Pathogenesis Of Autoimmune Rheumatic Diseases Research Articles

Features of proinflammatory activation of macrophages in patients with rheumatoid arthritis and systemic lupus erythematosus

Autoimmune rheumatic diseases (ARDs) are chronic pathological conditions that arise from an abnormal immune response and are accompanied by systemic inflammation. The most common ARDs include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The exact pathogenesis of ARDs remains unclear, but the complex influence of genetic, immunological and external environmental factors leads to the occurrence and further progression of ARDs. It has been shown that the cause of chronic inflammation may be proinflammatory activation of macrophages, in which an increase in the secretion of cytokines is observed. The aim of this study was to evaluate the inflammatory response of macrophages in patients with RA, SLE and SSc. Materials and methods. The study included 143 participants: 47 patients with RA, 45 patients with SLE, 34 patients with SSc, and 17 people without ARDs and other chronic diseases. Isolation of a primary culture of monocytes was carried out by centrifugation in a ficoll gradient using magnetic separation from the whole blood of study participants. Lipopolysaccharide (LPS) was added to stimulate cells along the proinflammatory pathway. Cell cultivation was carried out for 24 hours. Determination of basal and LPS-stimulated secretion of IL-8 by macrophages was carried out in the culture fluid using an enzyme-linked immunosorbent assay (ELISA). Proinflammatory activation of macrophages was calculated as the ratio of LPS-stimulated and basal IL-8 secretion. Research results. Basal secretion of IL-8 by macrophages was statistically significantly higher in the groups of patients with RA and SSc compared with the SLE and control groups. LPS-stimulated secretion of IL-8 by macrophages in the SSc group had statistically higher values compared to the RA and SLE groups. Proinflammatory activation of macrophages was reduced in the group of patients with RA compared to patients with SLE and the control group, and was also statistically significantly lower in patients with SSc compared to the control group.

EBNA-1 antibody and autoimmune rheumatic diseases: A Mendelian Randomization Study

BackgroundNumerous studies have investigated a possible correlation between Epstein-Barr virus (EBV) and autoimmune rheumatic diseases (ARDs). However, establishing a cause-and-effect relationship remains a challenging endeavor. This study employs Mendelian randomization to examine the impact of EBV nuclear antigen-1 antibody (EBNA-1) antibody levels on the susceptibility to nine distinct ARDs, including rheumatoid arthritis (RA), primary Sjogren's syndrome (PSS), systemic lupus erythematosus (SLE), undifferentiated reactive arthritis (UA), systemic sclerosis (SSc), adult-onset Still's disease (AOSD), psoriatic arthritis (PsA), dermatomyositis (DM), and ankylosing spondylitis (AS). MethodsThe researchers applied a two-sample Mendelian randomization approach, utilizing online data from separate cohorts of European descent. We drew upon data from GWAS related to EBNA-1 antibody levels and the nine autoimmune-related disorders. Our primary analyses predominantly relied on the Inverse Variance Weighted methodology, complemented by a range of sensitivity assessments. ResultsOur analysis revealed significant direct associations between EBNA-1 antibody levels and the risk of developing PSS (95 % CI: 0.44 to 0.85, p = 0.003), PsA (95 % CI: 0.36 to 0.99, p = 0.044), AS (95 % CI: 0.07 to 0.88, p = 0.031), and UA (95 % CI: 0.56 to 0.96, p = 0.025). These results remained consistent through comprehensive sensitivity analyses. However, no clear associations were found for the other specified conditions. ConclusionsOur findings provide compelling evidence that EBNA-1 antibody levels play a role in developing ARDs. These findings enhance our understanding of ARD pathogenesis and hold substantial promise for developing potential treatment strategies.

Methylation of T and B Lymphocytes in Autoimmune Rheumatic Diseases.

The role of abnormal epigenetic modifications, particularly DNA methylation, in the pathogenesis of autoimmune rheumatic diseases (ARDs) has garnered increasing attention. Lymphocyte dysfunction is a significant contributor to the pathogenesis of ARDs. Methylation is crucial for maintaining normal immune system function, and aberrant methylation can hinder lymphocyte differentiation, resulting in functional abnormalities that disrupt immune tolerance, leading to the excessive expression of inflammatory cytokines, thereby exacerbating the onset and progression of ARDs. Recent studies suggest that methylation-related factors have the potential to serve as biomarkers for monitoring the activity of ARDs. This review summarizes the current state of research on the impact of DNA and RNA methylation on the development, differentiation, and function of T and B cells and examines the progress of these epigenetic modifications in studies of six specific ARDs: systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, juvenile idiopathic arthritis, and ankylosing spondylitis. Additionally, we propose that exploring the interplay between RNA methylation and DNA methylation may represent a novel direction for understanding the pathogenesis of ARDs and developing novel treatment strategies.

Research progress of SREBP and its role in the pathogenesis of autoimmune rheumatic diseases.

Autoimmune rheumatic diseases comprise a group of immune-related disorders characterized by non-organ-specific inflammation. These diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, among others. Typically involving the hematologic system, these diseases may also affect multiple organs and systems. The pathogenesis of autoimmune rheumatic immune diseases is complex, with diverse etiologies, all associated with immune dysfunction. The current treatment options for this type of disease are relatively limited and come with certain side effects. Therefore, the urgent challenge remains to identify novel therapeutic targets for these diseases. Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix-leucine zipper transcription factors that regulate the expression of genes involved in lipid and cholesterol biosynthesis. The expression and transcriptional activity of SREBPs can be modulated by extracellular stimuli such as polyunsaturated fatty acids, amino acids, glucose, and energy pathways including AKT-mTORC and AMP-activated protein kinase (AMPK). Studies have shown that SREBPs play roles in regulating lipid metabolism, cytokine production, inflammation, and the proliferation of germinal center B (GCB) cells. These functions are significant in the pathogenesis of rheumatic and immune diseases (Graphical abstract). Therefore, this paper reviews the potential mechanisms of SREBPs in the development of SLE, RA, and gout, based on an exploration of their functions.

COVID-19 and rheumatic diseases: A mini-review.

Joint pain and arthralgia can be manifestations of COVID-19, and studies evaluating long COVID symptoms identified the persistence of these disorders. Moreover, some case reports highlighted the development of new inflammatory arthritis in patients with COVID-19, suggesting a possible relation. Viral infections and rheumatic diseases share a documented relationship; they have been associated with genetic and environmental risk factors responsible for some of them. There is crosstalk between viruses and the immune system during the development of several rheumatic diseases. Moreover, infections may participate in the pathogenesis of autoimmune rheumatic diseases and contribute to patient mortality. Therefore, it is crucial to provide a clearer insight into the interaction between viral infections and rheumatic diseases. Here, we provide a mini-review of the current literature with the aim of shedding light on the relationship between COVID-19 and rheumatic or musculoskeletal diseases, which is still unclear. Specifically, we examined several aspects: risk for the rheumatic population of acquiring the virus or developing severe symptoms, similarities of COVID-19 and arthritis, the possible rheumatic consequence of COVID-19, of rheumatic drugs and vaccines, and COVID-19 prevention in rheumatic patients through vaccination.

MiRNAs as Biomarkers and Possible Therapeutic Strategies in Rheumatoid Arthritis.

Within the past years, more and more attention has been devoted to the epigenetic dysregulation that provides an additional window for understanding the possible mechanisms involved in the pathogenesis of autoimmune rheumatic diseases. Rheumatoid arthritis (RA) is a heterogeneous disease where a specific immunologic and genetic/epigenetic background is responsible for disease manifestations and course. In this field, microRNAs (miRNA; miR) are being identified as key regulators of immune cell development and function. The identification of disease-associated miRNAs will introduce us to the post-genomic era, providing the real probability of manipulating the genetic impact of autoimmune diseases. Thereby, different miRNAs may be good candidates for biomarkers in disease diagnosis, prognosis, treatment and other clinical applications. Here, we outline not only the role of miRNAs in immune and inflammatory responses in RA, but also present miRNAs as diagnostic/prognostic biomarkers. Research into miRNAs is still in its infancy; however, investigation into these novel biomarkers could progress the use of personalized medicine in RA treatment. Finally, we discussed the possibility of miRNA-based therapy in RA patients, which holds promise, given major advances in the therapy of patients with inflammatory arthritis.

Epigenetics, pregnancy and autoimmune rheumatic diseases.

Autoimmune rheumatic diseases (ARDs) are chronic conditions with a striking female predominance, frequently affecting women of childbearing age. Sex hormones and gender dimorphism of immune response are major determinants in the multifactorial pathogenesis of ARDs, with significant implications throughout reproductive life. Particularly, pregnancy represents a challenging condition in the context of autoimmunity, baring profound hormonal and immunologic changes, which are responsible for the bi-directional interaction between ARDs outcome and pregnancy course. In the latest years epigenetics has proven to be an important player in ARDs pathogenesis, finely modulating major immune functions and variably tuning the significant gender effects in autoimmunity. Additionally, epigenetics is a recognised influencer of the physiological dynamic modifications occurring during pregnancy. Still, there is currently little evidence on the pregnancy-related epigenetic modulation of immune response in ARDs patients. This review aims to overview the current knowledge of the role of epigenetics in the context of autoimmunity, as well as during physiologic and pathologic pregnancy, discussing under-regarded aspects in the interplay between ARDs and pregnancy pathology. The outline of a new ongoing European project will be presented.

Role of the eNOS Uncoupling and the Nitric Oxide Metabolic Pathway in the Pathogenesis of Autoimmune Rheumatic Diseases.

Atherosclerosis and its clinical complications constitute the major healthcare problems of the world population. Due to the central role of endothelium throughout the atherosclerotic disease process, endothelial dysfunction is regarded as a common mechanism for various cardiovascular (CV) disorders. It is well established that patients with rheumatic autoimmune diseases are characterized by significantly increased prevalence of cardiovascular morbidity and mortality compared with the general population. The current European guidelines on cardiovascular disease (CVD) prevention in clinical practice recommend to use a 1,5-factor multiplier for CV risk in rheumatoid arthritis as well as in other autoimmune inflammatory diseases. However, mechanisms of accelerated atherosclerosis in these diseases, especially in the absence of traditional risk factors, still remain unclear. Oxidative stress plays the major role in the endothelial dysfunction and recently is strongly attributed to endothelial NO synthase dysfunction (eNOS uncoupling). Converted to a superoxide-producing enzyme, uncoupled eNOS not only leads to reduction of the nitric oxide (NO) generation but also potentiates the preexisting oxidative stress, which contributes significantly to atherogenesis. However, to date, there are no systemic analyses on the role of eNOS uncoupling in the excess CV mortality linked with autoimmune rheumatic diseases. The current review paper addresses this issue.

Nivel de estrés, medido a través de la Escala de Estrés Percibido (EEP-10), y su asociación con la actividad de la enfermedad en pacientes con Artritis Reumatoidea

Stress is a risk factor in the pathogenesis of autoimmune rheumatic diseases. Objective: to evaluate the association between disease activity in patients with RA. Secondary: to evaluate the association of perceived stress levels with other activity indexes (SDAI, CDAI, DAS28 and IAS) as well as with disability, anxiety and depression and quality of life.

Autoimmune rheumatic disease IgG has differential effects upon neutrophil integrin activation that is modulated by the endothelium

The importance of neutrophils in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), is increasingly recognised. Generation of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs) by activated neutrophils are both thought to contribute to pathology; although the underlying mechanisms, particularly the effects of IgG autoantibodies upon neutrophil function, are not fully understood. Therefore, we determined whether purified IgG from patients with SLE or RA have differential effects upon neutrophil activation and function. We found that SLE- and RA-IgG both bound human neutrophils but differentially regulated neutrophil function. RA- and SLE-IgG both increased PMA-induced β1 integrin-mediated adhesion to fibronectin, whilst only SLE-IgG enhanced αMβ2 integrin-mediated adhesion to fibrinogen. Interestingly, only SLE-IgG modulated neutrophil adhesion to endothelial cells. Both SLE- and RA-IgG increased ROS generation and DNA externalisation by unstimulated neutrophils. Only SLE-IgG however, drove DNA externalisation following neutrophil activation. Co-culture of neutrophils with resting endothelium prevented IgG-mediated increase of extracellular DNA, but this inhibition was overcome for SLE-IgG when the endothelium was stimulated with TNF-α. This differential pattern of neutrophil activation has implications for understanding SLE and RA pathogenesis and may highlight avenues for development of novel therapeutic strategies.

The clinical and pathogenetic value of Foxp3+ T regulatory cells in rheumatoid arthritis

T regulatory cells (Tregs) play a key role in the immune system due to the suppression of a hyperimmune response to autoantigens and opportunistic enteric microorganisms. In recent years, there has been evidence that Tregs can suppress various immunoinflammatory responses to a wide range of physiological and pathological stimuli, including microorganisms, tumor cells, allogeneic grafts, and fetal cells. Tregs express a broad spectrum of membrane molecules that determine their functional activity and make it possible to identify these cells; however, none has discovered a universal surface marker that would distinguish this cell subpopulation from a pool of T lymphocytes. The most specific intracellular marker for Tregs is the nuclear transcription factor Foxp3 that is of fundamental importance in the development of Tregs and their inhibitory function. The results of the vast majority of studies indicate that there are increased numbers of Tregs in the synovial fluid of patients with rheumatoid arthritis (RA); however, the data on the level of this cell population in their peripheral blood are very contradictory. The majority of investigators have observed a decrease in the percentage of circulating Tregs while other studies have revealed its increase or no differences from the corresponding value of healthy donors or patients with osteoarthritis. It is believed that a quantitative defect in CD4+CD25+Foxp3+CD127 regulatory cells is especially characteristic of early RA and associated with the risk of the latter in asymptomatic patients positive for anti-cyclic citrullinated peptide antibodies. The use of disease-modifying antirheumatic drugs and biologic agents is accompanied by a certain change in the level and functional activity of Tregs, which is responsible for the therapeutic effect of the medicaments. Thus, an important part is assigned to Tregs in the pathogenesis of autoimmune rheumatic diseases, RA in particular. The decrease in the level and functional activity of Tregs is likely to underlie the development of uncontrolled chronic inflammation leading to multiple organ damages.

Evaluation of Heat Shock Proteins 70 (HSP70) and some Risk Factors in Sera of Rheumatoid Arthritis Patients in Thi-Qar Province

Heat shock proteins (HSPs)were synthesized under different kinds of stress conditions and act as molecular chaperones for protein molecules. These proteins were first found in cells that were exposed to high temperature, they are called shock protein. Several risk factors are involved in the pathogenesis of autoimmune rheumatic diseases, including genetic factors, smoking, chronic infections, sex hormones, stress and HSP 70. In this present study the role of heat shock protein 70 was investigated in pathogenesis and immune response in rheumatoid arthritis (RA). This study was conducted onfifty samples of rheumatoid arthritis patients. In addition twenty samples of superficially healthy volunteers. All these samples were used for determining the concentration of HSP70. The results of study demonstrate the existence of high significant difference (P≤0.001), between patients and control group when the concentration of HSP70 was measured for all samples. This study also demonstrates slight statistical differences (P≤0.05), among studied groups when taken into consideration the gender, age groups and characteristics of smoking. It is concluded that the concentration of HSP70 is increasing at the beginning of the disease and it is higher in RA patients compared with control, also it is higher in female than in male groups.

Endothelial nitric oxide synthase gene polymorphisms and the risk of osteonecrosis of the femoral head in systemic lupus erythematosus

Nitric oxide (NO), a short-lived gaseous free radical, is a potent mediator of biological responses involved in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Nitric oxide also serves as an important signal in physiological processes, including angiogenesis, thrombosis, and bone turnover, which are known to be related to the pathogenesis of osteonecrosis. We investigated whether NOS3 gene polymorphisms are associated with risk of osteonecrosis of the femoral head (ONFH). Five polymorphisms in the NOS3 gene were genotyped using TaqMan assays in 306 controls, 150 SLE patients, and 50 SLE patients with ONFH (SLE_ONFH). We found that Asp258Asp and Glu298Asp (G894T) polymorphisms in the NOS3 gene were significantly associated with risk of ONFH. Additionally, we calculated haplotype frequencies of a linkage disequilibrium (LD) block in NOS3 (rs1799983 - rs1800780) and tested for haplotype associations. The haplotypes G-A and T-A showed significant protective (P = 1.6 × 10(-3); OR 0.39, 95 % confidence intervals (CI) 0.22-0.7) and increased risk (P = 2.0 x 10(-5)-6.0 x 10(-4); OR 3.17-3.73) effects for ONFH, respectively. These results suggest that exonic NOS3 polymorphisms may increase the risk of ONFH in Korean SLE patients.

Epigenetic alterations in autoimmune rheumatic diseases

The potential roles of epigenetic alterations in the pathogenesis of autoimmune rheumatic diseases are raising great expectations among clinicians and researchers. Epigenetic mechanisms regulate gene expression and are sensitive to external stimuli, bridging the gap between environmental and genetic factors. Considerable evidence of epigenetic changes, particularly altered patterns of DNA methylation, exists in diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. The importance of such changes in the pathology of rheumatic diseases has been demonstrated by examining the relationship between gene-specific methylation and SLE in monozygotic twins discordant for the disease, in whom genetic variability is excluded as a cause for discordance. Several studies have highlighted the importance of the tissue-specificity of DNA methylation changes, an aspect which-in contrast with genetic analysis-must be considered when designing epigenetic studies. Here I discuss the proposed mechanisms and implications of DNA methylation changes in the pathogenesis of autoimmune rheumatic diseases, the prospects for future epigenetic studies in rheumatology, the relevance of specific DNA methylation markers and the potential use of drugs with an epigenetic effect in the clinical management of these diseases.

Assessment of Proinflammatory Th1 Cytokines (IL18-IFN ) and Th2 Cytokine (IL13) Concentrations in patients with Autoimmune Rheumatic Diseases (Systemic Lupus Erythematosus, Rheumatoid Artharitis and Systemic Sclerosis)

Objective: Several cytokines play a role in the production of autoantibodies and the pathogenesis of rheumatic diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (SS). This study investigated serum concentration of the proinflammatory Th1 cytokine; IL18 and its inducer IFNg, the study also investigated serum concentration of proinflammatory Th2­ cytokine; IL13, to explain the role of Th1 and Th2 in the pathogenesis of autoimmune rheumatic diseases (SLE, RA and SS) Patients and methods: IL18, IFNg and IL13 levels were evaluated by enzyme linked immunosorbent assay (ELISA). Four groups were included in this study. Group I: Comprised (15) patients of SLE. Group II: Comprised (15) patients of RA. Group III: Comprised (15) patients with SS. Group IV: Control group consisted of (15) sex and age matched healthy controls. Results: Serum levels of IL18 was significantly higher in SLE (3138.200± 1413.096 pg/ml)& RA(3336.667± 921.839 pg/ml) than control group(86.647± 35.370 pg/ml ), while IL18­ in SS had no statistically significant difference between patients (103.634± 50.593 pg/ml) and control group (86.647± 35.370 pg/ml).The cut off level was 257.75 pg/ml . IFNg was significantly higher in SLE patients (5.439±1.430 IU/ml) and RA patients (2.973± 0.598 IU/ml ) than control group(0.580 ± 0.234 IU/ml) ,while IFNg in SS had no statistically significant difference (0.592± 0.245IU/ml) than control group (0.580 ± 0.234 IU/ml) .The cut off level was1.2 IU/ml . As regard IL13 it was significantly higher in SLE patients (55.673±6.892 pg/ml) ,RA patients (59.587±12.183 pg/ml) and SS (61.550± 12.047 pg/ml) than control group (21.427± 7.274 pg/ml ) .The cut off level was 44.4 pg/ml .There was significant positive correlation of IL18/ IL13 and IFNg / IL13 ratio in SLE and RA , while significant negative correlation of IL18/ IL13 and IFNg / IL13 ratio in SS. Conclusion: There was a significant increase of both Th1 cytokines (IL18 and IFNg) and Th2­ cytokine (IL13) in SLE and RA with Th1 predominance,while predominance of Th2­ cytokine (IL13) in SS than Th1 cytokine (IL18 and IFNg). This result suggests that IL18, INFg and IL13 could be involved in the pathogenesis of autoimmune rheumatic diseases.

Assessment of Proinflammatory Th1 Cytokines (IL18-IFN ) and Th2‌ Cytokine (IL13) Concentrations in patients with Autoimmune Rheumatic Diseases (Systemic Lupus Erythematosus, Rheumatoid Artharitis and Systemic Sclerosis)

Objective: Several cytokines play a role in the production of autoantibodies and the pathogenesis of rheumatic diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (SS). This study investigated serum concentration of the proinflammatory Th1 cytokine; IL18 and its inducer IFNg, the study also investigated serum concentration of proinflammatory Th2­ cytokine; IL13, to explain the role of Th1 and Th2 in the pathogenesis of autoimmune rheumatic diseases (SLE, RA and SS) Patients and methods: IL18, IFNg and IL13 levels were evaluated by enzyme linked immunosorbent assay (ELISA). Four groups were included in this study. Group I: Comprised (15) patients of SLE. Group II: Comprised (15) patients of RA. Group III: Comprised (15) patients with SS. Group IV: Control group consisted of (15) sex and age matched healthy controls. Results: Serum levels of IL18 was significantly higher in SLE (3138.200± 1413.096 pg/ml)& RA(3336.667± 921.839 pg/ml) than control group(86.647± 35.370 pg/ml ), while IL18­ in SS had no statistically significant difference between patients (103.634± 50.593 pg/ml) and control group (86.647± 35.370 pg/ml).The cut off level was 257.75 pg/ml . IFNg was significantly higher in SLE patients (5.439±1.430 IU/ml) and RA patients (2.973± 0.598 IU/ml ) than control group(0.580 ± 0.234 IU/ml) ,while IFNg in SS had no statistically significant difference (0.592± 0.245IU/ml) than control group (0.580 ± 0.234 IU/ml) .The cut off level was1.2 IU/ml . As regard IL13 it was significantly higher in SLE patients (55.673±6.892 pg/ml) ,RA patients (59.587±12.183 pg/ml) and SS (61.550± 12.047 pg/ml) than control group (21.427± 7.274 pg/ml ) .The cut off level was 44.4 pg/ml .There was significant positive correlation of IL18/ IL13 and IFNg / IL13 ratio in SLE and RA , while significant negative correlation of IL18/ IL13 and IFNg / IL13 ratio in SS. Conclusion: There was a significant increase of both Th1 cytokines (IL18 and IFNg) and Th2­ cytokine (IL13) in SLE and RA with Th1 predominance,while predominance of Th2­ cytokine (IL13) in SS than Th1 cytokine (IL18 and IFNg). This result suggests that IL18, INFg and IL13 could be involved in the pathogenesis of autoimmune rheumatic diseases.

Type I interferons: crucial participants in disease amplification in autoimmunity

A significant body of data implicates the type I interferon (IFN) pathway in the pathogenesis of autoimmune rheumatic diseases. In these disorders, a self-reinforcing cycle of IFN production can contribute to immunopathology through multiple mechanisms. Type I IFN cytokines are pleiotropic in their effects, mediating antiviral and antitumor activities, and possess numerous immunomodulatory functions for both the innate and adaptive immune responses. A key principle of the type I IFN system is rapid induction and amplification of the signaling pathway, which generates a feed-forward loop of IFN production, ensuring that a vigorous antiviral immune response is mounted. Although such feed-forward pathways are highly adaptive when it comes to rapid and effective virus eradication, this amplification can be maladaptive in immune responses directed against host tissues. Such feed-forward loops, however, create special opportunities for therapy.

Association of the nitric oxide synthase (eNOS) gene polymorphism with increased risk for both lupus glomerulonephritis and rheumatoid arthritis in a single genetically homogeneous population

Nitric oxide (NO), a short-lived gaseous free radical, synthesized from L-arginine by NO synthases (NOS), is a potent mediator of biologic responses involved in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Most biological necessary NO is produced by the family of three NOS. To date, several functionally relevant genetic polymorphisms in the eNOS gene have been associated with various vascular, infectious and autoimmune diseases. To our knowledge, no study has explored these polymorphisms for both SLE and RA in the same population. The objective of this study was to investigate the influence of the eNOS gene intron 4 a/b VNTR polymorphism (a 27-base-pair tandem repeat-based polymorphism) on susceptibility to SLE and RA in patients living in the island of Crete, a genetically homogeneous population. A group of 145 healthy subjects and 190 SLE patients were included in this study. Similarly, a second group of 235 healthy controls and 202 RA patients were analysed. In both cases, patients and controls were sex- and age-matched. Herein we report that the presence of a/b genotype of the eNOS gene may act as a risk factor not for the presence of SLE but for the development of glomerulonephritis (OR 2.71, 95% CI: 1.4-5.2), while it may be a susceptibility gene for RA (OR: 2.005, 95% CI: 1.31-3.07). Thus, in our population, the a/b genotype of the eNOS gene represents a severity rather than a susceptibility genotype for SLE.

Doenças reumáticas auto-imunes em indivíduos infectados pelo HTLV-1

O HTLV-1 foi o primeiro retrovírus humano a ser associado às doenças malignas leucemia e linfoma de células T do adulto (LLTA). Ele está relacionado também a uma doença inflamatória crônica do sistema nervoso central (SNC) conhecida como paraparesia espástica tropical/mielopatia associada ao HTLV-1 (PET/MAH). O HTLV-1 tem sido implicado na patogênese de várias doenças auto-imunes, tais como: diabetes, esclerose múltipla, dermatite infectiva, uveíte e artropatia. Ao longo dos anos, a infecção retroviral tem assumido um importante papel na patogênese das doenças reumáticas auto-imunes. Partículas semelhantes aos retrovírus têm sido identificadas em tecidos de pacientes com artrite reumatóide (AR), síndrome de Sjögren, lúpus eritematoso sistêmico (LES) e polimiosite. A síndrome de Sjögren e a AR têm sido as doenças reumáticas mais encontradas nos pacientes infectados pelo HTLV-1, sendo a freqüência mais elevada nos pacientes com mielopatia. A alta prevalência de síndrome de Sjögren e de AR entre os indivíduos com mielopatia sugere que a carga viral e a resposta inflamatória exacerbada, que concorrem para o desenvolvimento da mielopatia, devem também influenciar no desenvolvimento das doenças reumáticas auto-imunes.

Autoantibodies to heterogeneous nuclear ribonucleoproteins

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are among the most abundant proteins in the eukaryotic cell nucleus and play a direct role in several aspects of the RNA life including splicing, export of the mature RNAs and translation. To date, ∼30 proteins have been identified. A growing body of evidence points to hnRNPs as an important target of the autoimmune response in rheumatic diseases. Autoantibodies to A and B proteins of the hnRNP complex have been detected in late 1980s in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Beyond their role as diagnostic test in clinical practice, these autoantibodies are starting to be regarded as important tools to obtain deeper insight into the pathogenesis of autoimmune rheumatic diseases. Furthermore, new anti-hnRNP antibodies have been recognized in the last ten years extending the spectrum of anti-hnRNP reactivity in different autoimmune disorders.