Distinct clinical characteristics of anti-Ro/SSA-negative primary Sjögren's syndrome: data from a nationwide cohort for Sjögren's syndrome in Korea.

OBJECTIVES: To investigate clinical characteristics of patients with primary Sjögren's syndrome (SS) who were negative for anti-Ro/SSA antibody but positive for minor salivary gland biopsy (MSGB) compared to patients who presented positivity for anti-Ro/SSA antibody. METHODS: The data of 355 patients from the Korean Initiative of primary Sjögren's Syndrome (KISS), a nationwide prospective cohort for primary SS in Korea, were analysed. All patients fulfilled the 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) classification criteria. Of these patients, 326 were positive for anti-Ro/SSA antibody and 29 were antibody-negative, although they had positive findings in MSGB. Various clinical features including all kinds of tests for evaluating secretory function, disease-related clinical indices and serological values available in the cohort were compared between the two groups. RESULTS: The anti-Ro/SSA-negative group showed less rheumatoid factor positivity (p<0.001), leucopenia (p=0.003), hyper-gammaglobulinaemia (p<0.001), lower serum ß2-microglobulin level (p=0.034), more anti-centromere antibody positivity (p<0.001), higher score in dryness domain of EULAR SS patient-reported index (p=0.048) and more positivity for peripheral nervous system domain in EULAR SS disease activity index and loss of teeth in SS disease damage index (p=0.021 and 0.041, respectively) than patients who were positive for anti-Ro/ SSA antibody. CONCLUSIONS: Primary SS patients who are negative for anti-Ro/SSA antibody have different clinical characteristics compared to patients who are positive for such antibody in Korea. Therefore, clinicians should consider MSGB in patients with suspicious symptoms who are anti-Ro/SSA-negative.

The association of disease activity, pro-inflammatory cytokines, and neurotrophic factors with depression in patients with rheumatoid arthritis.

Inflammation and trophic factors (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor-1) are associated with depression in the general population. Rheumatoid arthritis (RA) is a chronic representative inflammatory autoimmune disease; however, the association of disease activity, pro-inflammatory cytokines, and neurotrophic factors with depression has not been sufficiently investigated. Therefore, we determined the prevalence of depression and risk factors for depression and deterioration of depressive symptoms in RA patients. In addition, we analyzed the association between disease activity, pro-inflammatory cytokines, trophic factors, and depression in RA (N = 474). Demographic and laboratory data were examined, and routine assessment of patient index data 3 (RAPID 3) and disease activity score 28-joint count C-reactive protein (DAS 28-CRP) was performed to assess disease activity of RA. Depression was measured using the Korean version of the Beck Depression Inventory-second edition (K-BDI II). A K-BDI score ≥18 was considered the cut-off for depression in accordance with a previous validation study. The serum level of pro-inflammatory cytokines and neurotrophic factors was assessed by enzyme-linked immune sorbent assay. The prevalence of depression was 32.4% in patients with RA. The severity of disease activity of RA (RAPID 3 score [OR 2.34; 95% confidence interval, CI 1.22-4.51], DAS 28-CRP [≥3.2] [OR 1.60, 95% CI 1.01-2.53]) and severity of fatigue (OR 1.26 95% CI 1.15-1.38) were associated with depression and deterioration of depressive symptoms in the multivariate analysis. Among the components of RAPID 3 and DAS 28-CRP, patient assessment for global health and abilities for daily performance were more related to depression. The level of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-alpha) was not related to depression. The level of BDNF was significantly lower in RA patients with depression and was negatively correlated with K-BDI II score. Depression was related with the level of fatigue, low expression of BDNF, and high RA disease activity, which was associated with impaired ability to perform activities of daily life. Strict control of fatigue and disease activity to improve one's capacity to perform daily life activities would be important to regulate depression. The level of BDNF might be one of the possible biomarkers to predict or monitor depression in patients with RA.

Performance of the 2016 ACR-EULAR classification criteria for primary Sjogren's syndrome in a Korean cohort.

This study compared the performance of the newly proposed 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria to the 2002 American-European Consensus Group (AECG) and 2012 ACR classification criteria for primary Sjogren's syndrome (pSS) in well-characterized Korean patients. Patients with pSS from 12 university-affiliated hospitals in Korea were enrolled from October 2013 to January 2017. Clinical and laboratory data were reviewed. For the validation set, patients who underwent evaluation tests to rule out pSS at Seoul St. Mary's hospital from November 2016 to December 2017 were analyzed. Baseline registry data were available in 458 patients, and 328 patients had sufficient data to determine the fulfillment of each criteria set. All three sets of criteria were met by 307 patients (93.6%). The newly proposed 2016 ACR/EULAR criteria were met by 325 patients (99.1%). The 2002 AECG and 2012 ACR criteria were met by 325 (99.1%) and 310 patients (94.5%), respectively. In a validation cohort consisting of 161 patients with pSS-related symptoms/signs, the sensitivity and specificity of the 2016 ACR/EULAR criteria were 100% [95% confidence interval (CI), 96.11-100.00] and 81.8% [95% CI, 76.15-94.26], respectively. Agreement between the 2016 criteria and 2012 or 2002 criteria was high (Cohen's kappa 0.736 and 0.769, respectively). The newly proposed 2016 ACR/EULAR criteria were met by most patients diagnosed with pSS according to previous criteria and showed higher sensitivity and lower specificity compared with both previous criteria sets.

Multiple malignancies in a patient with limited granulomatosis with polyangiitis without immunosuppressive therapy.

Here, we report the case of a 69-year-old man with limited granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis) who developed papillary thyroid cancer, adenocarcinoma of the stomach, and myelodysplastic syndrome following glucocorticoid treatment. This is the first report to present multiple malignancies in a patient with limited GPA without immunosuppressive treatment. Thus, our report supports the notion that limited GPA itself can be associated with the development of malignancy.

Vitamin C neuroprotection against dose-dependent glutamate-induced neurodegeneration in the postnatal brain.

Glutamate-induced excitotoxicity due to over-activation of glutamate receptors and associated energy depletion (phosphorylation and activation of AMPK) results in neuronal cell death in various neurological disorders. Restoration of energy balance during an excitotoxic insult is critical for neuronal survival. Ascorbic acid (vitamin C), an essential nutrient with well-known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. In this study, we reported the therapeutic efficacy of vitamin C in response to glutamate-induced excitation, resulting in energy depletion and apoptosis in the hippocampus of the developing rat brain. A single subcutaneous injection of glutamate at two different concentrations (5 and 10 mg/kg) in postnatal day 7 rat pups increased brain glutamate levels and increased the protein expression of neuronal apoptotic markers. Both doses of glutamate upregulated the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2, cytochrome-c release, caspase-3 activation and the expression of PARP-1. However, co-treatment of vitamin C (250 mg/kg) with glutamate decreased brain glutamate levels and reversed the changes induced by glutamate in the developing hippocampus. Interestingly, only a high dose of glutamate caused the phosphorylation and activation of AMPK and induced neuronal cell death, whereas a low dose of glutamate failed to mediate these effects. Vitamin C supplementation reduced the glutamate-induced phosphorylation of AMPK and attenuated neuronal cell death, as assessed morphologically by Fluoro Jade B in the hippocampal CA1 region of the developing brain. Taken together, our results indicated that glutamate in both concentrations is toxic to the immature rat brain, whereas vitamin C is pharmacologically effective against glutamate-induced neurodegeneration.

High vegetable consumption and regular exercise are associated with better quality of life in patients with gout.

BACKGROUND/AIMS: The Gout Impact Scale (GIS), a part of the Gout Assessment Questionnaire 2.0, is used to measure gout-specific health-related quality of life (HRQOL). Although several studies have been conducted on the factors affecting the HRQOL of patients with gout, few have focused on lifestyle factors. This study aimed to investigate the correlation between lifestyle habits and HRQOL using the GIS in patients with gout. METHODS: We used data from the Urate-Lowering TheRApy in Gout (ULTRA) registry, a prospective cohort of Korean patients with gout treated at multiple centers nationwide. The patients were aged ≥18 years and met the 2015 American College of Rheumatology/European League Against Rheumatism gout classification criteria. They were asked to complete a GIS and questions regarding their lifestyle habits at enrollment. RESULTS: The study included 232 patients. 'Gout concern overall' scores in the GIS were significantly lower in patients who exercised more frequently and consumed soft drinks and meat less, and 'well-being during attack' scores were significantly lower in patients who consumed vegetables and exercised more frequently. The frequency of vegetable consumption had a negative linear relationship with the 'well-being during attack' and 'gout concern during attack' scores (p = 0.01, p = 0.001, respectively). The frequency of exercise had a negative linear relationship with the 'gout concern overall' and 'gout concern during attack' scores (p = 0.04 and p = 0.002, respectively). CONCLUSION: Patients with gout who frequently consumed vegetables and exercised regularly experienced less impact of gout, exhibiting a better GIS that represented HRQOL.

A Case of Palisaded Neutrophilic and Granulomatous Dermatitis Associated with an Initial Presentation in Ankylosing Spondylitis.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is an inflammatory dermatosis associated with systemic immune-mediated diseases such as rheumatoid arthritis, systemic sclerosis, lupus erythematosus, and ulcerative colitis. Histologically, serial development of leukocytoclastic vasculitis is shown from an early stage, which can progress to palisading granuloma in the fully developed stage and to fibrosis in the final stage. A 32-year-old man presented with ankylosing spondylitis showing multiple erythematous papules on his fingers, elbows, knees, and left auricle. Histologic examination from his skin lesion revealed a perforating palisading granuloma with leukocytoclastic vasculitis, which was consistent with PNGD. Therefore, this study reported a case of PNGD accompanied by ankylosing spondylitis as an initial presentation.

Peptoniphilus gorbachii alleviates collagen-induced arthritis in mice by improving intestinal homeostasis and immune regulation.

Introduction: The intricate connection between gut microbiota and rheumatoid arthritis (RA) pathogenesis has gained prominence, although the specific microbial species contributing to RA development remain largely unknown. Recent studies have sought to comprehensively explore alterations in the human microbiome, focusing on identifying disease-related microbial species through blood analysis. Consequently, this study aimed to identify RA-associated microbial species using a serum microbial array system and to investigate the efficacy and underlying mechanisms of potential microbial species for RA treatment. Methods: Serum immunoglobulin M levels against 384 intestinal microbial species were assessed using a microbial microarray in patients with RA and healthy individuals. We investigated the therapeutic potential of the identified microbial candidate regarding arthritis development, immune responses, gut barrier function, and gut microbiome using a collagen-induced arthritis (CIA) mouse model. Results: Our findings revealed significant alterations in antibody levels against 36 microbial species in patients with RA compared to healthy individuals. Notably, the antibody levels against Peptoniphilus gorbachii (PG) were decreased in patients with RA and exhibited an inverse correlation with RA disease activity. In vitro experiments demonstrated that PG produced acetate and butyrate, while exhibiting anti-inflammatory properties. In CIA mice, PG administration suppressed arthritis symptoms, reduced the accumulation of inflammatory monocytes in the mesenteric lymph nodes, and downregulated gene expression of pro-inflammatory cytokines in the ileum. Additionally, PG supplementation restored intestinal barrier integrity and partially resolved gut microbial dysbiosis in CIA mice. The fecal microbiota in PG-treated mice corresponded to improved intestinal barrier integrity and reduced inflammatory responses. Conclusion: This study highlights the potential of serum-based detection of anti-microbial antibodies to identify microbial targets at the species level for RA treatment. Moreover, our findings suggest that PG, identified through the microbial microarray analysis, holds therapeutic potential for RA by restoring intestinal barrier integrity and suppressing the immunologic response associated with RA.

Factors for achieving target serum uric acid levels after initiating urate-lowering therapy in patients with gout: results from the ULTRA registry.

Achieving target serum uric acid (SUA) levels is important in gout management. Guidelines recommend lowering SUA levels to < 6 mg/dL; however, many patients fail to reach this target, even with uric acid-lowering therapy (ULT). This study investigated clinical characteristics of target SUA achievers among Korean patients with gout. This study used data from the ULTRA registry, a nationwide inception cohort established in September 2021 that enrolls patients with gout who initiate ULT. Demographic, clinical, and laboratory data were collected at baseline; the 6-month follow-up. Patients were divided into two groups: target achievers (SUA level < 6 mg/dL at 6 months) and non-achievers. The mean participant (N = 117) age was 56.1 years, and 88.0% were male. At 6 months, 83 patients (70.9%) reached target SUA levels. Target achievers had better drug adherence (≥ 80%) to ULT (97.6% vs. 76.5%; p < 0.01) than non-achievers. Target non-achievers had a higher percentage of a family history of gout (32.4% vs. 10.8%; p < 0.01) and less antihypertensive agent use (38.2% vs. 59.0%; p = 0.03) than target achievers. Multivariate regression analysis revealed that good adherence to ULT, the absence of a family history of gout, and antihypertensive agent use were key factors associated with achieving target SUA levels at 6 months.

Promising Therapeutic Effects of Embryonic Stem Cells-Origin Mesenchymal Stem Cells in Experimental Pulmonary Fibrosis Models: Immunomodulatory and Anti-Apoptotic Mechanisms.

Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DW-MSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.

Erratum to ''Characterization of the regulatory roles of the SUMO.

BACKGROUND: Type 1 diabetes is a multi-factorial autoimmune disease that results from the destruction of insulin-producing ß cells of the pancreas; both genetic and environmental factors are thought to contribute to its development. Recently, a novel gene encoding small ubiquitin-like modifier protein 4 (SUMO4) was cloned and a single nucleotide substitution (M55V) was found to be strongly associated with type 1 diabetes. SUMO4 was shown to interact with IκBα and inhibit NFκB transcriptional activity. The M55V substitution of SUMO4 may affect its ability to modify IκBα by sumoylation, and so lead to activation of NFκB and transcription of genes implicated in the development of type 1 diabetes. However, the effects of sumoylation on immune cells are poorly understood. METHODS: Human SUMO1, 2, 3, 4 and mouse SUMO2 (mSUMO2) were cloned and overexpressed in T and B cells using retroviral transduction. We then investigated whether SUMO overexpression affected their functions in vitro. To study the function of mSUMO2 in vivo, we made transgenic mice overexpressing mSUMO2 in T cells and pancreatic ß cells and compared them with transgenic mice expressing a super-repressor of NFκB (a dominant negative form of NFκB, IκBαΔN) in T cells. Diabetes was induced in the two groups of mice by i.p. injection of streptozotocin. RESULTS: Human SUMO1, 2, 3, 4 and mSUMO2 were all found to negatively regulate the transcriptional activity of T and B cells. Supporting this idea, mSUMO2 overexpression in T cells suppressed the production of both Th1 and Th2 cytokines unlike T cells from the IκBαΔN mice. However, transgenic mice overexpressing mSUMO2 had the same susceptibility to diabetes as wild type whereas the mice overexpressing IκBαΔN Tg were completely protected against diabetes. CONCLUSION: These results indicate that at least in T cells, whereas NFκB has pro-apoptotic activity, mSUMO2 plays a more complex role in the development of autoimmune diabetes. The relative influence of NFκB and sumoylation on the development of autoimmune diabetes in vivo may vary depending on the developmental stage and cell type.

Employee perception of corporate social responsibility authenticity: A multilevel approach.

Stakeholder interest in the accuracy of Environment Social and Governance (ESG) data and Corporate Social Responsibility (CSR) authenticity has increased, as more companies are disclosing their ESG data. Employees are one of the most important stakeholders of a company, and they have access to more CSR information than other external stakeholders. Employees have a dual role of observing and participating in CSR. Employee perceptions of CSR authenticity play a key role in the positive effects of CSR. In this study, the research model was analyzed through multilevel analysis to contribute to the literature on the mechanism by which CSR affects employees' job attitudes and perceptions of CSR authenticity. First, hypothesis testing confirmed that external CSR is positively associated with employees' perceptions of CSR authenticity. Second, CSR authenticity mediates a positive relationship between external CSR and emotional commitment. As the direct effect of external CSR on emotional commitment was not statistically significant, it could be confirmed that the full mediation relationship was significant through CSR authenticity. This study makes three theoretical contributions to the literature on employees' perceptions of CSR. First, it examines the mechanism of the impact of CSR on employees. By examining the mechanism by which employees recognize and interpret CSR, this study attempts to uncover the black box that CSR affects employees. Second, this study contributes to the literature on CSR authenticity by explaining the mediating role of CSR authenticity in the relationship between CSR and employee job attitudes through construal level theory. Finally, this study contributes to the employee-based CSR literature by analyzing the effect of CSR as an organizational-level variable on emotional commitment as an individual-level variable through multilevel structural equation modeling (MSEM).

Recent Advances in Basic and Clinical Aspects of Rheumatoid Arthritis-associated Interstitial Lung Diseases.

Rheumatoid arthritis (RA) is a common autoimmune disease that mainly affects the joints and systemic organs, such as the skin, eyes, heart, gastrointestinal tract, and lungs. In particular, among various pulmonary involvements, interstitial lung disease (ILD) is closely related to the selection of anti-rheumatic drugs and the long-term prognosis of patients with RA. Although the exact pathogenesis of RA-ILD is not well defined, several mechanistic pathways, similar to those of idiopathic pulmonary fibrosis, have been elucidated recently. Conversely, RA-related autoantibodies, including anti-cyclic citrullinated peptide antibody, are detectable in circulation and in the lungs, even in the absence of articular symptoms. RA-ILD can also predate years before the occurrence of joint symptoms. This evidence supports the fact that local dysregulated mucosal immunity in the lung causes systemic autoimmunity, resulting in clinically evident polyarthritis of RA. Because the early diagnosis of RA-ILD is important, imaging tests, such as computed tomography and pulmonary function tests, are being used for early diagnosis, but there is no clear guideline for the early diagnosis of RA-ILD and selection of optimal disease-modifying anti-rheumatic drugs for the treatment of patients with RA with ILD. In addition, the efficacy of nintedanib, a new anti-fibrotic agent, for RA-ILD treatment, has been investigated recently. This review collectively discusses the basic and clinical aspects, such as pathogenesis, animal models, diagnosis, and treatment, of RA-ILD.

Serum IGF-1 in patients with rheumatoid arthritis: correlation with disease activity.

OBJECTIVE: Insulin-like growth factor (IGF)-1 participates in modulating immunity and inflammation. Its bioactivity is controlled by six IGF-binding proteins (IGFBP-1 to IGFBP-6). In particular, the IGFBP-3 level is reportedly linked to the disease activity of rheumatoid arthritis (RA), consistent with our previous study. Therefore, the present study aimed to reproduce the previous results. RESULTS: The serum IGFBP-3 level was not significantly different among the three groups according to disease activity based on the DAS28-ESR/CRP (p > 0.05) but was significantly different between the low- and high-disease-activity groups based on the DAS28-CRP (p = 0.036). Meanwhile, the interleukin-6 (IL-6) level moderately correlated with DAS28-CRP (Spearman's rho = 0.583, p < 0.001).

The combination of metallothionein and superoxide dismutase protects pancreatic ß cells from oxidative damage.

BACKGROUND: Reactive oxygen species are considered an important cause of the death of pancreatic ß cells, thereby triggering the development of type 2 diabetes as well as failure of islet transplantation. The biological properties of metallothionein (MT) and superoxide dismutase (SOD) are likely to be related to their antioxidant and free-radical scavenging abilities, but their access across biological membranes is limited. METHODS: We investigated whether Tat-MT and Tat-SOD fusion protein could be introduced into islets by a novel protein transduction technology and protect them from oxidative damage. We used 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and Annexin V/propidium iodide assays to analyse cell viability, and assessed expression of apoptosis marker proteins by Western blotting. We examined the protective effect of Tat-MT and Tat-SOD on the development of diabetes and on graft failure after syngeneic islet transplantation into Otsuka Long Evans Tokushima Fatty (OLETF) rats and Imprinting Control Region (ICR) mice, respectively. RESULTS: Tat-MT and Tat-SOD were successfully delivered into the rat islets, and reactive oxygen species, nitric oxide, glucolipotoxicity-induced cell death, cytokine injury, and DNA fragmentation due to ischaemia-reperfusion in pancreatic ß cells were significantly reduced. In addition Tat-MT and Tat-SOD treatment protected OLETF rats from developing diabetes, and enhanced the survival of antioxidant-treated islets transplanted into the renal capsules of diabetic mice. CONCLUSIONS: Transduction of Tat-MT and Tat-SOD proteins offers a new strategy for protecting against the development of diabetes by relieving oxidative stress.

Characterization of the regulatory roles of the SUMO.

BACKGROUND: Type 1 diabetes is a multi-factorial autoimmune disease that results from the destruction of insulin-producing ß cells of the pancreas; both genetic and environmental factors are thought to contribute to its development. Recently, a novel gene encoding small ubiquitin-like modifier protein 4 (SUMO4) was cloned and a single nucleotide substitution (M55V) was found to be strongly associated with type 1 diabetes. SUMO4 was shown to interact with IκBα and inhibit NFκB transcriptional activity. The M55V substitution of SUMO4 may affect its ability to modify IκBα by sumoylation, and so lead to activation of NFκB and transcription of genes implicated in the development of type 1 diabetes. However, the effects of sumoylation on immune cells are poorly understood. METHODS: Human SUMO1, 2, 3, 4 and mouse SUMO2 (mSUMO2) were cloned and overexpressed in dendritic, T and B cells using retroviral transduction. We then investigated whether SUMO overexpression affected their functions in vitro. To study the function of mSUMO2 in vivo, we made transgenic mice overexpressing mSUMO2 in T cells and pancreatic ß cells and compared them with transgenic mice expressing a super-repressor of NFκB (a dominant negative form of NFκB, IκBαΔN) in T cells. Diabetes was induced in the two groups of mice by i.p. injection of streptozotocin. RESULTS: Human SUMO1, 2, 3, 4 and mSUMO2 were all found to negatively regulate the transcriptional activity of T, B and dendritic cells. Although mSUMO2 overexpression in dendritic cells did not alter the expression of major histocompatibility complex class II proteins or B7, IL-1, IL-6 and IL-7, IL-12 expression decreased, switching Th1-directed immune responses into Th2 responses. Unlike T cells from the IκBαΔN mice, mSUMO2 overexpression in T cells suppressed the production of both Th1 and Th2 cytokines. Whereas the mice overexpressing IκBαΔN were completely protected against diabetes, those expressing mSUMO2 had the same susceptibility to diabetes as wild type. CONCLUSION: These results indicate that at least in T cells, whereas NFκB has pro-apoptotic activity, mSUMO2 plays a more complex role in the development of autoimmune diabetes. The relative influence of NFκB and sumoylation on the development of autoimmune diabetes in vivo may vary depending on the developmental stage and cell type.

A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis.

OBJECTIVE: Nuclear factor-kappaB (NF-kappaB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF-kappaB, might have antiarthritic effects. METHODS: An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally. RESULTS: In vitro experiments demonstrated that AdA20 suppressed NF-kappaB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor alpha in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus-injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF-kappaB signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF-kappaB. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study. CONCLUSION: These results suggest that using A20 to block the NF-kappaB pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA.

Dietary alpha lipoic acid supplementation prevents synovial inflammation and bone destruction in collagen-induced arthritic mice.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by chronic inflammation and joint destruction. In this study, we investigated whether dietary supplementation with alpha lipoic acid (ALA) suppresses collagen-induced arthritis (CIA) in mice. Mice were randomly divided into three groups: (1) a control CIA group was fed a normal diet, (2) a CIA group was fed a 0.1% ALA diet (average ALA intake of 160 mg/kg/day), and (3) a CIA group was fed a 0.5% ALA diet (average ALA intake of 800 mg/kg/day). The ALA-fed mice showed a decreased incidence and severity of arthritis compared to the normal diet group. Radiographic findings revealed a dramatic decrease in bone destruction, and histological findings showed extensively suppressed pathological changes in the ALA-fed mice. The ALA-fed mice exhibited inhibited generation of tartrate resistant acid phosphatase (TRAP)-positive osteoclasts in vivo. Additionally, ALA-fed mice reduced production of various proinflammatory cytokines and the soluble receptor activator of NF-κB ligand (sRANKL) in the joint tissues and the sera. In conclusion, dietary supplementation with ALA attenuated inflammatory responses and bone destruction in CIA mice.