Accumulation Of Immune Complexes Research Articles

The impact of the COVID-19 pandemic on the incidence and clinical course of IgA vasculitis in paediatric patients

Introduction and objective: Immunoglobulin A vasculitis is an autoimmune disorder resulting from immune complex accumulation in small blood vessels, causing skin, joint, abdominal, and kidney manifestations. This study evaluated the impact of the COVID-19 pandemic on the incidence and clinical course of immunoglobulin A vasculitis in paediatric patients. Materials and methods: A retrospective analysis of medical records from a single university paediatric hospital was performed to compare 117 patients presenting with immunoglobulin A vasculitis before and 57 after the COVID-19 epidemic announcement in Poland on 20 March 2020. Laboratory results, hospitalisation duration, preceding infections, clinical presentation, history of allergies and COVID-19 vaccinations, and the proportion of immunoglobulin A vasculitis patients among all admissions were analysed. Results: The study of 174 patients showed that their average age during the pandemic (5.51 ± 3.10) was significantly lower than pre-pandemically (6.98 ± 3.67) (p < 0.05). Before the pandemic, more hospitalised patients had immunoglobulin A vasculitis (1.14%) compared to during the pandemic (0.47%) (p < 0.05). Food allergies were also more common during the pandemic (20.8%) than before (8.8%) (p < 0.05). No significant differences were found in hospitalisation duration, and the incidence of immunoglobulin A vasculitis nephritis and abdominal symptoms (p = 0.194, p = 0.381, p = 0.968, respectively). Three patients had COVID-19 infection at admission. Conclusions: The pandemic led to fewer immunoglobulin A vasculitis hospitalisations but did not alter the clinical course of the disease or the incidence of immunoglobulin A vasculitis nephritis. In the context of the resurgence of COVID-19 infections, it is important to consider them as potential factors affecting immunoglobulin A vasculitis. Ongoing research is essential to understand these dynamics and guide effective clinical management of immunoglobulin A vasculitis amidst the evolving COVID-19 setting.

A noninvasive method of diagnosing membranous nephropathy using exosomes derived from urine.

Membranous nephropathy (MN) is a specific autoimmune disease affecting kidneys. It is characterized by the accumulation of immune complexes in the glomerular basement membrane. Renal biopsy is currently the standard procedure to confirm the diagnosis, although the presence of autoantibodies against the phospholipase A2 receptor (PLA2R) can also help diagnose. In this study, we aimed to investigate the potential of urinary exosomes as noninvasive markers for diagnosing MN. Exosomes were extracted from urine samples of five patients with MN and four healthy controls. The concentration of PLA2R was measured in both urine and isolated exosomes using enzyme-linked immunosorbent assay techniques. The measurements were adjusted based on the urine creatinine (UCr) level of each participant. The levels of PLA2R/UCr were investigated in urine and urine-derived exosomes from patients and controls. Results of the analysis revealed significantly higher expression of PLA2R/UCr in patients compared to the control group (p < 0.05). Furthermore, the expression level of PLA2R/UCr was higher in urine-derived exosomes than in urine samples. Additionally, a positive correlation was observed between the expression levels of PLA2R/UCr and the urine protein-to-creatinine ratio, with urine-derived exosomes exhibiting a stronger correlation than urine samples. Studies have indicated that measuring exosomal PLA2R/UCr levels in urine could be a noninvasive method for diagnosing MN. Using urine-derived exosomes could also reduce the burden of performing a biopsy on patients and facilitate follow-up treatment, such as monitoring for future recurrence.

Leprosy reactions: Unraveling immunological mechanisms underlying tissue damage in leprosy patients.

Leprosy is a chronic granulomatous infectious and disabling disease caused by two mycobacteria, Mycobacterium leprae and Mycobacterium lepromatosis. Acute inflammatory responses, known as leprosy reactions, are significant contributors to disabilities. Three types of leprosy reactions have been identified based on excessive cytokine release (e.g. type 1) or the accumulation of immune complexes in tissues inducing multiorgan damage (e.g. types 2 and 3). The type of leprosy reaction has implications on treatment and management strategies, yet are not well understood by health workers caring for leprosy patients. We attempt to describe the immunologic mechanisms behind the different leprosy reactions and the rationale for tailoring clinical treatment and management to the particular type of leprosy reaction based on the underlying immunologic situation.

Uncommon elegance: Nephrotic surprises in adult immunoglobulin A vasculitis

Abstract: Henoch–Schönlein purpura (HSP) is a form of small-vessel vasculitis caused by the accumulation of immune complexes containing immunoglobulin A antibodies. It is usually seen in childhood. When the disease is considered in terms of nephritis, its incidence in children is reported to be between 20% and 54%. Hematuria and nephritic proteinuria are common in the course of the disease. However, nephrotic proteinuria is extremely rare. This article presents the case of an individual who was diagnosed with HSP as an adult, characterized by vasculitis. The patient did not present with arthritis or arthralgia during follow-up but developed gastrointestinal bleeding. In particular, nephrotic proteinuria was observed during follow-up.

Modern ideas about the etiopathogenesis of rheumatoid arthritis

This review reflects modern ideas about the etiology and pathogenesis of Rheumatoid arthritis (RA). The disease is believed to be caused by various external or internal stress factors in individuals with a genetic predisposition. Under modern concepts, RA is an autoimmune disease, and the basis of its pathogenesis is the defects of the regulatory mechanisms providing the activation of the immune system against various stimuli. The onset of RA is in the peripheral lymphoid organs. Dendritic cells activate T-lymphocytes, activating B-lymphocytes through cytokines and costimulatory molecules, and cause the synthesis of autoantibodies, the accumulation of immune complexes in the joints, and the development of rheumatoid synovitis. B-lymphocytes secrete rheumatoid factor (RF), antibodies to cyclic citrulline peptide (ACCP), and proinflammatory cytokines and also activate T-lymphocytes by indicating signaling molecules. During T-lymphocyte activation, CD4+ Th-cells interact with HLA, MHC-II molecules, and costimulatory molecules located on the surface of antigen-presenting cells. This interaction activates a signaling pathway leading to the maturation of CD4+ cells, resulting in the activation of pro-inflammatory CD8+ T-lymphocytes. CD4+ Th cells also play an important role in RA regeneration through the secretion of cytokines and chemokines, the important immunomodulators of cellular immunity.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Mayo Clinic Consensus Report on Membranous Nephropathy: Proposal for a Novel Classification

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%–90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Heavy Metals and Cardiovascular Disease on Wetlands

Heavy metals are metal elements with a relatively high density compared to water. One area that is vulnerable to heavy metal pollution is the wetland environment. In South Kalimantan, an alkaline land area, pollution is mainly caused by mining activities, especially coal mining and oil palm plantation activities. The presence of heavy metals in the sediments of the Martapura River in South Kalimantan, which have passed the threshold for sediment contamination, includes Mn, Fe and Hg. The potential link between chronic heavy metal exposure and cardiovascular disease (CVD) has several implications. Although the cardiovascular system is not usually viewed as the main target of heavy metal toxicity, imbalances in antioxidant protection mechanisms lead to oxidative stress in cells as a major effect of heavy metal exposure. Heavy metals can cause oxidative stress by producing reactive oxygen species (ROS). Heavy metals are associated with an increase in systemic inflammation. They can lead to impaired immune function and accumulation of immune complexes, causing CVD, including the uncontrolled release of inflammatory cytokines, kidney damage, and central nervous system stimulation. However, some research results are contradictory and say no relationship exists between heavy metals, such as mercury, and cardiovascular disease. The presence of heavy metals is still a health risk in wetlands. Metal content that crosses this threshold can be a cause or a risk factor for cardiovascular disease. The effects of heavy metal content, such as mercury, on health, especially cardiovascular disease, are still not fully understood, requiring further investigation and research.

CLEC18A Impairs Phagocytosis by Reducing FcγRIIA Expression and Arresting Autophagosome-Lysosome Fusion.

Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related extrahepatic manifestation that is characterized by the abnormal presence of immune complexes (ICs). This may be due to the reduced uptake and clearance of ICs. The C-type lectin member 18A (CLEC18A) is a secretory protein that is expressed abundantly in hepatocytes. We previously observed that CLEC18A increased significantly in the phagocytes and sera of patients with HCV, particularly those with MC. Herein, we explored the biological functions of CLEC18A in the MC syndrome development of patients with HCV by using an in vitro cell-based assay with quantitative reverse transcription-PCR, immunoblotting, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. HCV infection or Toll-like receptor 3/7/8 activation could induce CLEC18A expression in Huh7.5 cells. Upregulated CLEC18A interacts with Rab5 and Rab7 and enhances type I/III interferon production to inhibit HCV replication in hepatocytes. However, overexpressed CLEC18A suppressed phagocytic activity in phagocytes. Significantly decreased levels of the Fc gamma receptor (FcγR) IIA were found in the neutrophils of HCV patients, particularly in those with MC (P < 0.005). We demonstrated that CLEC18A could inhibit FcγRIIA expression in a dose-dependent manner through the production of NOX-2-dependent reactive oxygen species to impair the uptake of ICs. Additionally, CLEC18A suppresses the Rab7 expression that is induced by starvation. Overexpressed CLEC18A does not affect autophagosome formation but does reduce the recruitment of Rab7 to autophagosomes, thereby retarding the maturation of autophagosomes and affecting autophagosome-lysosome fusion. We offer a novel molecular machinery with which to understand the association of HCV infection with autoimmunity and propose that CLEC18A may act as a candidate biomarker for HCV-associated MC. IMPORTANCE During infection, the host immune system produces cellular factors to protect against pathogen invasion. However, when the immune response overreacts and there is dysregulated cytokine homeostasis, autoimmunity occurs following an infection. We identified a cellular factor that is involved in HCV-related extrahepatic manifestation, namely, CLEC18A, which is expressed abundantly in hepatocytes and phagocytes. It inhibits HCV replication in hepatocytes by interacting with Rab5/7 and enhancing type I/III IFN expression. However, overexpressed CLEC18A inhibited FcγRIIA expression in phagocytes to impair phagocytosis. Furthermore, the interaction between CLEC18A and Rab5/7 may reduce the recruitment of Rab7 to autophagosomes and thereby retard autophagosome maturation and cause immune complex accumulation. A decreasing trend in CLEC18A levels that was accompanied by reduced HCV RNA titers and diminished cryoglobulin was observed in the sera of HCV-MC patients after direct-acting antiviral therapy. CLEC18A may be used for the evaluation of anti-HCV therapeutic drug effects and could be a potential predisposing factor for the development of MC syndrome.

Mapping antigens of membranous nephropathy: almost there

Membranous nephropathy (MN) is characterized by subepithelial accumulation of immune complexes along the glomerular basement membranes. The immune complexes compromise IgG and the corresponding target antigen. Recent advances have led to the discovery of novel target MN antigens. In this study, by Caza et al., 7 novel "putative" antigens are proposed. Target antigens can now be identified in approximately 90% of cases of MN. In addition to describing another 10 novel putative antigens, we propose a working algorithm for evaluating the target antigens in MN.

Autoantigen spermatid nuclear transition protein 1 enhances pro-inflammatory cytokine production stimulated by anti-DNA autoantibodies in macrophages

IntroductionLupus nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE), is associated with high fatality rate in patients. The pathogenesis of lupus nephritis is complex and has not been fully elucidated. Kidney inflammation, renal cell damage, and accumulation of immune complexes in the glomerular basement membrane often occur in patients with lupus nephritis. Spermatid nuclear transition protein 1 (TNP1) might be a potentially interesting autoantigen in exploring the pathogenesis and therapy of lupus nephritis.ObjectiveThis study aimed to explore the effect of TNP1 and its complexes with anti-double-stranded DNA antibodies on the levels of interleukin-6 (IL-6) and interferon-α (IFN-α) in vitro.MethodsWe studied the effect of the synthetic peptide of the autoantigen on the pathogenic characteristics of the G2-6 and G5-8 antibodies in mouse macrophages, using enzyme-linked immunosorbent assay, quantitative RT-PCR, western blotting, and flow cytometry.ResultsThe antibodies exhibited cross-reactivity to spermatid TNP1 in direct-binding and competitive enzyme-linked immunosorbent assay. Results of quantitative RT-PCR and western blotting revealed that the antibodies alone enhanced the levels of IL-6 and IFN-α transcripts and proteins, respectively. Flow cytometry revealed that treatment with the autoantigen enhanced the cell-penetrating activities of G2-6 and G5-8 and remarkably increased the cytokine levels.ConclusionTNP1 enhanced the cell-penetrating activities of anti-dsDNA auto-Abs, G2-6 and G5-8, and remarkably increased the levels of IL-6 and IFN-α in macrophages, suggesting that TNP1 and cell-penetrating pathogenic anti-dsDNA auto-Abs is potential targets for future therapeutic approaches to treat LN/SLE.

Pharmacological actions of anifrolumab (Saphnelo®) and clinical trial results as a treatment for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease which causes damaging inflammation in multiple organs via the accumulation of immune complexes. SLE pathogenesis is associated with type I interferons (IFNs), which are central and reflective of disease activity in SLE. Even before clinical development of disease, genetic and environmental contributions to IFN production lead to abnormal innate and adaptive immune activation. Through the Janus kinase-signal transducer and activator of transcription signaling pathway, IFN play a central role in the immunopathogenicity of SLE. Thus, IFN-blocking therapy may be used to regulate inflammation in individuals with SLE. Food and Drug Administration (FDA)-approved anifrolumab (Saphnelo®), which is a human IgG1κ monoclonal antibody that binds to subunit 1 of the type I interferon receptor with high specificity and affinity, was also approved for the treatment of adult patients with moderate to severe SLE who are receiving standard therapy by Pharmaceuticals and Medical Device Agency (PMDA), in Japan in September 2021; anifrolumab is administered as an intravenous infusion, 300 mg over a 30-minute period, every 4 weeks. In this article, we reviewed the actions of type I IFN and anifrolumab as a treatment for SLE.

Targeted Delivery of Chloroquine to Antigen-Presenting Cells Enhances Inhibition of the Type I Interferon Response.

Systemic lupus erythematosus (SLE) causes damaging inflammation in multiple organs via the accumulation of immune complexes. These complexes activate plasmacytoid dendritic cells (pDCs) via toll-like receptors (TLRs), contributing to disease pathogenesis by driving the secretion of inflammatory type I interferons (IFNs). Antimalarial drugs, such as chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE. However, they require ∼3 months of continuous use before achieving therapeutic efficacy and can accumulate in the retinal pigment epithelium with chronic use, resulting in retinopathy. We hypothesized that poly(ethylene glycol)-b-poly(propylene sulfide) filamentous nanocarriers, filomicelles (FMs), could directly deliver CQ to pDCs via passive, morphology-based targeting to concentrate drug delivery to specific immune cells, improve drug activity by increased inhibition of type I IFN, and enhance efficacy per dose. Healthy human peripheral blood mononuclear cells were treated with soluble CQ or CQ-loaded FMs, stimulated with TLR agonists or SLE patient sera, and type I IFN secretion was quantified via multi-subtype IFN-α ELISA and MX1 gene expression using real-time reverse transcription-quantitative polymerase chain reaction. Our results showed that 50 μg CQ/mg FM decreased MX1 expression and IFN-α production after TLR activation with either synthetic nucleic acid agonists or immune complex-rich sera from SLE patients. Cellular uptake and biodistribution studies showed that FMs preferentially accumulate in human pDCs and monocytes in vitro and in tissues frequently damaged in SLE patients (i.e., kidneys), while sparing the eye in vivo. These results showed that nanocarrier morphology enables drug delivery, and CQ-FMs may be equally effective and more targeted than soluble CQ at inhibiting SLE-relevant pathways.

Calcineurin and Systemic Lupus Erythematosus: The Rationale for Using Calcineurin Inhibitors in the Treatment of Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical presentations that can affect almost all organ systems. Lupus nephritis (LN) is a severe complication that affects approximately half of the systemic erythematosus lupus (SLE) patients, which significantly increases the morbidity and the mortality risk. LN is characterized by the accumulation of immune complexes, ultimately leading to renal failure. Aberrant activation of T cells plays a critical role in the pathogenesis of both SLE and LN and is involved in the production of inflammatory cytokines, the recruitment of inflammatory cells to the affected tissues and the co-stimulation of B cells. Calcineurin is a serine-threonine phosphatase that, as a consequence of the T cell hyperactivation, induces the production of inflammatory mediators. Moreover, calcineurin is also involved in the alterations of the podocyte phenotype, which contribute to proteinuria and kidney damage observed in LN patients. Therefore, calcineurin inhibitors have been postulated as a potential treatment strategy in LN, since they reduce T cell activation and promote podocyte cytoskeleton stabilization, both being key aspects in the development of LN. Here, we review the role of calcineurin in SLE and the latest findings about calcineurin inhibitors and their mechanisms of action in the treatment of LN.

The matrix of SDS integrated with linear hydrophilic polymer for resolution of high- and low-molecular weight hyaluronic acids in MEKC

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, when not effectively treated. The aim of this study was to discover new targets for the diagnosis and treatment of MN. A reliable mouse model of MN was used by the administration of cationic bovine serum albumin (cBSA). Mice with MN exhibited proteinuria, histopathological changes, and accumulation of immune complexes in the glomerular basement membrane. Label-free proteomics analysis was performed to identify changes in protein expression, and the overexpressed proteins were evaluated. There were 273 proteins that showed significantly different expression in mice with MN, as compared to the controls. String analysis showed that functions related to cellular catabolic processes were downregulated in MN. Among the differentially expressed proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2) were upregulated in the kidneys of mice with MN, as demonstrated by immunohistochemistry (IHC), and this upregulation was observed in both the tubular cells and glomeruli. Both shRNA-mediated knockdown of PHB1 or PHB2 inhibited tumor suppressor p53 expression and significantly promoted podocyte proliferation. In addition, both PHB1 and PHB2 were responsible for cBSA-induced cytotoxicity. Microarray analysis further revealed that the upregulation of PHB1 and PHB2 may be due to a blockage of proteasome activity. These data demonstrate that the upregulation of PHB2 is involved in cBSA-mediated podocyte cytotoxicity, which may lead to MN development. © 2019

T lymphocytes in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is the main cause of end-stage renal disease. IgAN is characterized by the accumulation of immune complexes in the circulation, which contain abnormal levels of IgA. IgAN primarily results from galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 deposition in the renal mesangium, causing local proliferation and matrix expansion. Gd-IgA1 has been confirmed as one of the key effectors in the pathogenesis of IgAN, but the origin of Gd-IgA1 is not clear. Recent studies have shown that Gd-IgA1 deposition could be the result of mucosally primed plasma cells and is associated with T cell dysregulation. T cells contribute to the IgA response and play an important role in the development of IgAN. In the present review, the latest discoveries regarding the role of T lymphocytes in the pathogenesis of IgAN have been summarized. Understanding these advances will allow novel therapeutic strategies for the treatment of IgAN.

Involvement of prohibitin 1 and prohibitin 2 upregulation in cBSA-induced podocyte cytotoxicity

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, when not effectively treated. The aim of this study was to discover new targets for the diagnosis and treatment of MN. A reliable mouse model of MN was used by the administration of cationic bovine serum albumin (cBSA). Mice with MN exhibited proteinuria, histopathological changes, and accumulation of immune complexes in the glomerular basement membrane. Label-free proteomics analysis was performed to identify changes in protein expression, and the overexpressed proteins were evaluated. There were 273 proteins that showed significantly different expression in mice with MN, as compared to the controls. String analysis showed that functions related to cellular catabolic processes were downregulated in MN. Among the differentially expressed proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2) were upregulated in the kidneys of mice with MN, as demonstrated by immunohistochemistry (IHC), and this upregulation was observed in both the tubular cells and glomeruli. Both shRNA-mediated knockdown of PHB1 or PHB2 inhibited tumor suppressor p53 expression and significantly promoted podocyte proliferation. In addition, both PHB1 and PHB2 were responsible for cBSA-induced cytotoxicity. Microarray analysis further revealed that the upregulation of PHB1 and PHB2 may be due to a blockage of proteasome activity. These data demonstrate that the upregulation of PHB2 is involved in cBSA-mediated podocyte cytotoxicity, which may lead to MN development.

MON-009 CLINICOPATHOLOGICAL ASSOCIATIONS OF INTRARENAL VASCULAR LESIONS IN SEVERE LUPUS NEPHRITIS

Kidney involvement in systemic lupus, known as Lupus nephritis, is most often due to glomerular immune complex accumulation, which leads to glomerular inflammation and, if unchecked, also involves the renal interstitium. The reported incidence of clinically important kidney disease in systemic lupus is about 38%.

Large vessel vasculopathy in a patient with systemic lupus erythematosus: a case report

BackgroundVasculopathy in systemic lupus erythematosus is a rare form of vascular involvement characterized by non-inflammatory vascular injury with the accumulation of immune complexes in the walls of the arteries, resulting in luminal narrowing. While previous reports have demonstrated vasculitis in the large vessels or vasculopathy in the small vessels, vasculopathy in large vessels has not yet been reported.Case presentationWe present the case of a 43-year-old Japanese woman with peripheral large vessel vasculopathy associated with systemic lupus erythematosus. She presented a 7-year history of progressive headaches and intermittent claudication, although she had no atherosclerotic risk factors. Vascular ultrasonography and enhanced computed tomography showed multiple vascular stenoses and occlusion. The histological findings of her left temporal artery revealed narrowing of the lumen caused by intimal thickening without inflammatory cells and the deposition of immunoglobulin G, complement component 3, and fibrinogen in the wall of the intima. Beraprost and cilostazol improved arterial occlusion without immunosuppressive therapy.ConclusionsLarge vessel vasculopathy should be considered another potential cause of arterial stenoses and occlusion in patients with lupus when they have peripheral arterial disease despite having no atherosclerotic risk factors.

The proteasome activator REGγ counteracts immunoproteasome expression and autoimmunity

For quite a long time, the 11S proteasome activator REGɑ and REGβ, but not REGγ, are known to control immunoproteasome and promote antigen processing. Here, we demonstrate that REGγ functions as an inhibitor for immunoproteasome and autoimmune disease. Depletion of REGγ promotes MHC class I-restricted presentation to prime CD8+ T cells in vitro and in vivo. Mice deficient for REGγ have elevation of CD8+ T cells and DCs, and develop age-related spontaneous autoimmune symptoms. Mechanistically, REGγ specifically interacts with phosphorylated STAT3 and promotes its degradation in vitro and in cells. Inhibition of STAT3 dramatically attenuates levels of LMP2/LMP7 and antigen presentation in cells lacking REGγ. Importantly, treatment with STAT3 or LMP2/7 inhibitor prevented accumulation of immune complex in REGγ−/− kidney. Moreover, REGγ−/− mice also expedites Pristane-induced lupus. Bioinformatics and immunohistological analyses of clinical samples have correlated lower expression of REGγ with enhanced expression of phosphorylated STAT3, LMP2 and LMP7 in human Lupus Nephritis. Collectively, our results support the concept that REGγ is a new regulator of immunoproteasome to balance autoimmunity.