Role In Pathogenesis Of Systemic Lupus Erythematosus Research Articles

#1843 Deletion of IL17-producing follicular helper T cells restrains the germinal center reaction in systemic lupus erythematosus

Abstract Background and Aims Systemic lupus erythematosus (SLE) is an autoimmune disorder in which autoantibody formation can lead to severe kidney pathology. Interleukin (IL)17-producing T cells have been suggested to play an important role in the pathogenesis of SLE, and IL-17 inhibition was shown to ameliorate SLE pathology in lupus-prone mice. Moreover, the frequency of circulating follicular helper T (Tfh) cells, a T cell subset that orchestrates the maturation of high-affinity antibodies in the germinal center of secondary lymphoid organs, is associated with disease activity in SLE. Increased frequencies of IL17-producing Tfh have been reported in SLE patients compared to controls, but their role in SLE pathogenesis is still unknown. Method By leveraging the B6.Sle1NZM2410/AegYaa strain, we generated lupus-prone mice in which IL17-producing Tfh cells could be either fate-mapped (SLE Tfh17-FM, Il17aCRERosaLoxSTOPLox-YFPSle1+/+Yaa+) or fate-mapped and selectively depleted by intraperitoneal diphtheria toxin (DT) administration (SLE Tfh17-DTR, Il17aCRERosaLoxSTOPLox-YFPCxcr5LoxSTOPLox-DTRSle1+/+Yaa+). Tfh17-FM and Tfh17-DTR mice (both Sle1−/−Yaa−) were used as controls. Results Tfh17 comprised approximately 0.4% of total splenic Tfh in SLE mice at 6 weeks of life, and DT administration caused potent and selective depletion of these cells in the SLE Tfh17-DTR strain (Fig. 1A). Early Tfh17 deletion from week 4 to week 9 did not modify the increased Tfh frequency observed at 20 weeks in SLE mice, but resulted in long-term reduction of splenic germinal center (GC) B cells and plasmacells (Fig. 1B-C). IL17 receptor A was overexpressed in non-GC B cells and plasmacells of SLE mice compared to controls, suggesting a possible increased susceptibility of these subsets to IL17 (Fig. 1D). SLE Tfh17-DTR mice treated with DT displayed a trend towards decreased anti-DNA levels compared to SLE Tfh17-FM (Fig. 1E), but both glomerular immunocomplex deposition and renal pathology were not significantly impacted (Fig. 1F-G). Conclusion The germinal center reaction is affected by selective depletion of IL17-producing Tfh cells in SLE mice, with reduced differentiation of GC B cells and plasmacells. The modest effect of Tfh17 depletion on autoantibody levels and lupus nephritis pathology suggests that other Tfh subsets may play a role in GC-derived autoantibody generation. In addition, extrafollicular sources may also contribute to autoantibody production in SLE.

CAR-T Cells for Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an abnormal inflammatory response against nuclear antigens with consequent tissue damage. Autoreactive B cells and auto-antibodies have a fundamental role in SLE pathogenesis. Lupus nephritis (LN) has a great impact on patients' survival and quality of life and still represents and unmet clinical need due to the lack of specific treatments and to the poor response to conventional immunosuppression. Regulatory T cells (Tregs) physiologically maintain the immune tolerance and are impaired in SLE. Polyclonal Treg transfer obtained unsatisfactory results due to the low number of disease-relevant antigen-specific cells. Chimeric Antigen Receptors (CARs) are molecules capable of redirecting T cell specificity. CAR-Tregs proved effective in pre-clinical mouse models of autoimmunity. We aimed at developing a CAR-Treg based product to be employed in SLE in particular in LN. We isolated Tregs from Healthy Donors Peripheral Blood Mononuclear Cells (PBMCs) and expanded them with IL-2 and rapamycin. We transduced Tregs with a Lentiviral Vector encoding for a second-generation anti-CD19 CAR, considering the relevant role of autoreactive B cells and autoantibodies in SLE. Engineered cells retained their immune suppressive capabilities upon polyclonal stimulation. Noticeably, they acquired new antigen-specific suppressive capacities, being able to block autologous B cell proliferation. We set up a humanized mouse model of SLE. In vivo, CAR-Tregs delayed the occurrence of B cell lymphopenia, producing immunomodulatory cytokines and without showing toxicity or reprogramming towards Th17 pro-inflammatory cells. In inflamed organs, CAR-Tregs restored the normal composition of the immune system. In conclusion, we efficiently generated anti-CD19 CAR-Tregs and proved their efficacy both in vitro and in an in vivo humanized mouse model of lupus.

Multi-Omic Insights into the Mutational Landscape and Dysregulated Transcriptional Programs of Autoimmune B-Cells in Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with diverse manifestations, from mild and sporadic to severe and life-threatening. SLE heterogeneity arises from various factors, including genetic, epigenetic, and immune niche-related features (Kaul et al., 2016; Jenks et al., 2018). However, the exact interactions and hierarchy between these features remain unclear. Recent studies have found somatic mutations in genes typically mutated in B-cell lymphomas, in subsets of B-cells that are associated with SLE pathogenesis (Piotrowski et al., 2015; Pullabhatla et al., 2018; Singh et al., 2020; Brown et al., 2022). These mutations may support B-cell clonal bursts, but direct information from clinical specimens on the impact of these mutations on B-cell lineages and their influence on SLE progression or malignant transformation is missing. To define the somatic mutational landscape of B-cells in SLE, we first profiled peripheral blood mononuclear cells obtained from a pilot cohort of four SLE patients using whole-exome sequencing (WES; 200X depth). Following GATK best practices (Van der Auwera and O'Connor, 2020), we identified somatic alterations in DDX11 [variant allele frequency (VAF): 10.2%], DNMT3A [VAF: 3.4%]; PMS2 [VAF: 47.9%], and BICD1 [VAF: 47.3%]; these genes have been linked to lymphoid malignancies and SLE pathogenesis (Piotrowski et al., 2015; Pullabhatla et al., 2018; Niroula et al., 2021; Saeed et al., 2021). We validated the presence of the top-identified mutations using droplet digital PCR technology on sorted B-cell subsets (naïve, memory, and double-negative [DN; CD19 hiIgD loCD27 lo]) from these SLE patients. DN cells are a heterogeneous subtype of autoreactive memory B-cells that play a crucial role in SLE pathogenesis being the precursors of autoantibody producing plasma cells (Wei et al., 2007; Jenks et al., 2018). To investigate the transcriptional and epigenetic alterations in the mutation-harboring B-cells, we then conducted single-cell multi-omic sequencing. We profiled sorted activated B-cells (CD19 hiIgD lo) from the four SLE cases, to largely exclude non-autoreactive naïve B-cells. To maintain a comparison with naïve B cells, we included a small proportion of these cells in the input. In total, we analyzed 35,339 cells, and identified different B-cell subsets with distinct gene expression patterns, including DN cells ( n = 1,437 cells; ZEB2 hiTRAF5 lo, Jenks et al., 2018). To uncover, in an unbiased way, transcriptional differences between B-cell subsets, we catalogued variation in transcriptomic signatures derived from the scRNA data using consensus non-negative matrix factorization. We found a unique gene expression program exclusively present in DN cells ( Panel A), which includes key genes implicated in immune regulation and the development of autoimmunity, such as PTPN22 (Chung & Criswell, 2007; Tizaoui et al., 2021) . Pathway analysis of the DN-specific program revealed an enrichment of complement system genes (FDR = 0.074; Hallmark), which are crucial for immune regulation and tolerance, such as CBLB (Tang et al., 2019). Notably, in DN cells from one of the SLE samples carrying lymphoma/SLE-associated mutations in BICD1, PMS2, DDX11, we observed an altered expression of this gene program compared to DN cells from other samples ( P-value = 3.6x10 -11; Panel A, inset), suggesting that a malfunctioning complement system in DN cells may lead to an overly active immune response (Weinstein et al., 2021). In line with this notion, using chromatin accessibility profiles as a measure of transcription factor (TF) regulatory activities, we showed increased activity of TFs involved in interferon-dependent innate immune response and in B-cell activation and differentiation (RFX and OCT-1, respectively; FDR < 0.05), in the DN B-cells of this sample ( Panel B). In summary, we uncovered a unique transcriptional program associated with autoimmune DN B-cells. This program showed enrichment in key genes and pathways involved in immune response regulation. The disruption of this program, accompanied by the somatic SLE-associated mutations, may lead to overactivation of DN B cells, ultimately contributing to autoimmunity. Further analyses involving a larger cohort of clinical specimens are needed to directly link B-cell genotypes with their transcriptional and epigenetic programs and to elucidate the role of the identified mutations in SLE pathobiology.

The development of litifilimab (BIIB 059) for cutaneous and systemic lupus erythematosus.

This review describes the litifilimab (BIIB 059) development program to date for systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE). Plasmacytoid dendritic cells (pDCs), major producers of type I interferons (IFN-I), play a key role in SLE pathogenesis. Litifilimab, a humanized monoclonal antibody, binds to BDCA2, a protein uniquely expressed on pDCs. The consequence of BDCA2 ligation is the inhibition of IFN-I as well as IFN-III, cytokine and chemokine production. Phase I and II LILAC trial parts A and B achieved primary end points in SLE and CLE patients, confirming the importance of pDCs and IFN-I in SLE and CLE. Litifilimab is currently being evaluated in phase III trials in both SLE and CLE.

Possible Role of Dysbiosis of the Gut Microbiome in SLE.

The resident gut microbiota serves as a double-edged sword that aids the host in multiple ways to preserve a healthy equilibrium and serve as early companions and boosters for the gradual evolution of our immune defensive layers; nevertheless, the perturbation of the symbiotic resident intestinal communities has a profound impact on autoimmunity induction, particularly in systemic lupus erythematosus (SLE). Herein, we seek to critically evaluate the microbiome research in SLE with a focus on intestinal dysbiosis. SLE is a complex and heterogeneous disorder with self-attack due to loss of tolerance, and there is aberrant excessive immune system activation. There is mounting evidence suggesting that intestinal flora disturbances may accelerate the formation and progression of SLE, presumably through a variety of mechanisms, including intestinal barrier dysfunction and leaky gut, molecular mimicry, bystander activation, epitope spreading, gender bias, and biofilms. Gut microbiome plays a critical role in SLE pathogenesis, and additional studies are warranted to properly define the impact of gut microbiome in SLE, which can eventually lead to new and potentially safer management approaches for this debilitating disease.

Platelets are a major player and represent a therapeutic opportunity in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and organ injury with a premature mortality due to cardiovascular diseases. Platelets, that are primarily known for their role in hemostasis, have been shown to play an active role in the pathogenesis and in the progression of immune-mediated inflammatory diseases. Here we summarize the evidence of their roles in SLE pathogenesis which supports the development of targeted treatments. Platelets and their precursors, the megakaryocytes, are intrinsically different in SLE patients compared with healthy controls. Different triggers related to innate and adaptive immunity activate platelets which release extracellular vesicles, soluble factors and interact with immune cells, thereby perpetuating inflammation. Platelets are involved in organ damage in SLE, especially in lupus nephritis and participate in the heightened cardiovascular mortality. They also play a clear role in antiphospholipid syndrome which can be associated with both thrombocytopenia and thrombosis. To tackle platelet activation and their interactions with immune cells now constitute promising therapeutic strategies in SLE.

Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus

BackgroundPatients with systemic lupus erythematosus (SLE) have autoantibodies against the L1-encoded open-reading frame 1 protein (ORF1p). Here, we report (i) which immune cells ORF1p emanates from, (ii) which L1 loci are transcriptionally active, (iii) whether the cells express L1-dependent interferon and interferon-stimulated genes, and (iv) the effect of inhibition of L1 ORF2p by reverse transcriptase inhibitors.ResultsL1 ORF1p was detected by flow cytometry primarily in SLE CD66b+CD15+ regular and low-density granulocytes, but much less in other immune cell lineages. The amount of ORF1p was higher in neutrophils from patients with SLE disease activity index (SLEDAI) > 6 (p = 0.011) compared to patients with inactive disease, SLEDAI < 4. Patient neutrophils transcribed seven to twelve human-specific L1 loci (L1Hs), but only 3 that are full-length and with an intact ORF1. Besides serving as a source of detectable ORF1p, the most abundant transcript encoded a truncated ORF2p reverse transcriptase predicted to remain cytosolic, while the two other encoded an intact full-length ORF2p. A number of genes encoding proteins that influence L1 transcription positively or negatively were altered in patients, particularly those with active disease, compared to healthy controls. Components of nucleic acid sensing and interferon induction were also altered. SLE neutrophils also expressed type I interferon-inducible genes and interferon β, which were substantially reduced after treatment of the cells with drugs known to inhibit ORF2p reverse transcriptase activity.ConclusionsWe identified L1Hs loci that are transcriptionally active in SLE neutrophils, and a reduction in the epigenetic silencing mechanisms that normally counteract L1 transcription. SLE neutrophils contained L1-encoded ORF1p protein, as well as activation of the type I interferon system, which was inhibited by treatment with reverse transcriptase inhibitors. Our findings will enable a deeper analysis of L1 dysregulation and its potential role in SLE pathogenesis.

Significance of Interleukin 23 in Systemic Lupus Patients: Relation to Disease Activity and Damage Indices

Dysregulation of both cellular and humoral immune responses is central in systemic lupus erythematosus (SLE) pathogenetic mechanisms. Proinflammatory cytokines, such as interleukin 23 (IL23), and their roles in promoting such dysregulation have recently been highly considered. This research compared IL23 serum levels in 85 Egyptian SLE patients and 85 healthy controls. Then, IL23 level was correlated to various SLE disease parameters, disease activity, and damage indices. IL23 serum levels were significantly elevated in SLE patients versus healthy individuals. Furthermore, IL23 levels were positively correlated with SLE disease activity index (SLEDAI) and were positively correlated with arthritis, seizures, consumption of complements (C3, C4), and with parameters of nephritis (hematuria, pyuria, casts, and proteinuria). A positive correlation was also found between IL23 levels and oral prednisolone dose. IL23 has higher levels in the serum of SLE patients, and is correlated to activity of the disease, especially lupus nephritis. Further researchis needed to explore its exact role in SLE pathogenesis and whether it can be considered a potential biomarker or therapeutic target in SLE.

ASSOCIATION OF EPSTEIN-BARR VIRUS WITH SYSTEMIC LUPUS ERYTHEMATOSUS BY LIMITED MATERIALS: PATIENT CHARACTERISTICS AND CLINICAL MANIFESTATIONS IN YEMEN

Background and aims: Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease with damage to many organs due to the production of auto-antibodies, including auto-antibodies to renal antigen, vascular tissue antigens, brain antigens, ribosomes, nuclear antigens, and phospholipids. This study was conducted to determine patient characteristics and clinical manifestations of systemic lupus erythematosus and to find out the association of positive IgG with high titer of EBV-VCA with clinical features of SLE patients. Materials and Methods: In this cross-sectional study, 142 patients with SLE diagnosed based on American College of Rheumatology criteria were selected. All were included in the study after obtaining informed consent for participation. Whole blood samples were taken and serum was separated to determine anti-EBV IgG antibodies using the ELISA method and assessment with the SLE. Results: Female represent 81% of the total patients, while male represent only 19%, with ratio male: female equal to 1: 4.3, most of the patients were adults over 20 years old, with mean age ± SD was 35.8 ± 13.7 years. The most common signs were joint pain (95.1%), fever (92.3%), persistent fatigue (83.8%), followed by joint swelling (69.7%), photosensitivity (54.4%), renal involvement (52.8%), weigh loss (49.3%) and alopecia (49.3%), while other SLE signs were less frequent. Conclusion: EBV may have an important role in SLE pathogenesis and activity, SLE male: female ratio equals 1:4.3, most patients were adults over 20 years of age, and the most common signs of SLE were joint pain, fever and persistent fatigue. Peer Review History: Received: 2 September 2022; Revised: 11 October; Accepted: 15 November, Available online: 15 November 2022 Academic Editor: Dr. Iman Muhammad Higazy, National Research Center, Egypt, imane.higazy@hotmail.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Rima Benatoui,Laboratory of Applied Neuroendocrinology, Department of Biology, Faculty of Science, Badji Mokhtar University Annaba, Algeria. benattouiryma@gmail.com Similar Articles: THE ASSOCIATION OF EPSTEIN-BARR VIRUS ANTIBODIES WITH RHEUMATOID ARTHRITIS AMONG YEMENI PATIENTS IN SANA’A CITY

Altered Circulating Follicular T Helper Cell Subsets and Follicular T Regulatory Cells Are Indicators of a Derailed B Cell Response in Lupus, Which Could Be Modified by Targeting IL-21R.

Systemic lupus erythematosus (SLE) is characterized by the breakdown of self-tolerance, the production of high-affinity pathogenic autoantibodies and derailed B cell responses, which indicates the importance of central players, such as follicular T helper (TFH) subsets and follicular T regulatory (TFR) cells, in the pathomechanism of the disease. In this study, we aimed to analyze the distribution of the circulating counterparts of these cells and their association with disease characteristics and B cell disproportions in SLE. We found that the increased percentage of activated circulating TFH (cTFH) and cTFR cells was more pronounced in cutaneous lupus; however, among cTFH subsets, the frequency of cTFH17 cells was decreased in patients with lupus nephritis. Furthermore, the decreased proportion of cTFH17 cells was associated with low complement C4 levels and high disease activity scores. We also investigated whether the blocking of the IL-21 receptor (IL-21R) with an anti-IL-21R monoclonal antibody inhibits the B cell response, since IL-21 primarily produced by TFH cells potentially promotes humoral immunity. We observed that anti-IL-21R inhibited plasmablast generation and immunoglobulin production. Our study demonstrated that, besides cTFR/cTFH imbalance, cTFH17 cells play a crucial role in SLE pathogenesis, and modulating cTFH-B cell interaction through the IL-21/IL-21R pathway may be a promising therapeutic strategy to suppress the pathological B cell response.

MDSCs participate in the pathogenesis of diffuse pulmonary hemorrhage in murine lupus through mTOR-FoxO1 signaling

Diffuse pulmonary hemorrhage (DPH) is a common respiratory complication in patients with systemic lupus erythematosus (SLE). Our previous study found that myeloid-derived suppressor cells (MDSCs) have an important role in SLE pathogenesis. In this study, we further examined the role of MDSCs in the DPH mice model. We first observed an increased proportion of MDSCs and impaired immunosuppressive function in bronchoalveolar lavage fluid (BALF) and peritoneal cavity in the DPH mice model induced by pristane. By injecting anti-Gr-1 antibody, we found that MDSCs clearance can significantly alleviate DPH symptoms. The detection of downstream molecules proved that the mTOR signaling pathway was obviously activated in purified DPH MDSCs. After treatment of DPH model mice with AMPK agonist metformin, mammalian target of rapamycin (mTOR) inhibitor INK128, and rapamycin, respectively, we observed that inhibition of the mTOR signal alleviated DPH symptoms, inhibited the expansion of mononuclear MDSCs (M-MDSCs) and the differentiation of pro-inflammatory M1 macrophages (M1), which, in turn, promoted the expansion of granulocytes MDSCs (G-MDSCs) and differentiation of anti-inflammatory M2 macrophages (M2). We then demonstrated that inhibition of the mTOR signal increased the expansion of G-MDSCs, promoted M-MDSCs differentiation into M2 and inhibited their differentiation into M1 by administering TLR7 agonist R848 in vitro to simulate lupus environment. In addition, we also observed increased forkhead box-O1 (FoxO1) expression in M-MDSCs and macrophages after mTOR signal inhibition, both in vivo and in vitro. After down-regulation of FoxO1 by siRNA transfection, the regulatory effects of mTOR signal inhibition on M-MDSCs, M1 and M2 were reversed. Taken together, inhibition of the AMPK/mTOR signal could alleviate lupus-like diffuse lung injury by inducing M-MDSCs to differentiate into M2 by up-regulating FoxO1.

Profound inhibition of CD73-dependent formation of anti-inflammatory adenosine in B cells of SLE patients.

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease that leads to a breakdown of tolerance to self-antigens resulting in inflammation and organ damage. The anti-inflammatory activity of CD73-derived adenosine is well documented, however, its role in SLE pathogenesis is unknown.MethodsHuman peripheral blood immune cells were obtained from adult SLE patients (SLE) and healthy controls (HC). Expression and activity of purinergic ectoenzymes were assessed by qRT-PCR, flow cytometry and HPLC. Genes encoding purinergic ectoenzymes in SLE patients were analysed with targeted DNA sequencing.FindingsAmong circulating immune cells (both in HC and SLE), CD73 was most highly expressed on B cells, which was mirrored by high enzymatic activity only in HC. CD73 protein molecular weight was unchanged in SLE, however, the enzymatic activity of CD73 on SLE B cells was almost fully abolished. Accordingly, AMP accumulated in cultured SLE B cells. A similar discrepancy between protein expression and enzymatic activity was observed for NAD-degrading CD38 on SLE B cells. No differences were found in the rate of extracellular ATP degradation and expression of CD39, CD203a/c, and CD157. DNA sequencing identified no coding variants in CD73 in SLE patients.InterpretationWe describe a new pathomechanism for SLE, by which inactivation of CD73 on B cells produces less anti-inflammatory adenosine, resulting in immune cell activation. CD73 inactivation was not due to genetic variation but may be related to posttranslational modification.FundingThe German Research Council, Medical Faculty of the Heinrich-Heine-University Duesseldorf, Hiller Research Foundation, and Cardiovascular Research Institute Duesseldorf.

The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients

BackgroundAutoreactive B cells are well recognized as key participants in the pathogenesis of systemic lupus erythematosus (SLE). However, elucidating the particular subset of B cells in producing anti-dsDNA antibodies is limited due to their B cell heterogeneity. This study aimed to identify peripheral B cell subpopulations that display autoreactivity to DNA and contribute to lupus pathogenesis.MethodsFlow cytometry was used to detect total B cell subsets (n = 20) and DNA autoreactive B cells (n = 15) in SLE patients’ peripheral blood. Clinical disease activities were assessed in SLE patients using modified SLEDAI-2 K and used for correlation analyses with expanded B cell subsets and DNA autoreactive B cells.ResultsThe increases of circulating double negative 2 (DN2) and activated naïve (aNAV) B cells were significantly observed in SLE patients. Expanded B cell subsets and DNA autoreactive B cells represented a high proportion of aNAV B cells with overexpression of CD69 and CD86. The frequencies of aNAV B cells in total B cell populations were significantly correlated with modified SLEDAI-2 K scores. Further analysis showed that expansion of aNAV DNA autoreactive B cells was more related to disease activity and serum anti-dsDNA antibody levels than to total aNAV B cells.ConclusionOur study demonstrated an expansion of aNAV B cells in SLE patients. The association between the frequency of aNAV B cells and disease activity patients suggested that these expanded B cells may play a role in SLE pathogenesis.

Beyond Neuropsychiatric Manifestations of Systemic Lupus Erythematosus: Focus on Post-traumatic Stress Disorder and Alexithymia.

To deepen the comprehension of the role of specific psychological conditions in the pathogenesis and in the treatment of systemic lupus erythematosus (SLE). Specifically, the present comprehensive review aims at examining the association between SLE, alexithymia (AT)-a personality construct referring to the inability to identify, describe, and express sensations, emotions, and physical state-and post-traumatic stress disorder (PTSD), to infer potential biological relationships between these psychopathological issues and disease course, and to draw up a research agenda on gray areas of these topics. Whereas several studies document the presence of neuropsychiatric symptoms in patients with SLE, psychological distress, alexithymia, and post-traumatic manifestations are usually neglected by healthcare professionals and poorly investigated in research contexts. However, the interplay of these aspects, which affect physiologic stress coping mechanisms, potentially plays an important role in SLE pathogenesis. In particular, research documents that cytokine repertoire pattern alteration and hypothalamic-pituitary-adrenal axis impairment leading to inflammation and pain represent the main links between emotional health and immunity. AT and PTSD seem to be common in patients with SLE and account for multiple aspects of SLE-related morbidity. Furthermore, abnormal processing of stressful stimuli as hallmarks of PTSD and AT might promote neuroendocrine dysfunction and dysregulated immunity, thus contributing to the pathogenesis of SLE. A comprehensive, multidisciplinary clinical approach, based on a cooperation between immunologists, rheumatologists, neurologists, and mental health professionals, is crucial to promote patients' global health.

Increased TIM-3+PD-1+ NK cells are associated with the disease activity and severity of systemic lupus erythematosus

It is well established that natural killer (NK) cells are dysregulated in systemic lupus erythematosus (SLE) patients. However, the functions of NK cells and the mechanisms regulated by them in SLE remain incompletely understood. Patients with SLE were recruited from The First Affiliated Hospital of Nanchang University, and their clinical characteristics and treatments were recorded. The expression levels of T cell immunoglobulin mucin-3 (TIM-3) and programmed cell death protein 1 (PD-1) on NK cells were examined using flow cytometry. The correlations between the increase in TIM-3+PD-1+ NK cells in the SLE patients and clinical traits, including inflammatory markers, auto-antibodies, disease activity and severity of SLE, were examined. The TIM-3+NK cells, PD-1+NK cells and TIM-3+PD-1+ NK cells were significantly increased in the SLE patients. The increase in TIM-3+PD-1+ NK cells in the patients with SLE was associated with erythrocyte sedimentation rate, C-reactive protein, anti-double stranded DNA, anti-ribosomal P, SLE disease activity index and clinical features. The frequency of TIM-3+PD-1+NK cells in SLE patients with a cardiovascular disease (CVD) was significantly lower than that in SLE patients without a CVD. Moreover, the increased TIM-3+PD-1+ NK cells were significantly decreased in SLE patients following treatment. The present study suggested that the increased TIM-3+PD-1+ NK cells were associated with the disease activity and severity of SLE and may play a role in SLE pathogenesis.

Understanding the Relationships Between Type I Interferon, STAT4, and the Production of Interleukin‐21 and Interferon‐γ by Follicular Helper T Cells in Lupus: Comment on the Article by Dong et al

Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune diseases, characterized by loss of self-tolerance and production of multiple autoantibodies. Although the mechanism of SLE has remained elusive, accumulating evidence indicates that altered follicular helper T (Tfh) cells differentiation, function, and regulation may have an important role in SLE pathogenesis [1-3].

MRNA expression analysis confirms CD44 splicing impairment in systemic lupus erythematosus patients.

Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease characterized by several immunological alterations. T cells have a peculiar role in SLE pathogenesis, moving from the bloodstream to the peripheral tissues, causing organ damage. This process is possible for their increased adherence and migration capacity mediated by adhesion molecules, such as CD44. Ten different variant isoforms of this molecule have been described, and two of them, CD44v3 and CD44v6 have been found to be increased on SLE T cells compared to healthy controls, being proposed as biomarkers of disease and disease activity. The process of alternative splicing of CD44 transcripts is not fully understood. We investigated the mRNA expression of CD44v3 and CD44v6 and also analyzed possible CD44 splicing regulators (ESRP1 molecule and rs9666607 CD44 polymorphism) in a cohort of SLE patients compared to healthy controls. This study involved 18 SLE patients and 18 healthy controls. Total RNA and DNA were extracted by peripheral blood mononuclear cells. The expression study was conducted by quantitative RT-polymerase chain reaction, using SYBR Green protocol. Genotyping of rs9666607 SNP was performed by direct sequencing. CD44v6 mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). CD44v3/v6 mRNA ratio in healthy controls was strongly unbalanced towards isoform v3 compared to SLE patients (p = 0.002) and decreased progressively from healthy controls to the SLE patients in remission and those with active disease (p = 0.015). The expression levels of CD44v3 and CD44v6 mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator ESRP1 expression positively correlated with CD44v6 expression in healthy controls (p = 0.02, Pearson r = 0.532) but not in SLE patients. The variant A allele of rs9666607 of CD44 was associated with higher level of global CD44 mRNA (p = 0.04) but not with the variant isoforms. In SLE patients, the increase in CD44v6 protein correlates with a higher transcript level of this isoform, confirming an impairment of CD44 splicing in the disease, whose regulatory mechanisms require further investigation.

Potential role of viral infection and B cells as a linker between innate and adaptive immune response in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that involves several organ systems. Although B cells play a key role in SLE pathogenesis, the mechanisms behind B cell dysregulation in SLE development remained controversial. Finding the modules containing highly co-expressed genes in B cells could explain biological pathways involved in the pathogenesis of SLE, which may further support the reasons for the altered function of B cells in SLE disease. A total of three microarray gene expression datasets were downloaded from Gene Expression Omnibus. SLE samples were prepared from the purified B lymphocyte cells of the patients who have not received immunosuppressive drugs as well as high dose immunocytotoxic therapies or steroids. A weighted gene co-expression network was then constructed to find the relevant modules implicated in the SLE progression. Among 17 identified modules, 3 modules were selected through mapping to STRING and finding the ones that had highlyconnection at the protein level. These modules clearly indicate the involvement of several pathways in the pathogenesis of SLE including viral infection, adaptive immune response, and innate immune response in B lymphocytes. The WGCN analysis further revealed the co-expressed genes involved in both innate and adaptive immune systems. Mix infections and primary immunodeficiency might also dysregulate B lymphocytes, which may facilitate SLE development. As such, identifying novel biomarkers and pathways in lupus would be of importance.

Rhupus Syndrome Presenting as Interstitial Lung Disease: A Case Report

Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) are characterised by two distinct immunopathological activities, the T-helper 2 cells play a vital role in pathogenesis of SLE while T-helper 1 cells play an important role in RA. Organ involvement in Rhupus syndrome is relatively rare. Here, authors present a case of 59-year-old female who came with complaints of multiple joint pain (involving small and large joints) for a year and dyspnoea for 6 months without co-morbidities, on examination she had pallor, impaired percussion note and velcro crepitations in bilateral infrascapular region, her Pulmonary function test revealed a restrictive pattern and High-Resolution CT (HRCT) chest revealed sub-pleural reticulations involving lower lobes, she was diagnosed as RA with Interstitial Lung Disease (ILD) and started on hydroxycholoroquine, sulfasalazine and prednisolone. During follow-up after 6 months she developed a hyperpigmented rash over cheeks and bridge of nose, non-painful oral ulcers with Anti-Nuclear Antibodies (ANA) showing speckled positivity and Extractable Nuclear Antigen (ENA) panel showing positive anti-ds DNA and negative anti-histone, here with, we present a case of Rhupus syndrome presented with ILD. Recognising this condition is important as treatment varies between Rhupus syndrome and SLE or RA.

Serum tenascin-c in systemic lupus erythematosus and association with clinical expression of the disease

Background: Tenascin-C (TN-C) is a pro-inflammatory glycoprotein with various biological functions. TN-C plays a major role in cell adhesion, migration, proliferation, and cellular signaling through the induction of pro-inflammatory cytokines. Aim of the Work: This study was designed to investigate the relationship between serum TN-C levels and disease activity in patients with systemic lupus erthromatosus. Subjects and Methods: This is a case–control observational study that was carried out on 68 participants and divided into two groups. Group A included 34 systemic lupus erythematosus (SLE) patients and Group B included (34) apparently healthy volunteers. They were age and sex matched with the patients. Clinical examination as well as routine laboratory investigations confirmed their healthy status. All patients were subjected to full history taking, through clinical examination, laboratory investigations as C-reactive protein, erythrocyte sedimentation rate, C3, C4, ANA, and anti-dsDNA. Serum TN-C estimation of serum TN-C was done for SLE patients and the control group using double-antibody sandwich enzyme-linked immunosorbent assay. Disease activity of SLE patients was assessed according to SLE disease activity index 2000 score. Results: Serum level of TN-C was higher in SLE patients than healthy control but with no statistically significant difference (P > 0.05). There was highly statistically significant difference (P Conclusion: Serum TN-C level is elevated in SLE patients and correlates with disease activity which indicates its possible role in SLE pathogenesis. Thus, TN-C may provide a novel research target for the pathogenesis and therapy of SLE.