Organ Damage In Systemic Lupus Erythematosus Research Articles

Predictors of Organ Damage in Systemic Lupus Erythematosus in the Asia Pacific Region: A Systematic Review.

Irreversible organ damage is common in patients with systemic lupus erythematosus (SLE). Despite evidence of increased prevalence and severity of SLE in Asia Pacific, organ damage is less well studied in this region. This systematic review aims to identify predictors of organ damage in SLE in the Asia Pacific region. We searched Medline, PubMed, Embase, and Web of Science for observational studies on organ damage in adult patients with SLE in Asia Pacific from August 31, to September 5, 2022. Study selection and data extraction were completed by two independent reviewers using Covidence systematic review software. Risk of bias was assessed using the Newcastle-Ottawa Scale and Joanna Briggs Institute tool. Significant results from univariable and multivariable analyses were synthesized from included studies. Thirty-eight eligible studies were selected from 1999 to 2022; 22 (58%) of these reported organ damage at study enrollment and 19 (50%) reported damage accrual, as measured by the Systemic Lupus International Collaborating Clinic/American College of Rheumatology Damage Index. Factors predictive of organ damage included older age, glucocorticoid use, longer disease duration, and disease activity. Lupus nephritis was a risk factor for renal and overall damage accrual. Hydroxychloroquine was protective against overall organ damage. Predictors of organ damage in SLE in Asia Pacific are similar to other regions. Although glucocorticoid use is a modifiable risk factor for organ damage, the impact of immunosuppressives and biologic therapies needs further investigation. Effective strategies in early disease are needed to minimize initial organ damage as it predicts subsequent damage accrual.

Ocular fundus changes and association with systemic conditions in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and systems. Ocular involvement is estimated to manifest in one-third of individuals with SLE, of which lupus retinopathy and choroidopathy represent the severe subtype accompanied by vision impairment. Advancements in multimodal ophthalmic imaging have allowed ophthalmologists to reveal subclinical microvascular and structural changes in fundus of patients with SLE without ocular manifestations. Both ocular manifestations and subclinical fundus damage have been shown to correlate with SLE disease activity and, in some patients, even precede other systemic injuries as the first presentation of SLE. Moreover, ocular fundus might serve as a window into the state of systemic vasculitis in patients with SLE. Given the similarities of the anatomy, physiological and pathological processes shared among ocular fundus, and other vital organ damage in SLE, such as kidney and brain, it is assumed that ocular fundus involvement has implications in the diagnosis and evaluation of other systemic impairments. Therefore, evaluating the fundus characteristics of patients with SLE not only contributes to the early diagnosis and intervention of potential vision damage, but also holds considerate significance for the evaluation of SLE vasculitis state and prediction of other systemic injuries.

COX5A as a potential biomarker for disease activity and organ damage in lupus.

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with limited therapeutic targets or clinical outcome predictors. This study aimed to gain more insights into the underlying immunological pathways and prognostic biomarkers of SLE. Integrated analyses of RNA-seq data from 64 SLE and 62 healthy controls, examining 27 immune cell types to explore the key pathways and driver genes in SLE pathogenesis. Single-cell RNA sequencing data from the skin and kidney were used to determine the association of COX5A expression with organ damage. The associations of COX5A with SLE phenotypes were further evaluated in two independent cohorts, and receiver operating characteristic (ROC) curves were constructed to assess the value of COX5A as a biomarker for disease activity and organ damage in SLE. We found that oxidative phosphorylation (OXPHOS) is the most significantly altered metabolic pathway in SLE, especially in effector T cells. Notably, we identified an OXPHOS-related enzyme, COX5A, whose expression was significantly higher in effector T cells than in naïve T cells and showed associations with disease activity, organ damage, and steroid treatment of SLE. Furthermore, ROC curves showed that COX5A is a robust biomarker for disease activity, kidney involvement, and new-onset skin lesions, with the area under the curve (AUC) values of 0.880, 0.801, and 0.805, respectively. Our results identified the OXPHOS signature as a prominent feature in SLE T cells, and COX5A as a potential candidate biomarker for disease activity and organ damage in SLE.

Association of urine Interleukin-8 (IL-8) with renal impairment in lupus patients

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with clinical manifestations that vary between individuals with progressive and irreversible SLE organ damage. Recently, it has become known that Interleukin-8 (IL-8) levels in the blood rise in SLE patients compared to healthy people. The increase of IL-8 causes kidney inflammation by promoting the release of the Neutrophil Extracellular Traps (NET) complex, which supports further renal damage. This study aims to evaluate the association of urine interleukin-8 with renal impairment in SLE patients. Methods: A total of 45 lupus participants—22 with and 23 without renal abnormalities—had their urine collected. The interleukin-8 concentration was measured using an enzyme-linked immunosorbent assay (ELISA)—renal impairment criteria based on renal biopsy or ACR 1997 criteria. Mann-Whitney and Spearman correlation tests were employed in the statistical analysis. Data were analyzed using SPSS version 25.0 for Windows. Results: There was no significant difference in IL-8 urine levels between the SLE group with renal impairment (111.27±59.03 pg/ml) and the SLE group without renal impairment (125.76±66.62 pg/ml) was not significant (p=0.67). Urine IL-8 also did not significantly correlate with blood neutrophil count, leukocyte count and leukocyturia (p>0.05). Conclusion: In lupus patients, urine Interleukin-8 levels are not associated with renal impairment.

Platelets are a major player and represent a therapeutic opportunity in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and organ injury with a premature mortality due to cardiovascular diseases. Platelets, that are primarily known for their role in hemostasis, have been shown to play an active role in the pathogenesis and in the progression of immune-mediated inflammatory diseases. Here we summarize the evidence of their roles in SLE pathogenesis which supports the development of targeted treatments. Platelets and their precursors, the megakaryocytes, are intrinsically different in SLE patients compared with healthy controls. Different triggers related to innate and adaptive immunity activate platelets which release extracellular vesicles, soluble factors and interact with immune cells, thereby perpetuating inflammation. Platelets are involved in organ damage in SLE, especially in lupus nephritis and participate in the heightened cardiovascular mortality. They also play a clear role in antiphospholipid syndrome which can be associated with both thrombocytopenia and thrombosis. To tackle platelet activation and their interactions with immune cells now constitute promising therapeutic strategies in SLE.

Clinical research progress of novel biologics for the treatment of lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is one of the most common manifestations of severe organ damage in SLE, and also an important cause of disability and death. Its pathogenesis is associated with immune abnormalities such as immune cells, cytokines, and immune complex deposition. Traditional immunosuppressive therapy has been unable to meet the treatment needs of patients while bringing them toxic effects. In recent years, targeted therapies have emerged, and several novel biologics have gradually entered people's sight. This review will briefly introduce the pathogenesis of LN and the mechanism of biological targets, and summarize and analyze the clinical trials of new biologics for treating LN. Although not all biologics show positive results in clinical trials, the experience learned from these trials can help researchers adjust and plan future trial programs to seek better treatment methods.

CD98 defines a metabolically flexible, proinflammatory subset of low-density neutrophils in systemic lupus erythematosus.

Low-density neutrophils (LDN) are a distinct subset of neutrophils rarely detected in healthy people but appear in the blood of patients with autoimmune diseases, including systemic lupus erythematosus (SLE), and are mobilised in response to granulocyte colony-stimulating factor (G-CSF). The aim of this study was to identify novel mechanisms responsible for the pathogenic capacity of LDN in SLE. Neutrophils were isolated from donors treated with G-CSF, and whole-cell proteomic analysis was performed on LDN and normal-density neutrophils. CD98 is significantly upregulated in LDN from G-CSF donors and defines a subset of LDN within the blood of SLE patients. CD98 is a transmembrane protein that dimerises with L-type amino acid transporters. We show that CD98 is responsible for the increased bioenergetic capacity of LDN. CD98 on LDN mediates the uptake of essential amino acids that are used by mitochondria to produce adenosine triphosphate, especially in the absence of glucose. Inhibition of CD98 reduces the metabolic flexibility of this population, which may limit their pathogenic capacity. CD98+ LDN produce more proinflammatory cytokines and chemokines than their normal density counterparts and are resistant to apoptosis, which may also contribute to tissue inflammation and end organ damage in SLE. CD98 provides a phenotypic marker for LDN that facilitates identification of this population without density-gradient separation and represents a novel therapeutic target to limit its pathogenic capacity.

Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus.

Up to 60% of patients with systemic lupus erythematosus (SLE) experience autonomic symptom. Sympathetic nervous system damage can cause dysfunction of the bone marrow that activates inflammatory cells, potentially causing multiple organ damage. We hypothesized that sympathetic nervous system damage would induce bone marrow dysfunction with multiple organ damage in SLE, and that multiple organ damage could be improved by therapy targeting the nervous system. Here, we showed that damage to autonomic nerves and Schwann cells occurred in the bone marrow and central nervous system of SLE model mice. A neurotoxic drug increased mortality and induced severe neuropathy and multiple organ damage, while a neuroprotective drug prevented multiple organ damage. The administration of bone marrow-derived mesenchymal stromal cells (BMSCs) cultured on a 3-dimensional fiber scaffold improved bone marrow neuropathy, skin lesions, kidney function, and mortality. Our results reveal that bone marrow neuropathy influence multiple organ damage associated with SLE, and improvement of bone marrow neuropathy by intrathecal injection of BMSC may be a target for SLE multiple-organ damage.

Abstract MP24: Selective Activation Of DMV Neurons Improves Renal Injury In Systemic Lupus Erythematosus

The cholinergic anti-inflammatory pathway is a vagally-mediated mechanism that controls inflammation. Our published data suggest that an impaired cholinergic anti-inflammatory pathway contributes to hypertension and renal disease in female mice with systemic lupus erythematosus (SLE), since pharmacological potentiation of the efferent vagus via administration of galantamine reduces renal inflammation, mean arterial pressure (MAP) and glomerulosclerosis. The aim of the current study is to selectively target neurons within the dorsal motor nucleus of the vagus (DMV) to stimulate the efferent vagus and the cholinergic anti-inflammatory pathway using designer receptors exclusively activated by designer drugs (DREADDs). We hypothesized that selective activation of DMV neurons would reduce inflammation, eliminating the associated end organ damage in SLE. To study this, female SLE ( NZBWF1 ) and parental control ( NZW ) mice received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or pAAV-hSyn-mCherry (control virus) into the DMV at 31 weeks of age using the following coordinates with calamus as reference: 0 mm caudal, 0.25 mm lateral and 0.48 mm ventral. Two weeks post-microinjection, DREADD agonist CNO (3mg/kg) was administered subcutaneously for 2 weeks starting at 33 weeks. At 35 weeks, mice were housed in metabolic cages for urine collection and catheters were implanted in the carotid artery for MAP measurement. Mice were subsequently euthanized and the brain collected to confirm the site of virus microinjection. Selective activation of DMV neurons decreased the incidence of albuminuria [> 300 mg/dL; 66% (4 out of 6) vs. 0% (0 out of 7)], urinary leukocytes [62.5% (5 out of 8) vs. 50% (3 out of 6)] and blood in the urine [50% (4 out of 8) vs. 16% (1 out of 6)] in SLE mice. MAP did not significantly change with the chemogenetic activation of DMV neurons in SLE mice or parental controls (SLE/control virus: 146 ± 6, n=7; SLE/Gq DREADD: 142 ± 3, n=6; NZW/control virus: 126 ± 4, n=4; NZW/Gq DREADD: 132 ± 2, n=5). These results suggests that this timeline of selective activation of DMV neurons in SLE mice reduces renal injury without altering blood pressure, but future studies will confirm the effect on hypertension and renal inflammation in SLE mice

Effects of melatonin supplementation on serum oxidative stress markers and disease activity in systemic lupus erythematosus patients: A randomised, double-blind, placebo-controlled trial.

Considering pathological significance of oxidative stress in systemic lupus erythematosus (SLE), current research aimed to evaluate the effects of melatonin supplementation on oxidative stress markers and disease activity in SLE. In this randomised double-blind, placebo-controlled trial, 32 SLE females were selected and randomly assigned into two groups to take 10mg/day melatonin or placebo for 12weeks. Before and after trial, serum malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured and disease activity was determined by Systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K). Twenty-five patients (13 in the melatonin and 12 in the placebo groups) completed the trial. Melatonin supplementation caused significant reduction in serum MDA compared with baseline (P=.003) and placebo group (P=.004). Serum TAC level did not change significantly in the melatonin group compared with baseline and placebo group (P>.05). Furthermore, melatonin supplementation did not cause significant change in disease activity compared to baseline and placebo group (P>.05). This study demonstrated affirmative effects of melatonin in decreasing oxidative stress in SLE patients without any effect on disease activity. Further investigations are required to affirm these primitive findings and to achieve concise conclusions.What's known Free radical damage and oxidative stress has a remarkable function in systemic lupus erythematosus (SLE) pathogenesis. Products derived from oxidative modification cascades are found in biological fluids and their redundancy has a correlation with disease activity and organ damage in SLE. Dietary supplements, which decrease oxidative stress, would be useful in managing SLE. Melatonin is a potent antioxidant and has anti-inflammatory and immunomodulatory characteristics. Limited in vitro and animal studies are available indicating desirable effects of melatonin in preventing from SLE organ damage, thereby opening a new area of investigation that can contribute to using melatonin as a therapy or co-therapy for SLE. What's new Melatonin supplementation caused significant reduction in serum MDA compared with baseline and placebo group. Serum TAC level did not change significantly in the melatonin group compared with baseline and placebo group. Furthermore, melatonin supplementation did not cause significant change in disease activity compared to baseline and placebo group.

Clinical disease activity and flare in SLE: Current concepts and novel biomarkers.

Systemic lupus erythematosus (SLE) is a complex and heterogeneous systemic autoimmune disease associated with innate and adaptive immune dysregulation. SLE occurs primarily in females of childbearing age, with increased prevalence and severity in minority populations. Despite improvements in treatment modalities, SLE patients frequently experience periods of heightened disease activity and flare that can lead to permanent organ damage, increased morbidity, and early mortality. Such outcomes impair quality of life and inflict a significant socioeconomic burden. Predicting changes in SLE disease activity could allow for closer monitoring and preemptive treatment, but existing clinical, demographic and serologic markers have been only modestly predictive. Novel, proactive approaches to clinical disease management are thus critically needed. Panels of blood biomarkers can detect a breadth of immune pathway dysregulation that captures SLE heterogeneity and disease activity. Alterations in the balance of pro-inflammatory and regulatory soluble mediators have been associated with changes in clinical disease activity and are detectable several weeks prior to clinical flare occurrence. A soluble mediator score has been highly predictive of impending flare in both European American and African American SLE patients, and this score does not require a priori knowledge of specific pathway activation in the patient. We review current concepts of disease activity and flare in SLE, focusing on the potential of novel blood biomarkers to characterize and predict changes in disease activity. Measuring the disordered immune response in SLE in this way promises to improve disease management and prevent organ damage in SLE.

MicroRNAs in Systemic Lupus Erythematosus: a Perspective on the Path from Biological Discoveries to Clinical Practice.

MicroRNAs (miRNAs) play essential roles in immune abnormalities and organ damage of systemic lupus erythematosus (SLE). Current findings have indicated potential clinical applications of miRNAs for combating SLE. Here, we review recent evidence which support the notions that miRNAs can be novel biomarkers and therapeutic agents for SLE. Following years of the studies of the expression patterns of miRNAs in both peripheral blood cells and body fluids, such as plasma and urine, several miRNAs or miRNA combinations have been associated with disease activity and specific organ damage. In depth analysis reveals complex and multiple roles of certain miRNAs in the pathogenesis of SLE. Manipulating miRNA expression shows in vivo therapeutic effects in lupus mouse models. MiRNAs contribute to the immune disorders and organ damage in SLE. MiRNA based biomarkers and therapies have the potential to be viable options for the treatment of SLE.

Analysis of 20-year survival rate and prognostic indicators of systemic lupus erythematosus

Objective: To analyze the 20-year survival rate, causes of death and predictors of systemic lupus erythematosus (SLE). Methods: A retrospective analysis was performed on 217 newly SLE patients who were diagnosed and treated by Peking University People's Hospital before June 2008. The clinical features and serologic data were studied. Survival rate of SLE patients over time, living conditions, causes of death and prognostic indicators of mortality were studied. Results: The 10-, 15-and 20-year cumulative survival rate was 90.3%,88.1%and 79.6%, respectively. Infection and lupus encephalopathy were the main causes of death. Cox regression analysis revealed that lupus nephritis, neuropsychiatric systemic lupus erythematosus and age at the diagnosis were independent risk determinants for mortality. Conclusion: Prognosis of SLE remains to be improved. Early diagnosis, control of SLE organ damage and infection prevention are critical to improve survival of SLE patients.

Pan-Immunome Initiative: Building an integrated T and B cell receptor repertoire map for immune-related diseases

Abstract The human adaptive immune system provides protection which is directly triggered by the receptors on the surfaces of T cells (TCRs) and B cells (BCRs). However, up till now, there are still difficulties in precise diagnosis for some immune related diseases. Here, we proposed a pan-immunome initiative, building an integrated T and B cell receptor repertoire map for immune related disease. As the early stage of this project, we have established a pan-immune-repertoire database (PIRD, https://db.cngb.org/pird/). We have collected more than 15,000 samples comprising 15 sorts of diseases. All samples have been amplified TCR b chain repertoire and sequenced using high throughput sequencer. We took systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) as examples for in-depth analysis. Significant differences of V, J and V-J pairing usage between SLE or RA and control groups were found and could be utilized as classification variables to discriminate the three groups (V: AUC>0.99). 228 SLE-associated and 169 RA-associated TCRs were identified using statistical test. A statistical model was generated to diagnose diseases using those disease-associated TCRs, with high specificity and sensitivity. Interestingly, lower overall diversities and massive expanded clones were observed in both SLE and RA samples, and higher TCR heterogeneity in SLE was found than in RA. However, clones related to specific organ damage in SLE were not observed. Besides, we have also been able to classify the TRB repertoire data of multiple diseases using an ensemble decision tree model. Thus, the immune repertoire data could reflect the individual immune status and serve as a powerful biomarker for molecular classification of immune related diseases.

Glucocorticoids Induced End Organs Damage in Patients with Systemic Lupus Erythematosus

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects multiple organs and requires long term treatment with GCs. GC-related end organ damage in SLE appears in the form of: osteoporosis, Avascular Necrosis (AVN), cataracts, diabetes (DM) and cardiovascular disease. Aim of the work: the present work was to assess the prevalence of the complications in SLE patients who were treated with GCs for long periods and with moderate to severe cumulative steroid doses. Patients and Methods: This study was done on 50 SLE patients who fulfilled the SLICC criteria for diagnosis of SLE. All patients subjected to full history taking, clinical examination, slit-lamp examination to assess cataract, laboratory investigations (ESR, CRP, FBS, 2-H PP, CBC, C3, C4 and anti-dsDNA), DEXA scan, MRI scan (when needed), SLEDAI score and SLICC score assessments. All data were collected, tabulated and statistically analyzed. Results: Regarding the frequency of steroid induced complications, 38% were osteopenic, while 18% were osteoporotic patients. 10% had AVN. 18% had cataract. 14% had DM. There was very strong relationship between steroid duration and the frequency of DM and cataract. But in osteopenia, osteoporosis and AVN, there were weak relationship regarding steroid duration. There was very strong relationship between cumulative steroid dose and the frequency of DM, cataract, osteoporosis and AVN. There was no relationship between age and osteoporosis and AVN but in cataract and DM, there was strong relationship. There was no relationship between sex and complications (DM, cataract, osteopenia, osteoporosis and AVN). There was no relationship between disease activity (measured by SLEDAI score) and frequency of steroid complications (DM, cataract, osteopenia, osteoporosis and AVN). There was strong relationship between end organ damage (measured by SLICC damage index) and frequency of steroid complications (DM, cataract, osteoporosis and AVN). Conclusion: Steroid intake (duration and dose) were major risk factors for developing end organ damage in SLE patients.

The role of neutrophils in organ tissue damage in SLE

Abstract Neutrophils are the most abundant leukocytes in Human blood, but it is not clear whether neutrophils exert an important role in the pathogenesis of organ tissue damage in systemic lupus erythematosus (SLE). We used lupus-prone mouse model and model of lupus serum-induced tissue inflammation in mouse to investigate the role of neutrophils in the organ damage of SLE. We found that there was a little neutrophil infiltration in the inflammatory sites of skin, liver, brain and joint in lupus-prone mice. We also found that there was also little neutrophil infiltration in the site of skin inflammation induced by lupus serum in normal mouse. The severity of skin inflammation induced by lupus serum was not significantly decreased in mice with neutrophil depletion compared to ones without neutrophil depletion. But we found that neutrophils were actually involved in tissue injury induced by lupus IgG. Further studies showed that lupus IgG stimulated and activated neutrophils, and cause the death of neutrophils. Studies also confirmed that Fas plays an important role in neutrophils apoptosis. Our study indicates that neutrophils participate in the early stage of lupus organ damage, and then they died through activation-mediated apoptosis. These findings promote the understanding of the role of neutrophils in the tissue injury with SLE.

Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage

Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of MFG-E8 leads to uncontrolled early pulmonary and peritoneal inflammation and tissue damage in mice with pristane-induced lupus. Consistent with these findings, MFG-E8-deficient mice that are exposed to pristane show enhanced neutrophil accumulation and increased neutrophil death, including apoptosis, necrosis and NETosis, as well as impaired phagocytosis of macrophages. The consequences are the expansion of diffuse pulmonary hemorrhage, increased anti-nuclear antibody, anti-dsDNA antibody and anti-neutrophil cytoplasmic antibody levels, and enhanced immune complexes deposition and neutrophil extracellular traps (NETs) formation in the lung and kidney tissues of MFG-E8-deficient mice exposed to pristane. In patients with SLE and mice with pristane-induced lupus, neutrophil accumulation is elevated, which depends on higher expression of the surface receptor CXCR2. After pretreatment with recombinant MFG-E8, the surface expression of CXCR2 on neutrophil is downregulated, and the MFG-E8 deletion increase CXCR2 expression by ~40%. These studies indicate that MFG-E8 reduces neutrophil migration and NETosis via downregulating surface CXCR2 expression in parallel with its role in the phagocytosis of apoptotic neutrophils, suggesting that MFG-E8 may serve as a therapeutic agent for attenuating the early inflammatory responses of SLE and protect patients from lupus-related damage.

Genetics of human lupus nephritis

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by immune complex formation with multi-organ manifestations. Lupus nephritis (LN) is one of the most severe types of organ damage in SLE, and it clearly contributes to increased morbidity and mortality due to SLE. LN occurs more frequently and is more severe in non-European ancestral backgrounds, although the cause of this disparity remains largely unknown. Genetic factors play an important role in the pathogenesis of SLE. Although many SLE susceptibility genes have been identified, the genetic basis of LN is not as well understood. While some of the established general SLE susceptibility genes are associated with LN, recent discoveries highlight a number of genes with renal functions that are specifically associated with LN. Some of these genes associated with LN help to explain the disparity in the prevalence of nephritis between individuals with SLE, and also partially explain differences in LN between ancestral backgrounds. Moreover, not only the gene mutations, but also post-translational modifications seem to play important roles in the pathogenesis of LN. Overall it seems likely that a combination of general SLE susceptibility genes cooperate with LN specific risk genes to result in the genetic propensity for LN. In this review, we will outline the genetic contribution to LN and describe possible roles of LN susceptibility genes.

Calcium/Calmodulin‐Dependent Kinase IV Facilitates the Recruitment of Interleukin‐17–Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell–Driven Inflammatory Diseases

ObjectiveThe recruitment of interleukin‐17 (IL‐17)–producing T helper (Th17) cells to inflammatory sites has been implicated in the development of organ damage in inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). To define the mechanism of calcium/calmodulin‐dependent kinase IV (CaMKIV) activation of Th17 cell recruitment to target tissues, we performed anti–glomerular basement membrane antibody–induced glomerulonephritis (AIGN) experiments in mice and studied samples from patients with SLE.MethodsWe induced experimental AIGN in CaMKIV‐sufficient or CaMKIV‐deficient mice and compared histology, Th17 cell–related chemokine expression, and numbers of IL‐17–producing cells in kidneys. We also evaluated the efficacy of the CaMKIV inhibitor KN‐93 in AIGN‐induced kidney disease. The expression of CCR6 in memory CD4+ T cells before AIGN induction was analyzed by flow cytometry. We investigated the correlation between CCR6 expression in peripheral blood and the severity of glomerulonephritis in patients with SLE.ResultsCaMKIV‐deficient mice displayed less glomerular injury after induction of AIGN. Kidney infiltration by IL‐17–producing CD4+ T cells along with CCR6 and CCL20 expression were significantly decreased in CaMKIV‐deficient mice. Similarly, treatment of mice with KN‐93 improved clinical and pathologic outcomes. Expression and function of CCR6 in peripheral blood memory CD4+ T cells was decreased in CaMKIV‐deficient mice. Expression of CCR6 correlated positively with severity of organ damage in SLE patients.ConclusionCaMKIV inhibition represents a novel therapeutic strategy for treatment of Th17 cell–mediated tissue damage in inflammatory diseases.

Serum Myeloperoxidase Level in Systemic Lupus Erythematosus.

SYSTEMIC lupus erythematosus (SLE) is a sys- temic autoimmune disease. Several mechanisms have been put forward as underlying the loss of self-tolerance and development of organ dysfunction, such as genetic, environmental, hormonal and immunoregulatory factors.1In recent years, oxidative stress is considered as an important factor in the atherogenesis of SLE.2Morgenet al3 illustrated elevated levels of protein oxidation in serum from patients with SLE, which may play a role in the pathogenesis of chronic organ damage in SLE.