Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation.

Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNA-Seq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance.

Osteoimmunology research in rheumatoid arthritis: From single-cell omics approach.

ABSTRACT: Cellular immune responses as well as generalized and periarticular bone loss are the key pathogenic features of rheumatoid arthritis (RA). Under the pathological conditions of RA, dysregulated inflammation and immune processes tightly interact with skeletal system, resulting in pathological bone damage via inhibition of bone formation or induction of bone resorption. Single-cell omics technologies are revolutionary tools in the field of modern biological research.They enable the display of the state and function of cells in various environments from a single-cell resolution, thus making it conducive to identify the dysregulated molecular mechanisms of bone destruction in RA as well as the discovery of potential therapeutic targets and biomarkers. Here, we summarize the latest findings of single-cell omics technologies in osteoimmunology research in RA. These results suggest that single-cell omics have made significant contributions to transcriptomics and dynamics of specific cells involved in bone remodeling, providing a new direction for our understanding of cellular heterogeneity in the study of osteoimmunology in RA.

The rapid inhibition of B-cell activation markers by belimumab was associated with disease control in systemic lupus erythematosus patients.

Objective: To examine the kinetics of B cell subsets and activation markers in the early stage of belimumab treatment and their correction with treatment response. Methods: We enrolled 27 systemic lupus erythematosus (SLE) patients receiving 6 months belimumab treatment. Flow cytometry was used to test their B cell subsets and activation markers (including CD40, CD80, CD95, CD21low, CD22, p-SYK and p-AKT). Results: During belimumab treatment, SLEDAI-2K declined, the proportions of CD19+ B cells and naïve B cells decreased, whereas the switched memory B cells and non-switched B cells increased. The larger variations of the B cell subsets and the activation markers were in the first 1 month than the other later time frames. The ratio of p-SYK/p-AKT on non-switched B cell at 1 month was associated with the SLEDAI-2K decline rate in the 6 months of belimumab treatment. Conclusion: B cell hyperactivity was rapidly inhibited in the early stage of belimumab treatment, and the ratio of p-SYK/p-AKT may predict SLEDAI-2K decline. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT04893161?term=NCT04893161&draw=2&rank=1; identifier: NCT04893161.

Peripheral immunophenotypes associated with the flare in the systemic lupus erythematosus patients with low disease activity state.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by clinical heterogeneity and flare unpredictability. It was still unclear for the association between SLE flare and immunophenotypes. Flow cytometric analysis defined the B and T subsets of the low disease activity state (LDAS) patients and healthy controls. Principal components analysis (PCA) and cluster analysis (CA) distinguished the immunophenotypes. Compared with the 66 healthy controls, the 93 LDAS patients had higher proportions of plasma cells, double negative B cells, naïve B cells and CD8+T cells, and lower proportions of unswitched memory B cells and CD4+T cells. PCA showed the abnormalities of T and B cell axes. CA divided the patients into 3 groups. The memory B cells group had the lower flare risk compared with the non-memory B cells group (including naïve B cells group and T cells group). The immunophenotypes were associated with SLE flare in the LDAS patients.

The proportion and phenotypic changes of CD4+CD25-Foxp3+ T cells in patients with untreated rheumatoid arthritis.

OBJECTIVE: CD4+CD25+Foxp3+ regulatory T (Treg) cell-mediated immunosuppression is an essential mechanism of rheumatoid arthritis (RA). However, little is known regarding the specific role of CD4+CD25-Foxp3+ Treg cells in RA. This study aimed to investigate the frequency of circulating CD4+CD25-Foxp3+ Treg cells and their role in RA. METHODS: Sixty-one untreated RA patients and 40 healthy controls (HCs) were enrolled in this study. The proportion of CD4+CD25-Foxp3+ T cells and CD4+CD25+Foxp3+ Tregs; the levels of CTLA4, GITR, Helios, and ICOS; and the production of IL-17A, IFN-γ, and IL-10 were assessed by flow cytometry. The correlation of CD4+CD25-Foxp3+ T cells and CD4+CD25+Foxp3+ Tregs with the clinical indicators was conducted by Spearman correlation analysis. RESULTS: The proportion of CD4+CD25-Foxp3+ T cells was elevated in RA and positively correlated with disease activity. CD4+CD25-Foxp3+ T cells expressed less Helios and produced more IFN-γ than conventional Tregs in RA. Additionally, the proportion of CD4+CD25-Foxp3+ T cells was positively correlated with DAS28 score, IgG titer, and anti-CCP titer. CONCLUSIONS: These data indicate that CD4+CD25-Foxp3+ T cells in RA exhibit several different functional properties from conventional Tregs and are correlated with RA disease activity.

Low positivity rates for HBeAg and HBV DNA in rheumatoid arthritis patients: a case-control study.

BACKGROUND: The rates of hepatitis B virus (HBV) infection in rheumatoid arthritis (RA) patients are controversial when considering the reported outcomes. It was speculated that HBV infection status was altered after RA, and variations inn HBV infection rates became apparent. METHODS: To compare the positive proportions of hepatitis B e antigen (HBeAg) and HBV DNA, a retrospective case-control study was performed between 27 chronic hepatitis B (CHB) patients with RA and 108 age- and gender-matched CHB patients. In addition, the positivity rates of hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) were surveyed among the 892 RA patients. RESULTS: Compared to CHB patients, CHB patients with RA exhibited lower rates of HBeAg positivity (11.1% vs. 35.2%, P = 0.003), HBV DNA positivity (37.0% vs. 63.9%, P = 0.007) and ALT elevation (11.1% vs. 35.2%, P = 0.024). In the 892 RA patients, the prevalence of HBsAg (3.0%) was lower than that reported in the Chinese national data (7.2%), whereas the anti-HBc positivity rate of 44.6% was higher than that of 34.1%. CONCLUSION: HBV infection status was altered after suffering from RA. Compared to the matched CHB patients, low positive proportions of HBeAg and HBV DNA were observed for CHB patients with RA.

SLC7A5 expression is up-regulated in peripheral blood T and B lymphocytes of systemic lupus erythematosus patients, associating with renal damage.

Metabolic reprogramming of immune cells has been proven to be important for systemic lupus erythematosus (SLE). This study aims to understand the role of SLC7A5, an amino acid transporter, in SLE. We analyzed SLC7A5 mRNA expression of SLE patients compared to healthy controls using GEO database, and found that it was increased in CD4+ T cells and CD19+ B cells. We then confirmed the expression up-regulation using flow cytometry and found that the proportion of SLC7A5+ cells and its expression were increased in peripheral blood T and B cells from SLE patients. Importantly, SLC7A5 expression in T and B cells was positively correlated with blood urea nitrogen and serum creatinine. Therefore, we conclude that SLC7A5, up-regulating in circulating T and B cells, correlates with kidney function, suggesting its potential role in mediating renal damage in SLE, which provides novel insight into SLE pathogenesis and provides a potential biomarker for disease.

Biomarkers of joint metabolism and bone mineral density are associated with early knee osteoarthritis in premenopausal females.

INTRODUCTION: Biomarkers of bone and cartilage metabolism were proposed as early diagnosis indicators for knee osteoarthritis (OA), however, which were influenced by disease stage, age, and menopause state. Accurate diagnosis indicators are eagerly awaited. The current study aims to investigate associations of joint metabolism biomarkers and bone mineral density (BMD) with early knee OA in males and premenopausal females before age 50 years. METHOD: A total of 189 patients aged before 50 years with early knee OA and 152 healthy participants were enrolled. Levels of bone biomarkers (PINP, OC, and CTX-I) and cartilage biomarkers (PIIANP, COMP, CTX-II, and MMP-3) were assessed. BMD was measured at the lumbar, femoral neck, and hip. Multivariate regression analyses were performed to evaluate the relationship between biomarkers, BMD, and early knee OA. RESULTS: Serum COMP, urine CTX-II and BMD at femoral neck and hip were increased in premenopausal patients as compared to control; with serum PINP and OC reduced. Meanwhile, serum COMP, urine CTX-II, and BMD at femoral neck and hip showed positive associations with premenopausal early knee OA, while serum PINP had negative association. However, in male patients, only serum COMP was higher than control, and no association of biomarkers or BMD was found with early knee OA. CONCLUSIONS: The joint metabolism biomarkers and BMD showed multiple associations with early knee OA in premenopausal females, but not in males aged before 50 years. It was suggested that sex differences should be taken into account when evaluating cartilage and bone metabolism in early knee OA. Key Points • The joint metabolism biomarkers and BMD are associated with early knee OA in premenopausal females, but not in males aged before 50 years. • Sex differences should be taken into account when evaluating cartilage and bone metabolism in early knee OA.

Alterations of peripheral blood B cell subsets in Chinese patients with adult idiopathic inflammatory myopathies.

OBJECTIVES: Abnormalities and hyperactivation of B cells have been described in idiopathic inflammatory myopathies (IIM). However, little is known about changes in the homeostasis of peripheral blood B cells in adult IIM patients. The aim of this study was to identify phenotypic alterations of B cell subsets and their relation to the overall clinical profile. METHODS: Blood samples were collected from 25 adult IIM patients and 15 healthy controls. Peripheral B cell subsets were classified into non-switched memory B cells (CD19+CD27+lgD+), switched memory B cells (CD19+CD27+lgD-), double-negative (DN) memory B cells (CD19+CD27-lgD-) and naïve B cells (CD19+CD27-lgD+) based on their surface phenotype as measured by flow cytometry. The clinical profile of IIM and its correlation with B cell subsets was further evaluated. RESULTS: Frequencies of CD19+ B cells and naïve B cells were increased in adult IIM patients compared with healthy controls (p=0.005 and p<0.001, respectively) and the frequency of memory B cells was decreased (p<0.001). Moreover, patients with a rash had lower non-switched memory B cells proportion (p=0.032). Patients with anti-MDA5+ antibodies had higher CD19+ B cells proportion than anti-ARS+ patients (p=0.046). Patients who were not receiving treatment had elevated levels of CD19+ B cells and naïve B cells along with reduced non-switched memory B cells compared with patients who were receiving treatment (p=0.021, p=0.036 and p=0.032, respectively). CONCLUSIONS: Our findings demonstrate abnormalities in the homeostasis of the B cell subsets present in adult IIM patients, characterised by expanded CD19+ B cells and naïve B cells but reduced memory B cells. Phenotypic abnormalities of B cell subsets are associated with the presence of a rash, with anti-MDA5 positivity and with treatment.

QTc interval prolongation in the patients with primary biliary cholangitis.

BACKGROUND: The QT interval prolongation was associated with fatal arrhythmias and cardiac death. However, there were not adequate data to clarify the situation of QT interval prolongation in primary biliary cholangitis (PBC) patients. The aim of this study was to clarify the rate and the associated risk factors of corrected QT (QTc) interval prolongation in PBC patients. METHODS: From January 2016 to December 2020, PBC patients were retrospectively enrolled. The rate of QTc interval prolongation was surveyed and the associated risk factors were clarified by univariate and multivariate analyses. RESULTS: Among the 189 PBC patients, 24.3% (46/189) had the QTc interval prolongation. The univariate analysis showed that age, Child-Pugh classification, creatinine, international normalized ratio (INR), and platelet (PLT) were associated with QTc interval prolongation in the PBC patients. The multivariate analysis further showed only age (p = .028) and Child-Pugh classification (p = .035) were the associated risk factors. It had the highest risk of QTc interval prolongation (as high as 64.3%) in the patients who were more than 62.5 years old and with Child-Pugh C. CONCLUSION: The QTc interval prolongation was frequent in PBC patients, especially in the patients with decompensated cirrhosis. The rate of QTc interval prolongation was as high as 64.3% in the PBC patients who were more than 62.5 years old and classified as Child-Pugh C.

Elevated CD19+Siglec-10+ B cell levels are correlated with systemic lupus erythematosus disease activity.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell dysregulation and the breakdown of self-tolerance, leading to pathogenic autoantibody production. Human Siglec-10 is a member of the sialic acid-binding immunoglobulin-type lectin (Siglec) family and a B cell surface coreceptor that inhibits B cell receptor-induced signalling. However, to date, no report has investigated CD19+Siglec-10+ B cells in SLE patients. Thus, this study aimed to measure the population of CD19+Siglec-10+ B cells in patients with SLE and its correlation with disease activity. METHODS: Flow cytometry was employed to measure the population of CD19+Siglec-10+ B cells in peripheral blood mononuclear cells (PBMCs) of both SLE patients and healthy controls (HCs). The correlation of the proportion of CD19+Siglec-10+ B cells with the values of SLE disease activity was analysed. PBMCs from HCs were challenged with serum from active SLE, inactive SLE, or HCs, and the proportion of CD19+Siglec-10+ B cells was then assessed. The effect of dexamethasone (DEX) or hydroxychloroquine (HCQ) treatment on the proportion of CD19+Siglec-10+ B cells in PBMCs from SLE patients was also determined. RESULTS: The proportion of CD19+Siglec-10+ B cells in SLE patients was significantly elevated (P < 0.05), correlated positively with the SLEDAI score (r = 0.304; P = 0.018) and negatively with complement component 3 (C3) (r = -0.283; P = 0.04). In vitro assays indicated that sera from active SLE patients could significantly enhance the proportion of CD19+Siglec-10+ B cells (P < 0.05), while HCQ treatment significantly attenuated their proportions (P < 0.01). CONCLUSIONS: The elevation of CD19+Siglec-10+ B cells and their correlation with disease activity may suggest a role for Siglec-10 in the pathogenesis and progression of SLE and provide a serum biomarker for SLE activity.

Assessment of Low Bone Mineral Density in Untreated Patients with Takayasu's Arteritis.

Chronic inflammation affects bone metabolism and accelerates bone loss. This study is aimed at analyzing the prevalence of low bone mineral density (LBMD) in patients with untreated Takayasu's arteritis (TA) and risk factors. Forty untreated TA patients were enrolled, including 38 premenopausal women and 2 men before 50 years old. The control group included 60 age- and gender-matched healthy persons. Bone mineral density (BMD) of lumbar vertebrae and hip in patients with TA and the control group was measured by the dual-energy X-ray method. Serum 25OHD and ß-CTX were also measured. The lumbar BMD of TA patients (0.89 ± 0.11 g/cm2) was significantly lower than that of the healthy control (0.97 ± 0.11 g/cm2). The prevalence of LBMD at the lumbar spine (17.50%) was significantly higher than that of the control group (3.33%). However, there was no significant difference at the hip. The 25OHD of TA patients was lower than that of healthy controls, while the level of ß-CTX was higher. The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in patients with LBMD were higher than those in patients with normal BMD. According to univariate correlation analysis, there was a significant negative correlation between LDL-C and lumbar BMD. Binary logistic regression analysis showed that LDL-C was an important factor affecting the occurrence of LBMD in patients with TA (OR = 25.269, P = 0.02). Our result reveals bone loss in TA patients, which hints the relationship among inflammation, lipid metabolism, and bone metabolism.

Role of vitamin D/VDR nuclear translocation in down-regulation of NF-κB/NLRP3/caspase-1 axis in lupus nephritis.

BACKGROUND: Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis. AIM OF THE STUDY: This study explored the therapeutic effect of VDR agonist on LN and its molecular mechanism to inhibit NLRP3 signalling. METHODS: C57BL/6 mice, lupus-prone MRL/lpr mice, and VDR agonist paricacitol-treated MRL/lpr mice (300 ng/kg/mouse per dose, 5 times/week for 8 weeks from 8 weeks old) were used to assess kidney histopathology and measure proteinuria, serum anti-ds-DNA antibody and expression of NF-κB/NLRP3/caspase-1/IL-1ß/IL-18 axis. We used mouse renal tubular epithelial cells (mRTECs) to identify protein-protein interactions and examine the effects of paricalcitol. RESULTS AND CONCLUSION: LN pathogenesis decreased after paricalcitol treatment. We observed a marked improvement in renal pathology and a time-dependent decrease urine protein and serum anti-dsDNA antibody levels. In 16-week-old MRL/lpr LN mice, the upregulated expression of NLRP3/caspase-1/IL-1ß/IL-18 axis was significantly downregulated after paricalcitol treatment. Paricalcitol can reverse the apoptosis induced by anti-dsDNA antibody via the NF-κB/NLRP3/caspase-1/IL-1ß/IL-18 axis in mRTECs. Furthermore, paricalcitol suppressed NF-κB nuclear translocation by competitively binding to importin-4. In summary, the VDR agonist can alleviate LN by modulating the NF-κB/NLRP3/caspase-1/IL-1ß/IL-18 axis and suppressing the NF-κB nuclear translocation.

Celastrol Exerts Cardioprotective Effect in Rheumatoid Arthritis by Inhibiting TLR2/HMGB1 Signaling Pathway-Mediated Autophagy.

OBJECTIVE: Rheumatoid arthritis (RA) is a kind of chronic inflammatory disease characterized by the release of inflammatory cytokines and cardiomyocyte apoptosis, which lead to increased riskfor heart diseases. This study aims to explore the possible effect and mechanism of Celastrol on RA induced cardiac impairments in rats. METHODS: Collagen induced RA wistar rat models (CIA) were established for the measurement on secondary foot swelling degree, polyarthritis index score, spleen and thymus index. Pathological morphology was observed using H&E staining. Heart fibrosis was measured after Sirius red staining, while cell apoptosis was determined by TUNEL staining. For in vitro experiments, rat cardiomyocytes were isolated to determine the inflammatory cytokine secretion and cell apoptosis using ELISA and flow cytometry, respectively. Protein expressions of related index and autophagy were detected by Western blot and immunofluorescence. RESULTS: CIA rat model was successfully established and characterized by severe secondary foot swelling degree, and increased polyarthritis index score and spleen and thymus index. Synovial hyperplasia, disordered cardiomyocytes, cell infiltration and fibrosis were also observed in CIA rat model. Compared with CIA model, Celastrol treatment could suppress the release of inflammatory cytokines, including TNF-α, IL-6, IL-1ß, as well as inhibiting the expressions of Bax, cleaved caspase3, collagen I, collagen III and α-SMA. In addition to that, Celastrol treatment can attenuate cell apoptosis and fibrosis of cardiomyocytes and elevate Bcl-2 expression. RA induced cell autophagy can be suppressed by Celastrol through inhibiting the activation of TLR2/HMGB1 signal pathway. CONCLUSION: Celastrol can regulate TLR2/HMGB1 signal pathway to suppress autophagy and therefore exert cardioprotective effect in RA.

Clinical markers combined with HMGB1 polymorphisms to predict efficacy of conventional DMARDs in rheumatoid arthritis patients.

The efficacy of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for rheumatoid arthritis (RA) patients was limited. However, there were no predictive markers for poor csDMARDs outcome. Clinical information of RA patients was collected and the high-mobility group box 1 (HMGB1) polymorphisms (rs4145277, rs2249825, rs1412125 and rs1045411) were examined. Among the 252 patients, 31.0% had no response of csDMARDs. Anti-citrullinated protein antibody (ACPA)-positive, C-reactive protein (CRP) and Disease Activity Score (DAS) 28- erythrocyte sedimentation rate (ESR) were the associated factors, which (DAC:DAS 28 > 4.7 and ACPA-positive and CRP > 7.1 mg/L) was used to predict poor csDMARDs outcome, the sensitivity and specificity was 87.2% and 60.9%, respectively. Among those DAC patients, the refractory RA rate in the rs2249825 GG genotype patients was 83.3%, the specificity was 98.5%. The clinical markers (DAC) and rs2249825 GG genotype can be used to predict poor csDMARDs outcome.

Altered frequencies of memory B cells in new-onset systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease, characterized by B cell hyperactivity and pathogenic autoantibodies formation. The objective of this study is to evaluate the distribution of B cell subsets in patients with SLE. We included patients with SLE followed in First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, China. Flow cytometry was used to measure frequencies of B cell subsets, including memory B cells, switched memory B cells, non-switched memory B cells, double-negative memory B cells, and naïve B cells in 130 patients with SLE and 55 healthy controls. The different distributions of B cell subsets were further evaluated by their associations with disease activity and clinical manifestation. SLE patients showed significant alteration of B cell subsets, including lower frequency of non-switched memory B cells and higher double-negative memory B cells. The frequencies of B cell subsets also varied between new-onset SLE patients and chronic SLE patients. Frequencies of total memory B cells, switched memory B cells, and non-switched memory B cells were lower in new-onset SLE patients and frequency of naïve B cells was higher compared with healthy controls. Chronic SLE patients showed increased switched memory B cells and double-negative memory B cells. In addition, switched memory B cells and double-negative B cells were higher in patients with lupus nephritis (LN) regardless of disease activity. Our findings suggested that abnormalities of the B cell subsets homeostasis might contribute to the pathogenesis of SLE.

Prevalence of depression and anxiety in rheumatoid arthritis patients and their associations with serum vitamin D level.

Vitamin D deficiency may be associated with depression in the general population. This study aimed to describe the prevalence of depression and anxiety in rheumatoid arthritis (RA) patients from Northwestern China and identify associations of Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) scores with serum vitamin D level in these patients. We recruited 161 RA patients inform the First Affiliated Hospital of Xi'an Jiaotong University during Nov. 2016 to Feb. 2017. All patients completed a survey including HAMD and HAMA scales. RA activity (DAS28) was scored by a rheumatologist, and serum 25-OH-D3 levels were measured by electrochemiluminescence immunoassay. The data were analyzed using the SPSS16.0 based on "possible and probable" cut points for HAMD and HAMA. About 62 and 60% of patients had some degrees of depression and anxiety, respectively. The mean of serum 25-OH-D3 levels in RA patients with depression was 15.24 ± 8.78 ng/mL, which was significantly lower than those without depression (24.68 ± 10.98 ng/mL, p = 0.009). Despite negative correlations between serum 25-OH-D3 level and the score of HAMD (r = - 0.520, p < 0.001) or HAMA (r = - 0.469, p < 0.001), there was a positive correlations between DAS28and the score of HAMD (r = 0.459, p = 0.001) or HAMA (r = 0.486, p < 0.001). The multivariate logistic regression showed that disease duration, serum 25-OH-D3 level, and treatment of tumor necrosis factor inhibitor were associated with depression/anxiety in RA patients. Our study shows a high prevalence of depression and anxiety in RA patients from Northwestern China. Both disease activity of RA and low serum 25-OH-D3 level are associated with the severity of depression and anxiety. It is imperative for clinicians to screen hypovitaminosis of vitamin D and depression/anxiety in RA patients.

Diminished serum repetin levels in patients with schizophrenia and bipolar disorder.

Repetin (RPTN) protein is a member of S100 family and is known to be expressed in the normal epidermis. Here we show that RPTN is ubiquitously expressed in both mouse and human brain, with relatively high levels in choroid plexus, hippocampus and prefrontal cortex. To investigate the expression of RPTN in neuropsychiatric disorders, we determined serum levels of RPTN in patients with schizophrenia (n = 88) or bipolar disorder (n = 34) and in chronic psychostimulant users (n = 91). We also studied its expression in a mouse model of chronic unpredictable mild stress (CUMS). The results showed that serum RPTN levels were significantly diminished in patients with schizophrenia and bipolar disorder or in psychostimulant users, compared with healthy subjects (n = 115) or age-matched controls (n = 92) (p < 0.0001). In CUMS mice, RPTN expression in hippocampus and prefrontal cortex was reduced with progression of the CUMS procedure; the serum RPTN level remained unchanged. Since CUMS is a model for depression and methamphetamine (METH) abuse induced psychosis recapitulates many of the psychotic symptoms of schizophrenia, the results from this study may imply that RPTN plays a potential role in emotional and cognitive processing; its decrease in serum may indicate its involvement in the pathogenesis of schizophrenia and bipolar disorder.