Biological functions and affected signaling pathways by Long Non-Coding RNAs in the immune system.

Recently, the various regulative functions of long non-coding RNAs (LncRNAs) have been well determined. Recently, the vital role of LncRNAs as gene regulators has been identified in the immune system, especially in the inflammatory response. All cells of the immune system are governed by a complex and ever-changing gene expression program that is regulated through both transcriptional and post-transcriptional processes. LncRNAs regulate gene expression within the cell nucleus by influencing transcription or through post-transcriptional processes that affect the splicing, stability, or translation of messenger RNAs (mRNAs). Recent studies in immunology have revealed substantial alterations in the expression of lncRNAs during the activation of the innate immune system as well as the development, differentiation, and activation of T cells. These lncRNAs regulate key aspects of immune function, including the manufacturing of inflammatory molecules, cellular distinction, and cell movement. They do this by modulating protein-protein interactions or through base pairing with RNA and DNA. Here we review the current understanding of the mechanism of action of lncRNAs as novel immune-related regulators and their impact on physiological and pathological processes related to the immune system, including autoimmune diseases. We also highlight the emerging pattern of gene expression control in important research areas at the intersection between immunology and lncRNA biology.

The role of Nrf2 in immune cells and inflammatory autoimmune diseases: a comprehensive review.

INTRODUCTION: Nrf2 regulates mild stress, chronic inflammation, and metabolic changes by regulating different immune cells via downstream signaling. Collection of information about the role of Nrf2 in inflammatory autoimmune diseases will better understand the therapeutic potential of targeting Nrf2 in these diseases. AREAS COVERED: In this review, we comprehensively discussed biological function of Nrf2 in different immune cells, including Nrf2 preventing oxidative tissue injury, affecting apoptosis of immune cells and inflammatory cytokine production. Moreover, we discussed the role of Nrf2 in the development of inflammatory autoimmune diseases. EXPERT OPINION: Nrf2 binds to downstream signaling molecules and then provides durable protection against different cellular and organ stress. It has emerged as an important target for inflammatory autoimmune diseases. Development of Nrf2 modulator drugs needs to consider factors such as target specificity, short/long term safety, disease indication identification, and the extent of variation in Nrf2 activity. We carefully discussed the dual role of Nrf2 in some diseases, which helps to better target Nrf2 in the future.

Stable excess mortality in a multiple sclerosis cohort diagnosed 1970-2010.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is associated with excess mortality. The use of disease-modifying treatments (DMTs) has recently been associated with survival benefits. METHODS: A regional MS database was linked with national registries. People with MS (pwMS) diagnosed in 1971-2010 were included and followed up until the end of the year 2019. Five matched controls were acquired for every person with MS. DMTs included in the analyses were interferon and glatiramer acetate. RESULTS: Median follow-up time of the 1795 pwMS was 20.0 years (range 0.1-48.7 years). Survival did not differ between decades of diagnosis (p = 0.20). Amongst pwMS, male sex (adjusted hazard ratio [aHR] 1.70; 95% confidence interval [CI] 1.41-2.06), higher age at diagnosis (aHR 1.83; 95% CI 1.65-2.03 per 10-year increment) and primary progressive disease course (aHR 1.29; 95% CI 1.04-1.60) were independently associated with poorer survival. DMT use was associated with better survival (p < 0.0001) and better survival during follow-up (aHR 0.56; 95% CI 0.38-0.81). Compared to matched controls, median life expectancy was 8-9 years shorter in pwMS with survival diverging from controls during the first decade after diagnosis, more clearly in men than women. CONCLUSION: Despite DMT use being associated with better survival, relative life expectancy of pwMS did not change over five decades in Western Finland. Male sex was an independent risk factor for death amongst pwMS, but excess mortality was higher in women. More work and methods are needed to improve survival in pwMS.

Protein kinase R is highly expressed in dermatomyositis and promotes interferon-beta-induced muscle damage.

OBJECTIVES: Dermatomyositis (DM) has been consistently linked to the type I interferon (IFN-I) pathway. However, the precise pathogenesis remains incompletely elucidated. We aimed to explore potential molecular mechanisms and identify promising therapeutic targets in DM. METHODS: We employed bioinformatics analysis to investigate molecular signatures, aiming to shed light on the pathogenesis of DM. The expression of protein kinase R (PKR) in DM muscle tissues was determined by real-time quantitative PCR, western blot and immunohistochemistry (IHC) analysis. We then assessed the sensitivity and specificity of sarcoplasmic PKR expression by IHC in a consecutive DM cohort and other diseases in this retrospective study. Furthermore, IFN-ß was used to stimulate myoblasts and myotubes, and the relationship between PKR and IFN-ß-induced pathogenic molecules was investigated in vitro. RESULTS: Bioinformatics analysis indicated two primary pathological processes: viral infection and the IFN-I signalling pathway. We subsequently verified that PKR was notably expressed in the cytoplasm of myofibers in DM patients. The sensitivity and specificity of sarcoplasmic PKR expression in DM were 84.6% and 97.6%, respectively. In vitro studies revealed that IFN-ß upregulates the expression of PKR, along with several molecules associated with DM muscle damage. Conversely, inhibiting PKR has been shown to downregulate IFN-ß-induced pathogenic molecules in both myoblasts and myotubes. CONCLUSIONS: We observed that PKR exhibits specific expression in the cytoplasm of DM muscle and inhibiting PKR ameliorates IFN-ß-induced muscle damage in vitro. These findings provide insights into the diagnostic and therapeutic roles of PKR in DM.

Performance of the Systemic Lupus Erythematosus Risk Probability Index (SLERPI) in a cohort of Colombian population.

OBJECTIVE: To evaluate the performance of the Systemic Lupus Erythematosus Risk Probability Index (SLERPI) in Colombian patients with systemic lupus erythematosus (SLE). METHODS: The Colombian cohort included 435 SLE patients and 430 controls with other autoimmune diseases (ADs). Clinical and serological data were collected, and SLE was indicated by SLERPI scores > 7. The American College of Rheumatology (ACR)-1997, Systemic Lupus International Collaborating Clinics (SLICC)-2012, and European League Against Rheumatism (EULAR)/ACR-2019 criteria were used as reference standards. The impact of overt polyautoimmunity (PolyA) on SLERPI performance was assessed. Additionally, multivariate lineal regression analysis was performed to evaluate the contribution of SLERPI features to the overall SLERPI score. RESULTS: SLE patients had higher SLERPI scores (P < 0.0001), with almost 90% meeting "definite" lupus criteria. Main factors influencing SLERPI included immunological disorder (ß:44.75, P < 0.0001), malar/maculopapular rash (ß:18.43, P < 0.0001), and anti-nuclear antibody positivity (ß:15.65, P < 0.0001). In contrast, subacute cutaneous lupus erythematosus/discoid lupus erythematosus (ß:2.40, P > 0.05) and interstitial lung disease (ß:-21.58, P > 0.05) were not significant factors to the overall SLERPI score. SLERPI demonstrated high sensitivity for SLE, both for the overall SLE group and for those without overt PolyA (95.4% and 94.6%, respectively), but had relatively low specificity (92.8% and 93.7%, respectively). The model showed high sensitivity for hematological lupus (98.8%) and lupus nephritis (96.0%), but low sensitivity for neuropsychiatric lupus (93.2%). Compared to the ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria, SLERPI yielded the highest sensitivity and lowest specificity. CONCLUSION: SLERPI efficiently identified SLE patients in a Colombian cohort, showing high sensitivity but low specificity. The model effectively distinguishes SLE patients, even in the presence of concurrent overt PolyA. Key Points •SLERPI has a high sensitivity, but low specificity compared to ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria in the Colombian population. •Within the SLERPI score, immunological disorder, malar/maculopapular rash, and anti-nuclear antibody positivity are the strongest predictors of SLE. •SLERPI model can efficiently distinguish patients with SLE, regardless of concomitant overt PolyA. •SLERPI demonstrates high sensitivity in identifying hematological and nephritic subphenotypes of SLE.

Hepatitis a vaccine immunogenicity and boostability in adults receiving immunosuppressive therapy and adults living with HIV: a prospective single-Centre cohort study.

INTRODUCTION: Hepatitis A (hepA) vaccination is highly immunogenic in healthy individuals, however there is uncertainty about the immunogenicity in immunocompromised populations (ICPs). METHODS: In this prospective cohort study, people living with HIV (PLWH), patients on immunosuppressive mono- and combination therapy, and controls received two hepA vaccine doses at months 0 and 6-12, or three combined hepA/B vaccine doses at months 0, 1 and 6-12. Antibody levels were measured before and at different time-points post-vaccination (T2, 6, 8, 12 months). The primary endpoint was the seroconversion rate (SCR) at T8, defined as hepA antibodies ≥20 mIU/ml. To assess boostability, an additional vaccine dose was administered 1-5 years after T12 in those with antibodies < 50 mIU/ml, with antibody measurements before and seven days after the booster dose. RESULTS: We included 150 participants. At T2 SCRs ranged between 35-58% in ICPs versus 94% in controls. Among PLWH, patients on monotherapy, combination therapy and controls SCRs at T8 were 33/34 (97%), 32/34 (94%), 25/30 (83%) and 28/28 (100%) respectively. The booster dose resulted in 71% additional seroconversion (17/24), with only patients using combination therapy not responding. CONCLUSIONS: HepA vaccination is highly immunogenic in virologically suppressed PLWH and patients on immunosuppressive monotherapy, with SCRs after the complete hepA vaccination schedule similar to controls and adequate booster responses in case of waning immunity. However, patients using immunosuppressive combination therapy as well as all ICPs who did not receive the complete hepA vaccination schedule, are at risk of non-response to vaccination and post-vaccination antibody measurements are recommended.

Polyautoimmunity and multiple autoimmune syndrome in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: The coexistence of neuromyelitis optica spectrum disorders (NMOSD) with other autoimmune diseases (AID) has been increasingly reported. The prevalence and significance of this association are not fully understood. OBJECTIVES: This study aimed to compare the clinical and laboratory characteristics in NMOSD patients with and without AID. METHODS: Retrospective cross-sectional observational study was conducted involving adults meeting NMOSD criteria followed in a neuroimmunology clinic at a tertiary center. Descriptive analysis of clinical/paraclinical/treatment/outcome data collected from the medical records was compared between NMOSD patients with AID (polyautoimmunity) and those without AID. RESULTS: From a cohort of 46 NMOSD patients, 16 (34.8 %) patients, mostly women around 40 years of age, presented with polyautoimmunity: 10 anti-AQP4 positive, 4 anti-MOG positive, and 2 seronegative. Five different organ -specific AID, and six systemic AID were identified in the polyautoimmunity patients group, in addition to 6 cases of multiple autoimmune syndrome. The AID manifestation preceded NMOSD in 10 (62.5 %) patients, with a median interval of 7 years. The NMOSD with polyautoimmunity and NMOSD without AID groups had similar initial clinical manifestations with optic neuritis and/or myelitis being most frequent. Inflammatory CSF, namely elevated proteins, was more common in the polyautoimmunity group (13.0 % in NMOSD vs. 31.3 % in NMOSD+AID, p = 0.003). After a 10±6 years follow-up period, more patients with polyautoimmunity had a relapsing disease (75.0 % in NMOSD vs. 46.7 % in NMOSD+AID, p = 0.012) but no difference in the functional outcome evaluated by the EDSS score was identified. CONCLUSIONS: Polyautoimmunity was common in AQP4 positive NMOSD patients leading to a significantly higher risk of disease recorrence. The presence of polyautoimmunity and multiple autoimmune syndrome in NMOSD patients suggests the existence of common susceptibility factors or pathophysiological mechanisms, emphasizing the importance of a multidisciplinary approach to those patients.

Current progress in CRISPR-Cas systems for autoimmune diseases.

A body develops an autoimmune illness when its immune system mistakenly targets healthy cells and organs. Eight million people are affected by more than 80 autoimmune diseases. The public's and individuals' well-being is put at risk. Type 1 diabetes, lupus, rheumatoid arthritis, and multiple sclerosisare autoimmune diseases. Tissue injury, nociceptive responses, and persistent inflammation are the results of these stresses. Concerns about healthcare costs, health, and physical limitations contribute to these issues. Given their prevalence, it is crucial to enhance our knowledge, conduct thorough research, and provide all-encompassing support to women dealing with autoimmune diseases. This will lead to better public health and better patient outcomes. Most bacteria's immune systems employ CRISPR-Cas, a state-of-the-art technique for editing genes. For Cas to break DNA with pinpoint accuracy, a guide RNA employs a predetermined enzymatic pathway. Genetic modifications started. After it was developed, this method was subjected to much research on autoimmune diseases. By modifying immune pathways, CRISPR gene editing can alleviate symptoms, promote immune system tolerance, and decrease autoimmune reactivity. The autoimmune diseases that CRISPR-Cas9 targets now have no treatment or cure. Results from early clinical trials and preclinical studies of autoimmune medicines engineered using CRISPR showed promise. Modern treatments for rheumatoid arthritis,multiple sclerosis, and type 1 diabetes aim to alter specific genetic or immune mechanisms. Accurate CRISPR editing can fix autoimmune genetic disorders. Modifying effector cells with CRISPR can decrease autoimmune reactions. These cells include cytotoxic T and B lymphocytes. Because of improvements in delivery techniques and kits, CRISPR medications are now safer, more effective, and more accurately targeted. It all comes down to intricate immunological reactions and unexpected side consequences. Revolutionary cures for autoimmune problems and highly personalized medical therapies have been made possible by recent advancements in CRISPR.

Current progress in CAR-based therapy for kidney disease.

Despite significant breakthroughs in the understanding of immunological and pathophysiological features for immune-mediated kidney diseases, a proportion of patients exhibit poor responses to current therapies or have been categorized as refractory renal disease. Engineered T cells have emerged as a focal point of interest as a potential treatment strategy for kidney diseases. By genetically modifying T cells and arming them with chimeric antigen receptors (CARs), effectively targeting autoreactive immune cells, such as B cells or antibody-secreting plasma cells, has become feasible. The emergence of CAR T-cell therapy has shown promising potential in directing effector and regulatory T cells (Tregs) to the site of autoimmunity, paving the way for effective migration, proliferation, and execution of suppressive functions. Genetically modified T-cells equipped with artificial receptors have become a novel approach for alleviating autoimmune manifestations and reducing autoinflammatory events in the context of kidney diseases. Here, we review the latest developments in basic, translational, and clinical studies of CAR-based therapies for immune-mediated kidney diseases, highlighting their potential as promising avenues for therapeutic intervention.

Adeno-associated virus-based gene therapy treats inflammatory kidney disease in mice.

Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.

High risk of misclassification of acute Parvovirus B19 infection into a systemic rheumatic disease.

Objectives: Parvovirus B19 most frequently causes epidemics of erythema infectiosum in children but also affects adults often leading to rheumatologic manifestations. While the serum profile allows the diagnosis, manifestations may mimic autoimmune conditions. The aim was to evaluate the proportion of patients with acute Parvovirus B19 infection fulfilling classification criteria for rheumatic diseases (RA and SLE). Methods: We evaluated the clinical and serological features of 54 patients diagnosed with acute Parvovirus B19 infection seeking rheumatological attention between March and June 2024. Results: The majority of patients were females (78%), with a mean (s.d.) age of 45 (13) years and 54% could not recall any known exposure. Fifty-one/54 (94%) had arthralgia, 27 (50%) arthritis (oligoarthritis in 67% of them), 24 (44%) fever, 19 (35%) skin rash and 7 (13%) purpura. Symptoms resolution generally occurred within 6 weeks. Complement levels were low in 14/33 (42%) tested patients, while the presence of serum ANA, anti-dsDNA, anti-phospholipids and rheumatoid factor was detected in 21/38 (55%), 10/26 (38%), 6/12 (50%) and 5/37 (13%) patients, respectively. Classification criteria for SLE were fulfilled in 93% of ANA-positive patients and RA criteria in 38% of patients with arthritis. Conclusions: Parvovirus B19 infection manifestations may vary and nearly all patients with positive serum ANA fulfil the classification criteria for SLE. The risk of misclassification in patients with viral infection should not be overlooked.

When Rare Meets Reality: A Case of Kikuchi-Fujimoto Disease in Tertiary Care Center.

Kikuchi-Fujimoto disease is a very rare disease, basically involving young adults and ubiquitously distributed. It is characterized by fever and benign lymph node swelling. The distinguishing features of this disease are cervical lymphadenopathy, constitutional symptoms resembling tuberculosis, and its penchant to affect young people of Oriental or Asian descent, especially women. We describe an instance of a 42-year-old female who arrived with multiple neck swellings. On physical examination, there was palpable right-sided cervical lymphadenopathy, while laboratory investigations were essentially within normal limits except for raised erythrocyte sedimentation rate and anemia. After cefepime and nonsteroidal anti-inflammatory medications were administered, symptoms subsided, and lymphadenopathy receded in the patient. This case supports the importance of histological evaluation to reach an exact diagnosis and guide treatment and the need to consider Kikuchi-Fujimoto disease in the differential diagnosis of lymphadenopathy.

The molecular basis of the immunomodulatory effects of natural products: A comprehensive review.

BACKGROUND: Natural products (NPs) have long been recognized for their potential to modulate the immune system, offering a natural and holistic approach to enhancing immune function. In recent years, the immunomodulation effects of various natural products have attained significant attention. PURPOSE: This article provides an overview of the role of natural products in immunomodulation, exploring their mechanisms of action, common types of NPs with immunomodulation properties, clinical applications, as well as considerations for their safety and efficacy. METHODS: Extensive research has been conducted to compile important discoveries on the immunomodulatory properties of NPs through thorough searches of multiple databases such as PubMed, Science Direct, and Scopus up until January 2024. RESULTS: By decreasing the levels of Th2 cytokines and pro-inflammatory cytokines, the results suggested that NPs have the ability to modulate the immune system. Therefore, NPs alleviate inflammation in various disorders such as asthma and cancer. Furthermore, the observed increase in CD4 cells and IFN-É£/IL4 levels, along with an increased IFN-c/IL4 ratio, indicates a stimulatory effect of NPs on Th1 activity in various inflammatory conditions. Therefore, NPs regulate the immune system by inhibiting T-cells and decreasing the growth of young B-cell lymphoma cells. CONCLUSION: Reviewing studies indicated that NPs have the potential to serve as immunomodulatory candidates for treating disorders characterized by immune dysregulation. However, additional experimental and clinical studies are necessary before these agents can be implemented in clinical settings.

Long-term outcomes in antibody-negative autoimmune encephalitis: a retrospective study.

BACKGROUND AND OBJECTIVE: Despite constituting one-third of suspected autoimmune encephalitis (AE) patients, antibody-negative cases without typical AE features are understudied. We aim to characterize the clinical phenotypes and long-term outcomes of "possible only" and "probable" AE cases. METHODS: We conducted a retrospective analysis of adult patients evaluated at Mayo Clinic's Autoimmune Neurology Clinic (01/01/2006-12/31/2020), meeting diagnostic criteria for "possible only" or "probable but antibody-negative" AE, with ≥ 1 year of follow-up. All patients underwent neural antibody testing. RESULTS: Among fifty-one patients, six had a change in diagnosis (non-autoimmune, 2) and were excluded from further analysis. Forty-five patients were analyzed [median age, 61 years (range 20-88); female, 21 (47%); median follow-up, 36 months (range 12-174)]. A nadir modified Rankin Scale (mRS) ≥ 3 was recorded in 41/45 (91%). CSF was inflammatory in 20/44 (45%) and MRI had encephalitic changes in 21/45 (47%). Unclassified neural-specific IgG staining on tissue-based assay was detected in five (11%). Two patients (4%) had paraneoplastic causation. Relapses (> 3 months from onset) were noted in 14 (31%). Memory dysfunction (69%), attention deficits (38%), and gait instability (29%) were the most frequent at the last follow-up. Most patients (76%) were independent at the last follow-up and only two required an assistive device to ambulate; 11 patients (24%) had poor neurological outcome (mRS ≥ 3). Higher mRS score and gait assistance requirement at 3 months were predictive of poor outcome (P ≤ 0.01). DISCUSSION: Despite significant disability at initial disease stages, most antibody-negative AE patients regain independent functioning. Early functional status and gait assistance requirements may predict long-term prognosis.

Reporting quality and risk of bias of randomized controlled trials of Chinese herbal medicine for multiple sclerosis.

Background: Multiple sclerosis (MS) is the most common non-traumatic disabling disease affecting young adults. A definitive curative treatment is currently unavailable. Many randomized controlled trials (RCTs) have reported the efficacy of Chinese herbal medicine (CHM) on MS. Because of the uncertain quality of these RCTs, the recommendations for routine use of CHM for MS remain inconclusive. The comprehensive evaluation of the quality of RCTs of CHM for MS is urgent. Methods: Nine databases, namely, PubMed, Embase, Web of Science, Cochrane Library, EBSCO, Sinomed, Wanfang Database, China National Knowledge Infrastructure, and VIP Database, were searched from inception to September 2023. RCTs comparing CHM with placebo or pharmacological interventions for MS were considered eligible. The Consolidated Standards of Reporting Trials (CONSORT) and its extension for CHM formulas (CONSORT-CHM Formulas) checklists were used to evaluate the reporting quality of RCTs. The risk of bias was assessed using the Cochrane Risk of Bias tool. The selection criteria of high-frequency herbs for MS were those with cumulative frequency over 50% among the top-ranked herbs. Results: A total of 25 RCTs were included. In the included RCTs, 33% of the CONSORT items and 21% of the CONSORT-CHM Formulas items were reported. Eligibility title, sample size calculation, allocation concealment, randomized implementation, and blinded description in CONSORT core items were reported by less than 5% of trials. For the CONSORT-CHM Formulas, the source and authentication method of each CHM ingredient was particularly poorly reported. Most studies classified the risk of bias as "unclear" due to insufficient information. The top five most frequently used herbs were, in order, Radix Rehmanniae Preparata, Radix Rehmanniae Recens, Herba Epimedii, Scorpio, and Poria. No serious adverse effect had been reported. Conclusions: The low reporting of CONSORT items and the unclear risk of bias indicate the inadequate quality of RCTs in terms of reporting completeness and result validity. The CONSORT-CHM Formulas appropriately consider the unique characteristics of CHM, including principles, formulas, and Chinese medicinal substances. To improve the quality of RCTs on CHM for MS, researchers should adhere more closely to CONSORT-CHM Formulas guidelines and ensure comprehensive disclosure of all study design elements.

Association of autoimmune diseases with the occurrence of osteoarthritis: a gene expression and Mendelian randomization study.

Background: Observational studies have indicated a potential association between autoimmune diseases and the occurrence of Osteoarthritis (OA), with an increased risk of mortality among affected patients. However, whether a causal relationship exists between the two remains unknown. Methods: In the Mendelian randomization (MR) study, we accessed exposure Genome-wide association study (GWAS) data from both the MRC Integrative Epidemiology Unit (MRC-IEU) and the FinnGen consortium. GWAS data for OA were obtained from MRC-IEU. We employed univariable, multivariable, and reverse MR analyses to explore potential associations between autoimmune disorders and OA. Additionally, a two-step mediation MR analysis was performed to investigate indirect factors possibly influencing the relationship between autoimmune disorders and OA. Afterward, we conducted an observational analysis to further explore the relationship between autoimmune disease and occurrence as well as of OA using a real-world database (the MIMIC-IV database). Based on public gene expression sequencing data, we further explored the potential shared pathogenesis between autoimmune diseases and OA. Results: In our univariable MR study, we identified five autoimmune diseases that are associated with OA. These include Celiac disease (OR = 1.061, 95% CI = 1.018-1.105, p = 0.005), Crohn's disease (OR = 1.235, 95% CI = 1.149-1.327, p = 9.44E-09), Ankylosing spondylitis (OR = 2.63, 95% CI = 1.21-5.717, p = 0.015), RA (OR = 1.082, 95% CI = 1.034-1.133, p = 0.001), and Ulcerative colitis (OR = 1.175, 95% CI = 1.068-1.294, p = 0.001). In the mediation effect analysis, it was found that there is no correlation between cytokines and autoimmune diseases and OA. Based on transcriptome data analysis, it was found that metabolism-related pathways play a key role in the co-morbidity of autoimmune diseases and OA. Conclusion: Our findings revealed that genes associated with Celiac disease, Crohn's disease, Ankylosing spondylitis, RA, and Ulcerative colitis were independently linked to the development of OA. Furthermore, we conducted an analysis of potential pathogenic genes between these diseases and OA, offering a novel approach for the simultaneous treatment of multiple conditions.

Discovery of novel nitrofuran PROTAC-like compounds as dual inhibitors and degraders targeting STING.

Aberrant activation of the innate immune molecule STING can initiate inflammation and autoimmune diseases. Small molecule inhibitors targeting STING have demonstrated therapeutic efficacy against these conditions. Moreover, employing degradants to target STING represents a novel approach to drug design strategy. Consequently, we have designed and synthesized a series of covalent degradants targeting STING. Among them, compound P8 exhibited the highest degradation capacity, with a 24-h DC50 of 2.58 µM in THP-1 cells. In THP-1 cells, P8 specifically degraded STING proteins through the lysosomal pathway, acting as dual a degrader and inhibitor to manifest anti-inflammatory effects. Conversely, in RAW264.7 cells, P8 solely acted as an inhibitor without exhibiting degradative capacity towards the STING protein level. Additionally, P8 displayed renal-protective properties in a cisplatin-induced acute kidney injury model. These results highlight the significant potential of further investigating compound P8.

Clinical and Sociodemographic Features of Alopecia Areata in Five Colombian Cities: An Analysis of the RENAAC Registry. / [Artículo traducido] Características clínicas y sociodemográficas de la alopecia areata en 5 ciudades colombianas: un análisis del RENAAC.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by non-scaring hair loss and preservation of hair follicles. The information available on disease course, and clinical features of AA is scarce worldwide, and almost nonexistent in Colombia. OBJECTIVE: To determine the clinical and sociodemographic characteristics of patients diagnosed with AA who presented to a dermatology consultation in five Colombian cities. MATERIAL AND METHODS: This was a retrospective and multicenter study on data from an ongoing National Registry of Alopecia Areata in Colombia (RENAAC) collected in Bogota, Cali, Cartagena, Barranquilla, and Medellin, Colombia from March 2022 through April 2023. Data was recorded in a standardized form by trained physicians. The variables were expressed as measures of central tendency and dispersion, and absolute and relative frequencies. RESULTS: A total of 562 patients were included, 59.4% of whom were women, aged between 15 and 49 years (63.9%) with a mean disease course of 1.7 years. The most common finding was multiple plaque (53.2%), the predominant AA subtype was patchy (71.4%), and 29.5% of the patients had a past dermatological history, 18.3% had a past endocrinological history, and 8.9% had a past psychiatric history. The treatments most widely used were steroid injections (76.4%), 5% topical minoxidil (46.4%), followed by high-potency corticosteroids (42.5%). STUDY LIMITATIONS AND CONCLUSIONS: AA was slightly predominant in women. As seen in other populations, this disease had an earlier onset in men vs women. Presentation in pediatric age was uncommon. The previous history of other dermatological diseases was checked in almost one third of the patients. Analysis of the co-presentation of AA with other autoimmune diseases is biased due to excluding patients with systemic erythematous lupus from the study.

Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold.

The calcium release activated calcium (CRAC) channel is highly expressed in T lymphocytes and plays a critical role in regulating T cell proliferation and functions including activation of the transcription factor nuclear factor of activated T cells (NFAT), cytokine production and cytotoxicity. The CRAC channel consists of the Orai pore subunit and STIM (stromal interacting molecule) endoplasmic reticulum calcium sensor. Loss of CRAC channel mediated calcium signaling has been identified as an underlying cause of severe combined immunodeficiency (SCID), leading to drastically weakened immunity against infections. Gain-of-function mutations in Orai and STIM have been associated with tubular aggregated myopathy (TAM), a skeletal muscle disease. While a number of small molecules have shown activity in inhibiting the CRAC signaling pathway, the usefulness of those tool compounds is limited by their off-target activity against TRPM4 and TRPM7 ion channels, high lipophilicity, and a lack of understanding of their mechanism of action. We report structure-activity relationship (SAR) studies that resulted in the characterization of compound 4k [1-(cyclopropylmethyl)-N-(3-fluoropyridin-4-yl)-1H-indazole-3-carboxamie] as a fast onset, reversible, and selective CRAC channel blocker. 4k fully blocked the CRAC current (IC50: 4.9 µM) and the nuclear translocation of NFAT at 30 and 10 µM, respectively, without affecting the electrophysiological function of TRPM4 and TRPM7 channels. Computational modeling appears to support its direction binding to Orai proteins that form the transmembrane CRACchannel.

Osteoarthritis in People with Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Background: Arthritis, particularly osteoarthritis (OA), is a common synovial condition observed in individuals with multiple sclerosis (MS). Despite its high prevalence and significant impact on the quality of life of MS individuals, there is a gap in the current literature regarding the prevalence of OA in this population and its relation to MS pathology. This systematic review and meta-analysis aimed to estimate the prevalence of OA in the MS population and explore potential associations with demographic and MS-specific characteristics. Methods: Adhering to PRISMA guidelines, a systematic search of the MEDLINE PubMed, Scopus and Google Scholar databases was conducted. Results: Fifteen studies were included in the systematic review and meta-analysis. The aggregated prevalence of OA in the MS population was 27% (95% CI: 15-40%), with substantial heterogeneity (I2 = 99.9%). Sensitivity analysis, excluding one study, showed a prevalence of 21% (95% CI: 16-28%). The risk ratio of OA in MS versus controls was 1.07 (95% CI: 0.84-1.37), indicating no significant difference. Meta-regression revealed no associations between OA prevalence and age or disease duration in MS patients. Conclusions: This study reports a 21-27% prevalence of OA in people with MS. Understanding the implications of OA in pain and mobility domains, as well as the challenges in distinguishing OA symptoms from MS manifestations, underscores the need for further research to elucidate the pathophysiological mechanisms and interactions between these conditions. Additional studies are warranted to enhance clinical management and improve outcomes for individuals with MS and co-existing OA.