Research on hsa-miR-155-3p and hsa-miR-155-5p as biomarkers for systemic sclerosis and their role in regulating biological behavior

Objective: This study was to investigate the role of hsa-miR-155-3p and hsa-miR-155-5p as biomarkers and regulators of biological behavior in Systemic Sclerosis. Methods: A total of 10 SSc patients and 10 healthy controls were selected for the study. The expression levels of hsa-miR-155-3p and hsa-miR-155-5p in peripheral blood mononuclear cells of SSc patients and healthy controls were measured using RT-qPCR. The diagnostic value of these miRNAs was explored using Receiver Operating Characteristic curve analysis. Pearson or Spearman correlation analysis was performed to assess the correlation between miRNAs and clinical indicators in SSc patients. Potential target genes of hsa-miR-155-3p and hsa-miR-155-5p were predicted using miRDB, Targetscan, and miRDIP databases. GO functional annotation, KEGG pathway enrichment analysis, protein-protein interaction network construction, and selection of central genes were conducted. Results: The expression levels of hsa-miR-155-3p and hsa- miR-155-5p were significantly higher in PBMCs of SSc patients compared to healthy controls (P<0.001). The ROC curve analysis showed that hsa-miR-155-3p and hsa-miR-155-5p had a high diagnostic value for SSc (AUC=1, P<0.001). Correlation analysis revealed that hsa- miR-155-3p, hsa-miR-155-5p, and clinical indicators such as high-resolution CT, neutrophil percentage, lymphocyte percentage, and albumin to globulin ratio were correlated (P<0.05). The signaling pathways enriched with target genes of hsa-miR-155-3p and hsa-miR-155- 5p were closely associated with the occurrence and development of SSc fibrosis, immunity, and inflammation. Conclusions: hsa-miR-155-3p and hsa-miR-155-5p may be involved in regulating the occurrence and development of SSc fibrosis, immunity, and inflammation. They have the potential to serve as biomarkers for clinical diagnosis and treatment of SSc.

Juvenile Systemic Sclerosis: About 9 Cases

Scleroderma is a rare disease with two primary forms: localized scleroderma (LS) and systemic sclerosis (SSc). Both are chronic conditions that can manifest in various patterns (subtypes) and are linked to extracutaneous involvement in pediatric patients. Juvenile SSc poses a higher risk of morbidity and mortality, with patients facing life-threatening complications such as lung, heart, and visceral organ fibrosis, and vasculopathy. In contrast, mortality is extremely rare in juvenile LS, but patients are susceptible to significant morbidity, leading to severe disfigurement and functional impairment. Treatment for scleroderma aims to control inflammation and address specific issues. An early diagnosis significantly enhances the overall outcome. This study conducts a retrospective descriptive analysis aiming to document the clinical manifestations, management approaches, and outcomes of systemic sclerosis in a cohort of nine children receiving treatment for juvenile systemic sclerosis at Pediatric B department of Mohammed VI University, Hospital Center in Marrakech, Morocco.

Adipose-derived stem cells:Pathophysiologic implications vs therapeutic potential in systemic sclerosis

Adipose-derived stem cells(ADSCs)residing in the stromal vascular fraction(SVF)of white adipose tissue are recently emerging as an alternative tool for stem cell-based therapy in systemic sclerosis(SSc),a complex connective tissue disorder affecting the skin and internal organs with fibrotic and vascular lesions.Several preclinical and clinical studies have reported promising therapeutic effects of fat grafting and autologous SVF/ADSC-based local treatment for facial and hand cutaneous manifestations of SSc patients.However,currently available data indicate that ADSCs may represent a double-edged sword in SSc,as they may exhibit a pro-fibrotic and anti-adipogenic phenotype,possibly behaving as an additional pathogenic source of pro-fibrotic myofibroblasts through the adipocyte-to-myofibroblast transition process.Thus,in the perspective of a larger employ of SSc-ADSCs for further therapeutic applications,it is important to definitely unravel whether these cells present a comparable phenotype and similar immunosuppressive,anti-inflammatory,anti-fibrotic and pro-angiogenic properties in respect to healthy ADSCs.In light of the dual role that ADSCs seem to play in SSc,this review will provide a summary of the most recent insights into the preclinical and clinical studies employing SVF and ADSCs for the treatment of the disease and,at the same time,will focus on the main findings highlighting the possible involvement of these stem cells in SSc-related fibrosis pathogenesis.

Transforming growth factor-β signaling in systemic sclerosis

Systemic sclerosis（SSc） is a complex, multiorgan autoimmune disease of unknown etiology. Manifestation of the disease results from an interaction of three key pathologic features including irregularities of the antigen-specific immune system and the non-specific Immune system, resulting in autoantibody production, vascular endothelial activation of small blood vessels, and tissue fibrosis as a result of fibroblast dysfunction. Given the heterogeneity of clinical presentation of the disease, a lack of universal models has impeded adequate testing of potential therapies for SSc. Regardless, recent research has elucidated the roles of various ubiquitous molecular mechanisms that contribute to the clinical manifestation of the disease. Transforming growth factor β（TGF-β） has been identified as a regulator of pathological fibrogenesis in SSc. Various processes, including cell growth, apoptosis, cell differentiation, and extracellular matrix synthesis are regulated by TGF-β,a type of cytokine secreted by macrophages and many other cell types. Understanding the essential role TGF-β pathways play in the pathology of systemic sclerosis could provide a potential outlet for treatment and a better understanding of this severe disease.

Gastrointestinal manifestations of systemic sclerosis:An updated review

Systemic sclerosis is an autoimmune disease characterized by vascular disease,fibrosis of the skin,and internal organ dysfunction.Gastrointestinal involvement is the most frequent complication of internal organs,impacting up to 90%of patients.Gastrointestinal involvement can affect any region of the gastrointestinal tract from the mouth to the anus,with a predominance of disorders being observed at the level of the upper digestive tract.The gastrointestinal involvement primarily involves the esophagus,small bowel,and rectum.The severity of gastrointestinal involvement affects quality of life and is a marker of worse prognosis and mortality in these patients.In this review,we describe the current findings regarding gastrointestinal involvement by this entity.

Expression of MMP-9 and TIMP-1 in Lesions of Systemic Sclerosis and Its Implications

In order to investigate the role of MMP-9 and TIMP-1 in the pathogenesis of systemic sclerosis, the expression of MMP-9 and TIMP-1 was immunohistochemically detected in skin lesions of the patients with diffuse cutaneous systemic sclerosis, skin lesions of the patients with limited cutaneous systemic sclerosis, and skin tissues of normal subjects. The results showed that the expression of MMP-9 in lesions of diffuse cutaneous systemic sclerosis was significantly lower than that of normal skins （P〈0.05）. However, no significant difference in the level of MMP-9 in the limited cutaneous systemic sclerosis and normal skin was found. Meanwhile, the expression of TIMP-1 in lesions of diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis were significantly higher than that of normal skins （both P〈0.05）. It was suggested that the expression of MMP-9 and TIMP-1 might play an important role in the development of systemic sclerosis.

Exploring the treatment of Systemic Sclerosis with Danggui (Angelica sinensis, AS)-Sini Decoction using GEO combined with Network pharmacology and Molecular docking

Background:To explore the relevant targets of the Chinese herbal medicine compound Danggui-Sini Decoction(DGSND)for the treatment of systemic sclerosis(SSc).Method:We used TCMSP to enlist ingredients and Swiss Target Prediction for targets fishing,and the protein names by UniProt for organized as gene symbol.Strawberry Perl was used to integrate the active ingredients and the drugs action target of DGSND,with Cytoscape 3.9.0 software to construct"Active ingredient-Drug target"network.Then,GEO database,GeneCards database,TTDdatabase,DisGENent database and MalaCards database for SSc-related disease target prediction,and then analyzed the active drug targets of DGSND and SSc-related targets of Danggui-Sini Decoction treat SSc.Then,the above results we combined with STRING database to visualize the Protein-protein interaction(PPI)network for the core targets of SSc,and performed Gene ontology(GO)functional analysis and Kyoto Encyclopedia of Genomics(KEGG)signaling pathway enrichment analysis for SSc-related targets treated with DGSND Result:DGSND contains 223 active ingredients including Sitogluside,Benzoylpaeoniflorin,(-)-Asarinin Palbinone,Glycyro,4'DMEP etc.which acts on Signal transducer and activator of transcription 3(STAT3),Tumor Necrosis Factor(TNF),Vascular endothelial growth factor(VEGFA),Nuclear factor kappa-B(NFκB1),Interleukin(IL1β,IL17),Mitogen-activated protein kinase(MAPK)and Janus Kinase(JAK)and many other genes totaling 176,mainly involved in 4 more biological processes 3 molecular functions and 3 cellular components.Conclusion:DGSND is primarily used to treat SSc by regulating calcium homeostasis,inflammatory signaling pathways and neural cell repair and apoptosis-related pathways within the body.

Network pharmacological study and molecular docking verification of Capparis spinosa in the treatment of systemic sclerosis

Objective:To explore the molecular mechanism of Capparis spinosa in the treatment of systemic sclerosis((SSC))based on network pharmacology.Methods:GEO,Genecards,Pharmgkb,TTD and Drugbank databases were used to obtain SSC targets,related literatures and Swisstargetprediction databases were used to obtain the main components of Citrus and their corresponding targets,and intersection was used to obtain prediction targets.Log in to the String database to analyze the protein interaction of the prediction target(PPI),further used Cytoscape to obtain the core gene by network topology analysis,and the core gene was docked with the main components of Capparis spinosa.The prediction targets were analyzed by gene ontology(GO)analysis and Kyoto encyclopedia of genes and genomes(KEGG)pathway analysis using R software.Results:A total of 15 active components and their targets were obtained,3171 SSC targets were obtained,and 66 predicted targets were obtained by intersection.Ten PPI core genes such as VEGFA,TNF,AKT1,PTGS2 and MMP9 were obtained by topological analysis.GO analysis involved many biological processes such as reactive oxygen species metabolic process、protein kinase B signaling、regulation of inflammatory response、phosphatidylinositol 3-kinase signaling and so on.KEGG pathway analysis showed PI3K-Akt signaling pathway,Proteoglycans in cancer,Focal adhesion,Rap1 signaling pathway and other signaling pathways.Conclusion:The molecular mechanism of Capparis spinosa in the treatment of SSC is predicted by the method of network pharmacology,which provides theoretical basis and data support for the basic research of Citrus officinalis in the treatment of SSC.

Lower Extremity Ulcers in Patients with Systemic Sclerosis

Introduction: Cutaneous manifestations of systemic sclerosis (SSc) include skin ulceration;4% - 12% of patients with SSc develop lower extremity ulcers of various etiologies. Limited data, significant morbidity, and substantial cost of wound care led us to undertake this study to describe and identify risk factors. Methods: After Institutional Review Board approval, we identified 30 patients with SSc and lower extremity ulcers over a 10-year period at a single center with an SSc clinic, which were included in a descriptive analysis. Results: Median age of onset of lower extremity ulcers was 59.5 years (range 20 - 84). Ninety percent of patients were female, 60% were Caucasian, 63% had limited SSc, 13% diffuse SSc and 23% an overlap syndrome. Immunomodulators or steroids were prescribed in 53%;hypercoagulable state identified in 16%. Ulcers were attributed to venous stasis (27%), SSc (20%), trauma (20%), arterial disease (17%), and multifactorial/unknown (17%). In patients with ulcers attributed to SSc, age at onset was lower (45.5 vs 59.5 years). Biopsies generally did not contribute to management. Multidisciplinary treatment was routine;20% required amputation, 10% endovascular intervention, 20% frequent surgical debridement, 10% hyperbaric oxygen, 26% local treatment and antibiotics and 13% received immunosuppression for wound treatment. Conclusion: Lower extremity ulcers are a serious clinical problem in patients with SSc. The clinical exam, venous dopplers, ankle-brachial indices and assessment of vascular risk factors helped define causality. In younger patients, ulcers were more frequently attributed to SSc and these patients were more likely to be on immunosuppressants/DMARDS, possibly indicating severe phenotype of SSc.

Detection of Ⅴ,Ⅲ and Ⅰ Type Collagens of Dermal Tissues in Skin Lesions of Patients with Systemic Sclerosis and Its Implication

This study investigated the contents and distribution of collagen Ⅴ （Col Ⅴ） in skin lesions of the patients with systemic sclerosis （SSc） and its roles in the pathogenesis. The contents and distribution for α1 chain of collagen type Ⅰ, Ⅲ and V [α1 （Ⅰ）, α1 （Ⅲ） and α1 （Ⅴ）] in skin lesions of 36 patients with SSc （9 cases of mild fibrosis, 14 moderate, and 13 severe） were detected by using im- munohistochemical SP method. Six cases of normal skin tissues served as controls. The results showed that there was diffuse distribution for three kinds of collagens in dermis. The deep staining α1 （Ⅰ） and α1 （Ⅲ） masses or bands were seen in reticular layer, while α1 （Ⅴ） was distributed more ho- mogeneously. From control to weak, moderate and severe fibrosis stages, α1 （Ⅰ）, α1 （Ⅲ） and α1 （V） showed a gradually increased trend in skin lesions （P〈0.05）. α1 （Ⅴ） was obviously elevated in skin lesions at early stage and persisted in whole fibrotic process and risen in greater contents, while α1 （Ⅰ） and α1 （Ⅲ） were to go higher late and were apparently elevated at moderate and late stages. Com- pared with α1 （Ⅰ）, α1 （Ⅴ） took leading increase at early stage in skin lesions （P〈0.01）, and had more elevated contents than α1 （Ⅲ） at moderate and late stages. The fibrotic changes in dermal reticular layer occurred earlier than those in papillary layer, and the abnormalities of α1 （Ⅴ）/α1 （I） ratio ap- peared before α1 （Ⅲ）/α1 （Ⅰ） ratio. It was concluded that a lot of α1 （Ⅴ） began to deposit in greater contents prior to α1 （Ⅰ） and α1 （Ⅲ） at early stage in SSc and persisted in whole fibrotic process. The changes of α1 （Ⅴ） contents in reticular layer occurred earlier than those in papillary layer, and it sug- gested that the fibrosis in reticular layer appeared earlier.

Causes and predictors of mortality in South Africans with systemic sclerosis

Background:There is a dearth of mortality data on systemic sclerosis(SSc)in sub-Saharan Africa.We undertook a retrospective study of causes and predictors of death in low-income indigent South Africans with SSc.Methods:A retrospective records review of clinicodemographic,laboratory,and outcome data of SSc patients attending a state-funded tertiary Rheumatology service in South Africa.Results:Most of the 164 patients were Black(92.7%)and female(87.8%).The mean(SD)age at diagnosis and follow-up duration were 42.6(12.9)and 5.5(5.6)years,respectively.The majority(75.6%)had diffuse cutaneous SSc(dcSSc);and digital pits/ulcers,interstitial lung disease(ILD),and pulmonary hypertension(PH)were documented in 73.6%,55.0%,and 38.3%,respectively.There were 56 known deaths and an equal number of patients were lost to follow-up.Deaths resulted from ILD complicated by PH(42.9%),infections(8.9%),cardiac disease(7.1%),and malignancies(3.6%).Estimated 5-and 10-year survival rates for patients with known outcomes were 58%and 42%,respectively.Independent predictors of death were renal dysfunction and cor pulmonale.Conclusion:Most patients in this study of South Africans had dcSSc and poor outcomes.Known deaths resulted from cardiorespiratory complications of ILD complicated by PH.Cor pulmonale and renal dysfunction were independent predictors of death.

Micro RNAs Regulating Signaling Pathways:Potential Biomarkers in Systemic Sclerosis

Systemic sclerosis （SSc） is a multisystem fibrotic and autoimmune disease. Both genetic and epigenetic elements mediate SSc pathophysiology. This review summarizes the role of one epigenetic element, known as microRNAs （miRNAs）, involved in different signaling pathways of SSc pathogenesis. The expression of key components in transforming growth factor-β （TGF-β） signaling pathway has been found to be regulated by miRNAs both upstream and downstream of TGF-β. We are specifically interested in the pathway components upstream of TGF-β, while miRNAs in other signaling pathways have not been extensively studied. The emerging role of miRNAs in vasculopathy of SSc suggests a promising new direction for future investigation. Elu- cidation of the regulatory role of miRNAs in the expression of signaling factors may facilitate the discovery of novel biomarkers in SSc and improve the understanding and treatment of this disease.

MSCs-laden injectable self-healing hydrogel for systemic sclerosis treatment

As a novel cellular therapy, the anti-inflammatory and immunomodulatory virtues of mesenchymal stem cells (MSCs) make them promising candidates for systemic sclerosis (SSc) treatment. However, the clinical efficacy of this stratagem is limited because of the short persistence time, poor survival, and engraftment of MSCs after injection in vivo. Herein, we develop a novel MSCs-laden injectable self-healing hydrogel for SSc treatment. The hydrogel is prepared using N, O-carboxymethyl chitosan (CS-CM) and 4-armed benzaldehyde-terminated poly-ethylene glycol (PEG-BA) as the main components, imparting with self-healing capacity via the reversible Schiff-base connection between the amino and benzaldehyde groups. We demonstrate that the hydrogel laden with MSCs not only promoted the proliferation of MSCs and increased the cellular half-life in vivo, but also improve their immune-modulating functions. The tube formation assay indicates that the MSCs could significantly pro-mote angiopoiesis. Moreover, the MSCs-laden hydrogel could inhibit fibrosis by modulating the synthesis of collagen and ameliorate disease progression in SSc disease model mice after subcutaneous injection of bleo-mycin. All these results highlight this novel MSCs-laden hydrogel and its distinctive functions in treatment of chronic SSc, indicating the additional potential to be used widely in the clinic.

Clinical Efficacy and Safety of Bathing with Chinese Medicine Taohong Siwu Decoction(桃红四物汤) for Treatment of Diffuse Cutaneous Systemic Sclerosis:A Randomized Placebo-Controlled Trial

Objective：To examine the efficacy and safety of bathing therapy with Taohong Siwu Decoction（桃红四物汤,TSD） in the treatment of early-stage,mild-moderate diffuse cutaneous systemic sclerosis（dc SSc）.Methods：This randomized,placebo-controlled trial enrolled 148 men and women（18–60 years） with dc SSc（disease duration 12 months） and baseline modified Rodnan skin score（MRSS） 10.Patients were randomized into a TSD group（71 cases bathing with TSD plus oral prednisone） or control group（71 cases bathing with placebo plus oral prednisone）.Bathing（40 ℃,30 min） of the upper and lower limbs was carried out once daily for 12 consecutive weeks.The primary outcome measure was MRSS;secondary outcomes were Raynaud＇s phenomenon（RP） score,quality of life（QOL）,physician visual analogue scale（VAS）,patient VAS,percent predicted diffusing capacity for carbon monoxide（DLCO）,percent predicted forced vital capacity（FVC）,erythrocyte sedimentation rate（ESR）,C-reactive protein（CRP） level and overall treatment effect.Results：The final analysis included 135 patients（control group,68 cases;TSD group,67 cases）.Primary and secondary outcome measures after 2 weeks of treatment showed no improvement（versus baseline） in both groups,with no differences between groups.At 12 weeks,QOL,physician VAS,patient VAS,ESR and CRP were improved in both groups,but MRSS and RP score were improved only in the TSD group（all P〈0.05）.MRSS,RP score,QOL,physician VAS,patient VAS,ESR and CRP differed significantly between groups（all P〈0.05）.Meanwhile,the overall treatment effect was significantly higher in the TSD group than in the control group（P〈0.05）.Adverse events in the two groups were similar（P〉0.05）.Conclusions：Bathing with TSD plus oral prednisone achieves better outcomes than oral prednisone alone in patients with dcS Sc and is not associated with serious adverse events.

Mesenchymal stem cell as a novelapproach to systemic sclerosis;currentstatus and future perspectives

Systemic sclerosis is a rare chronic autoimmune disease with extensive microvascular injury, damage of endothelialcells, activation of immune responses, and progression of tissue fibrosis in the skin and various internal organs.According to epidemiological data, women’s populations are more susceptible to systemic sclerosis than men. Untilnow, various therapeutic options are employed to manage the symptoms of the disease. Since stem cell-basedtreatments have developed as a novel approach to rescue from several autoimmune diseases, it seems that stemcells, especially mesenchymal stem cells as a powerful regenerative tool can also be advantageous for systemicsclerosis treatment via their remarkable properties including immunomodulatory and anti-fibrotic effects.Accordingly, we discuss the contemporary status and future perspectives of mesenchymal stem cell transplantationfor systemic sclerosis.

Systemic sclerosis with portal hypertensive ascites responded to corticosteroid treatment

We describe a case of systemic sclerosis （SSc） complicated with portal hypertensive ascites which did not improve with diuretics and ascitic drainage. When corticosteroid added, her ascites diminished dramatically. Though portal hypertension can be imputed to other causes, such as polycystic liver in this case, it can occur in limited SSc with positive anti-centromere antibody and respond to corticosteroid treatment.

Role of Epigenetics in the Pathogenesis of Systemic Sclerosis

Systemic sclerosis(SSc)is characterized by immune dysfunction,vasculopathy,chronic fibrosis of skin and internal organs with complex etiology.With the rapid development and the application in biomedicine of epigenetics,accumulating evidence has shown that epigenetics plays an important role in the pathogenesis of SSc.Environmental factors via epigenetics are needed to trigger and maintain for the disease in the subjects with genetic predisposition to SSc.The role of epigenetics in the pathogenesis of SSc includes hypermethylation of the promoter region of nitric oxide synthase and bone morphogenetic protein receptors II,up-regulation of histone deacetylases 4 and 5 expression,and down-regulation of miR-193b and miR-152 in endothelial cells inducing vascular dysfunction;DNA hypermethylation and hypoacetylation of histone H3 and H4 in Friend leukemia virus integration 1 and Kruppel-like factor 5 genes,and the abnormal expression of miR-29,miR-129-5p and miR-135b in fibroblasts causing excessive fibrosis;DNA hypomethylation in the promoter regions of CD11a and CD70 genes in CD4+T cells resulting in immune dysfunction.Studies on the role of epigenetics in SSc are of great significance for better understanding the pathogenic machanism of SSc,which is helpful to find new molecular targets for treating SSc,and consequently,improve the prognosis of SSc.

Associations of autoantibodies and clinical profile of the patients with systemic sclerosis

Background:Systemic sclerosis is characterized by the involvement of organs and the presence of specific antibodies.The objectives of this study were to identify the autoantibodies and to determine their association with the selected clinical features of the disease among Bangladeshi systemic sclerosis patients.Methods:This cross-sectional study was performed at the rheumatology outpatient clinic of Bangabandhu Sheikh Mujib Medical University.Autoantibodies against nine systemic sclerosis-specific antigens were tested using an enzyme-linked immunoassay immunoblot kit.Several clinical features of patients with positive and negative autoantibody were examined by χ^(2) or Fisher's exact tests.Results:A total of 71 patients with systemic sclerosis(66;93.0%female)were included.Their mean age at disease onset was 33.2 years.Fifty-seven(80.3%)patients had diffuse cutaneous subtype.Out of nine autoantibodies,four were positive,anti-topoisomerase-I(57.7%),anti-U1 ribonucleic protein(21.1%),anti-RNA polymerase Ⅲ(18.3%),and anticentromere antibodies(4.2%).Eleven(15.5%)patients were negative for any antibodies and 11 patients were positive for at least two autoantibodies.Anti-U3-RNP,anti-PMScl,anti-Ku,and anti-Th/To auto antibodies were absent in all patients.Anti-RNA polymerase III was associated with raised pulmonary arterial systolic pressure(PASP)and anti-U1-RNP with decreased forced vital capacity(FVC).Conclusions:Anti-topoisomerase-I was the commonest autoantibody in patients with systemic sclerosis in Bangladesh.Anti-RNA polymerase III antibody had significant association with raised PASP and anti-U1-RNP with decreased FVC.

Role of Helicobacter pylori infection in autoimmune systemic rheumatic diseases

The relationship between infection and autoimmunity has been increasingly defined over the last 20 years. The systemic rheumatic diseases are characterized by dysregulation of the immune system resulting in a loss of tolerance to self-antigen. The exact etiology for the majority of these diseases is unknown; however, a complex combination of host and environmental factors are believed to play a pivotal role. Helicobacter pylori(H. pylori) is one of the most widely studied infectious agents proposed as agents triggering autoimmune response. The persistent presence of H. pylori in the gastric mucosa results in chronic immune system activation with ongoing cytokine signaling, infiltration of gastric mucosa by neutrophils, macrophages, lymphocytes, as well as production of antibodies and effector T-cells. Various mechanisms have been proposed in an attempt to explain the extra-intestinal manifestations of H. pylori infections. These include: molecular mimicry, endothelial cell damage, superantigens and microchimerism. I performed a systematic literature review using the keywords "rheumatoid arthritis", "Sjgren's syndrome", "systemic sclerosis", "systemic lupus erythematosus","Helicobacter pylori " and "pathogenesis". A systematic literature search was carried out in MEDLINE; EMBASE; Cochrane Library and ACR/EULAR meeting abstracts. In systemic rheumatic diseases H. pylori infection prevalence alone should not be expected to provide sufficient evidence for or against a pathologic role in the disease. In this article Ⅰ review studies examining the potential involvement of H. pylori infection in autoimmune systemic rheumatic diseases. Further studies of the immunological response to H. pylori and its role in the pathogenesis of systemic rheumatic diseases are warranted.

Role of IL-2/IL-2 receptor in pathogenesis of autoimmune disorders:Genetic and therapeutic aspects

Interleukin-2(IL-2)is an important cytokine that plays a key role in the immune response.The IL-2 receptor(IL-2R)is composed of three subunits,alpha,beta,and gamma,with the alpha subunit having the highest affinity for IL-2.Several studies reported that immune dysregulation of IL-2 may cause tissue injury as well as damage leading to the pathogenesis of various autoimmune diseases such as acute necrotizing vasculitis in systemic lupus erythematosus(SLE),inflammatory synovitis in rheumatoid arthritis(RA),salivary and lacrimal gland dysfunction in Sjogren syndrome(SS),obliterative vasculopathy fibrosis in systemic sclerosis(SSc),and inflammatory demyelination in multiple sclerosis(MS).The aim of this review paper was to examine the role of IL-2/IL-2R in various autoimmune disorders,taking into account recent advancements and discoveries,gaps in the current literature,ongoing debates,and potential avenues for future research.The focus of this review is on systemic lupus erythematosus,rheumatoid arthritis,systemic sclerosis,sjogren syndrome,and multiple sclerosis,which are all linked to the malfunctioning of IL-2/IL-2R.In genetic studies,gene polymorphisms of IL-2 such as IL-2330/T,IL-2330/G,and rs2069763 are involved in increasing the risk of SLE.Furthermore,genetic associations of IL-2/IL-2R such as rs791588,rs2281089,rs2104286,rs11594656,and rs35285258 are significantly associated with RA susceptibility.The IL-2 polymorphism including rs2069762A,rs6822844T,rs6835457G,and rs907715T are significant connections with systemic sclerosis.In addition,rs2104286(IL-2),rs11594656(IL-2RA),rs35285258(IL-2RB)gene polymorphism significant increases the risk of multiple sclerosis.In therapeutic approaches,low-dose IL-2 therapy could regulate Tfr and Tfh cells,resulting in a reduction in disease activity in the SLE patients.In addition,elevated sIL-2R levels in the peripheral blood of SLE patients could be linked to an immunoregulatory imbalance,which may contribute to the onset and progression of SLE.Consequently,sIL-2R could potentially be a target for future SLE therapy.Moreover,Low dose-IL2 was well-tolerated,and low levels of Treg and high levels of IL-21 wereassociated with positive responses to Ld-IL2 suggested to be a safe and effective treatment for RA.Additionally,low-dose IL-2 treatment improves the exocrine glands'ability to secrete saliva in SS-affected mice.Whereas,Basiliximab targets the alpha chain of the IL-2 receptor suggested as a potential treatment for SSc.Also,pre-andpost-treatment with Tregs,MDSCs,and IL-2 may have the potential to prevent EAE induction in patients with MS.It is suggested that further studies should be conducted on IL-2 polymorphism in Sjogren syndrome.