New and emerging therapies for systemic lupus erythematosus.

Systemic Lupus Erythematosus (SLE) and lupus nephritis treatment is still based on non-specific immune suppression despite the first biological therapy for the disease having been approved more than a decade ago. Intense basic and translational research has uncovered a multitude of pathways that are actively being evaluated as treatment targets in SLE and lupus nephritis, with two new medications receiving FDA approval in the last 3 years. Herein we provide an overview of targeted therapies for SLE including medications targeting the B lymphocyte compartment, intracellular signaling, co-stimulation, and finally the interferons and other cytokines.

Journal Club: Anti-CD19 Chimeric Antigen Receptor T Cell Therapy for Refractory Systemic Lupus Erythematosus.

OBJECTIVE: Despite substantial advances in the treatment of systemic lupus erythematosus (SLE), some patients do not respond to the current state-of-the art therapies. This study assessed the tolerability and efficacy of CD19 chimeric antigen receptor (CAR) T cells in a small series of seriously ill and treatment-resistant patients with SLE. METHODS: Five patients with SLE (four female patients and one male patient) with a median age of 22 (range 18-24) years, a median disease duration of 4 (range 1-9) years, and active disease (median Systemic Lupus Erythematosus Disease Activity Index score of 16 [range 8-16]) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use CAR-T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded, and reinfused at a dose of 1 × 106 CAR T cells per kilogram of body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. RESULTS: CAR T cells expanded in vivo and led to deep depletion of B cells, improvement of clinical symptoms, and normalization of laboratory parameters, including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to definition of remission in SLE criteria was achieved in all five patients after 3 months, and the median Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (range 2). Drug-free remission was maintained during longer follow-up (median of 8 [range 12] months after CAR-T cell administration) and even after the reappearance of B cells, which was observed after a mean (±SD) of 110 ± 32 days after CAR-T cell treatment. Reappearing B cells were naive and showed non-class-switched B cell receptors. CAR-T cell treatment was well tolerated, with only mild cytokine release syndrome. CONCLUSION: These data suggest that CD19 CAR-T cell therapy was feasible, tolerable, and effective in this small case series of refractory SLE. Nevertheless, larger placebo-controlled trials are warranted.

Undifferentiated Connective Tissue Disease: Comprehensive Review.

PURPOSE OF REVIEW: Undifferentiated connective tissue disease (UCTD) is characterized by the presence of clinical symptoms of a systemic autoimmune disease in addition to laboratory evidence of autoimmunity with the patients not fulfilling any of the widely used classification criteria for classic autoimmune diseases. The presence of UCTD as a separate entity versus an early stage of such diseases as systemic lupus erythematosus (SLE) or scleroderma has long been debated. Given the uncertainty regarding this condition, we performed a systematic review on the topic. RECENT FINDINGS: UCTD can be subcategorized as evolving (eUCTD) or stable UCTD (sUCTD) based on its evolution towards a definable autoimmune syndrome. Analyzing the data from six UCTD cohorts published in the literature, we found that 28% of patients have an evolving course with the majority developing SLE or rheumatoid arthritis within 5-6 years of the UCTD diagnosis. From the remaining patients, 18% do achieve remission. Published treatment regimens were similar to other mild autoimmune diseases with low-dose prednisone, hydroxychloroquine, and NSAID. One-third of patients did need immune suppressive medications. Importantly, the reported outcomes were excellent with survival rates of more than 90% over 10 years. It has to be noted though that as data on patient related outcomes are not available to date, the exact impact of this condition on quality of life is unclear. UCTD is a mild autoimmune condition with generally good outcomes. There is still great uncertainty though regarding diagnosis and management. Going forward, consistent classification criteria are needed to advance UCTD research and eventually provide authoritative guidance on the management of the condition.

Estimating glucocorticoid-related morbidity in lupus nephritis using the glucocorticoid toxicity index.

OBJECTIVE: Lupus nephritis (LN) is often treated with high doses of glucocorticoids (GCs). The glucocorticoid toxicity index (GTI) was developed by expert consensus to quantify GC toxicity. To date, the GTI has not been shown to correlate with GC exposure in patients with LN. METHODS: We performed a retrospective cohort study of patients with biopsy-confirmed LN between 2006 and 2016. Cumulative GC exposure and GTI scores were determined via medical record review. Both the aggregate improvement score (GTI-AIS) and the cumulative worsening score (GTI-CWS) were calculated. We performed linear regression to determine the association between GC exposure and GTI scores at 1 year and 5 years following kidney biopsy. RESULTS: This study included 49 patients with a mean age of 33.3 (SD 9.5) years. Mean GC exposure was 23.0 mg prednisone-equivalents per day through year 1 and 9.9 mg prednisone-equivalents per day through year 5. At 5 years, higher GC exposure was associated with higher GTI-AIS (p < 0.001) and GTI-CWS (p = 0.002), and this association persisted in multivariate analysis adjusting for age, sex, race, induction medication, and nephritis class (p = 0.026 for AIS, p = 0.012 for CWS). At 1 year, GC exposure was not associated with GTI scores (p = 0.70 for AIS; p = 0.58 for CWS). CONCLUSION: In this cohort study, the GTI was associated with cumulative steroid exposure at 5 years after diagnosis. In patients with LN, the GTI may serve as a useful outcome measure in future LN trials evaluating the steroid sparing effect of novel therapies.

Role of Platelet-Bound C4d (PC4d) in Predicting Risk of Future Thrombotic Events in Systemic Lupus Erythematosus.

OBJECTIVE: Platelet-bound complement activation product C4d (PC4d) levels correlate with history of thrombosis in patients with systemic lupus erythematosus (SLE). The present study evaluated whether PC4d levels could assess risk of future thrombosis events. METHODS: PC4d level was measured by flow cytometry. Thromboses were confirmed by electronic medical record data review. RESULTS: The study included 418 patients. Nineteen events (13 arterial and 6 venous) occurred in 15 subjects in the 3 years post-PC4d level measurement. PC4d levels above the optimum cutoff of 13 mean fluorescence intensity (MFI) predicted future arterial thrombosis with a hazard ratio of 4.34 (95% confidence interval [95% CI] 1.03-18.3) (P = 0.046) and a diagnostic odds ratio (OR) of 4.30 (95% CI 1.19-15.54). Negative predictive value of PC4d level of ≤13 MFI for arterial thrombosis was 99% (95% CI 97-100%). Although a PC4d level of >13 MFI did not reach statistical significance for prediction of total thrombosis (arterial and venous) (diagnostics OR 2.50 [95% CI 0.88-7.06]; P = 0.08), it was associated with all thrombosis (n = 70 historic and future arterial and venous events in the 5 years pre- to 3 years post-PC4d level measurement) with an OR of 2.45 (95% CI 1.37-4.32; P = 0.0016). In addition, the negative predictive value of PC4d level of ≤13 MFI for all future thrombosis events was 97% (95% CI 95-99%). CONCLUSIONS: A PC4d level of >13 MFI predicted future arterial thrombosis and was associated with all thrombosis. Patients with SLE presenting with a PC4d level of ≤13 MFI had high probability of not experiencing arterial or any thrombosis in the 3 years afterwards. Taken together, these findings indicate that PC4d levels may help predict the risk of future thrombosis events in SLE.

Implementing a Virtual Flipped Classroom in a Rheumatology Fellowship Program.

OBJECTIVE: Active learning opportunities within graduate medical education may be underused. We aimed to assess whether active learning strategies increase after implementing a faculty development workshop and transitioning rheumatology fellowship didactics to a virtual flipped classroom. METHODS: We measured baseline faculty use of active learning strategies during lectures within the Introductory Rheumatology Curriculum by calculating an "active learning score" from a cognitive learning theory assessment tool. We held a faculty development workshop demonstrating active teaching strategies and encouraged using a flipped classroom for fellowship didactics. Because of the COVID-19 pandemic, the strategies were discussed in a virtual classroom setting where the intervention phase would occur. We compared active learning scores before and after the intervention for lectures within the Introductory Rheumatology Curriculum. The primary outcome was the change in active teaching scores preintervention versus postintervention. RESULTS: Active learning scores increased in 14 of the 16 lectures, with a mean score increase of 4.7 of 24 points (95% confidence interval 2.3-7.2). Paired t-test analyses comparing active learning scores preintervention and postintervention for each lecture confirmed that results were highly statistically significant (P < 0.001). Despite faculty hesitancy to teach within a virtual environment, faculty satisfaction remained high postintervention. CONCLUSION: A virtual flipped classroom increased the use of active learning strategies within the Introductory Rheumatology Curriculum. Faculty satisfaction remained high despite modest increases in time spent updating their presentations. Fellows and faculty reported a largely positive experience within the virtual classroom.

Seroconversion among rituximab-treated patients following SARS-CoV-2 vaccine supplemental dose.

Rituximab (RTX) is a very effective treatment for autoimmune rheumatic diseases (AIRD), but it increases infection risk and impairs vaccine responses. Herein we evaluated the antibody response of RTX-treated patients to the supplemental COVID-19 vaccine. After the supplemental dose, 53.1% of patients had detectable antibody titers. Only 36% of patients who did not mount an antibody response after the original vaccine series did have detectable antibodies after the supplemental dose (seroconversion). Patients with undetectable CD20+ cell levels did not seroconvert while hypogammaglobulinemia was associated with a 15-times decrease in the likelihood of seroconversion. Although we noted 11 COVID-19 infections after the supplemental dose, no patients who received monoclonal antibodies pre-exposure prophylaxis had COVID-19 afterwards. We propose that patients receiving RTX should continue to be prioritized for prophylaxis measures and that vaccination should be timed after B cell recovery wherever possible.

The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription.

Aberrant IL-17A expression together with reduced IL-2 production by effector CD4+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report that Sirtuin 2 (SIRT2), a member of the family of NAD+-dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while promoting their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K, activation of the mTORC1/HIF-1α/RORγt pathway and induction of Th17-cell differentiation. Additionally, SIRT2 was shown to be responsible for the deacetylation of c-Jun and histones at the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, bound directly to the Sirt2 promoter and promoted its transcription. AK-7, a SIRT2 inhibitor, limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis in mice and limited disease in lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated the ability of these cells to differentiate into Th17 cells and promoted the generation of IL-2-producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential in the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new SLE therapies.

Immunogenicity of SARS-CoV-2 vaccination in rituximab-treated patients: Effect of timing and immunologic parameters.

Rituximab (RTX), an important therapeutic option for patients with rheumatic diseases, has been shown to reduce immune responses to various vaccines. We asked whether following SARS-CoV-2 vaccination, response rates in RTX treated patients are reduced and whether specific patient characteristics influence the responses. We recruited patients on chronic RTX therapy undergoing anti-SARS-CoV2 vaccination and measured the post-vaccination anti-spike IgG antibody levels. The median time from pre-vaccination RTX infusion to vaccination and from vaccination to the post-vaccination RTX infusion was 20.5 weeks and 7.2 weeks respectively. Only 36.5% of patients developed measurable titers of IgG anti-SARS-CoV-2 spike antibody after vaccination. Hypogammaglobulinemia (IgG and/or IgM) but not timing of vaccination, B cell numbers, or concomitant immune suppressive medications, correlated with sero-negativity (p = 0.004). Our results underscore the fact that even after B cell reconstitution, RTX induced chronic hypogammaglobulinemia significantly impairs the ability of the immune system to respond to SARS-CoV-2 vaccination.

Estrogen-Induced hsa-miR-10b-5p Is Elevated in T Cells From Patients With Systemic Lupus Erythematosus and Down-Regulates Serine/Arginine-Rich Splicing Factor 1.

OBJECTIVE: Autoimmune diseases affect women disproportionately more than men. Estrogen is implicated in immune cell dysfunction, yet its precise molecular roles are not fully known. We recently identified new roles for serine/arginine-rich splicing factor 1 (SRSF1) in T cell function and autoimmunity. SRSF1 levels are decreased in T cells from patients with systemic lupus erythematosus (SLE) and are associated with active disease and comorbidity. However, the molecular mechanisms that control SRSF1 expression are unknown. Srsf1 messenger RNA (mRNA) has a long 3'-untranslated region (3'-UTR), suggesting posttranscriptional control. This study was undertaken to investigate the role of estrogen and posttranscriptional mechanisms of SRSF1 regulation in T cells and SLE. METHODS: In silico bioinformatics analysis of Srsf1-3'-UTR revealed multiple microRNA (miRNA; miR)-binding sites. Additional screening and literature searches narrowed down hsa-miR-10b-5p for further study. Peripheral blood T cells from healthy individuals and SLE patients were evaluated for mRNA and miRNA expression by quantitative reverse transcription-polymerase chain reaction, and SRSF1 protein levels were assessed by immunoblotting. T cells were cultured with ß-estradiol, and transient transfections were used to overexpress miRNAs. Luciferase assays were used to measure 3'-UTR activity. RESULTS: We demonstrated that estrogen increased hsa-miR-10b-5p expression in human T cells, and hsa-miR-10b-5p down-regulated SRSF1 protein expression. Mechanistically, hsa-mir-10b-5p regulated SRSF1 posttranscriptionally via control of its 3'-UTR activity. Importantly, hsa-miR-10b-5p expression levels were elevated in T cells from healthy women compared to healthy men and also elevated in T cells from SLE patients. CONCLUSION: We identified a previously unrecognized molecular link between estrogen and gene regulation in immune cells, with potential relevance to systemic autoimmune disease.

Rituximab-associated hypogammaglobulinemia in autoimmune rheumatic diseases: a single-center retrospective cohort study.

B-cell targeted therapies, such as rituximab (RTX), are used widely in autoimmune rheumatic diseases (AIRD). RTX can cause hypogammaglobulinemia and predispose patients to infections. Herein, we asked whether the underlying diagnosis influences the risk for hypogammaglobulinemia in patients treated with RTX. All patients who received RTX infusions and carried a diagnosis of rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), or connective tissue disease (CTD) were included in this single-center retrospective cohort study. We used STATA® for analysis: Chi-square test was used for comparing categorical variables. Based on distribution, continuous variables were compared using the t test/ANOVA or the Wilcoxon/Kruskal-Wallis tests. Of the 163 patients who received RTX for an AIRD, 60 with pre- and post- RTX immunoglobulins were analyzed. A higher incidence of post-treatment hypogammaglobulinemia was seen in AAV (45%) compared to RA (22%) and CTD (9.1%) groups (p = 0.03). Glucocorticoid exposure of 10 mg or more was identified as a significant risk factor for hypogammaglobulinemia. Finally, we observed a higher number of clinically significant infections per person in the AAV group than in the RA and CTD groups. We observed an increased incidence of hypogammaglobulinemia in the RTX-treated AAV group, with almost half of patients developing post-RTX hypogammaglobulinemia. The rate of infections per person was highest in the AAV group. Screening immunoglobulins were not consistently measured pre- and post-RTX. Results highlight a need for increased awareness of the role of immunoglobulin measurement before maintenance doses of RTX, especially in patients with AAV and steroid exposure.

ADAM9 enhances Th17 cell differentiation and autoimmunity by activating TGF-ß1.

The a disintegrin and metalloproteinase (ADAM) family of proteinases alter the extracellular environment and are involved in the development of T cells and autoimmunity. The role of ADAM family members in Th17 cell differentiation is unknown. We identified ADAM9 to be specifically expressed and to promote Th17 differentiation. Mechanistically, we found that ADAM9 cleaved the latency-associated peptide to produce bioactive transforming growth factor ß1, which promoted SMAD2/3 phosphorylation and activation. A transcription factor inducible cAMP early repressor was found to bind directly to the ADAM9 promoter and to promote its transcription. Adam9-deficient mice displayed mitigated experimental autoimmune encephalomyelitis, and transfer of Adam9-deficient myelin oligodendrocyte globulin-specific T cells into Rag1-/- mice failed to induce disease. At the translational level, an increased abundance of ADAM9 levels was observed in CD4+ T cells from patients with systemic lupus erythematosus, and ADAM9 gene deletion in lupus primary CD4+ T cells clearly attenuated their ability to differentiate into Th17 cells. These findings revealed that ADAM9 as a proteinase provides Th17 cells with an ability to activate transforming growth factor ß1 and accelerates its differentiation, resulting in aberrant autoimmunity.

Splicing factor SRSF1 limits IFN-γ production via RhoH and ameliorates experimental nephritis.

OBJECTIVE: CD4 T helper 1 (Th1) cells producing IFN-γ contribute to inflammatory responses in the pathogenesis of SLE and lupus nephritis. Moreover, elevated serum type II IFN levels precede the appearance of type I IFNs and autoantibodies in patient years before clinical diagnosis. However, the molecules and mechanisms that control this inflammatory response in SLE remain unclear. Serine/arginine-rich splicing factor 1 (SRSF1) is decreased in T cells from SLE patients, and restrains T cell hyperactivity and systemic autoimmunity. Our objective here was to evaluate the role of SRSF1 in IFN-γ production, Th1 differentiation and experimental nephritis. METHODS: T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-γ production and Th1 differentiation by flow cytometry. RNA sequencing was used to assess transcriptomics profiles. RhoH was silenced by siRNA transfections in human T cells by electroporation. RhoH and SRSF1 protein levels were assessed by immunoblots. RESULTS: Deletion of Srsf1 in T cells led to increased Th1 differentiation and exacerbated nephrotoxic serum nephritis. The expression levels of RhoH are decreased in Srsf1-deficient T cells, and silencing RhoH in human T cells leads to increased production of IFN-γ. Furthermore, RhoH expression was decreased and directly correlated with SRSF1 in T cells from SLE patients. CONCLUSION: Our study uncovers a previously unrecognized role of SRSF1 in restraining IFN-γ production and Th1 differentiation through the control of RhoH. Reduced expression of SRSF1 may contribute to pathogenesis of autoimmune-related nephritis through these molecular mechanisms.

Interleukin 23 is elevated in the serum of patients with SLE.

Aim: Interleukin-23 (IL-23) is a cytokine that promotes the differentiation of T cells into pro-inflammatory Th17. We have previously shown that IL-23 is upregulated in systemic lupus erythematosus (SLE) patients and lupus prone mice. As SLE is highly heterogeneous, we asked whether IL-23 production correlates with different manifestations of the disease.Methods: We recruited 56 subjects who fulfilled the ACR criteria for SLE. Interleukin-23 was measured in the serum by ELISA.Results: IL-23 levels were positively correlated with the overall SLE disease activity as measured with the SLEDAI. Moreover, IL-23 correlated with the skin, renal domains of SLEDAI and arthritis but not with cytopenias or serositis. IL-23 did also correlate with anti-dsDNA antibody positivity and inversely correlated with C3 levels. We found no relationship between patients' demographics, prior disease manifestations, medications, or autoantibody profile and IL-23 levels. No immunomodulatory medication seemed to be affecting IL-23 levels suggesting that current medications used in SLE are not as effective in shutting down the IL-23/IL-17 axis. Conclusions: IL-23 levels track SLE disease activity mostly in the renal, skin and musculoskeletal domains. Our data suggest that IL-23 inhibitors may be helpful in combination with current standard of care in alleviating arthritis, renal and cutaneous manifestations of the disease.

Serine/threonine phosphatase PP2A is essential for optimal B cell function.

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro-activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1afl/fl (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.

Splicing factor SRSF1 controls T cell homeostasis and its decreased levels are linked to lymphopenia in systemic lupus erythematosus.

OBJECTIVE: Lymphopenia is a frequent clinical manifestation and risk factor for infections in SLE, but the underlying mechanisms are not fully understood. We previously identified novel roles for the RNA-binding protein serine arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in signalling and cytokine production in human T cells. SRSF1 is decreased in T cells from patients with SLE and associates with severe disease. Because SRSF1 controls the expression of apoptosis-related genes, we hypothesized that SRSF1 controls T cell homeostasis and, when reduced, leads to lymphopenia. METHODS: We evaluated SRSF1 expression in T cells from SLE patients by immunoblots and analysed its correlation with clinical parameters. T cell conditional Srsf1 knockout mice were used to evaluate lymphoid cells and apoptosis by flow cytometry. Quantitative PCR and immunoblots were used to assess Bcl-xL mRNA and protein expression. SRSF1 overexpression was performed by transient transfections by electroporation. RESULTS: We found that low SRSF1 levels correlated with lymphopenia in SLE patients. Selective deletion of Srsf1 in T cells in mice led to T cell lymphopenia, with increased apoptosis and decreased expression of the anti-apoptotic Bcl-xL. Lower SRSF1 expression correlated with low Bcl-xL levels in T cells and lower Bcl-xL levels associated with lymphopenia in SLE patients. Importantly, overexpression of SRSF1 rescued survival of T cells from patients with SLE. CONCLUSION: Our studies uncovered a previously unrecognized role for SRSF1 in the control of T cell homeostasis and its reduced expression as a molecular defect that contributes to lymphopenia in systemic autoimmunity.

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections.

Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

Targeting cytokines to treat autoimmunity.

Monoclonal antibodies, small molecules and soluble receptors that target cytokines have revolutionized the treatment of autoimmune and autoinflammatory diseases. The articles that are presented in this special issue of Clinical Immunology analyze the basic science, the clinical implications and the future directions of cytokine targeting in these diseases.

Glutaminase 1 Inhibition Reduces Glycolysis and Ameliorates Lupus-like Disease in MRL/lpr Mice and Experimental Autoimmune Encephalomyelitis.

OBJECTIVE: Glutaminase 1 (Gls1) is the first enzyme in glutaminolysis. The selective Gls1 inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) suppresses Th17 development and ameliorates experimental autoimmune encephalomyelitis (EAE). The present study was undertaken to investigate whether inhibition of glutaminolysis is beneficial for the treatment of systemic lupus erythematosus (SLE), and the involved mechanisms. METHODS: MRL/lpr mice were treated with BPTES or vehicle control, and disease activity was examined. Then naive CD4+ T cells from patients with SLE were cultured under Th17-polarizing conditions with BPTES or vehicle. Furthermore, using newly generated Gls1 conditional-knockout mice, in vitro Th17 differentiation was examined, and EAE was induced in the mice. Glutaminolysis and glycolysis were measured with an extracellular flux analyzer. The expression of hypoxia-inducible factor 1α (HIF-1α) was examined by Western blotting. RESULTS: Treatment of MRL/lpr mice with BPTES improved autoimmune pathology in a Th17-dependent manner. T cells from patients with SLE treated with BPTES displayed decreased Th17 differentiation (P < 0.05). Using the conditional-knockout mice, we demonstrated that both in vitro Th17 differentiation (P < 0.05) and the development of EAE were dependent on Gls1. Gls1 inhibition reduced glycolysis and the expression of HIF-1α protein, which induces glycolysis. CONCLUSION: We demonstrated that inhibition of glutaminolysis represents a potential new treatment strategy for patients with SLE and Th17-related autoimmune diseases. Mechanistically, we have shown that inhibition of glutaminolysis affects the glycolysis pathway by reducing HIF-1α protein in Th17 cells.