Autoimmune Diseases Research Articles

OA24 Extended oligoarthritis with proximal muscle weakness and antinuclear antibody positivity associated with a novel genetic variant of uncertain significance in lipopolysaccharide-responsive and beige-like anchor protein (LRBA) gene

Abstract Introduction LRBA deficiency is associated with recurrent infections and immune dysregulation, particularly autoimmune cytopenias, enteropathy and intestitial lung disease, and in a few cases chronic polyarthritis and uveitis. Case description A girl presented at three years old with history of not walking for two months with no history of trauma or fever. Examination revealed arthritis in her ankles and knees. Ultrasound showed synovial thickening in both knees and small effusion to hips. There was no evidence of uveitis at presentation. Her bloods showed raised C-Reactive Protein (CRP) 33 mg/L and Erythrocyte Sedimentation rate (ESR) 45 mm/h. Anti-nuclear and anti-centromere antibodies were positive. Diagnosis was made of oligoarticular JIA and she was treated with intra-articular steroids in both knees and ankles and was started on oral prednisolone, weekly oral methotrexate. On subsequent clinic review, she had started to walk with mild restriction to internal rotation of hips and difficulty in getting up from sitting. She was started on regular hydrotherapy, physiotherapy and occupational therapy. From five to 11 years old, she had four flares of uveitis, treated with prednisolone eye drops; and two flares of arthritis, treated with steroids. Her methotrexate was changed to subcutaneous and at eight years of age she was also started on subcutaneous adalimumab fortnightly. Due to prolonged proximal muscle weakness, abnormal gait and chronic pain in leg joints without clinical or radiological evidence of synovitis during clinic reviews, she underwent thorough neurological work up which was inconclusive for myopathies. Her creatinine kinase levels, thyroid profile, MRI brain and spine were normal. Genetic work up showed two variants in the LRBA gene, one pathogenic and the other was variant of uncertain significance (VUS). Her CTLA4 expression was normal by flow cytometry. Discussion Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Key learning points • There is no single diagnostic investigation for JIA as the aetiology is complex and there are currently no specific clinical guidelines of when to consider genetic testing in patients with JIA. With the mainstreaming of genetic services and improved access to cheaper, advanced next-generation sequencing, we should consider looking into monogenic conditions that mimic JIA. • The case illustrates the challenges of determining whether VUS are pathogenic in causing arthritis, or just incidental findings. Compound heterozygous LRBA may present within a spectrum of clinical features, further analysis with CTLA4 expression by flow cytometry and genetic analysis of siblings and parents will be helpful. • Compound heterozygous LRBA variation has different clinical manifestation which needs personalised treatment. Treatment with abatacept (a soluble CTLA4 immunoglobulin fusion protein) which is reported in a case series of LRBA deficiency. Risks of continuous immunosuppressive treatment need to be balanced with more definitive hematopoietic stem cell transplantation (HSCT) previously used to achieved complete remission in LRBA deficiency.

Bispecific killer engager for targeted depletion of PD-1 positive lymphocytes: A new avenue for autoimmune disease treatment

Bispecific killer engager for targeted depletion of PD-1 positive lymphocytes: A new avenue for autoimmune disease treatment

A first-in-human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults.

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B-cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN-303; TACI vTD-Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild-type TACI-Fc or BAFF- or APRIL-specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first-in-human study in healthy adults, povetacicept was well-tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose-dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2-3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on-target reductions in antibody-secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease-related biomarker galactose-deficient-immunoglobulin A1 (Gd-IgA1), and were superior to results reported for wild-type TACI-Fc. These data strongly support further development of povetacicept for the treatment of B-cell-mediated automimmune diseases.

Therapeutic potential of natural coumarins in autoimmune diseases with underlying mechanisms

Autoimmune diseases encompass a wide range of disorders characterized by disturbed immunoregulation leading to the development of specific autoantibodies, which cause inflammation and multiple organ involvement. However, its pathogenesis remains unelucidated. Furthermore, the cumulative medical and economic burden of autoimmune diseases is on the rise, making these diseases a ubiquitous global phenomenon that is predicted to further increase in the coming decades. Coumarins, a class of aromatic natural products with benzene and alpha-pyrone as their basic structures, has good therapeutic effects on autoimmune diseases. In this review, we systematically highlighted the latest evidence on coumarins and autoimmune diseases data from clinical and animal studies. Coumarin acts on immune cells and cytokines and plays a role in the treatment of autoimmune diseases by regulating NF-κB, Keap1/Nrf2, MAPKs, JAK/STAT, Wnt/β-catenin, PI3K/AKT, Notch and TGF-β/Smad signaling pathways. This systematic review will provide insight into the interaction of coumarin and autoimmune diseases, and will lay a groundwork for the development of new drugs for autoimmune diseases.

PANoptosis in autoimmune diseases interplay between apoptosis, necrosis, and pyroptosis

PANoptosis is a newly identified inflammatory programmed cell death (PCD) that involves the interplay of apoptosis, necrosis, and pyroptosis. However, its overall biological effects cannot be attributed to any one type of PCD alone. PANoptosis is regulated by a signaling cascade triggered by the recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by various sensors. This triggers the assembly of the PANoptosome, which integrates key components from other PCD pathways via adapters and ultimately activates downstream execution molecules, resulting in cell death with necrotic, apoptotic, and pyroptotic features. Autoimmune diseases are characterized by reduced immune tolerance to self-antigens, leading to abnormal immune responses, often accompanied by systemic chronic inflammation. Consequently, PANoptosis, as a unique innate immune-inflammatory PCD pathway, has significant pathophysiological relevance to inflammation and autoimmunity. However, most previous research on PANoptosis has focused on tumors and infectious diseases, leaving its activation and role in autoimmune diseases unclear. This review briefly outlines the characteristics of PANoptosis and summarizes several newly identified PANoptosome complexes, their activation mechanisms, and key components. We also explored the dual role of PANoptosis in diseases and potential therapeutic approaches targeting PANoptosis. Additionally, we review the existing evidence for PANoptosis in several autoimmune diseases and explore the potential regulatory mechanisms involved.

Two-Sample Mendelian Randomization Study Identifies Tissue-Dependent Risk Genes in Autoimmune Diseases

Autoimmune diseases are among the most prevalent diseases across the world with genetic and environmental factors that contribute to their etiology. Because the exact causes of autoimmune diseases are largely unknown, a Mendelian randomization (MR) approach is used here to examine the potential causal association between gene expression levels and disease risk across various tissues. Specifically, this study focuses on six autoimmune diseases including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus. Several of these diseases are currently treatable with immunosuppressants that target specific genes, such as TNF-alpha, IL-23, CD20, and more. In this study, a two-sample MR analysis is performed with multitissue expression quantitative trait loci (eQTLs) and large-scale genome-wide association studies to investigate how gene expression can influence the risk of developing these diseases. Our results show that genes HLA-DQA1/2, HLA-DRB1/6, HLA-DQB2, C4A, CYP21A2, and HLA-DQB1-AS1 have a high causal effect across several diseases and tissues, and almost all of these findings originate from the major histocompatibility complex (MHC) region on Chromosome 6. Our findings support the current knowledge of genes associated with these diseases while also revealing novel genes that can be used for drug therapies in the future. Although several drug therapies currently exist to treat this selection of autoimmune diseases, we provide further insights into the main, common pathways responsible for autoimmune disease pathogenesis and discuss novel genes that lack research focus.

Optic Neuritis and its Prevalence in Immunocompromised Patients: A Review Article

Optic neuritis is an inflammation that affects the optic nerve, causing vision loss, eye pain, and changes in color perception. The condition can be associated with autoimmune diseases such as multiple sclerosis (MS) or infections, especially in immunocompromised individuals such as HIV/AIDS patients or those undergoing chemotherapy. In these individuals, optic neuritis usually results from opportunistic infections like toxoplasmosis and syphilis, complicating diagnosis and treatment. In immunocompetent patients, optic neuritis may indicate autoimmune diseases like MS or neuromyelitis optica (NMO), with better prognoses when treated early with corticosteroids. However, in immunocompromised individuals, the prognosis tends to be worse due to underlying infections and a limited response to immunosuppressive treatment. The management of optic neuritis involves anti-inflammatory therapies and, in cases of infections, specific antimicrobials. Continuous clinical and visual follow-up is also crucial. Studies suggest that clinical outcomes vary depending on the etiology and the patient's immune status, highlighting the need for personalized therapeutic strategies. Early diagnosis is critical to improving vision and quality of life for patients.

TM9SF1 expression correlates with autoimmune disease activity and regulates antibody production through mTOR-dependent autophagy

BackgroundTransmembrane 9 superfamily member 1 (TM9SF1) is involved in inflammation. Since both inflammatory and autoimmune diseases are linked to immune cells regulation, this study investigated the association between TM9SF1 expression and autoimmune disease activity. As B cell differentiation and autoantibody production exacerbate autoimmune disease, the signaling pathways involved in these processes were explored.MethodsTm9sf1−/− mouse rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) models were used to verify the relationship between gene expression and disease severity. Peripheral blood mononuclear cells (PBMCs) from 156 RA and 145 SLE patients were used to explore the relationship between TM9SF1 expression and disease activity. The effectiveness of TM9SF1 as a predictor of disease activity was assessed using multiple logistic regression and receiver operating characteristic (ROC) curves. The signaling pathways regulated by TM9SF1 in B cell maturation and antibody production were conducted by plasma cell induction experiment in vitro.ResultsThe Tm9sf1−/− RA and SLE model mice produced fewer autoantibodies and showed reduced disease severity relative to wild-type (WT) mice. TM9SF1 levels in PBMCs of patients were higher than those in healthy controls, and were reduced in patients with low disease activity relative to those with active RA and SLE. Furthermore, TM9SF1 levels were positively linked with autoantibody titers and pro-inflammatory cytokine levels in both diseases. ROC analyses indicated TM9SF1 outperformed several important clinical indicators in predicting disease activity (area under the curve (AUC) were 0.858 and 0.876 for RA and SLE, respectively). In vitro experiments demonstrated that Tm9sf1 knockout blocked differentiation of B cells into antibody-producing plasma cells by activating mTOR and inhibiting autophagy, and mTOR inhibitors such as rapamycin could reverse this effect.ConclusionsThe primary finding was the identification of the molecular mechanism underlying autophagy regulation in B cells, in which Tm9sf1 knockout was found to modulate mTOR-dependent autophagy to block B cell differentiation into antibody-secreting plasma cells. It was also found that TM9SF1 expression level in PBMCs was an accurate indicator of disease activity in patients with RA and SLE, suggesting its clinical potential for monitoring disease activity in these patients.

Immune-Mediated Inflammatory Diseases, Dyslipidemia, and Cardiovascular Risk: A Complex Interplay.

Individuals with autoimmune inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, are at increased risk for cardiovascular disease. While these diseases share common features of systemic inflammation, the impact of individual autoimmune inflammatory conditions on circulating lipids and lipoproteins varies by specific disease, disease activity, and the immune-suppressing medications used to treat these conditions. A common feature observed in many autoimmune inflammatory diseases is the development of a proatherogenic dyslipidemic state, characterized by dysfunctional HDLs (high-density lipoproteins) and increased oxidation of LDLs (low-density lipoproteins). Various disease-modifying antirheumatic drugs also have complex and variable effects on lipids, and it is critical to take this into consideration when evaluating lipid-related risk in individuals with immune-mediated inflammatory conditions. This review aims to critically evaluate the current understanding of the relationship between immune-mediated inflammatory diseases and dyslipidemia, the underlying mechanisms contributing to atherogenesis, and the impact of various pharmacotherapies on lipid profiles and cardiovascular risk. We also discuss the role of lipid-lowering therapies, particularly statins, in managing residual risk in this high-risk population and explore the potential of emerging therapies with complementary anti-inflammatory and lipid-lowering effects.

Serotonin and adrenaline as inhibitors of neutrophil extracellular traps formation (experimental study)

Regulation of the NETosis can provoke cancer, inflammatory and autoimmune diseases and become a basis for effective targeted therapy. The aim: to study the modifying effects of serotonin and adrenaline on NETosis during phagocytosis in rats.Materials and methods.Wistar rats were divided into control (solvent, 0.9% NaCl solution) and experimental (serotonin and adrenaline 1.43 and 0.143 mg/kg body weight, respectively) groups. Intraperitoneal injection of test substances was carried out 90 minutes before blood sampling, in which phagocytic activity (PhA), phagocytic index (PhI) and degree of suicidal neutrophil NETosis were determined: with total and partial chromatin decondensation (TCD, PCD, accordingly). A paired Student’s t test was used to compare groups with numerical values and McNemar’s test (for dichotomous variables). Pearson’s linear correlation coefficient (rxy) was assessed to measure a linear relationship between time points.Results.The administration of adrenaline contributed to NETosis inhibition by 41.5% compared to control group (p 0.001), serotonin — by 27.6% (p 0.001). The ratio of neutrophils with total and partial chromatin decondensation for control group was 1.0:0.9; for serotonin and adrenaline it changed to 1.0:1.7 and 1.0:1.4, respectively. Relative to control group, phagocytic index after serotonin administration increased by 4.9%, in case of adrenaline, on the contrary, it decreased by 12.4% (p 0.01). A high positive correlation was revealed between NETosis and phagocytic index for control group and experimental group with adrenaline: rxy= 0.823–0.997. For phagocytic index and NETosis in these groups there was a high negative (rxy= –0.714–(–0.871)) and a noticeable positive correlation for serotonin (rxy= 0.638).Conclusion.Serotonin and adrenaline in therapeutic dosages have a pronounced inhibitory effect on NETosis, which may pave the avenue for increasing the effectiveness of therapy for immunoinflammatory and oncological diseases. The use of serotonin is preferable because it has additional immunomodulatory effects and cause no direct stimulation ofα- andβ-adrenergic receptors.

Metabolic impact of low dose IL-2 therapy for primary Sjögren's Syndrome in a double-blind, randomized clinical trial.

Low-dose interleukin 2 (Ld-IL2) is increasingly being explored as an immune-modulating treatment for autoimmune diseases which mainly affect T cell subsets. This study investigates the metabolic effects of Ld-IL2 therapy in patients with primary Sjögren's syndrome (pSS). A total of 60 patients were recruited to conduct a double-blind, randomized clinical trial. Of these patients, 50% (30/60) received Ld-IL2 therapy along with standard treatment for 12 weeks, followed by 12 weeks of follow-up. The effectiveness was evaluated by Sjögren's Tool for Assessing Response (STAR). An untargeted analysis was performed to profile hydrophilic metabolites. Metabolic profiling revealed significant alterations post-treatment, notably in metabolites like acetyl-CoA, ascorbic acid, and glutathione, which are beneficial in managing autoimmune diseases. In addition, the levels of metabolite accumulation were correlated with variations in immune cell subsets (p< 0.05), particularly Tregs. Moreover, patients exhibiting a specific metabolic profile, including lower serum levels of isoleucine, ADP, Thymidine 5'-triphosphate, and other metabolites, had a high response rate (91.7%-98.6%), as indicated by the receiver operating characteristic (ROC) curve. These findings suggest that Ld-IL2 therapy influences metabolic pathways in pSS, offering insights into the systemic effects of Ld-IL2 therapy beyond immune modulation. ClinicalTrials.gov number, NCT02464319. Key Points •Metabolic alteration in pSS is significantly associated with Ld-IL2 therapy. •Metabolic changes correlate with variations in immune cell subsets, particularly Tregs. •Metabolic profiling could be a valuable tool in guiding Ld-IL2 therapy choices for pSS patients.

Possible involvement of Toll-like receptor 8-positive monocytes/macrophages in the pathogenesis of Sjögren’s disease

BackgroundSjögren’s disease (SjD) is an autoimmune disease marked by lymphocytic infiltration of salivary and lacrimal glands, leading to glandular dysfunction, where CD4-positive helper T (Th) cells and their cytokines are crucial in the pathogenesis. Recent studies have demonstrated that Toll-like receptors (TLRs), particularly those recognizing immune complexes containing DNA and RNA, contribute to Th cell activation in various autoimmune diseases. This study explores the expression and function of these TLRs in SjD.MethodsDNA microarray analysis of salivary gland tissue from six SjD patients and real-time PCR (n = 32) was used to identify overexpressed TLRs. Single-cell RNA sequencing (scRNA-seq) was performed using tissue lesions and integrated with published scRNA-seq data from tissues and peripheral blood mononuclear cells to examine gene expression in macrophages and monocytes. Finally, multi-color immunofluorescence staining was conducted to confirm TLR8 expression and function in SjD lesions (n = 19).ResultsDNA microarray analysis revealed the up-regulation of TLR8, along with other TLRs and innate immune response genes in SjD. Real-time PCR showed significant up-regulation of TLR7 and TLR8. TLR8 up-regulated in both analyses. In scRNA-seq analysis, the TLR8-expressing cluster comprised macrophages and monocytes, which also produced T cell activation genes like CD86. TLR8-positive macrophages infiltrated inflammatory sites and frequently expressed CD86 in quantitative imaging approaches.ConclusionsThese results suggest that infiltrating monocytes and macrophages may produce cytokines and chemokines through TLR8 stimulation, potentially enhancing B7 molecule expression, promoting the adaptive immune response, and contributing to SjD pathogenesis.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients of Bullous Pemphigoid with or without Parkinson's Disease.

High positivity rate of skin phosphorylated α-synuclein (P-SYN) was observed in Parkinson's disease (PD). Bullous pemphigoid (BP) is one of the most common autoimmune skin diseases associated with PD. Our aim was to investigate whether BP patients might be a targeted risk population for the screening of skin P-SYN. Skin P-SYN expression was evaluated by immunohistochemistry in BP patients with/without PD. Twenty-two BP patients with PD, 24 BP patients without PD, and seven healthy donors were enrolled. Colocalization of P-SYN and PGP9.5 was found in all BP patients, but only one healthy control, whereas BP patients with PD showed higher expression than BP patients without PD (mean ± standard deviation, 10.7 ± 6.7 vs. 7.3 ± 3.2; P = 0.027). Positive expression was mainly observed in basement membrane zone and dermis. These results indicated BP patients might be a targeted risk population for the screening of skin P-SYN, which was helpful for the detection of PD early. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Role of Gut Microbioma in Human Health: Exploring the Impact on Metabolism, Immunity, and Neurological Disorders

Abstract: The human microbiota has been progressively accepted for its role in sustaining overall health and well-being. The gut microflora vigorously communicates with the host metabolic system that exert influence on the progression, maturation, immune cells development and immune homeostasis maintenance. For the proper functioning of the immune system a diversified and steady gut microflora is needed, while “Dysbiosis” or an imbalance in the gut microbioma will lead to autoimmune and inflammatory diseases. The gut microbiota provides shape to our immune response and contribute to host protection against pathogen or bacterium through mechanisms such as the transformation of pro- inflammatory cytokine production, regulatory T-cell inductor and by intestinal mucosaql barrier. In addition to gut microbiota can affect our neurological function and play a key role in the pathogenesis of psychological disorders such as autism, depression, anxiety, Parkinson and Alzheimer’s disease. Gut microbiota can regulate neurological disorders by supplementing them with fecal transplantation, probiotics and antibiotics. An important parameter to consider gut microbioma disorder is Firmicutes/ Bacteroidetes.

Infiltrations of plasma cells in synovium predict inadequate response to Adalimumab in Rheumatoid Arthritis patients

ObjectiveRheumatoid arthritis (RA) is a clinically heterogeneous and complex autoimmune disease, making the prediction of therapeutic responses a significant challenge. This study aims to assess the role of clinical and synovial biomarkers in predicting poor response to adalimumab treatment in RA patients.MethodsThis single-center prospective study included 56 RA patients who had an inadequate response to methotrexate (MTX). At baseline, comprehensive assessments including complete blood count, liver and kidney function tests, blood glucose levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), as well as counts of swollen and tender joints, Health Assessment Questionnaire (HAQ) score, pain visual analogue scale (VAS) scores, and DAS28-CRP scores were conducted. Synovial biopsies were performed, followed by an efficacy evaluation at 12 weeks of adalimumab treatment. Patients not meeting the ACR20 criteria were classified into the non-responder group, with the remainder categorized as the responder group.ResultsOut of the participants, 24 (42.9%) failed to achieve ACR20 with adalimumab treatment. Non-responders exhibited higher infiltration of plasma cells in the synovium. Multivariate logistic regression analysis identified the presence of plasma cells as an independent risk factor for inadequate response to adalimumab.ConclusionInadequate responses to adalimumab in RA patients were associated with increased plasma cell infiltrations in the synovium. These findings suggest a promising target for tailored therapies in rheumatoid arthritis.

HLA-DRB1*01 predicts treatment outcome in juvenile idiopathic arthritis: A retrospective-prospective cohort study.

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory autoimmune disease in childhood, significantly contributing to both short- and long-term disability. While certain human leukocyte antigen (HLA) class II alleles are known to be associated with specific subgroups of JIA, emerging evidence suggests a strong correlation between these alleles and treatment response. This study involved 143 JIA patients diagnosed according to International League of Associations for Rheumatology criteria. Each patient underwent HLA class II typing, including HLA-B27, as well as tests for rheumatoid factor (RF) and antinuclear antibodies (ANA). Comprehensive rheumatological assessments were conducted at diagnosis, with follow-ups at three and six months post-onset. After six months of methotrexate (MTX) treatment, patients were categorized as responders or non-responders. Responders achieved clinically inactive disease based on the American College of Rheumatology Provisional Criteria for Defining Clinical Inactive Disease and Clinical Remission. Non-responders, who did not reach clinically inactive disease after six months of treatment, required the addition of another non-biological disease-modifying antirheumatic drug (DMARD) or a biological DMARD. Our analysis revealed that the HLA-DRB1*01 allele is a significant prognostic marker for therapeutic response, predicting therapeutic resistance (P=0.01). The most prevalent HLA-DRB1 alleles in the treatment-resistant group were HLA-DRB1*08:11 (11.3%), HLA-DRB1*01:01 (8.5%), HLA-DRB1*01:13, HLA-DRB1*04:11 (7%), HLA-DRB1*08:13, and HLA-DRB1*08:15 (4.2%). These findings highlight the critical role of HLA class II alleles in pediatric rheumatology, particularly in relation to treatment response and disease prognosis. In the era of personalized medicine, understanding the genetic contributions to treatment response and outcomes in JIA patients is essential. A key limitation of this study was the lack of comparison of treatment responses across different JIA subtypes. Future studies should prioritize evaluating MTX efficacy within specific JIA subgroups to enable a more tailored understanding of its effectiveness.

Prolactin: structure, receptors, and functions.

Prolactin (PRL) is a 23-kDa protein synthesized and secreted by lactotroph cells of the anterior pituitary gland but also by other peripheral tissues. PRL binds directly to a unique transmembrane receptor (PRLR), and the JAK2/signal transducer and activator of transcription 5 (Stat5) pathway is considered the major downstream pathway for PRLR signaling. To a lesser extent, PRL may be cleaved into the shorter 16-kDa PRL, also called vasoinhibin, whose signaling is not fully known. According to rodent models of PRL signaling inactivation and the identification of human genetic alterations in PRL signaling, a growing number of biological processes are partly mediated by PRL or its downstream effectors. In this review, we focused on PRL structure and signaling and its canonical function in reproduction. In addition to regulating reproductive functions, PRL also plays a role in behavior, notably in initiating nurturing and maternal behavior. We also included recent insights into PRL function in several fields, including migraines, metabolic homeostasis, inflammatory and autoimmune disease, and cancer. Despite the complexity of understanding the many functions of PRL, new research in this field offers interesting perspectives on physiological and pathophysiological processes.

Pathogenesis of psoriatic arthritis: new insights from a bone marrow perspective.

Psoriatic arthritis is an immune-mediated disease that primarily affects the skin and joints. It falls under the umbrella term of rheumatic diseases, which describes a group of closely related yet distinct disorders with many common underlying molecular pathways. Despite the distinct clinical manifestation of each disorder, the shared therapeutic strategies attest to the commonality of cellular and molecular underpinnings. Herein we provide a concise yet comprehensive overview of the interleukin (IL)-23/IL-17 axis and its involvement in mechanistic pathways leading to the pathogenesis of this dual skin and joint clinical manifestation which is characteristic of psoriatic arthritis and other rheumatic diseases. The interconnection between activated innate immune cells and adaptive immunity has transformed current thinking to include other organs such as the bone marrow as potential tissue of disease origin. A plethora of animal models and genetic studies converge on the critical role of IL-23/IL-17 axis, and highlight the importance of myeloid cell activation as common pathways between autoinflammatory and autoimmune diseases and chronic inflammation. These findings underscore the intricate immune mechanisms involved in inflammatory arthritis and highlight molecular mechanisms in disease pathogenesis. These insights pave the way for the development of novel diagnostic and therapeutic strategies, with a focus on translating these findings into improved clinical practice.

The role of the cGAS-STING pathway in chronic pulmonary inflammatory diseases

The innate immune system plays a vital role in the inflammatory process, serving as a crucial mechanism for the body to respond to infection, cellular stress, and tissue damage. The cGAS-STING signaling pathway is pivotal in the onset and progression of various autoimmune diseases and chronic inflammation. By recognizing cytoplasmic DNA, this pathway initiates and regulates inflammation and antiviral responses within the innate immune system. Consequently, the regulation of the cGAS-STING pathway has become a prominent area of interest in the treatment of many diseases. Chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis, are characterized by persistent or recurrent lung inflammation and tissue damage, leading to diminished respiratory function. This paper explores the mechanism of action of the cGAS-STING signaling pathway in these diseases, examines the development of STING inhibitors and nanomaterial applications, and discusses the potential clinical application prospects of targeting the cGAS-STING pathway in chronic inflammatory lung diseases.

Expression of lncRNAs NEAT1, PACERR, and GAS5 can be associated with disease activity in rheumatoid arthritis patients.

Long non-coding RNAs (lncRNAs) have long been considered molecular noise within the transcriptome, but over time it has been shown that they perform many important biological functions and are associated with various inflammatory and autoimmune diseases, including rheumatoid arthritis (RA). The aim of this study was to evaluate the association between circulating lncRNAs and RA activity. The study included 63 patients with well-established RA (median disease duration 12 years), 51.7 (13); mean (SD) aged, 88.9% women and 25 healthy controls (HCs) 51.8 (8.2) aged, 80% women. Quantitative real-time polymerase chain reaction was used to evaluate the plasma concentration levels of 6 lncRNAs: PACERR, NEAT1, HOTTIP, GAS5, MALAT1 and HIX003209. Among the tested molecules, 5 targets (PACERR, NEAT1, HOTTIP, GAS5 and HIX003209) had decreased concentration in RA patients compared to HCs. LncRNAs NEAT1, PACERR, and GAS5 showed differences between the severe disease activity group (the 28 joint disease activity score, DAS28>5.1) and HCs; (P = 0.02, P = 0.003 and P = 0.04, respectively). The multiple linear regression analysis indicated that GAS5 (P = 0.01) had the greatest impact on disease activity based on DAS28. Circulating plasma lncRNAs may be considered as supporting molecular markers associated with RA activity and may be useful in identifying disease exacerbation.