Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis Thu, 28 May 2015 13:38:36 +0000 In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4+ regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naïve CD4+ T cells to CD4+ regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4+ regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance.   Pascal Lapierre and Alain Lamarre Copyright © 2015 Pascal Lapierre and Alain Lamarre. All rights reserved. Harnessing the Microbiome to Enhance Cancer Immunotherapy Mon, 25 May 2015 07:05:44 +0000 The microbiota plays a key role in regulating the innate and adaptive immune system. Herein, we review the immunological aspects of the microbiota in tumor immunity in mice and man, with a focus on toll-like receptor (TLR) agonists, vaccines, checkpoint modulators, chemotherapy, and adoptive T cell transfer (ACT) therapies. We propose innovative treatments that may safely harness the microbiota to enhance T cell-based therapies in cancer patients. Finally, we highlight recent developments in tumor immunotherapy, particularly novel ways to modulate the microbiome and memory T cell responses to human malignancies. Michelle H. Nelson, Marshall A. Diven, Logan W. Huff, and Chrystal M. Paulos Copyright © 2015 Michelle H. Nelson et al. All rights reserved. Correlates of Protection for M Protein-Based Vaccines against Group A Streptococcus Mon, 25 May 2015 06:36:45 +0000 Group A streptococcus (GAS) is known to cause a broad spectrum of illness, from pharyngitis and impetigo, to autoimmune sequelae such as rheumatic heart disease, and invasive diseases. It is a significant cause of infectious disease morbidity and mortality worldwide, but no efficacious vaccine is currently available. Progress in GAS vaccine development has been hindered by a number of obstacles, including a lack of standardization in immunoassays and the need to define human correlates of protection. In this review, we have examined the current immunoassays used in both GAS and other organisms, and explored the various challenges in their implementation in order to propose potential future directions to identify a correlate of protection and facilitate the development of M protein-based vaccines, which are currently the main GAS vaccine candidates. Shu Ki Tsoi, Pierre R. Smeesters, Hannah R. C. Frost, Paul Licciardi, and Andrew C. Steer Copyright © 2015 Shu Ki Tsoi et al. All rights reserved. Trans-Species Polymorphism in Immune Genes: General Pattern or MHC-Restricted Phenomenon? Sun, 24 May 2015 13:00:40 +0000 Immunity exhibits extraordinarily high levels of variation. Evolution of the immune system in response to host-pathogen interactions in particular ecological contexts appears to be frequently associated with diversifying selection increasing the genetic variability. Many studies have documented that immunologically relevant polymorphism observed today may be tens of millions years old and may predate the emergence of present species. This pattern can be explained by the concept of trans-species polymorphism (TSP) predicting the maintenance and sharing of favourable functionally important alleles of immune-related genes between species due to ongoing balancing selection. Despite the generality of this concept explaining the long-lasting adaptive variation inherited from ancestors, current research in TSP has vastly focused only on major histocompatibility complex (MHC). In this review we summarise the evidence available on TSP in human and animal immune genes to reveal that TSP is not a MHC-specific evolutionary pattern. Further research should clearly pay more attention to the investigation of TSP in innate immune genes and especially pattern recognition receptors which are promising candidates for this type of evolution. More effort should also be made to distinguish TSP from convergent evolution and adaptive introgression. Identification of balanced TSP variants may represent an accurate approach in evolutionary medicine to recognise disease-resistance alleles. Martin Těšický and Michal Vinkler Copyright © 2015 Martin Těšický and Michal Vinkler. All rights reserved. Systemic Autoimmune Diseases 2014 Sun, 24 May 2015 07:34:03 +0000 Guixiu Shi, Jianying Zhang, Zhixin (Jason) Zhang, and Xuan Zhang Copyright © 2015 Guixiu Shi et al. All rights reserved. The Interactions between Innate Immunity and Microbiota in Gastrointestinal Diseases Wed, 20 May 2015 13:42:01 +0000 Danilo Pagliari, Ciriaco A. Piccirillo, Anis Larbi, and Rossella Cianci Copyright © 2015 Danilo Pagliari et al. All rights reserved. Achalasia—An Autoimmune Inflammatory Disease: A Cross-Sectional Study Wed, 20 May 2015 12:15:58 +0000 Idiopathic achalasia is a disease of unknown etiology. The loss of myenteric plexus associated with inflammatory infiltrates and autoantibodies support the hypothesis of an autoimmune mechanism. Thirty-two patients diagnosed by high-resolution manometry with achalasia were included. Twenty-six specimens from lower esophageal sphincter muscle were compared with 5 esophagectomy biopsies (control). Immunohistochemical (biopsies) and flow cytometry (peripheral blood) analyses were performed. Circulating anti-myenteric autoantibodies were evaluated by indirect immunofluorescence. Herpes simplex virus-1 (HSV-1) infection was determined by in situ hybridization, RT-PCR, and immunohistochemistry. Histopathological analysis showed capillaritis (51%), plexitis (23%), nerve hypertrophy (16%), venulitis (7%), and fibrosis (3%). Achalasia tissue exhibited an increase in the expression of proteins involved in extracellular matrix turnover, apoptosis, proinflammatory and profibrogenic cytokines, and Tregs and Bregs versus controls (). Circulating Th22/Th17/Th2/Th1 percentage showed a significant increase versus healthy donors (). Type III achalasia patients exhibited the highest inflammatory response versus types I and II. Prevalence of both anti-myenteric antibodies and HSV-1 infection in achalasia patients was 100% versus 0% in controls. Our results suggest that achalasia is a disease with an important local and systemic inflammatory autoimmune component, associated with the presence of specific anti-myenteric autoantibodies, as well as HSV-1 infection. J. Furuzawa-Carballeda, D. Aguilar-León, A. Gamboa-Domínguez, M. A. Valdovinos, C. Nuñez-Álvarez, L. A. Martín-del-Campo, A. B. Enríquez, E. Coss-Adame, A. E. Svarch, A. Flores-Nájera, A. Villa-Baños, J. C. Ceballos, and G. Torres-Villalobos Copyright © 2015 J. Furuzawa-Carballeda et al. All rights reserved. Anti-Phosphatidylserine/Prothrombin Antibodies Are Associated with Adverse Pregnancy Outcomes Wed, 20 May 2015 06:57:24 +0000 Objective. To determine the prevalence and clinical association of anti-phosphatidylserine/prothrombin antibodies (aPS/PT) in patients with a history of pregnancy complications relevant to antiphospholipid syndrome (APS). Materials and Methods. Two hundred and eleven patients with a history of (a) three or more consecutive miscarriages before 10th week of gestation (WG) (), (b) death of a morphologically normal fetus beyond 10th WG (), (c) premature birth of a morphologically normal neonate before 34th WG due to eclampsia, preeclamsia and placental insufficiency (), and (d) less than three unexplained consecutive miscarriages before 10th WG (). Subjects sera were analyzed for lupus anticoagulant (LA), anti-cardiolipin (aCL), anti--glycoprotein I (anti-GPI), and aPS/PT antibodies. Results. 41/169 (24.3%) of patients were positive for at least one measured aPL. The highest prevalence was found for aPS/PT and aCL (13.0% and 12.4%, resp.) followed by LA (7.7%) and anti-GPI (7.1%). 11/169 with APS-related obstetric manifestations had only aPS/PT. 17.8% of patients were positive for LA or aCL and/or anti-GPI; however when adding the aPS/PT results, an additional 7% of patients could be evaluated for APS. Conclusion. aPS/PT are associated with recurrent early or late abortions and with premature delivery irrespective of other aPL. Polona Žigon, Katja Perdan Pirkmajer, Matija Tomšič, Tanja Kveder, Borut Božič, Snežna Sodin Šemrl, Saša Čučnik, and Aleš Ambrožič Copyright © 2015 Polona Žigon et al. All rights reserved. Anti-Cyclic Citrullinated Peptide Antibodies and Severity of Interstitial Lung Disease in Women with Rheumatoid Arthritis Tue, 19 May 2015 12:52:50 +0000 Objective. To evaluate whether serum titers of second-generation anticyclic citrullinated peptide antibodies (anti-CCP2) are associated with the severity and extent of interstitial lung disease in rheumatoid arthritis (RA-ILD). Methods. In across-sectional study, 39 RA-ILD patients confirmed by high-resolution computed tomography (HRCT) were compared with 42 RA without lung involvement (RA only). Characteristics related to RA-ILD were assessed in all of the patients and serum anti-CCP2 titers quantified. Results. Higher anti-CCP2 titers were found in RA-ILD compared with RA only (medians 77.9 versus 30.2 U/mL, ). In the logistic regression analysis after adjustment for age, disease duration (DD), smoke exposure, disease activity, functioning, erythrocyte sedimentation rate, and methotrexate (MTX) treatment duration, the characteristics associated with RA-ILD were higher anti-CCP2 titers () and + RF (). In multivariate linear regression, the variables associated with severity of ground-glass score were anti-CCP2 titers () and with fibrosis score DD (), anti-CCP2 titers (), and MTX treatment duration (). Conclusions. Anti-CCP2 antibodies are markers of severity and extent of RA-ILD in HRCT. Further longitudinal studies are required to identify if higher anti-CCP2 titers are associated with worst prognosis in RA-ILD. Alberto Daniel Rocha-Muñoz, Manuel Ponce-Guarneros, Jorge Ivan Gamez-Nava, Eva Maria Olivas-Flores, Mayra Mejía, Pablo Juárez-Contreras, Erika Aurora Martínez-García, Esther Guadalupe Corona-Sánchez, Tania Marlen Rodríguez-Hernández, Mónica Vázquez-del Mercado, Mario Salazar-Páramo, Arnulfo Hernan Nava-Zavala, Ernesto German Cardona-Muñoz, Alfredo Celis, and Laura González-Lopez Copyright © 2015 Alberto Daniel Rocha-Muñoz et al. All rights reserved. Induction of Apoptosis Coupled to Endoplasmic Reticulum Stress through Regulation of CHOP and JNK in Bone Marrow Mesenchymal Stem Cells from Patients with Systemic Lupus Erythematosus Tue, 19 May 2015 09:01:55 +0000 Previous studies indicated that bone marrow mesenchymal stem cells (BM-MSCs) from patients with systemic lupus erythematosus (SLE) exhibited the phenomenon of apoptosis. In this study, we aimed to investigate whether apoptosis of BM-MSCs from SLE patients were dysregulated. In this paper, endoplasmic reticulum stress (ERS) was evidenced by increased expression of phosphorylated protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein-1 (IRE-1). We also found the activation of downstream target eukaryotic translation initiator factor 2α (eIF 2α) and CCAAT/enhancer-binding protein- (C/EBP-) homologous protein (CHOP) in BM-MSCs from SLE patients. Interestingly, we discovered that 4-phenylbutyric acid (4-PBA), a selective inhibitor of ERS, blocked the apoptosis of BM-MSCs from SLE patients and alleviated the level of Jun N-terminal kinase1/2 (JNK1/2) and CHOP. Furthermore, blockage of PERK signaling expression by siRNA not only significantly reduced the expression of CHOP, but also activated the anti-apoptotic regulator B-cell lymphoma-2 (Bcl-2). Blockage of IRE-1 or JNK1/2 by siRNA resulted in the decreased expression of JNK1/2 and proapoptosis protein Bcl-2 associated protein X (BAX). These results implicated that ERS-mediated apoptosis was a critical determinant of BM-MSCs from SLE patients. Genkai Guo, Yan Meng, Wei Tan, Yunfei Xia, Chun Cheng, Xiaolan Chen, and Zhifeng Gu Copyright © 2015 Genkai Guo et al. All rights reserved. Characterization of CD30/CD30L+ Cells in Peripheral Blood and Synovial Fluid of Patients with Rheumatoid Arthritis Tue, 19 May 2015 08:07:59 +0000 The CD30/CD30L signalling system has been implicated in the pathogenesis of several autoimmune and inflammatory conditions. In rheumatoid arthritis (RA), soluble CD30 (sCD30) levels reflect the recruitment of CD30+ T cells into the inflamed joints and correlate with a positive response to immunosuppressive therapy. The aim of our report was to clarify the role of CD30/CD30L signalling system in the pathogenesis of RA. Our analysis of the CD30L+ T cell subsets in peripheral blood (PB) and synovial fluid (SF) of RA patients and of the related cytokine profiles suggests the involvement of CD30/CD30L signalling in polarization of T cells towards a Th17 phenotype with proinflammatory features. Moreover, in RA SF nearly 50% of Treg cells express CD30, probably as an attempt to downmodulate the ongoing inflammation. We also show here that the engagement of CD30L on neutrophils stimulated with CD30/Fc chimera may play a crucial role in RA inflammation since activated neutrophils release IL-8, thus potentially amplifying the local inflammatory damage. In conclusion, the results obtained suggest that the complex CD30/CD30L signalling pathway is implicated in the pathogenesis and progression of RA synovitis through a concerted action on several immune effector cells. Alessandro Barbieri, Marzia Dolcino, Elisa Tinazzi, Antonella Rigo, Giuseppe Argentino, Giuseppe Patuzzo, Andrea Ottria, Ruggero Beri, Antonio Puccetti, and Claudio Lunardi Copyright © 2015 Alessandro Barbieri et al. All rights reserved. Clinical Characteristics of Cerebral Venous Sinus Thrombosis in Patients with Systemic Lupus Erythematosus: A Single-Centre Experience in China Tue, 19 May 2015 07:39:45 +0000 Clinical characteristics of systemic lupus erythematosus (SLE) patients complicated with cerebral venous sinus thrombosis (CVST) between 2000 and 2013 were analyzed through this retrospective, single-centre study. Of 4747 hospitalized SLE patients, 17 (0.36%, 12 females, average age 30) had CVST. Headache (88.2%) was the most common neurological symptom followed by nausea or vomiting (47.1%), conscious disturbance (41.2%), edema of eyelids or conjunctiva (35.3%), blurred vision or diplopia (35.3%), and seizure (35.3%). Increased intracranial pressure (ICP) occurred in 13 cases (76.5%). Magnetic resonance venography (MRV) detected thrombosis in the transverse (82.4%), sigmoid (52.9%), and sagittal (35.3%) sinuses, with frequent (70.6%) multiple sinus occlusions. Compared to SLE patients without CVST, SLE patients with CVST had a higher prevalence of thrombocytopenia and positive antiphospholipid antibodies and a higher SLE disease activity index (SLEDAI) score. 13 patients achieved improvement following glucocorticoids and immunosuppressants treatment, as well as anticoagulants, while 3 patients died at the hospital. CVST is relatively rare in SLE and tends to occur in active lupus patients. Intracranial hypertension is common but nonspecific clinical feature, so MRV evaluation is necessary to establish a diagnosis. Aggressive treatment for the rapid control of SLE activity combined with anticoagulants can improve the prognosis. Li Wang, Hua Chen, Yao Zhang, Wanli Liu, Wenjie Zheng, Xuan Zhang, and Fengchun Zhang Copyright © 2015 Li Wang et al. All rights reserved. HMGB1 Promotes Systemic Lupus Erythematosus by Enhancing Macrophage Inflammatory Response Tue, 19 May 2015 07:15:40 +0000 Background/Purpose. HMGB1, which may act as a proinflammatory mediator, has been proposed to contribute to the pathogenesis of multiple chronic inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE); however, the precise mechanism of HMGB1 in the pathogenic process of SLE remains obscure. Method. The expression of HMGB1 was measured by ELISA and western blot. The ELISA was also applied to detect proinflammatory cytokines levels. Furthermore, nephritic pathology was evaluated by H&E staining of renal tissues. Results. In this study, we found that HMGB1 levels were significantly increased and correlated with SLE disease activity in both clinical patients and murine model. Furthermore, gain- and loss-of-function analysis showed that HMGB1 exacerbated the severity of SLE. Of note, the HMGB1 levels were found to be associated with the levels of proinflammatory cytokines such as TNF-α and IL-6 in SLE patients. Further study demonstrated that increased HMGB1 expression deteriorated the severity of SLE via enhancing macrophage inflammatory response. Moreover, we found that receptor of advanced glycation end products played a critical role in HMGB1-mediated macrophage inflammatory response. Conclusion. These findings suggested that HMGB1 might be a risk factor for SLE, and manipulation of HMGB1 signaling might provide a therapeutic strategy for SLE. Mudan Lu, Shanshan Yu, Wei Xu, Bo Gao, and Sidong Xiong Copyright © 2015 Mudan Lu et al. All rights reserved. Lessons from Microglia Aging for the Link between Inflammatory Bone Disorders and Alzheimer’s Disease Tue, 19 May 2015 06:37:10 +0000 Bone is sensitive to overactive immune responses, which initiate the onset of inflammatory bone disorders, such as rheumatoid arthritis and periodontitis, resulting in a significant systemic inflammatory response. On the other hand, neuroinflammation is strongly implicated in Alzheimer’s disease (AD), which can be enhanced by systemic inflammation, such as that due to cardiovascular disease and diabetes. There is growing clinical evidence supporting the concept that rheumatoid arthritis and periodontitis are positively linked to AD, suggesting that inflammatory bone disorders are risk factors for this condition. Recent studies have suggested that leptomeningeal cells play an important role in transducing systemic inflammatory signals to brain-resident microglia. More importantly, senescent-type, but not juvenile-type, microglia provoke neuroinflammation in response to systemic inflammation. Because the prevalence of rheumatoid arthritis and periodontitis increases with age, inflammatory bone disorders may be significant sources of covert systemic inflammation among elderly people. The present review article highlights our current understanding of the link between inflammatory bone disorders and AD with a special focus on microglia aging. Zhou Wu and Hiroshi Nakanishi Copyright © 2015 Zhou Wu and Hiroshi Nakanishi. All rights reserved. The Novel PKCθ from Benchtop to Clinic Tue, 19 May 2015 06:25:56 +0000 The protein kinases C (PKCs) are a family of serine/threonine kinases involved in regulating multiple essential cellular processes such as survival, proliferation, and differentiation. Of particular interest is the novel, calcium-independent PKCθ which plays a central role in immune responses. PKCθ shares structural similarities with other PKC family members, mainly consisting of an N-terminal regulatory domain and a C-terminal catalytic domain tethered by a hinge region. This isozyme, however, is unique in that it translocates to the immunological synapse between a T cell and an antigen-presenting cell (APC) upon T cell receptor-peptide MHC recognition. Thereafter, PKCθ interacts physically and functionally with downstream effectors to mediate T cell activation and differentiation, subsequently leading to inflammation. PKCθ-specific perturbations have been identified in several diseases, most notably autoimmune disorders, and hence the modulation of its activity presents an attractive therapeutic intervention. To that end, many inhibitors of PKCs and PKCθ have been developed and tested in preclinical and clinical studies. And although selectivity remains a challenge, results are promising for the future development of effective PKCθ inhibitors that would greatly advance the treatment of several T-cell mediated diseases. Rouba Hage-Sleiman, Asmaa B. Hamze, Lina Reslan, Hadile Kobeissy, and Ghassan Dbaibo Copyright © 2015 Rouba Hage-Sleiman et al. All rights reserved. Influence of Anti-TNF and Disease Modifying Antirheumatic Drugs Therapy on Pulmonary Forced Vital Capacity Associated to Ankylosing Spondylitis: A 2-Year Follow-Up Observational Study Tue, 19 May 2015 06:21:29 +0000 Objective. To evaluate the effect of anti-TNF agents plus synthetic disease modifying antirheumatic drugs (DMARDs) versus DMARDs alone for ankylosing spondylitis (AS) with reduced pulmonary function vital capacity (FVC%). Methods. In an observational study, we included AS who had FVC% <80% at baseline. Twenty patients were taking DMARDs and 16 received anti-TNF + DMARDs. Outcome measures: changes in FVC%, BASDAI, BASFI, 6-minute walk test (6MWT), Borg scale after 6MWT, and St. George’s Respiratory Questionnaire at 24 months. Results. Both DMARDs and anti-TNF + DMARDs groups had similar baseline values in FVC%. Significant improvement was achieved with anti-TNF + DMARDs in FVC%, at 24 months, when compared to DMARDs alone (). Similarly, patients in anti-TNF + DMARDs group had greater improvement in BASDAI, BASFI, Borg scale, and 6MWT when compared to DMARDs alone. After 2 years of follow-up, 14/16 (87.5%) in the anti-TNF + DMARDs group achieved the primary outcome: FVC% ≥80%, compared with 11/20 (55%) in the DMARDs group (). Conclusions. Patients with anti-TNF + DMARDs had a greater improvement in FVC% and cardiopulmonary scales at 24 months compared with DMARDs. This preliminary study supports the fact that anti-TNF agents may offer additional benefits compared to DMARDs in patients with AS who have reduced FVC%. Alberto Daniel Rocha-Muñoz, Aniel Jessica Leticia Brambila-Tapia, María Guadalupe Zavala-Cerna, José Clemente Vásquez-Jiménez, Liliana Faviola De la Cerda-Trujillo, Mónica Vázquez-Del Mercado, Norma Alejandra Rodriguez-Jimenez, Valeria Díaz-Rizo, Viviana Díaz-González, Ernesto German Cardona-Muñoz, Ingrid Patricia Dávalos-Rodríguez, Mario Salazar-Paramo, Jorge Ivan Gamez-Nava, Arnulfo Hernan Nava-Zavala, and Laura Gonzalez-Lopez Copyright © 2015 Alberto Daniel Rocha-Muñoz et al. All rights reserved. The Influence and Role of Microbial Factors in Autoimmune Kidney Diseases: A Systematic Review Tue, 19 May 2015 05:47:01 +0000 A better understanding of the pathophysiology of autoimmune disorders is desired to allow tailored interventions. Despite increased scientific interest a direct pathogenic factor in autoimmune renal disease has been described only in a minority like membranous nephropathy or ANCA-associated vasculitis. Nonetheless the initial step leading to the formation of these antibodies is still obscure. In this review we will focus on the possible role of microbial factors in this context. Staphylococcus aureus may be a direct pathogenetic factor in granulomatosis with polyangiitis (GPA). Chronic bacterial colonization or chronic infections of the upper respiratory tract have been proposed as trigger of IgA vasculitis and IgA nephropathy. Interventions to remove major lymphoid organs, such as tonsillectomy, have shown conflicting results but may be an option in IgA vasculitis. Interestingly no clear clinical benefit despite similar local colonization with bacterial strains has been detected in patients with IgA nephropathy. In systemic lupus erythematosus injection of bacterial lipopolysaccharide induced progressive lupus nephritis in mouse models. The aim of this review is to discuss and summarize the knowledge of microbial antigens in autoimmune renal disease. Novel methods may provide insight into the involvement of microbial antigens in the onset, progression, and prognosis of autoimmune kidney disorders. Andreas Kronbichler, Julia Kerschbaum, and Gert Mayer Copyright © 2015 Andreas Kronbichler et al. All rights reserved. Effect of Leflunomide on the Abnormal Expression of Lipid Rafts and F-Actin in B Lymphocytes from Patients with Systemic Lupus Erythematosus Mon, 18 May 2015 14:27:34 +0000 Purposes. To investigate the possible changes in B cell subsets and in B cell expression patterns of lipid rafts (LRs) and F-actin in patients with SLE and whether leflunomide treatment may have effect on these changes. Methods. The B cell subsets and LRs expression were determined by flow cytometry and confocal microscopy, and F-actin expression was examined by confocal microscopy. Results. CD27+IgD+ B cell subsets were significantly decreased while CD38+CD95+ B cell subsets increased in SLE patients. The LRs levels of B cells were remarkably increased and positively correlated with SLEDAI and anti-dsDNA titer in SLE patients. The expression level of LRs was significantly higher in CD38+ B cells than CD38− B cells and negatively correlated with C3 levels. The increased expression of LRs was associated with reduced expression of F-actin in the B cells from active SLE patients. Furthermore, in vitro treatment of the cells with A771726 reduced the expression level of LRs, attenuated the overaggregation of LRs, and normalized the distribution of F-actin. Conclusions. There were abnormalities in B cell subsets and LRs and F-actin expression of B cell from SLE patients. Modulation of B cell expression of LRs and F-actin by LEF could be a potential therapeutic target for SLE. Guang Fu Dong, Xiao Zhang, De Ning He, Ling Li, and Guang Feng Zhang Copyright © 2015 Guang Fu Dong et al. All rights reserved. Clinical Characteristics of Concomitant Systemic Lupus Erythematosus and Primary Biliary Cirrhosis: A Literature Review Mon, 18 May 2015 13:56:50 +0000 Although autoimmune diseases often coexist, concomitant cases of systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC) are uncommon. In this review paper, 34 cases of SLE with concomitant PBC found in English and Japanese scientific literature and Japanese proceedings were reviewed and summarized, including cases with liver dysfunction complicated by SLE. Of the 34 reported concomitant cases of SLE and PBC, 97.1% (33/34) were females, and PBC was diagnosed initially in 69.0% (20/29), except for five cases in which both SLE and PBC were simultaneously diagnosed. Sjögren’s syndrome was the most common autoimmune disease complicating concomitant SLE and PBC (23.5%, 8/34). Five deaths have been reported: two elderly patients died of liver failure because of the worsening of PBC, and another two patients died from pulmonary infection associated with SLE pharmacotherapy. It is uncertain whether concomitant cases occur by chance or share a common immunological or genetic basis. Toru Shizuma Copyright © 2015 Toru Shizuma. All rights reserved. Methotrexate, Cyclosporine A, and Biologics Protect against Atherosclerosis in Rheumatoid Arthritis Mon, 18 May 2015 13:45:24 +0000 Introduction. The risk of cardiovascular disease is increased in rheumatoid arthritis (RA). A meta-analysis showed increased intima media thickness (IMT) in RA. It has been shown that disease modifying antirheumatic drugs (DMARDs) may influence the progression of atherosclerosis. However, it was suggested that biologics may be more efficient than other DMARDs (including methotrexate—MTX) in protecting against atherosclerosis. Objectives. The aim of this study was to assess the influence of different RA characteristics and treatment regimens on IMT and atherosclerotic plaques. Patients and Methods. 317 RA patients and 111 controls were included in the study. IMT was measured in carotid (CIMT) and femoral (FIMT) arteries. Arteries were screened for the presence of plaques. Results. CIMT, FIMT, and prevalence of plaques were lower in patients treated with methotrexate (MTX) ≥ 20 mg/wk, cyclosporine (CsA), or biologics than in patients treated with lower doses of MTX and other disease modifying antirheumatic drugs. No differences in IMT between patients treated with MTX ≥ 20 mg/wk, biologics, or CsA were found. Conclusions. We found a beneficial effect of MTX ≥ 20 mg/wk, biologics, and CsA on atherosclerosis. We do not confirm a stronger influence of biologics on IMT compared with therapeutic doses of MTX. Bartłomiej Kisiel, Robert Kruszewski, Aleksandra Juszkiewicz, Anna Raczkiewicz, Artur Bachta, Małgorzata Tłustochowicz, Jadwiga Staniszewska-Varga, Krzysztof Kłos, Krzysztof Duda, Romana Bogusławska-Walecka, Rafał Płoski, and Witold Tłustochowicz Copyright © 2015 Bartłomiej Kisiel et al. All rights reserved. Distribution of Peripheral Lymphocyte Populations in Primary Sjögren’s Syndrome Patients Mon, 18 May 2015 13:37:46 +0000 Purpose of this study was to evaluate the lymphocyte populations’ distribution changes in peripheral blood of patients with primary Sjögren’s syndrome (pSS). Lymphocyte populations’ distribution changes in peripheral blood of pSS patients were investigated in 52 patients with pSS and in 28 healthy controls by flow cytometry. We found decreased absolute count of CD3+ T cell population in pSS patients. Analysis of CD4+ T cell population showed significant proportion and absolute count differences in pSS patient’s blood with SSA/SSB antibodies (Abs) in comparison to controls. No significant differences were observed analyzing CD4+ and CD8+ Treg subpopulation. Proportion and absolute counts of Th17 cells were significantly lower in pSS patient’s blood. Absolute counts of CD8+ T cells were significantly lower in pSS patients in comparison to controls and also impaired proportion and absolute counts of CD8+ subpopulations according to CD27+ and CD57+ were observed. Absolute counts of NKT and NK cells were decreased in pSS with Abs. B cells proportion was increased only in blood of pSS with Abs. Lymphocyte distribution impairment can be due to genetically determined lymphopenia or lymphocyte migration from periphery to inflammatory sites or/and increased susceptibility to apoptosis. Gintaras Sudzius, Diana Mieliauskaite, Almantas Siaurys, Rita Viliene, Irena Butrimiene, Dainius Characiejus, and Irena Dumalakiene Copyright © 2015 Gintaras Sudzius et al. All rights reserved. Autoantibody to MDM2: A Potential Serological Marker of Systemic Lupus Erythematosus Mon, 18 May 2015 13:27:01 +0000 Introduction. Systemic lupus erythematosus (SLE) is one of the systemic autoimmune diseases characterized by the polyclonal autoantibody production. The human homologue of the mouse double minute 2 (MDM2) is well known as the negative regulator of p53. MDM2 has been reported to be overexpressed in SLE animal model and to promote SLE. Since abnormally expressed proteins can induce autoimmune response, anti-MDM2 autoantibody was examined in SLE patients. Methods. Anti-MDM2 antibody in sera from 43 SLE patients and 69 healthy persons was investigated by ELISA. Positive samples were further confirmed by western blotting. The immunological feathers of anti-MDM2 positive sera were analyzed by indirect immunofluorescence assay. Anti-p53 was also investigated in SLE patients by ELISA, and the correlation of anti-MDM2 and anti-p53 was analyzed. Results. The presence of anti-MDM2 in SLE patients was 23.30%, much higher than normal healthy persons (4.30%). These anti-MDM2 positive sera present a nuclear staining pattern. The presence of anti-p53 in SLE patients was 39.50%, and the titer of anti-MDM2 was positively correlated with anti-p53 in SLE patients. Conclusions. Anti-MDM2 autoantibody was detected at high prevalence in SLE patients. The detection of anti-MDM2 in SLE patients should be clinically useful. Yuan Liu, Liping Dai, Weihong Liu, Guixiu Shi, and Jianying Zhang Copyright © 2015 Yuan Liu et al. All rights reserved. Body Image Disturbances Have Impact on the Sexual Problems in Chinese Systemic Lupus Erythematosus Patients Mon, 18 May 2015 13:25:37 +0000 SLE might affect all aspects of life including sexual functioning; previous study found that body image disturbance (BID) was the most powerful predictors of impaired partner relationships and sexual function. The current study investigated the relationship among disease parameters, quality of life, the psychological status, BID, and sexual problems in Chinese patients with SLE. A self-report survey design was administered to 168 SLE patients and 210 healthy individuals. Our results showed that 86 (55.1%) SLE patients reported impaired relationships with a sexual partner or partners, and 100 (64.1%) patients reported impaired sexual function which were significantly higher than the control group (31.6%, 35.7%, rep.). Age, marital status, depression, and BIDQ were the most powerful predictors of impaired partner relationships, while BIDQ3 and education, disease activity, and depression were the most significant causes of impaired sexual function. The study for first time reported Chinese SLE patients had sexual problems and BID was associated with sexual problems. So, early detection and interventions might not only rehabilitate the patients and their loved ones, but also improve overall health outcomes and reduce the direct and indirect costs of their medical care. Biyu Shen, Yan He, Haoyang Chen, Chunmei Zhao, Li Zhu, Yingying Gao, Yunli Ren, Xueqing Wang, and Jingwei Liu Copyright © 2015 Biyu Shen et al. All rights reserved. The Role of Posttranslational Protein Modifications in Rheumatological Diseases: Focus on Rheumatoid Arthritis Mon, 18 May 2015 13:22:38 +0000 The definition of posttranslational modification (PTM) encompasses a wide group of chemical reactions that allow modification and modulation of protein functions. The regulation of PTMs is crucial for the activity and survival of the cells. Dysregulation of PTMs has been observed in several pathological conditions, including rheumatoid arthritis (RA). RA is a systemic autoimmune disease primarily targeting the joints. The three PTMs mainly involved in this disease are glycosylation, citrullination, and carbamylation. Glycosylation is essential for antigen processing and presentation and can modulate immunoglobulin activity. Citrullination of self-antigens is strongly associated with RA, as demonstrated by the presence of antibodies directed to anti-citrullinated proteins in patients’ sera. Carbamylation and its dysregulation have been recently associated with RA. Aim of this review is to illustrate the most significant alterations of these PTMs in RA and to evaluate their possible involvement in the pathogenesis of the disease. Andrea Mastrangelo, Tania Colasanti, Cristiana Barbati, Arbi Pecani, Danilo Sabatinelli, Monica Pendolino, Simona Truglia, Laura Massaro, Riccardo Mancini, Francesca Miranda, Francesca Romana Spinelli, Fabrizio Conti, and Cristiano Alessandri Copyright © 2015 Andrea Mastrangelo et al. All rights reserved. Treatment of Bullous Systemic Lupus Erythematosus Mon, 18 May 2015 13:20:42 +0000 Bullous systemic lupus erythematosus (BSLE) is an autoantibody-mediated vesiculobullous disease in patients with SLE. Autoimmunity in BSLE is characterized by the presence of circulating anti-type VII collagen antibodies. BSLE patients often present with multiple, tense, clear fluid-filled vesicles and bullae overlying erythematous edematous plaques. Skin biopsy from BSLE patients shows subepidermal bullae with numerous neutrophils and only occasional eosinophils. Furthermore, immunofluorescence examination showed linear deposition of lgG, lgA, C3, and C1q along the basement membrane zone. BSLE patients with corticosteroids treatment constantly do not receive a marked improvement, while dapsone generally dramatically improved the skin condition. Recently, it has been reported that quite a few cases of BSLE were successfully treated with other immune suppressive drugs. Therefore, a comprehensive review of the treatment of BSLE would be beneficial to cure the disease. Lihua Duan, Liying Chen, Shan Zhong, Ying Wang, Yan Huang, Yan He, Jie Chen, and Guixiu Shi Copyright © 2015 Lihua Duan et al. All rights reserved. GDF15(MIC1) H6D Polymorphism Does Not Influence Cardiovascular Disease in a Latin American Population with Rheumatoid Arthritis Mon, 18 May 2015 13:19:02 +0000 Objective. Rheumatoid arthritis (RA) is the most common autoimmune arthropathy worldwide. The increased prevalence of cardiovascular disease (CVD) in RA is not fully explained by classic risk factors. The aim of this study was to determine the influence of rs1058587 SNP within GDF15(MIC1) gene on the risk of CVD in a Colombian RA population. Methods. This was a cross-sectional analytical study in which 310 consecutive Colombian patients with RA and 228 age- and sex-matched controls were included and assessed for variables associated with CVD. The mixed cluster methodology based on multivariate descriptive methods such as principal components analysis and multiple correspondence analyses and regression tree (CART) predictive model were performed. Results. Of the 310 patients, 87.4% were women and CVD was reported in 69.5%. Significant differences concerning GDF15 polymorphism were not observed between patients and controls. Mean arterial pressure, current smoking, and some clusters were significantly associated with CVD. Conclusion. GDF15 (rs1058587) does not influence the development of CVD in the population studied. Jenny Amaya-Amaya, Adriana Rojas-Villarraga, Nicolas Molano-Gonzalez, Laura Montoya-Sánchez, Swapan K. Nath, and Juan-Manuel Anaya Copyright © 2015 Jenny Amaya-Amaya et al. All rights reserved. Decreased Frequency of Circulating Myelin Oligodendrocyte Glycoprotein B Lymphocytes in Patients with Relapsing-Remitting Multiple Sclerosis Mon, 18 May 2015 13:14:00 +0000 Although there is no evidence for a role of anti-MOG antibodies in adult MS, no information on B lymphocytes with MOG-committed BCR is available. We report here on the frequency of anti-MOG B cells forming rosettes with polystyrene beads (BBR) covalently bound to the extracellular domain of rhMOG in 38 relapsing-remitting patients (RRMS) and 50 healthy individuals (HI). We show a substantial proportion of circulating anti-MOG-BBR in both RRMS and HI. Strikingly, MOG-specific B cells frequencies were lower in MS than in HI. Anti-MOG antibodies measured by a cell-based assay were not different between MS patients and controls, suggesting a specific alteration of anti-MOG B cells in MS. Although anti-MOG-BBR were higher in CNS fluid than in blood, no difference was observed between MS and controls. Lower frequency of MOG-BBR in MS was not explained by an increased apoptosis, but a trend for lower proliferative capacity was noted. Despite an efficient B cell transmigration across brain derived endothelial cells, total and anti-MOG B cells transmigration was similar between MS and HI. The striking alteration in MOG-specific B cells, independent of anti-MOG antibody titers, challenges our view on the role of MOG-specific B cells in MS. Annie Elong Ngono, Maud Lepetit, Markus Reindl, Alexandra Garcia, Flora Guillot, Athénaïs Genty, Mélanie Chesneau, Marion Salou, Laure Michel, Fabienne Lefrere, Kathrin Schanda, Berthe-Marie Imbert-Marcille, Nicolas Degauque, Arnaud Nicot, Sophie Brouard, David-Axel Laplaud, and Jean-Paul Soulillou Copyright © 2015 Annie Elong Ngono et al. All rights reserved. Interleukin-23R rs7517847 T/G Polymorphism Contributes to the Risk of Crohn’s Disease in Caucasians: A Meta-Analysis Mon, 18 May 2015 13:07:34 +0000 The association between Interleukin-23R gene polymorphism and Crohn’s disease (CD) in Caucasians is still controversial. Thus, a meta-analysis was performed to evaluate the correlation between this gene variant and CD risk. We retrieved the available data from EMBASE and PUBMED until May 1, 2014, and evaluated the effect of rs7517847 in Caucasians. The significant associations were confirmed between rs7517847 and CD risk in dominant models (TT/TG versus GG: OR = 1.652, 95% CI 1.277, 2.137), allelic model (T allele versus G allele: OR = 1.327, 95% CI 1.198, 1.469), homozygote comparison (TT versus GG: OR = 1.890, 95% CI 1.465, 2.437), heterozygote comparison (TG versus GG: OR = 1.509, 95% CI 1.161, 1.960), and recessive model (TT versus TG/GG: OR = 1.409, 95% CI 1.279, 1.552). In conclusion, this meta-analysis demonstrates that rs7517847 is associated with the risk of CD in Caucasians. These findings show that IL-23R genes confer susceptibility to CD in the Caucasians. Li Zhang, Yunjie Lu, Yuzheng Ge, Yun Shi, Xing Wu, Qinghua Xu, Xiaoping Li, Ling Lu, Feng Zhang, and Guozhong Yao Copyright © 2015 Li Zhang et al. All rights reserved. The Emerging Functions of Long Noncoding RNA in Immune Cells: Autoimmune Diseases Mon, 18 May 2015 13:05:33 +0000 The long noncoding RNAs (lncRNAs) are RNA transcripts more than 200 nucleotides in length, which do not encode proteins. The lncRNAs are emerging as an important regulator of biological process, such as chromatin remodeling, gene transcription, protein transport, and trafficking through diverse mechanisms. The lncRNAs play crucial role in various multigenetics human diseases including cancers and neurological diseases and currently its role in autoimmune diseases is attracting many researchers. Recent studies have reported that differentiation and activation of immune cells, T cells, B cells, macrophages, and NK cells have correlation with lncRNAs, which have also an essential role in autoimmune diseases such as rheumatoid arthritis and SLE. Therefore, elucidation of the roles of lncRNAs in autoimmunity could be beneficial to understand the pathogenesis of autoimmune diseases. In this review article we attempt to highlight the recent progress regarding lncRNAs studies and summarize its role in autoimmune diseases. Keshav Raj Sigdel, Ao Cheng, Yin Wang, Lihua Duan, and YanLin Zhang Copyright © 2015 Keshav Raj Sigdel et al. All rights reserved. Pregnancy Associated with Systemic Lupus Erythematosus: Immune Tolerance in Pregnancy and Its Deficiency in Systemic Lupus Erythematosus—An Immunological Dilemma Mon, 18 May 2015 13:04:37 +0000 Pregnancy is a physiological condition that requires immune tolerance to the product of conception. Systemic lupus erythematosus (SLE) is a disease with well-represented immune mechanisms that disturb immune tolerance. The association of pregnancy with systemic lupus erythematosus creates a particular immune environment in which the immune tolerance specific of pregnancy is required to coexist with alterations of the immune system caused by SLE. The main role is played by T regulatory (Treg) cells, which attempt to regulate and adapt the immune system of the mother to the new conditions of pregnancy. Other components of the immune system also participate to maintain maternal-fetal immune tolerance. If the immune system of pregnant women with SLE is not able to maintain maternal immune tolerance to the fetus, pregnancy complications (miscarriage, fetal hypotrophy, and preterm birth) or maternal complications (preeclampsia or activation of SLE, especially in conditions of lupus nephritis) may occur. In certain situations this can be responsible for neonatal lupus. At the same time, it must be noted that during pregnancy, the immune system is able to achieve immune tolerance while maintaining the anti-infectious immune capacity of the mother. Immunological monitoring of pregnancy during SLE, as well as of the mother’s disease, is required. It is important to understand immune tolerance to grafts in transplant pathology. Cristina Gluhovschi, Gheorghe Gluhovschi, Ligia Petrica, Silvia Velciov, and Adrian Gluhovschi Copyright © 2015 Cristina Gluhovschi et al. All rights reserved.