR ligands, present in the circulation of SLE patients. Interestingly, elevated plasma levels of high mobility group box 1 (HMGB1), a classical DAMP, correlated with vWf release from TLR-stimulated platelets, suggesting that HMGB1 may also be released by platelets, thereby creating a positive feedback loop for platelet activation that contributes to inflammation. ConclusionOur study demonstrates normal platelet TLR expression and function together with increased circulating platelet-monocyte aggregates. In addition, a direct correlation was observed between plasma HMGB1 levels and platelet vWf release following TLR2 stimulation. This platelet behavior in a group of patients undergoing HCQ treatment suggests that platelets could play a role in the inflammatory state of SLE.

Transcriptomic and proteomic profiling reveals distinct pathogenic features of peripheral non-classical monocytes in systemic lupus erythematosus

Peripheral blood monocytes propagate inflammation in systemic lupus erythematosus (SLE). Three major populations of monocytes have been recognized namely classical (CM), intermediate (IM) and non-classical monocytes (NCM). Herein, we performed a comprehensive transcriptomic, proteomic and functional characterization of the three peripheral monocytic subsets from active SLE patients and healthy individuals. Our data demonstrate extensive molecular disruptions in circulating SLE NCM, characterized by enhanced inflammatory features such as deregulated DNA repair, cell cycle and heightened IFN signaling combined with differentiation and developmental cues. Enhanced DNA damage, elevated expression of p53, G0 arrest of cell cycle and increased autophagy stress the differentiation potential of NCM in SLE. This immunogenic profile is associated with an activated macrophage phenotype of NCM exhibiting M1 characteristics in the circulation, fueling the inflammatory response. Together, these findings identify circulating SLE NCM as a pathogenic cell type in the disease that could represent an additional therapeutic target.

Platelet LGALS3BP as a Mediator of Myeloid Inflammation in Systemic Lupus Erythematosus.

Platelets are mediators of inflammation with immune effector cell properties and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet-associated lectin, galactoside-binding, soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE and as a potential biomarker associated with clinical phenotypes. We performed RNA sequencing on platelets from patients with SLE (n=54) and on platelets from age-, sex-, and race/ethnicity-matched healthy controls (n=18) and measured LGALS3BP levels in platelet releasate and in circulating serum. We investigated the association between LGALS3BP levels and the prevalence, disease severity, and clinical phenotypes of SLE and studied platelet-mediated effects on myeloid inflammation. Platelets from patients with SLE exhibited increased expression of LGALS3BP (fold change 4.0, adjusted P=6.02 × 10-11 ). Platelet-released LGALS3BP levels were highly correlated with circulating LGALS3BP (R=0.69, P < 0.0001), and circulating LGALS3BP levels were correlated with the severity of disease according to the SLE Disease Activity Index (r=0.32, P=0.0006). Specifically, circulating LGALS3BP levels were higher in SLE patients with lupus nephritis than in patients with inactive disease (4.0 μg/ml versus 2.3 μg/ml; P < 0.001). Interferon-α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG-01) in a dose-dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced proinflammatory cytokine production by macrophages. Our results support that platelets act as potent effector cells that contribute to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity.

Clinical aspects of cutaneous lupus erythematosus.

Lupus erythematosus (LE) is an autoimmune inflammatory disease with a wide clinical spectrum from life-threatening multi-organ inflammation in systemic lupus erythematosus (SLE) to limited skin disease in cutaneous LE (CLE). The etiology of CLE is still not fully understood but a multifactorial genesis with genetic predisposition and certain environmental factors as triggers for the development are generally accepted features. Lesions can be induced and aggravated by UV-irradiation and smoking is linked to more severe forms of skin disease and to co-morbidity. Drugs, including many common medicines like antihypertensives, are known to induce subacute CLE (SCLE). The mechanisms involved have recently been shown to be part of the IFN-I pathway and new, specific treatments are currently in clinical trials. CLE is currently classified in subtypes based on clinical presentation and duration into acute CLE (ACLE), SCLE, and chronic CLE (CCLE). Distinct subtypes can be seen in individual patients or coexist within the same patient. Because of the confluent and overlapping picture between these subsets, serology, and histopathology constitute an important role guiding towards correct diagnose and there is ongoing work to update the classification. The Cutaneous Lupus Area Severity Index (CLASI) is a validated tool to measure activity and damage both in clinical trials but also for the clinician to evaluate treatment and follow the course of the disease among patients. CLE is known to have substantial impact on the life of those affected. Several tools have been proposed to measure QoL in these patients, currently Skindex-29 is probably the most used. Patient education is an important part of prevention of flares, including UV-protection and smoking cessation. First-line treatment includes topical corticosteroids as well as topical calcineurin inhibitors with the addition of systemic treatment with antimalarials in more severe or therapy resistant cases. Treatment specifically targeting CLE has been lacking, however novel potential therapies are in later phase clinical trials. In this review we aim to describe the different subsets of the cutaneous form in LE with focus on clinical aspects.

Binding of C1q to Galectin-3 Binding Protein on Microvesicles Released by Mononuclear Cells from Patients with Systemic Lupus Erythematosus

Background: Generation of galectin-3 binding protein (G3BP)-expressing microvesicles can be induced in-vitro by Toll-like receptor 9 ligation in mononuclear cells. Microvesicles co-expressing G3BP and double-stranded DNA are associated with active lupus nephritis. However, whether the microvesicular G3BP mainly deposits from circulation or is endogenously derived is unknown. In this study, we aim to delineate the origin of G3BP on in-vitro generated microvesicles by using serum as a source of native G3BP. Methods: G3BP-expressing microvesicles, generated by stimulation of systemic lupus erythematosus patient-derived mononuclear cells with the Toll-like receptor 9-agonist ODN2395, were incubated with normal human serum, heat-inactivated human serum, recombinant human C1q or human albumin. The expression of G3BP by microvesicles was examined by flow cytometry, and the binding of soluble recombinant human C1q to recombinant human G3BP was investigated by ELISA. Results: Approximately half of the microvesicles released from mononuclear cells expressed G3BP. Surprisingly, the staining was abrogated by incubation of the microvesicles with normal human serum, while incubation with heat-inactivated human serum did not have a similar effect. Reasoning that C1q might be the heat-labile factor blocking access of our G3BP antibody detection system, we incubated microvesicles with recombinant human C1q, which on average inhibited the detectable proportion of G3BP-bearing microvesicles by 87%. Soluble recombinant human C1q bound to immobilized recombinant human G3BP in a dose-dependent manner. Conclusion: Our data suggest that soluble C1q binds to G3BP on Toll-like receptor 9-induced microvesicles released from systemic lupus erythematosus patient-derived mononuclear cells. This interaction may exarcerbate inflammation in systemic lupus erythematosus but may also serve as a general mechanism for the appropriate clearance of these potentially pathogenic factors. Keywords: microvesicles, C1q, complement, clearance, Toll-like receptor 9, peripheral blood mononuclear cells, galectin-3 binding protein, systemic lupus erythematosus

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis

BackgroundCombinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression (“neighborhood” miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive.ResultsHere, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites (“seed overlap” miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, “seed overlap” miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive “seed overlap” is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes—those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both “seed overlap” and “neighborhood” miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes.ConclusionsOur study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.

Fighting Fatigue in Systemic Lupus Erythematosus: Experience of Dehydroepiandrosterone on Clinical Parameters and Patient-Reported Outcomes.

Manifestations related to ongoing inflammation in systemic lupus erythematosus (SLE) are often adequately managed, but patient-reported outcome measures (PROMs) support that fatigue and low quality of life (QoL) in the absence of raised disease activity remain major burdens. The adrenal hormone dehydroepiandrosterone (DHEA) has shown potential as a pharmacological agent for managing fatigue in mild SLE. We retrospectively evaluated data on dosage, disease activity, corticosteroid doses, concomitant antirheumatic drugs, and PROMs regarding pain intensity, fatigue, and well-being (visual analogue scales), QoL (EQ-5D-3L) and functional disability. A total of 15 patients with SLE were exposed to DHEA and 15 sex- and age-matched non-exposed SLE patients served as comparators. At baseline, 83% of the DHEA-exposed patients had subnormal DHEA concentration. The 15 subjects prescribed DHEA were exposed during a median time of 12 months (IQR 16.5) [range 3–81] and used a median daily dose of 50 mg of DHEA (IQR 25.0) [range 25–200]. Neither disease activity, nor damage accrual, changed significantly over time among patients using DHEA, and no severe adverse events were observed. Numerical improvements of all evaluated PROMs were seen in the DHEA-treated group, but none reached statistical significance. For DHEA-exposed patients, a non-significant trend was found regarding fatigue comparing baseline and 36 months (p = 0.068). In relation to SLE controls, the DHEA-exposed group initially reported significantly worse fatigue, pain, and well-being, but the differences diminished over time. In conclusion, DHEA was safe, but evidence for efficacy of DHEA supplementation in relation to PROMs were not found. Still, certain individuals with mild SLE, plagued by fatigue and absence of increased disease activity, appear to benefit from DHEA in terms of improved fatigue and QoL. Testing of DHEA concentration in blood should be performed before initiation, and investigation of other conditions, or reasons responsible for fatigue, must always be considered first.

GILZ regulates type I interferon release and sequesters STAT1

Glucocorticoids remain a mainstay of modern medicine due to their ability to broadly suppress immune activation. However, they cause severe adverse effects that warrant urgent development of a safer alternative. The glucocorticoid-induced leucine zipper (GILZ) gene, TSC22D3, is one of the most highly upregulated genes in response to glucocorticoid treatment, and reduced GILZ mRNA and protein levels are associated with increased severity of inflammation in systemic lupus erythematosus (SLE), Ulcerative Colitis, Psoriasis, and other autoimmune/autoinflammatory diseases. Here, we demonstrate that low GILZ permits expression of a type I interferon (IFN) signature, which is exacerbated in response to TLR7 and TLR9 stimulation. Conversely, overexpression of GILZ prevents IFN-stimulated gene (ISG) up-regulation in response to IFNα. Moreover, GILZ directly binds STAT1 and prevents its nuclear translocation, thereby negatively regulating IFN-induced gene expression and the auto-amplification loop of the IFN response. Thus, GILZ powerfully regulates both the expression and action of type I IFN, suggesting restoration of GILZ as an attractive therapeutic strategy for reducing reliance on glucocorticoids.

T-cell-derived Exosomal Proteins ECP and BPI Induce Cytokines and Tissue Inflammation in Systemic Lupus Erythematosus

Abstract T cells play critical roles in the pathogenesis of systemic lupus erythematosus (SLE). Serum-derived exosomes are increased in human SLE patients and are correlated with disease severity; however, the property of T-cell-derived exosomes from SLE patients remains unclear. We characterized proteins of SLE T cell-derived exosomes by exosome MACSPlex analysis and proteomics using T-cell supernatants from human SLE patients and healthy controls. We identified two exosoaml proteins, eosinophil cationic protein (ECP, also named human RNase 3) and bactericidal/permeability-increasing protein (BPI), which were overexpressed in SLE T-cell-derived exosomes and T cells. Both T-cell-specific ECP transgenic (Lck-ECP Tg) and BPI transgenic (Lck-BPI Tg) mice displayed multi-tissue inflammation. Lck-ECP and Lck-BPI Tg mice displayed early induction of serum IFN-γ levels and IL-1β levels, respectively. Single-cell RNA sequencing (scRNA-seq) showed the induction of IFN-γ mRNA and inflammatory pathways in ECP Tg T cells. ScRNA-seq also showed the reduction of Treg population in BPI Tg T cells; conversely, Treg differentiation was enhanced by BPI knockout. Remarkably, adoptively transferred ECP-containing or BPI-containing exosomes stimulated serum autoantibodies levels and induced nephritis/nephritis/arthritis in the recipient mice. Collectively, ECP or BPI overexpression in T-cell-derived exosomes or T cells are novel biomarkers and pathogenic factors for human SLE nephritis, hepatitis, and arthritis.

Ultraviolet light induces HERV expression to activate RIG-I signalling pathway in keratinocytes.

Skin inflammation and photosensitivity are common in lupus erythematosus (LE) patients, and ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) patients. Type I interferons (IFN) are upregulated in LE skin after UV exposure; however, the mechanisms to explain UVB-induced inflammation remain unclear. Here, we demonstrated that UVB irradiation-induced activation of human endogenous retroviruses (HERVs) plays a major role in the immune response. UVB-induced HERV-associated dsRNA transcription and subsequent activation of the innate antiviral RIG-I/MDA5/IRF7 pathway led to downstream transcription of interferon-stimulated genes, which promotes UVB-induced apoptosis and proliferation inhibition in keratinocytes through RIG-I and MDA5 pathways. Our findings indicate that UVB irradiation induces HERV-dsRNA overexpression, and the dsRNA-sensing innate immunity pathway promotes type I IFN production, which may be a potential mechanism of skin inflammatory response and skin lesion of SLE/DLE.

Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus.

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to “self” nucleic acids, LL37 acts as “danger signal,” leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while “fully-citrullinated” LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated “adjuvant-like” properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to “fully citrullinated-LL37,” “fully carbamylated-LL37” maintains both innate and adaptive immune-cells’ stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.

BPI overexpression suppresses Treg differentiation and induces exosome-mediated inflammation in systemic lupus erythematosus.

Background: Serum-derived exosomes are correlated with disease severity of human systemic lupus erythematosus (SLE). The proteins in the T-cell-derived exosomes from SLE patients could contribute to inflammation.Methods: We characterized proteins of T cell-derived exosomes from SLE patients and healthy controls by proteomics. To study the potential pathogenic role of the identified exosomal protein, we generated and characterized T-cell-specific transgenic mice that overexpressed the identified protein in T cells using immunohistochemistry, immunoblotting, and single-cell RNA sequencing.Results: We identified an overexpressed protein, bactericidal/permeability-increasing protein (BPI), in SLE T cells and T-cell-derived exosomes. T-cell-specific BPI transgenic (Lck-BPI Tg) mice showed multi-tissue inflammation with early induction of serum IL-1β levels, as well as serum triglyceride and creatinine levels. Interestingly, exosomes of Lck-BPI Tg T cells stimulated IL-1β expression of wild-type recipient macrophages. Remarkably, adoptive transfer of BPI-containing exosomes increased serum IL-1β and autoantibody levels in recipient mice. The transferred exosomes infiltrated into multiple tissues of recipient mice, resulting in hepatitis, nephritis, and arthritis. ScRNA-seq showed that Lck-BPI Tg T cells displayed a decrease of Treg population, which was concomitant with ZFP36L2 upregulation and Helios downregulation. Furthermore, in vitro Treg differentiation was reduced by BPI transgene and enhanced by BPI knockout.Conclusions: BPI is a negative regulator of Treg differentiation. BPI overexpression in T-cell-derived exosomes or peripheral blood T cells may be a biomarker and pathogenic factor for human SLE nephritis, hepatitis, and arthritis.

T Cell Metabolism: A New Perspective on Th17/Treg Cell Imbalance in Systemic Lupus Erythematosus.

The Th17/T-regulatory (Treg) cell imbalance is involved in the occurrence and development of organ inflammation in systemic lupus erythematosus (SLE). Metabolic pathways can regulate T cell differentiation and function, thus contributing to SLE inflammation. Increasingly, data have shown metabolism influences and reprograms the Th17/Treg cell balance, and the metabolic pattern of T cells is different in SLE. Notably, metabolic characteristics of SLE T cells, such as enhanced glycolysis, lipid synthesis, glutaminolysis, and highly activated mTOR, all favored Th17 differentiation and function, which underlie the Th17/Treg cell imbalance in SLE patients. Targeting metabolic pathways to reverse Th17/Treg imbalance offer a promising method for SLE therapy.

CD32a receptor in health and disease

Low-affinity Fcγ-receptors that recognize the Fc portion of immunoglobulin (Ig) molecules, usually being in antigen-bound state, thus representing a link between innate and adaptive immunity. They play a significant role in inflammatory and infectious diseases. Among them, a separate FcγRII family (CD32) is discerned, which is characterized by transmission of intracellular signal independently of the common γ-chain, they have one α-chain containing two extracellular immunoglobulin-like domains. FcγRII receptors are present in almost all cells of the innate immune system: monocytes and macrophages, neutrophils, eosinophils, dendritic cells, as well as on B-lymphocytes and platelets. They perform two main functions: target recognition, facilitation of phagocytosis and destruction of antibody-opsonized cells by monocytes/ macrophages (including pathogenic cells). In parallel, the phagocytes are activated via the cytokine synthesis stimulation. The FcγRIIA (CD32a) and FcγRIIC (CD32c) activating receptors, like as FcγRIIB (CD32b) inhibiting receptors are present among the members of the FcγRII family. The low-affinity FcγRII receptors bind to IgG, with immune complexes being their natural ligands. High levels of immune complexes are usually found in both chronic viral infections and autoimmune diseases. There are shown polymorphic variants of the CD32a gene, which can affect the receptor function, and, thereby, causing susceptibility for different infections, influence the development of autoimmune diseases and primary immunodeficiencies. Activation of the CD32a receptor induces the production of pro-inflammatory cytokines, including TNFα and interferons, that are involved into inflammation in systemic lupus erythematosus, Kawasaki disease, Graves’ disease and rheumatoid arthritis. It has been shown that antibacterial activity of platelets is carried out via the CD32a receptor. The study of CD32a expression in people The CD32a receptor is considered a biomarker of cells that are a reservoir of HIV infection. At the present time, however, many questions remain regarding the mechanisms of CD32a expression of on HIV-infected cells and the role of CD32a in the formation of an HIV reservoir and/or development of appropriate resistance. In addition to HIV infection, the significance of FcγR receptors is shown in other infectious diseases, for example, with influenza and dengue virus infections. Better understanding of the CD32a structure and function will help to assess its role in immunopathogenesis of different conditions. This review focuses on the role of CD32a in development of the normal immune response in normal state and various diseases.

T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy.

T cell subsets are critically involved in the development of systemic autoimmunity and organ inflammation in systemic lupus erythematosus (SLE). Each T cell subset function (such as effector, helper, memory or regulatory function) is dictated by distinct metabolic pathways requiring the availability of specific nutrients and intracellular enzymes. The activity of these enzymes or nutrient transporters influences the differentiation and function of T cells in autoimmune responses. Data are increasingly emerging on how metabolic processes control the function of various T cell subsets and how these metabolic processes are altered in SLE. Specifically, aberrant glycolysis, glutaminolysis, fatty acid and glycosphingolipid metabolism, mitochondrial hyperpolarization, oxidative stress and mTOR signalling underwrite the known function of T cell subsets in patients with SLE. A number of medications that are used in the careof patients with SLE affect cell metabolism, and the development of novel therapeutic approaches to control the activity of metabolic enzymes in T cell subsets represents a promising endeavour in the search for effective treatment of systemic autoimmune diseases.

Ultraviolet light induces increased T cell activation in lupus-prone mice via type I IFN-dependent inhibition of T regulatory cells

Ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) patients. Although type I interferons (IFN) are upregulated in SLE skin after UV exposure, the mechanisms to explain increased UVB-induced inflammation remain unclear. This paper compares the role of type I IFNs in regulating immune cell activation between wild-type and lupus-prone mice following UVB exposure. 10-week old female lupus-prone (NZM2328), wild-type (BALB/c) and iNZM mice (lack a functional type I IFN receptor on NZM2328 background) were treated on their dorsal skin with 100 mJ/cm2 of UVB for 5 consecutive days. Following UVB treatment, draining lymph node cell populations were characterized via flow cytometry and suppression assays; treated skin was examined for changes in expression of type I IFN genes. Only NZM2328 mice showed an increase in T cell numbers and activation 2 weeks post UVB exposure. This was preceded by a significant increase in UVB-induced type I IFN expression in NZM2328 mice compared to BALB/c mice. Following UVB exposure, both BALB/c and iNZM mice demonstrated an increase in functional T regulatory (TReg) cells; however, this was not seen in NZM2328 mice. These data suggest a skewed UVB-mediated T cell response in lupus-prone mice where activation of T cells is enhanced secondary to a type I IFN-dependent suppression of TReg cells. Thus, we propose type I IFNs are important for UVB-induced inflammation in lupus-prone mice and may be an effective target for prevention of UVB-mediated flares.