Subset Of Systemic Lupus Erythematosus Patients Research Articles

Exploring genetic and immune cell dynamics in systemic lupus erythematosus patients with Epstein-Barr virus infection via machine learning.

Epstein-Barr Virus (EBV) is a widespread virus implicated in various diseases, including Systemic Lupus Erythematosus (SLE). However, the specific genes and pathways altered in SLE patients with EBV infection remain unclear. We aimed to identify key genes and immune cells in SLE patients with EBV infection. The datasets of SLE (GSE50772 and GSE81622) or EBV infection (GSE85599 and GSE45918) were obtained from the Gene Expression Omnibus (GEO) database. Next, differential gene expression (DEGs) analysis were conducted to identify overlapping DEGs and then enrichment analysis was performed. Machine learning was applied to identify key genes. Validation was conducted using ROC curve analysis and expression level verification in test datasets and single-cell RNA sequencing. Immune cell infiltration patterns were analyzed using CIBERSORTx, and clinical data were reviewed for SLE patients. We identified 58 overlapping DEGs enriched in interferon-related pathways. Five overlapping DEGs (IFI27, TXK, RAPGEF6, PIK3IP1, PSENEN) were selected as key genes by machine learning algorithms, with IFI27 showing the highest diagnostic performance. The expression level of IFI27 was found higher in CD4 CTL, CD8 naïve and various B cell subsets of SLE patients with EBV infection. IFI27 showed significant correlation with B intermediate and CD4 CT. Clinical data showed lower CD4 T cell proportions in SLE patients with EBV infection. This study identifies IFI27 as a key gene for SLE patients with EBV infection, influencing CD4 CTL and B cell subtypes. These findings enhance the understanding of the molecular mechanisms linking SLE and EBV infection, providing potential targets for diagnostic and therapeutic strategies.

Vanin-2 is expressed in peripheral blood T cells and upregulated in SLE patients.

Members of the vanin gene family include VNN1, VNN2 and VNN3 in humans. Although the functions of vanins have been widely examined in myeloid cells, their expression and functions have not been clarified in T lymphocytes. This study aimed to elucidate the significance of Vanin-2 (VNN2) on human peripheral blood T lymphocytes and study its expression in systemic lupus erythematosus (SLE). The differential expression of Vanins was analysed by bioinformatics. VNN2 expressions in peripheral blood T cell subsets were analysed by single-cell RNA sequencing data and flow cytometry. Changes of VNN2 expression before and after T cell activation were further clarified by western blot. The function of VNN2+ cells was studied by granzyme B and perforin detection. Changes in VNN2+ proportions in T cell subsets of SLE patients were further analysed. In the present study, only VNN2 among vanins showed distinguishable expression in T cells. VNN2+ percentages were higher in CD8+ T cells than in CD4+ T cells. VNN2+ T cells were with a higher memory T cell composition. VNN2 expression was significantly increased after T cell stimulation. VNN2+ T cells had higher levels of granzyme B and perforin secretion than VNN2- T cells. Clinically, VNN2+ percentages in T cells of SLE patients were upregulated. Together, these data suggested that VNN2 is expressed in peripheral blood T cells characterized more granzyme B and perforin secretion, and increased VNN2+ T cells in SLE patients could reflect altered T cell functions in vivo.

Single-Cell Profiling of Bone Marrow B Cells and Early B Cell Developmental Disorders Associated With Systemic Lupus Erythematosus.

The peripheral B cell compartment is heavily disturbed in systemic lupus erythematosus (SLE), but whether B cells develop aberrantly in the bone marrow (BM) is largely unknown. We performed single-cell RNA/B cell receptor (BCR) sequencing and immune profiling of BM B cells and classified patients with SLE into two groups: early B cell (Pro-B and Pre-B) normal (EBnor) and EB defective/low (EBlo) groups. The SLE-EBlo group exhibited more severe disease activity and proinflammatory status, overaction of type I interferon signaling and metabolic pathways within the B cell compartment, and aberrant BCR repertoires compared with the SLE-EBnor group. Moreover, in one patient with SLE who was initially classified in the SLE-EBlo group, early B cell deficiency and associated abnormalities were largely rectified in a second BM sample at the remission phase. In summary, this study suggests that early B cell loss in BM defines a unique pathological state in a subset of patients with SLE that may play an active role in the dysregulated autoimmune responses.

Circulating lymphocyte subpopulations in patients with systemic lupus erythematosus and their correlation with disease activity.

The aim of the present study was to evaluate the overall alterations of peripheral blood lymphocyte subsets in patients with systemic lupus erythematosus (SLE). A total of 120 patients diagnosed with SLE and 64 health donors were enrolled. The lymphocyte subsets were detected using flow cytometry. Then the changes of lymphocyte subsets in patients and their correlation with disease activity were investigated. Compared with healthy controls, the counts of lymphocytes, T cells, B cells and NK cells in SLE patients were significantly decreased. Further analysis of T cells subpopulations revealed that the decrease in T cells counts in SLE patients was mainly attributed to a sharp decrease in CD4 + T cells counts. Meanwhile, there was a positive correlation between CD4 + T cells counts and serum complement 3 levels, and patients with lower CD4 + T cells counts had higher SLEDAI score. The counts of CD8 + T cells were comparable between SLE patients and controls, while the proportion of CD8 + T cells and cytotoxic T cells (CD8 + CD28 +) was prominently higher in SLE patients. Besides, the expression of HLA-DR on the surface of T and NK cells was significantly upregulated in SLE patients. Circulating lymphocyte subsets of SLE patients were seriously dysregulated, characterized by a decrease in CD4 + T cells and NK cells, as well as an increase in the proportion of activated T and NK cells. Reduction in CD4 + T cells in SLE patients was highly consistent with disease activity, indicating the crucial role of CD4 + T cells in the onset and progression of SLE.

Abnormal lower expression of GPR183 in peripheral blood T and B cell subsets of systemic lupus erythematosus patients

G protein-coupled receptor 183 (GPR183) has been indicated to mediate the migration and localisation of immune cells in T cell-dependent antibody responses. Systemic lupus erythematosus (SLE) is a canonical autoimmune disease involving B cell-mediated tolerance destruction and excessive pathogenic autoantibody production, in which multiple GPCRs play a role. To date, there has been no systematic study regarding the expression of GPR183 in lymphocyte subsets of SLE patients. In this research, firstly, we observed the expression trends of GRP183 in various T and B cell subsets in human tonsil tissues. These lymphocyte subsets include CD4+, CD8+, naïve T, effector T, Tfh, activated Tfh, Th1, Th2, Th17, Treg, CD19+CD27-, CD19+CD27+, naïve B, germinal centre B, memory B, and plasma cells. Further, compared with healthy controls (HCs), GPR183 expression levels in above peripheral blood lymphocyte subsets of patients with SLE were reduced overall. The differential expression of GPR183 expression between inactive and active SLE patients indicates that GPR183 expression may be concerned with the disease activity of SLE. This was further confirmed through the strong negative correlation with SLEDAI score and positive correlation with serum complement protein C3, C4 and C1q levels. Further receiver operating characteristic (ROC) curve analysis revealed that GPR183 expression in circulating CD27-IgD+ B cells may be beneficial in distinguishing between inactive and active SLE patients. In addition, type I interferon stimulation could down-regulate the expression of GPR183 in peripheral blood T and B cell subsets. Aberrant expression of GPR183 may provide some novel insights into disease activity prediction and underlying pathogenesis of SLE.

T Helper 2-Associated Immunity in the Pathogenesis of Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that mainly affects women in their reproductive years. A complex interaction of environmental and genetic factors leads to the disruption of immune tolerance towards self, causing overt immune activation and production of autoantibodies that attack multiple organs. Kidney damage, termed lupus nephritis, is the leading cause of SLE-related morbidity and mortality. Autoantibodies are central to propagating lupus nephritis through forming immune complexes and triggering complements. Immunoglobulin G (IgG) potently activates complement; therefore, autoantibodies were mainly considered to be of the IgG isotype. However, studies revealed that over 50% of patients produce autoantibodies of the IgE isotype. IgE autoantibodies actively participate in disease pathogenesis as omalizumab treatment, a humanized anti-IgE monoclonal antibody, improved disease severity in an SLE clinical trial. IgE is a hallmark of T helper 2-associated immunity. Thus, T helper 2-associated immunity seems to play a pathogenic role in a subset of SLE patients. This review summarizes human and animal studies that illustrate type 2 immune responses involved during the pathology of SLE.

Proportion of B cell subsets and Nrf2 mediated redox regulation in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is characterized by expansion of autoreactive lymphocytes and impaired management of oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays a significant role in maintaining the redox homeostasis of cell. The present study aims to investigate the frequency of peripheral B cell subsets and the redox regulation by Nrf2 in SLE patients with variable disease activity. For this, a total of forty (40) SLE patients and twenty (20) age and gender-matched healthy controls (HCs) were recruited where patients with SLEDAI < 6 were grouped as Inactive SLE (n = 20) and patients with SLEDAI ≥ 6 were grouped as Active SLE (n = 20). A proportion of peripheral B cell subsets, level of ROS and expression of Nrf2 and Keap1 were studied with the help of flow cytometry and multiplex cytokine bead assay was exploited to estimate the serological concentration of cytokines. The frequency of B cell subsets was significantly altered and correlated with SLEDAI score. Concentration of IFNα2, IFN-β, BAFF, APRIL and IL-6 was also raised in active SLE patients. Moreover, the level of cytosolic ROS was universally decreased while mitochondrial ROS was increased in B cell subsets. The expression of Nrf2 and Keap1 (a negative regulator of Nrf2) was significantly increased in B cell subsets of SLE patients. Here, it has been demonstrated that the frequency of peripheral B cell subsets varies with modification in the SLE disease activity. The given data also demonstrated that the expression of Nrf2 is significantly heightened in B cell subsets to deal with free radical stress.

Role of B-cell endogenous interferon beta in lupus nephritis

Abstract Lupus nephritis (LN) is histologically evident yet early diagnosis can be challenging since some patients do not exhibit overt clinical manifestations until advanced stages. The objective of the present study is to determine if B-cell expression of interferon beta (IFNβ) can be a unique systemic lupus erythematosus (SLE) clinical prognostic marker and if specific histopathologic features of LN can be identified in patients with elevated B-cell expression of IFNβ. A total of 80 patients who met the ACR/EULAR classification criteria of SLE were recruited. LN was identified in 41% (N=33). Multivariate regression analysis indicated a significant positive correlation between naïve B-cell IFNβ with race (African American &amp;gt; European American; P=0.006) and LN class (P&amp;lt;0.0001). Patients with elevated serum anti-Smith (P=0.01) and anti-DNA (P=0.013) exhibited significantly higher naïve B-cell IFNβ. B-cell IFNβ was further compared with renal histopathology microscopy findings on light, electron microscopy, and immunofluorescence (IF) (N=23). Patients with a higher percentage of IFNβ in naïve B cells showed increased segmental scaring (P=0.046). These patients also exhibited aggressive LN class (P=0.14), membranous pattern (P=0.15), and global sclerosis (P=0.18), although the differences were not significant. B-cell IFNβ did not show significant correlation with IgG, IgM, IgA, and C1q, and C3 in situ staining. The present study suggests that B-cell endogenous IFNβ may be developed into a unique target-based marker for the development and severity of LN. IFNβ blockade may be developed into an individualized therapy for this subset of SLE patients.

AB009. Successful treatment of severe systemic lupus erythematosus and psoriasis with IL-17A inhibition

The coexistence of psoriasis and systemic lupus erythematosus (SLE) is uncommon, with prevalence estimated at 0.5–5%. In this case, a 20-year-old woman with a history of severe SLE complicated by lupus nephritis and mesenteric vasculitis presented with a new rash on the face, scalp, and forearms. Skin biopsy revealed features of psoriasis within the epidermis, in addition to the palisaded neutrophilic granulomatous dermatitis within the dermis explained by her underlying SLE. Treatment options were considered in view of her possible cytokine profile and predominant inflammatory pathway. The Th17 pathway has been implicated as a common immune pathway in both diseases, leading to cytokine production including the proinflammatory cytokine interleukin-17A (IL-17A). Studies have shown increased level of IL-17A in the serum and involved tissues of patients with SLE as well as the biopsied plaques of psoriasis. Randomized control trials have shown efficacy of IL-17A inhibition in decreasing the severity and extent of psoriasis, and case reports have noted improvement in SLE activity scores in patients who had been refractory to other management strategies. This patient was treated with IL-17A inhibition, which dramatically improved her rash and allowed complete tapering of her baseline immunosuppressive regimen while maintaining SLE quiescence. This case demonstrates that there may be a subset of SLE patients who respond to IL-17A inhibition, particularly in the setting of overlap with diseases in which IL-17A inhibition has previously shown efficacy. Teaching point: IL-17A inhibition may be effective treatment for SLE overlapping with inflammatory diseases in which IL17A is known to play a role including psoriasis, seronegative spondyloarthropathies, and rheumatoid arthritis.

Partial Protection From Lupus-Like Disease by B-Cell Specific Type I Interferon Receptor Deficiency.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can present with many different permutations of symptom presentation. A large subset of SLE patients have been shown to present with elevated interferon stimulated gene (ISG) expression, and Type I IFNs (IFNαβ) have been shown to drive disease in murine models through global IFNα Receptor (IFNAR) knockouts. However, the disease contribution of distinct immune cell subsets in response to constitutively increased levels of IFNαβ is not fully understood. We utilized a B-cell specific IFNAR knockout (BΔIFNAR) on the B6.Nba2 spontaneous-lupus background to determine the contribution of IFNαβ stimulated B cells in disease. We found that IFNαβ signaling in B cells is driving increased splenomegaly, increased populations of activated B cells, and increased populations of germinal center (GC) B cells, memory B cells, and plasma blasts/cells, but did not affect the development of glomerulonephritis and immune-complex deposition. IFNAR expression by B cells also drove production of anti-chromatin IgG, and anti-dsDNA and -nRNP IgG and IgG2C auto-antibody levels, as well as increased Bcl2 expression, affecting GC B cell survival in B6.Nba2 mice.

Glucocorticoid Withdrawal in Lupus Nephritis: A Study Protocol and Literature Review

Although glucocorticoids (GCs) are the cornerstone for the treatment for systemic lupus erythematosus (SLE), they are associated with a number of adverse effects. Recently, an open randomized controlled trial (RCT) conducted in France showed that flares of SLE in 12 months were significantly more common with GCs withdrawal than continuation in stable patients. However, the study did not separately report results on subsets of SLE patients with organ threatening disease such as lupus nephritis (LN). We hereby present a literature review on GCs withdrawal in SLE and propose a protocol for a multicenter RCT in Hong Kong to evaluate the feasibility of withdrawal of low-dose GCs in stable LN patients who are in clinical remission.

A Young Lady with ANA negative SLE with Secondary Anti Phospholipid Syndrome

Systemic Lupus Erythematosus (SLE) is a chronic, inflammatory, autoimmune, multisystem connective tissue disease characterized by various autoantibodies to nuclear and cytoplasmic antigens and commonly affects the joints and a variety of organs due to an over activation of the body's immune system. There is wide heterogeneity in presentation of SLE patients, including lung, central nervous system, skin, kidney, and hematologic manifestations. The presence of antinuclear antibodies (ANA) in serum is generally considered a decisive diagnostic sign of SLE. However, a small subset of SLE patients who had the typical clinical features of SLE was reported to show persistently negative ANA tests. Our report describes a 24-yr-old female who presented with the clinical manifestations of SLE such as malar rash, photosensitivity, arthritis, oral ulcer and proteinuria. The serum autoantibodies were all negative except anti ribosomal P. She was also positive for lupus anti-coagulant. She was treated with oral prednisolone, hydroxychloroquine with topical tacrolimus and improved significantly. Three months after, repeat ANA and anti-ds DNA showed persistent negativity but lupus anti-coagulant remained positive. This case suggests that ANA may not be required in the pathogenesis of SLE.

Application of the 2019 European League Against Rheumatism/American College of Rheumatology systemic lupus erythematosus classification criteria in clinical practice: a single center experience.

Originally developed as research tools, different classification criteria sets for systemic lupus erythematosus (SLE) are also used to diagnose SLE in routine clinical care. The recently developed European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2019 criteria set is noted to perform better than previous SLE classification criteria. This study applied the new criteria schema to a tertiary center SLE cohort, ascertained its performance, and identified the clinical characteristics of patients who did not fulfill these criteria. From the 217 patients who were included, 11 (5%) did not meet the new criteria, mainly because of the antinuclear antibody entry criterion, resulting in a diagnostic sensitivity of 94%. Within this group, we found that constitutional and renal manifestations were unusual. Additionally, specific SLE antibodies as well as hypocomplementemia were less likely to be present. We did not observe a statistically significant difference in outcomes between the two groups of patients (fulfilling vs. unfulfilling the new criteria). We conclude that the EULAR/ACR criteria may misclassify a small subset of SLE patients with milder disease. It is important to be cognizant of key clinical and serologic features of these patients and treat them accordingly to prevent further irreversible damage.

Interleukin-17 and lupus: enough to be a target? For which patients?

The involvement of the interleukin (IL)-17 axis in many inflammatory and autoimmune diseases is now well established, and this has led to the development of successful targeted therapies. Its role in systemic lupus erythematosus (SLE) is less described, since SLE is characterized by the impairment of many other immune actors. However, results from animal models and patients strongly suggest that IL-17 and its producing cells are involved in SLE pathogenesis. Circulating levels of IL-17 are increased in lupus, and tissue staining shows the presence of IL-17-producing cells in organ lesions. Through different mechanisms, the IL-17 axis promotes autoantibody production, immune complex deposition, complement activation and then tissue damage. There are also many interactions with other immune and non-immune actors, which account for the broad spectrum of clinical manifestations and disease heterogeneity. SLE treatment faces challenges with many disappointing trials and persistent unmet needs. The identification of subsets of SLE patients with an IL-17-driven disease now constitutes the key priority before starting trials. More preclinical studies are needed to improve the selection of the right patients able to respond and tolerate the many inhibitors that are already available.

Neuronal BC RNA Transport Impairments Caused by Systemic Lupus Erythematosus Autoantibodies.

The etiology of the autoimmune disorder systemic lupus erythematosus (SLE) remains poorly understood. In neuropsychiatric SLE (NPSLE), autoimmune responses against neural self-antigens find expression in neurological and cognitive alterations. SLE autoantibodies often target nucleic acids, including RNAs and specifically RNA domains with higher-order structural content. We report that autoantibodies directed against neuronal regulatory brain cytoplasmic (BC) RNAs were generated in a subset of SLE patients. By contrast, anti-BC RNA autoantibodies (anti-BC abs) were not detected in sera from patients with autoimmune diseases other than SLE (e.g., rheumatoid arthritis or multiple sclerosis) or in sera from healthy subjects with no evidence of disease. SLE anti-BC abs belong to the IgG class of immunoglobulins and target both primate BC200 RNA and rodent BC1 RNA. They are specifically directed at architectural motifs in BC RNA 5' stem-loop domains that serve as dendritic targeting elements (DTEs). SLE anti-BC abs effectively compete with RNA transport factor heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) for DTE access and significantly diminish BC RNA delivery to synapto-dendritic sites of function. In vivo experiments with male BALB/c mice indicate that, upon lipopolysaccharide-induced opening of the blood-brain barrier, SLE anti-BC abs are taken up by CNS neurons where they significantly impede localization of endogenous BC1 RNA to synapto-dendritic domains. Lack of BC1 RNA causes phenotypic abnormalities including epileptogenic responses and cognitive dysfunction. The combined data indicate a role for anti-BC RNA autoimmunity in SLE and its neuropsychiatric manifestations.SIGNIFICANCE STATEMENT Although clinical manifestations of neuropsychiatric lupus are well recognized, the underlying molecular-cellular alterations have been difficult to determine. We report that sera of a subset of lupus patients contain autoantibodies directed at regulatory brain cytoplasmic (BC) RNAs. These antibodies, which we call anti-BC abs, target the BC RNA 5' domain noncanonical motif structures that specify dendritic delivery. Lupus anti-BC abs effectively compete with RNA transport factor heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) for access to BC RNAs. As a result, hnRNP A2 is displaced, and BC RNAs are impaired in their ability to reach synapto-dendritic sites of function. The results reveal an unexpected link between BC RNA autoantibody recognition and dendritic RNA targeting. Cellular RNA dysregulation may thus be a contributing factor in the pathogenesis of neuropsychiatric lupus.

Dnase1-deficient mice spontaneously develop a systemic lupus erythematosus-like disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease that has high morbidity and can result in multi-organ damage. SLE is characterized by dysregulated activation of T- and B-lymphocytes and the production of autoantibodies directed against nuclear components. The endonuclease deoxyribonuclease 1 (DNase1) is abundant in blood and a subset of SLE patients have mutations in DNASE1. Furthermore, a report showed that Dnase1-deficient mice develop an SLE-like disease, but these mice also carry a deletion of the gene adjacent to Dnase1, which encodes the chaperone TRAP1/HSP75. We generated a murine strain deficient in Dnase1 with an intact Trap1 gene to examine if a lack of DNase1 is responsible for the development of a spontaneous SLE-like disease. We show that the Dnase1-deficient mice do indeed develop an SLE-like phenotype with elevated autoantibody production by 9 months and kidney damage by 12 months. Notably, this model recapitulates the female bias seen in human SLE patients since female Dnase1-deficient mice produced the highest concentrations of autoantibodies and had more severe kidney damage than males. Since there is currently no cure for SLE the protective role of DNase1 as demonstrated in our study remains of great therapeutic interest.

A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity

Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using Toll-like receptor 7 (TLR7)-dependent mouse models of systemic lupus erythematosus (SLE), we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated by dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of L.reuteri in mice and fecal enrichment of Lactobacillus in a subset of SLE patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement, andmortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that promotes interferon pathways implicated in thepathogenesis of human autoimmunity.

Effect of Corticosteroids and Cyclophosphamide on Sex Hormone Profiles in Male Patients With Systemic Lupus Erythematosus or Systemic Sclerosis.

Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases that predominantly affect female patients, and therefore fewer investigations have been conducted in men. The aim of this study was to analyze sex hormone levels in male patients with SLE and those with SSc, compared to matched controls, in relation to the use of corticosteroids and cyclophosphamide (CYC). Sex hormone levels were measured in fasting blood samples from male patients with SLE (n = 71) and those with SSc (n = 29) and compared to population-based, age-matched male controls. Relevant hormone profiles were identified using cluster analysis. Male SLE patients had higher levels of luteinizing hormone (LH) (P < 0.0001) and more frequent bioactive testosterone deficiency (P = 0.02) than their matched controls. The current dosage of prednisolone correlated inversely with the levels of bioactive testosterone (r = -0.36, P = 0.03). Cluster analysis identified a subset of SLE patients with increased levels of follicle-stimulating hormone, LH, and prolactin as well as lower levels of bioactive testosterone (P < 0.0001) in relation to higher daily doses of prednisolone. In male SSc patients, levels of testosterone (P = 0.03) and bioactive testosterone (P = 0.02) were significantly lower than those in matched controls. Use of CYC during the previous year was associated with lower bioactive testosterone levels in both SLE patients (P = 0.02) and SSc patients (P = 0.01), after adjustment for age. The results of this study highlight the negative impact of corticosteroids on gonadal function in men with SLE. Furthermore, use of CYC during the year prior to study inclusion impaired bioactive testosterone levels in male patients with either SLE or SSc. Physicians should be more aware of the possibility of hypogonadism in male patients with autoimmune diseases. The need for hormonal supplementation remains to be formally evaluated in these patients.

Differential clearance mechanisms, neutrophil extracellular trap degradation and phagocytosis, are operative in systemic lupus erythematosus patients with distinct autoantibody specificities

Systemic lupus erythematosus (SLE) patients are generally presented with autoantibodies against either dsDNA or RNA-associated antigens (also known as extractable nuclear antigens, ENA) or both. However, the mechanisms and processes that lead to this distinctive autoantibody profile are not well understood. Defects in clearance mechanism i.e. phagocytosis may lead to enhanced microbial and cellular debris of immunogenic potential. In addition to defective phagocytosis, impaired neutrophil extracellular trap (NET) degradation has been recently reported in SLE patients. However, the extent to which both these clearance processes (NET-degradation and phagocytosis) are operative in serologically distinguished subsets of SLE patients is not established. Therefore, in this report, we evaluated NET-degradation and phagocytosis efficiency among SLE patients with different autoantibody specificities. SLE patients were classified into three subsets based on their autoantibody profile (anti-dsDNA, anti-ENA or both) as determined by ELISA. NET-degradation by SLE and control sera was assessed by sytox orange-based fluorescence assay. Neutrophil-mediated phagocytosis in the presence of SLE and control sera was determined by flowcytometry. The segregation of SLE patients revealed significant differences in NET-degradation and phagocytosis in SLE patients with autoantibodies against dsDNA and ENA. We report that NET-degradation efficiency was significantly impaired in SLE patients with anti-dsDNA autoantibodies and not in those with anti-ENA autoantibodies. In contrast to NET-degradation, neutrophil-mediated phagocytosis was impaired in all three subsets independent of autoantibody specificity. These observations suggest that varying clearance mechanisms are operative in SLE subsets with anti-dsDNA or anti-ENA autoantibodies. The results outlined in this manuscript also suggest that sub-grouping of SLE patients could be useful in delineating the molecular and pathological processes that are often missed when SLE patients are studied as a single group. Further, it will be imperative to propose that therapies targeted at improving NET clearance can be effective in anti-dsDNA+ SLE patients.

Novel Autoantigens Associated with Lupus Nephritis.

Systemic lupus erythematosus (SLE) is characterized by production of a variety of autoantibodies. Although anti-double-stranded DNA (anti-dsDNA) antibodies contribute to the pathogenesis of lupus nephritis (LN), they are not sufficient for diagnosis and evaluation of disease activity. To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system. We screened 17 proteins that showed higher positive signals in the active phase than in the inactive phase of SLE, and higher positive signals in the serum of SLE patient with nephritis than in that of patient without nephritis. Of these, two LN-associated autoantigens, ribosomal RNA-processing protein 8 (RRP8) and spermatid nuclear transition protein 1 (TNP1) were identified by immunoprecipitation and immunofluorescence of renal tissues. Circulating anti-RRP8 and anti-TNP1 autoantibodies were recognized and deposited as an immune complex (IC) in glomeruli. IC was deposited preferentially in glomeruli rather than in other organs in C57BL/6 mice injected with RRP8 or TNP1. ELISA analysis of sera from patients with various rheumatic diseases demonstrated reactivity for RRP8 and TNP1 in 20% and 14.7% of SLE patients, respectively, whereas there was little or no reactivity in patients with other rheumatic diseases. Among SLE patients, 63.6% and 45.5% of those with LN were positive for anti-RRP8 and anti-TNP1 antibodies, compared with 12.5% and 9.4% of SLE patients without nephritis, respectively. Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA. These proteins released from apoptotic cells form ICs with each autoantibody, and their ICs may become trapped at anionic sites in the glomerular basement membrane, leading to deposition in glomeruli. These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.