Journal of autoimmunity最新文献

Objective

To investigate the association between autoimmune diseases (AIDs) and bladder cancer (BC) at the genetic level using Mendelian randomization (MR).

Methods

Single nucleotide polymorphisms (SNPs) associated with the seven AIDs were extracted from the IEU GWAS database, and the SNPs were quality-controlled using strict screening criteria. The association between AIDs and BC risk was assessed by inverse-variance weighted (IVW), MR-Egger regression and Weighted median method. The heterogeneity of SNPs was evaluated by Cochran Q test. MR-Egger intercept test and MR-PRESSO global test were used to test the horizontal pleiotropy of SNPs. Both sides with potential causal associations were validated using the validation set.

Results

Our result showed that genetically predicted RA was significantly associated with an increased risk of BC (IVW OR = 1.214, 95 % CI = 1.062–1.388, P = 0.005). MS nominally increased the risk of BC (IVW OR = 1.095, 95 % CI = 1.005–1.193, P = 0.037), consistent with the results of the MR analysis of the BC validation cohort. However SLE, T1D, UC, CD, and MG were not causally associated with BC risk (P > 0.05). The sensitivity analyses showed that there was no heterogeneity or horizontal pleiotropy in our findings.

Conclusion

This study provides evidence of a causal relationship between AIDs and BC risk at the genetic level, confirming a causal relationship between RA and MS in increasing the risk of BC.

The link between type I IFN and adaptive immunity, especially T-cell immunity, in JDM still remained largely unclear. This study aimed to understand the effect of elevated type I IFN signaling on CD8⁺ T cell-associated muscle damage in juvenile dermatomyositis (JDM). This study used flow cytometry (FC) and RT‒PCR were used to examine the circulating cell ratio and type I IFN response. And scRNA-seq was used to examine peripheral immunity in 6 active JDM patients, 3 stable JDM patients, 3 juvenile IMNM patients and 3 age-matched healthy children. In vivo validation experiments were conducted using a mouse model induced by STING agonists and an experimental autoimmune myositis model (EAM). In vitro experiments were conducted using isolated CD8⁺ T-cells from JDM patients and mice. We found that active JDM patients showed an extensive type I IFN response and a decreased CD8⁺ T-cell ratio in the periphery (P < 0.05), which was correlated with muscle involvement (P < 0.05). Both new active JDM patients and all active JDM patients showed decreased CD8⁺ TCM cell ratios compared with age and gender matched stable JDM patients (P < 0.05). Compared with new pediatirc systemic lupus erythematosus (SLE) patients, new active JDM patients displayed decreased CD8⁺ T-cell and CD8⁺ TCM cell ratios (P < 0.05). Active JDM patient skeletal muscle biopsies displayed an elevated type I IFN response, upregulated MHC-I expression and CD8⁺ T-cell infiltration, which was validated in EAM mice. sc-RNAseq demonstrated that type I IFN signalling is the kinetic factor of abnormal differentiation and enhances the cytotoxicity of peripheral CD8⁺ T cells in active JDM patients, which was confirmed by in vivo and in vitro validation experiments. In summary, the elevated type I IFN signalling affected the differentiation and function of CD8⁺ T cells in active JDM patients. Skeletal muscle-infiltrating CD8⁺ T cells might migrate from the periphery under the drive of type I IFN and increased MHC I signals. Therapies targeting autoantigen-specific CD8⁺ T cells may represent a potential new treatment direction.

Granulomatosis with polyangiitis (GPA) is an autoimmune disorder characterized by recurrent relapses that can cause severe tissue damage and life-threatening organ dysfunction. Multiple immune cells and cytokines/chemokines are involved in the different stages of the disease. Immune profiling of patients may be useful for tracking disease activity, however, reliable immune signatures for GPA activity are lacking. In this study, we examined circulating immune profiles in GPA patients during active and remission disease states to identify potential immune patterns associated with disease activity.

The distribution and phenotypic characteristics of major circulating immune cells, and the profiles of circulating cytokines/chemokines, were studied on cryopreserved peripheral blood mononuclear cells from GPA patients (active, n = 20; remission, n = 20) and healthy controls (n = 20) leveraging a 40-color optimized multicolor immunofluorescence panel (OMIP-69) and in serum using a 46-plex Luminex multiplex assay, respectively.

Deep phenotyping uncovered a distinct composition of major circulating immune cells in active GPA and GPA in remission, with the most significant findings emerging within the monocyte compartment. Our detailed analysis revealed circulating monocyte diversity beyond the conventional monocyte subsets. We identified eight classical monocyte populations, two intermediate monocyte populations, and one non-classical monocyte population. Notably, active GPA had a higher frequency of CD45RA⁺CCR5⁺CCR6⁻CCR7^+/lowCD127⁻HLA-DR⁺CD2⁻ classical monocytes and a lower frequency of CD45RA⁻CCR5^-/lowCCR6⁻CCR7⁻CD127⁻HLA-DR⁺CD2^+/− classical monocytes, which both strongly correlated with disease activity. Furthermore, serum levels of CXCL1, CXCL2, and CCL20, all linked to monocyte biology, were elevated in active GPA and correlated strongly with disease activity.

These findings shed light on the circulating immune profile of GPA and may lead to immune signature profiles for assessing disease activity. Monocytes in particular may be studied further as potential markers for monitoring GPA.

Narcolepsy is a rare cause of hypersomnolence and may be associated or not with cataplexy, i.e. sudden muscle weakness. These forms are designated narcolepsy-type 1 (NT1) and -type 2 (NT2), respectively. Notable characteristics of narcolepsy are that most patients carry the HLA-DQB1*06:02 allele and NT1-patients have strongly decreased levels of hypocretin-1 (synonym orexin-A) in the cerebrospinal fluid (CSF). The pathogenesis of narcolepsy is still not completely understood but the strong HLA-bias and increased frequencies of CD4⁺ T cells reactive to hypocretin in the peripheral blood suggest autoimmune processes in the hypothalamus. Here we analyzed the transcriptomes of CSF-cells from twelve NT1 and two NT2 patients by single cell RNAseq (scRNAseq). As controls, we used CSF cells from patients with multiple sclerosis, radiologically isolated syndrome, and idiopathic intracranial hypertension. From 27,255 CSF cells, we identified 20 clusters of different cell types and found significant differences in three CD4⁺ T cell and one monocyte clusters between narcolepsy and multiple sclerosis patients. Over 1000 genes were differentially regulated between patients with NT1 and other diseases. Surprisingly, the most strongly upregulated genes in narcolepsy patients as compared to controls were coding for the genome-encoded MTRNR2L12 and MTRNR2L8 peptides, which are homologous to the mitochondria-encoded HUMANIN peptide that is known playing a role in other neurological diseases including Alzheimer's disease.

Introduction

The IL-12-IFNγ-Th1 and the IL-6-IL-23-Th17 axes are considered the dominant pathogenic pathways in Giant Cell Arteritis (GCA). Both pathways signal via activation of the downstream JAK/STAT proteins. We hypothesized that phosphorylated STAT (pSTAT) signatures in circulating immune cells may aid to stratify GCA-patients for personalized treatment.

Methods

To investigate pSTAT expression, PBMCs from treatment-naive GCA-patients (n = 18), infection controls (INF, n = 11) and age-matched healthy controls (HC, n = 15) were stimulated in vitro with IL-6, IL-2, IL-10, IFN-γ, M-CSF or GM-CSF, and stained with CD3, CD4, CD19, CD45RO, pSTAT1, pSTAT3, pSTAT5 antibodies, and analyzed by flow cytometry. Serum IL-6, sIL-6-receptor and gp130 were measured by Luminex. The change in percentages of pSTAT3+CD4+T-cells was evaluated at diagnosis and at 3 months and 1-year of follow-up. Kaplan-Meier analyses was used to asses prognostic accuracy.

Results

Analysis of IL-6 stimulated immune cell subsets revealed a significant decrease in percentages of pSTAT3+CD4+T-cells of GCA-patients and INF-controls compared to HCs. Following patient stratification according to high (median>1.5 pg/mL) and low (median<1.5 pg/mL) IL-6 levels, we observed a reduction in the pSTAT3 response in GCA-patients with high serum IL-6. Percentages of pSTAT3+CD4+T-cells in patients with high serum IL-6 levels at diagnosis normalized after glucocorticoid (GC) treatment. Importantly, we found that patients with low percentages of pSTAT3+CD4+T-cells at baseline require longer GC-treatment.

Conclusion

Overall, in GCA, the percentages of in vitro IL-6-induced pSTAT3+CD4+T-cells likely reflect prior in vivo exposure to high IL-6 and may serve as a prognostic marker for GC-treatment duration and may assist improving personalized treatment options in the future.

Primary sclerosing cholangitis (PSC) is an (auto)immune-mediated cholestatic liver disease with a yet unclear etiology. Increasing evidence points to an involvement of neutrophils in chronic liver inflammation and cirrhosis but also liver repair. Here, we investigate the role of the neutrophil extracellular trap (NET) component myeloperoxidase (MPO) and the therapeutic potential of DNase I and of neutrophil elastase (NE) inhibitor GW311616A on disease outcome in the multidrug resistance 2 knockout (Mdr2^−/−) mouse, a PSC animal model. Initially, we observed the recruitment of MPO expressing cells and the formation of NETs in liver biopsies of PSC patients and in Mdr2^−/− livers. Furthermore, sera of Mdr2^−/− mice contained perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA)-like reactivity similar to PSC patient sera. Also, hepatic NE activity was significantly higher in Mdr2^−/− mice than in wild type littermates. Flow cytometry analyses revealed that during disease development a highly active neutrophil subpopulation established specifically in the liver of Mdr2^−/− mice. However, absence of their MPO activity, as in MPO-deficient Mdr2^−/− mice, showed no effect on hepatobiliary disease severity. In contrast, clearance of extracellular DNA by DNase I reduced the frequency of liver-resident neutrophils, plasmacytoid dendritic cells (pDCs) and CD103⁺ conventional DCs and decreased cholangiocyte injury. Combination of DNase I with a pDC-depleting antibody was additionally hepatocyte-protective. Most importantly, GW311616A, an orally bioavailable inhibitor of human NE, attenuated hepatobiliary injury in a TNFα-dependent manner and damped hyperproliferation of biliary epithelial cells. Further, hepatic immigration and activity of CD11b⁺ DCs as well as the secretion of IFNγ by hepatic CD4 and CD8 T cells were reduced. Our findings delineate neutrophils as important participants in the immune cell crosstalk that drives cholestatic liver disease and identify NET components as potential therapeutic targets.

Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by joint inflammation and bone damage, that not only restricts patient activity but also tends to be accompanied by a series of complications, seriously affecting patient prognosis. Peroxisome proliferator-activated receptor gamma (PPARG), a receptor that controls cellular metabolism, regulates the function of immune cells and stromal cells. Previous studies have shown that PPARG is closely related to the regulation of inflammation. However, the role of PPARG in regulating the pathological processes of RA is poorly understood.

Materials and methods

PPARG expression was examined in the synovial tissues and peripheral blood mononuclear cells (PBMCs) from RA patients and the paw of collagen-induced arthritis (CIA) model rats. Molecular biology experiments were designed to examine the effect of PPARG and cannabidiol (CBD) on RAW264.7 cells and CIA rats.

Results

The results reveal that PPARG accelerates reactive oxygen species (ROS) clearance by promoting autophagy, thereby inhibiting ROS-mediated macrophage polarization and NLRP3 inflammasome activation. Notably, CBD may be a promising candidate for understanding the mechanism by which PPARG regulates autophagy-mediated inflammation.

Conclusions

Taken together, these findings indicate that PPARG may have a role for distinguishing between RA patients and healthy control, and for distinguishing RA activity; moreover, PPARG could be a novel pharmacological target for alleviating RA through the mediation of autophagy. CBD can act as a PPARG agonist that alleviates the inflammatory progression of RA.

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.

Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases.

CD6 is a glycoprotein expressed on CD4 and CD8 T cells involved in immunoregulation. CD318 has been identified as a CD6 ligand. The role of CD318 in T cell immunity is restricted as it has only been investigated in a few mice autoimmune models but not in human diseases. CD318 expression was thought to be limited to mesenchymal-epithelial cells and, therefore, contribute to CD6-mediated T cell activation in the CD318-expressing tissue rather than through interaction with antigen-presenting cells. Here, we report CD318 expression in a subpopulation of CD318⁺ myeloid dendritic (mDC), whereas the other peripheral blood populations were CD318 negative. However, CD318 can be induced by activation: a subset of monocytes treated with LPS and IFNγ and in vitro monocyte derived DCs were CD318⁺. We also showed that recombinant CD318 inhibited T cell function. Strikingly, CD318⁺ DCs suppressed the proliferation of autoreactive T cells specific for GAD65, a well-known targeted self-antigen in Type 1 Diabetes (T1D). Our study provides new insight into the role of the CD318/CD6 axis in the immunopathogenesis of inflammation, suggesting a novel immunoregulatory role of CD318 in T cell-mediated autoimmune diseases and identifying a potential novel immune checkpoint inhibitor as a target for intervention in T1D which is an unmet therapeutic need.