bluuebunny/crossref_metadata_2025 huggingface dataset:
Gluten Sensitivity in Multiple Sclerosis
Authors: Shor Dana Ben‐Ami , Barzilai Ori , Ram Maya , Izhaky David , Porat‐Katz Bat Sheva , Chapman Joab , Blank Miri , Anaya Juan‐Manuel , Shoenfeld Yehuda
Published: September 2009

Patients with neurological disease of unknown etiology sometimes present with antigliadin and antitissue transglutaminase antibodies. The association between these antibodies and multiple sclerosis has been previously suggested. The purpose of this study was to determine the prevalence of these antibodies in multiple sclerosis patients. We determined the level of serum immunoglobulin A and immunoglobulin G antigliadin and antitissue transglutaminase antibodies in 98 patients with multiple sclerosis. We found a highly significant increase in titers of immunoglobulin G antibodies against gliadin and tissue transglutaminase in the multiple sclerosis patients. Seven patients had a positive IgG AGA, whereas only 2 controls presented positive titers (P= 0.03). Four patients had positive IgG anti‐tTG while all the controls tested negative (P= 0.02). However, immunoglobulin A antibodies against gliadin and tissue transglutaminase were not statistically higher in the multiple sclerosis group in comparison to the control group. Our findings support the associations between antibodies against gliadin and tissue transglutaminase to multiple sclerosis. The specific role of these antibodies in the pathogenesis of multiple sclerosis remains uncertain and requires additional research. A gluten free diet should be considered in specific cases of patients who present with gluten antibodies.
Treatment with PEG‐interferon and Ribavirin for Chronic Hepatitis C Increases Neutrophil and Monocyte Chemotaxis
Authors: Giorgini Alessia , Capsoni Franco , Podda Mauro , Lleó Ana , Battezzati Pier Maria , Ongari Anna Maria , Selmi Carlo , Benetti Alberto , Malinverno Federica , Rossaro Lorenzo , Gershwin M. Eric , Zuin Massimo
Published: September 2009

The incidence of infections increases during treatment with pegylated interferon (PEG‐IFN) and ribavirin (RBV) for chronic hepatitis C (CHC). Despite a reduction in neutrophil count, there is no clear relationship between infection occurrence and neutropenia. In the present study we investigated whether HCV treatment alters leukocyte function. We studied cell chemotaxis, reactive oxygen species, neutrophil phagocytosis, CR3 expression, and plasma colony stimulating factors (CSF) in 20 healthy subjects and 20 patients with CHC (10 with cirrhosis) at baseline, during antiviral treatment (at 4, 12, 24 weeks), and 12 weeks after discontinuation. Our results demonstrate that neutrophil chemotaxis and oxidative burst significantly increased during treatment and returned to baseline at the end of therapy. CR3 neutrophil expression was enhanced in baseline CHC compared to controls but did not change during antiviral treatment. Chemotaxis, oxidative burst, phagocytosis, and CSF levels did not differ significantly between patients before treatment and control subjects or among CHC cases according to the presence of cirrhosis in either cell subpopulation. In conclusion, the innate immune cell activity is enhanced in patients with CHC during antiviral treatment and returns to normal after its discontinuation thus possibly playing a role in their susceptibility to infections.
Association of Polymorphisms in Interleukin‐10 Gene Promoter with Autoantibody Production in Patients with Rheumatoid Arthritis
Authors: Nemec Petr , Goldbergova Monika Pavkova , Gatterova Jindra , Vasku Anna , Soucek Miroslav
Published: September 2009

Interleukin‐10 (IL‐10) is a major anti‐inflammatory cytokine that plays a crucial role in the regulation of the immune system. Allelic polymorphisms in the IL‐10 gene promoter may contribute to the regulation of autoantibody production. To examine the association between both individuals IL‐10 single nucleotide polymorphisms and the production of autoantibodies and the radiographic progression of rheumatoid arthritis (RA), a total of 144 RA patients were recruited into the study. We found significant differences in genotype distribution of the ‐1082G/A polymorphism between IgG, IgA, and IgM rheumatoid factor(RF)‐positive/negative RA patients. We also found significant differences in allelic frequencies of the ‐3575T/A, ‐819C/T, and ‐592A/C polymorphisms between anticyclic citrullinated peptide (anti‐CCP)‐positive/negative RA patients. The haplotype TGAATA was found to be less frequent within anti‐CCP‐positive RA patients. Results obtained in this study provide evidence of an association between polymorphisms in IL‐10 gene promoter and the production of autoantibodies in RA patients.
Galectin‐10, Eosinophils, and Celiac Disease
Authors: De Re Valli , Simula Maria Paola , Cannizzaro Renato , Pavan Alessandro , De Zorzi Mari Angela , Toffoli Giuseppe , Canzonieri Vincenzo
Published: September 2009

Celiac disease (CD) is a chronic intestinal disease caused by intolerance to dietary wheat gluten in genetically susceptible individuals. There are a number of important open questions that impede the full explanation of the pathogenesis of this disease. We analyzed protein expression pattern in gut biopsies of CD subjects. Patients were selected and grouped according to histological inflammatory degree. Groups consisted of nine individuals with CD: three patients had a Marsh 0, three a Marsh I‐II, and three a Marsh III. All CD patients showed a human leukocyte antigen DQ2/8 variant. Controls were three individuals with an excluded CD diagnosis. For the first time, galectin‐10 expression was found related to the histological grade (P= 0.0092) and with the number of eosinophils in the lesion (P= 0.0040). Results suggest galectin‐10 is a novel marker for evaluating CD tissue damage and eosinophils as a possible target for therapeutic approaches. Moreover, our data provide insights into alterations associated with CD tissue damage and pathogenesis.
B‐Lymphocyte Stimulator and a Proliferation‐Inducing Ligand Serum Levels in IgA‐Deficient Patients With and Without Celiac Disease
Authors: Fabris Martina , De Vita Salvatore , Visentini Daniela , Fabro Cinzia , Picierno Alessia , Lerussi Alice , Villalta Danilo , Alessio Maria Grazia , Tampoia Marilina , Tonutti Elio
Published: September 2009

IgA deficiency (IgAD) is the most common form of immunodeficiency and frequently associates with autoimmunity, especially with celiac disease (CD). The mechanisms underlying IgAD and the development of autoimmunity are still relatively unknown. Elevated B‐lymphocyte stimulator (BLyS) and APRIL (a proliferation‐inducing ligand) serum levels characterize several autoimmune diseases. We herein investigated BLyS and APRIL serum levels in IgAD patients with and without CD and compared these patients to CD patients with normal IgA and control patients (HBDs). Compared to HBDs, IgAD patients demonstrated a significant increase of BLyS (P < 0.0001) and APRIL (P= 0.003) levels, and no differences were seen between patients with or without CD. While BLyS appeared similarly overexpressed in IgAD and CD patients, APRIL was significantly increased only in IgAD patients. Because APRIL promotes IgA production, its overexpression may represent a physiological mechanism of compensation. BLyS upregulation may be involved in the increased risk of autoimmune disease development characterizing people carrying IgAD.
Evaluation of a New ELISA Assay for Detection of BP230 Autoantibodies in Bullous Pemphigoid
Authors: Tampoia Marilina , Lattanzi Valeria , Zucano Antonietta , Villalta Danilo , Filotico Raffaele , Fontana Antonietta , Vena Gino Antonio , Di Serio Francesca
Published: September 2009

The diagnosis of bullous pemphigoid is based on clinical observations and on the presence of autoantibodies directed against proteins of the dermoepidermal junction. Human recombinant BP180 and BP230 peptides have been used to develop new quantitative enzyme immunoassays (EIA) for the detection of specific antibodies. This study evaluated the sensitivity and specificity of a new immunoassay for the detection of BP230 autoantibodies and clinical correlations. Serum samples were tested from patients with bullous pemphigoid, other skin diseases, and from healthy donors. Autoantibodies anti‐BP230 and anti‐BP180 were assayed using the EIA method. Diagnostic specificity for both tests was over 98%; diagnostic sensitivity was 90% and 60% for anti‐BP180 and anti‐BP230, respectively. IgG anti‐BP180 titers exhibited a significant correlation with disease activity. No patient in remission was positive for anti‐BP230. In conclusion, anti‐BP180 and anti‐BP230 assays are useful in the diagnosis of bullous pemphigoid and provide information on disease activity.
In Vitro Effects of Antiphospholipid Syndrome‐IgG Fractions and Human Monoclonal Antiphospholipid IgG Antibody on Human Umbilical Vein Endothelial Cells and Monocytes
Authors: Clemens Natascha , Frauenknecht Katrin , Katzav Aviva , Sommer Clemens , Von Landenberg Philipp
Published: September 2009

It has been shown that stimulation of endothelial cells and monocytes by antiphospholipid antibodies leads to a prothrombotic state involving upregulation of tissue factor (TF). We examined the in vitro effects of IgG fractions from patients with antiphospholipid syndrome (APS) and of a β‐2‐glycoprotein 1‐independent human monoclonal antiphospholipid antibody (HL‐5B) on human umbilical vein endothelial cells (HUVEC) in comparison to untreated cell controls and to exposure to monoclonal IgG control antibody. We also examined the effect of recombinant monocyte chemoattractant protein‐1 (MCP‐1) on peripheral blood monocytes. Stimulation of endothelial cells with APS IgG fractions or HL‐5B resulted in time‐dependent upregulation of MCP‐1 mRNA and protein expression. Stimulation with HL‐5B also led to time‐dependent upregulation of interleukin (IL)‐8 and intracellular adhesion molecule‐1 (ICAM‐1) mRNA and IL‐8 protein expressions. Stimulation of monocytes with recombinant MCP‐1 resulted in an upregulation of TF mRNA and TF protein. In conclusion these results might represent a mechanism for antiphospholipid antibody‐mediated thrombosis in APS patients.
Clinical Significance of Complement Deficiencies
Authors: Pettigrew H. David , Teuber Suzanne S. , Gershwin M. Eric
Published: September 2009

The complement system is composed of more than 30 serum and membrane‐bound proteins, all of which are needed for normal function of complement in innate and adaptive immunity. Historically, deficiencies within the complement system have been suspected when young children have had recurrent and difficult‐to‐control infections. As our understanding of the complement system has increased, many other diseases have been attributed to deficiencies within the complement system. Generally, complement deficiencies within the classical pathway lead to increased susceptibility to encapsulated bacterial infections as well as a syndrome resembling systemic lupus erythematosus. Complement deficiencies within the mannose‐binding lectin pathway generally lead to increased bacterial infections, and deficiencies within the alternative pathway usually lead to an increased frequency of Neisseria infections. However, factor H deficiency can lead to membranoproliferative glomerulonephritis and hemolytic uremic syndrome. Finally, deficiencies within the terminal complement pathway lead to an increased incidence of Neisseria infections. Two other notable complement‐associated deficiencies are complement receptor 3 and 4 deficiency, which result from a deficiency of CD18, a disease known as leukocyte adhesion deficiency type 1, and CD59 deficiency, which causes paroxysmal nocturnal hemoglobinuria. Most inherited deficiencies of the complement system are autosomal recessive, but properidin deficiency is X‐linked recessive, deficiency of C1 inhibitor is autosomal dominant, and mannose‐binding lectin and factor I deficiencies are autosomal co‐dominant. The diversity of clinical manifestations of complement deficiencies reflects the complexity of the complement system.
An Italian Multicenter Study for Application of a Diagnostic Algorithm in Autoantibody Testing
Authors: Bonaguri Chiara , Melegari Alessandra , Dall’Aglio PierPaolo , Ballabio Andrea , Terenziani Paolo , Russo Annalisa , Battistelli Luisita , Aloe Rosalia , Camisa Roberta , Campaniello Giovanna , Sartori Elisabetta , Monica Cesare
Published: September 2009

The presence in the serum of specific autoantibodies, such as antinuclear antibodies (ANA), anti‐double‐stranded DNA (anti‐dsDNA), and antiextractable nuclear antigens (anti‐ENA), is one of the diagnostic criteria for autoimmune rheumatic disease, and the requests for these tests in the last few years have grown remarkably. A guideline for reducing clinically inappropriate requests in autoantibody testing (ANA, anti‐dsDNA, anti‐ENA) has been applied in the Parma Hospital since 2007. The results for the period January–December 2007 were compared to those of the previous period January–December 2006, and a significant reduction in the number of anti‐dsDNA (23.9%) and anti‐ENA (20.7%) was found. The aim of this study was to assess the applicability of a similar guideline in a wide area (Parma, Modena, Piacenza, Reggio‐Emilia) with reference to the diagnosis of autoimmune rheumatic disease. This project, supported by a regional grant for innovative research projects, was started in January 2008 and consists of three different steps: (1) a study group of clinicians and laboratory physicians to evaluate the diagnostic criteria, the analytical procedures, and the number of tests performed in different hospitals; (2) developing common guidelines for autoantibody testing that takes into account the different clinical needs with the aim of improving efficiency and clinical effectiveness of diagnosis and monitoring; and (3) assessing compliance with the guidelines in the different hospitals that are evaluating the second‐level test (anti‐dsDNA, anti‐ENA) decrease. We think that the validation of guidelines for the laboratory diagnosis of autoimmune rheumatic disease can represent a tool for improving patients’ outcomes and economic efficiency.
Alexithymia in Systemic Lupus Erythematosus Patients
Authors: Barbosa Filipe , Mota Catarina , Alves Miguel , Alcântara Cristina , Rossiñol Bartolomeu , Patrício Patrícia , Barbosa António , Ferreira Carlos
Published: September 2009

This study aimed to determine the prevalence of alexithymic characteristics in patients with systemic lupus erythematosus (SLE), comparing them with a population of healthy subjects. Fifty‐three SLE patients [American College of Rheumatology (ACR) criteria] and 31 healthy volunteer subjects were administered validated scales for alexithymia (Toronto alexythimia scale‐20), psychopathology (brief symptom inventory; hospital anxiety and depression scale), personality dimensions (NEO five‐factor inventory), and quality of life (short form‐36 health survey). The SLE patient's clinical and laboratory evaluations were performed by computerized indicators of activity (SLE disease activity index), of accumulated damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index), length of disease, and therapy. A high prevalence of alexithymia was found in SLE patients. Alexithymia was associated with psychopathology, personality, and quality of life dimensions. Clinical variables and therapy were not correlated significantly with alexithymia, psychopathology, or quality of life dimensions. Multiple regression analysis showed that openness and depression were the two predictors for alexithymia in SLE patients. The present findings showed that alexithymia may play an important role in SLE patients. The difficulty in the management of emotions may lead to psychological distress and instability affecting the patient's quality of life, a relevant finding for the psychological, psychiatric, and clinical intervention and approach.
Infectious Serologies and Autoantibodies in Wegener's Granulomatosis and Other Vasculitides
Authors: Lidar Merav , Lipschitz Noga , Langevitz Pnina , Barzilai Ori , Ram Maya , Porat‐Katz Bat‐Sheba , Pagnoux Christian , Guilpain Philippe , Sinico Renato Alberto , Radice Antonella , Bizzaro Nicola , Damoiseaux Jan , Tervaert Jan Willem Cohen , Martin Javier , Guillevin Loïc , Bombardieri Stefano , Shoenfeld Yehuda
Published: September 2009

In this study we assess the presence of antibodies against infectious agents as well as for a variety of autoantibodies in an attempt to establish associations between various vasculitides and infections in order to shed light on the etiopathogenesis of these diseases and perhaps implicate a potential cure. Sera from patients with Wegener's granulomatosis (WG), polyarteritis nodosa, microscopic polyangiitis, Churg Strauss, and giant cell arteritis were compared to healthy control sera. Serum samples were assessed, using the Bio‐Rad BioPlex 2200, for the presence of Toxoplama gondii, cytomegalovirus (CMV), Epstein–Barr virus (EBV), Treponema pallidum, and Saccharomyces cerevisiae. Hepatitis B virus (HBV), hepatitis C virus (HCV), and anti‐Helicobacter pylori antibodies were assessed by ELISA. In addition, sera were tested for a panel of antibodies associated with thrombophilia as well as various autoantibodies. The prevalence of antibodies toward HCV and H. pylori was significantly higher among patients with WG. IgG antibodies toward T. gondii and IgM antibodies toward CMV were significantly more common among WG patients than among controls. WG patients exhibited more antibodies toward EBV viral capsid antigen IgG and EBV early antigen IgG compared to sera from healthy controls. In WG, positive associations were disclosed between CMV IgG antibodies and the presence of gastrointestinal manifestations and renal involvement, and there was a higher Birmingham vasculitis activity score in association with elevated titers of EBV viral capsid antigen IgG antibodies. Otorhinolaryngeal manifestations were more common in those with positive IgG antibodies for EBV early antigen. Our results unveil novel associations between WG and various infectious agents, including HCV, H. pylori, T. gondii, CMV, and EBV. In addition to putative roles in initiation and exacerbation of the vasculitic process, it seems that these infectious agents also modulate the clinical phenotype of the disease.
Human Leukocyte Antigen‐DRB1 and ‐DQB1 Genotyping in Lupus Patients with and without Antiphospholipid Syndrome
Authors: Kapitany Aniko , Tarr Tunde , Gyetvai Agnes , Szodoray Peter , Tumpek Judit , Poor Gyula , Szegedi Gyula , Sipka Sandor , Kiss Emese
Published: September 2009

We investigated the genetic background regarding major histocompatibility complex (MHC) II alleles in patients with systemic lupus erythematosus (SLE) only, in patients with SLE with secondary antiphospholipid syndrome (SLE+SAPS), and in patients whose clinical course began as primary antiphospholipid syndrome (PAPS) and subsequently progressed to SLE (PAPS+SLE) in order to explain the phenotypical differences found in our previous study. Those with primary or secondary APS present more thrombotic and less inflammatory activity. Fetal wastage was the highest in the PAPS+SLE group. We performed human leukocyte antigen (HLA)‐DRB1 and HLA‐DQB1 genotyping in 63 patients (26, 22, and 15 in SLE only, SLE+SAPS, and PAPS+SLE groups, respectively) and in 57 healthy controls, using PCR with sequence‐specific primers. We found that, as reported in the literature, the occurrence of DRB1*03 and DQB1*0201 alleles was higher in SLE patients than in controls, but these alleles were rare in the PAPS+SLE group (13% in PAPS+SLE vs. 46% in the SLE only group; P= 0.044). HLA‐DRB1*04 alleles were expressed frequently in both primary and secondary APS. DRB1*13, DQB1*06, and DQB1*0302 alleles were present more frequently in the PAPS+SLE patients than in the other groups, while the DQB1*0301 allele was rare. In this study we have shown that the SLE‐associated DRB1*03/DQB1*02 alleles occurred frequently in our lupus patients as well as in SLE patients with secondary APS. In patients who started as PAPS and later progressed to SLE, the allele frequency was fundamentally different. Taken together, our results confirmed that the HLA‐DRB1 and HLA‐DQB1 profile of PAPS and SAPS is different. Therefore it is unlikely that these alleles are responsible for the partly similar phenotype of the two groups.
Effects of Biologics on Vascular Function and Atherosclerosis Associated with Rheumatoid Arthritis
Authors: Kerekes György , Soltész Pál , Dér Henriett , Veres Katalin , Szabó Zoltán , Végvári Anikó , Shoenfeld Yehuda , Szekanecz Zoltán
Published: September 2009

Endothelial dysfunction and accelerated atherosclerosis lead to increased cardiovascular morbidity and mortality in rheumatoid arthritis (RA). Sustained inflammation is a major risk factor. Apart from traditional vasculoprotective agents, biologics may also exert favorable effects on the vasculature. Indeed, tumor necrosis factor‐α (TNF‐α) inhibitors agents may transiently improve endothelial function. There are conflicting data regarding the effects of biologics on atherosclerosis and arterial stiffness. Infliximab stimulates the number and differentiation of endothelial progenitor cells that lead to vascular repair. There may be differences in the effects of TNF blockers on dyslipidemia, as long‐term infliximab therapy may be proatherogenic, while some studies suggest that etanercept and adalimumab may exert beneficial effects on lipids. TNF blockers may decrease the incidence of cardiovascular events in RA. Preliminary data suggest that rituximab may also improve endothelial function and dyslipidemia. Further studies are needed to determine the net effects of biologics on the vasculature.
High‐sensitivity Detection of Autoantibodies Against Proteinase‐3 by a Novel Third‐generation Enzyme‐linked Immunosorbent Assay
Authors: Roggenbuck Dirk , Buettner Thomas , Hoffmann Lars , Schmechta Helmuth , Reinhold Dirk , Conrad Karsten
Published: September 2009

The aim of this study was to evaluate a novel third‐generation enzyme‐linked immunosorbent assay (ELISA) for the high‐sensitivity detection of autoantibodies to proteinase‐3 (PR3) in patients with Wegener's granulomatosis (WG). First‐ and second‐generation ELISA for the detection of antineutrophil cytoplasmic antibodies (ANCA) frequently demonstrate insufficient sensitivity due to inadequate presentation of autoantigenic epitopes. Human PR3 was immobilized on the solid phase of ELISA plates by anchoring technique. Anti‐PR3 reactivity was measured in 34 C‐ANCA positive patients with WG, 11 MPO‐ANCA–positive patients with other autoimmune vasculitides, 65 patients with systemic lupus erythematosus (SLE), and 137 healthy blood donors. Thirty‐three of 34 patients with WG (97.1%) showed positive anti‐PR3 IgG antibody reactivity. None of 11 MPO‐ANCA positive vasculitis patients, none of 137 blood donors, and 3 of 65 SLE patients expressed elevated IgG reactivity to PR3 (specificity: 98.4%). Comparison with another third‐generation ELISA did not reveal different qualitative results. However, there was no significant correlation between quantitative results of both assays. Receiver operating characteristic (ROC) curve analysis revealed a significantly better assay performance compared with first (direct)‐ and second (capture)‐generation assays (P= 0.011 and P= 0.001, respectively). Third‐generation (anchor) anti‐PR3 ELISA exhibit significantly higher sensitivity than previous generation assays. Anchoring of PR3 renders the granulocyte protein more autoantigenic compared with direct or capture immobilization.
Optimization of High‐throughput Autoantibody Profiling for the Discovery of Novel Antigenic Targets in Rheumatoid Arthritis
Authors: Somers Klaartje , Stinissen Piet , Somers Veerle
Published: September 2009

A major focus in rheumatoid arthritis (RA) research is the identification of the antigens that are targeted by the joint‐directed autoimmune response. B cells and associated autoantibodies have been studied in RA to identify the antigenic targets and to discover RA‐associated autoantibodies which can be used as disease markers. This research indicated the heterogeneity of the autoantibody profile in RA and the large overlap in antibody specificities with other rheumatic diseases pointing toward the need for multiplexing to identify an RA‐associated autoantibody profile. The discovery of antibodies directed against cyclic citrullinated peptides (ACPA) has led to great advances in RA research. This finding generated novel autoantigen suspects in ACPA‐positive RA patients, which comprise approximately two‐thirds of the entire RA population, namely citrullinated peptides and/or proteins. One‐third of the RA patients, however, do not show ACPA, and it is now postulated that ACPA‐positive and ACPA‐negative RA are two different disease entities with different genetic associations, pathogenesis, and etiology. The analysis of autoantibodies in ACPA‐negative RA could provide insight into the identity of antigenic targets and markers for this disease subtype. We report here the optimization of an unbiased, high‐throughput autoantibody profiling procedure based on cDNA phage display for the detection of novel autoantibody targets in ACPA‐negative RA. The discovery of specific autoantibodies in this RA subtype could lead to great advances in the diagnosis of these patients and could provide clues regarding disease etiology and pathogenesis of ACPA‐negative RA.
Val/Leu247 Polymorphism of β2‐glycoprotein I in Brazilian Patients with Antiphospholipid Syndrome—A Genetic Risk Factor?
Authors: Pernambuco‐Climaco Juliana M. , Brochado Maria Jose F. , Freitas Max Victor C. , Roselino Ana Maria F. , Louzada‐Junior Paulo
Published: September 2009

A genetic polymorphism of the β2‐glycoprotein I (β2‐GPI) is recognized by antiphospholipid antibodies (aPL) and may even play a role in the development of antiphospholipid syndrome (APS). The objectives of this study were to determine a Val/Leu SNP at position 247 of the β2‐GPI gene in Brazilian patients with APS and to compare these data with clinical and laboratory manifestations. Polymorphism assignment was performed by PCR followed by Rsa I restriction endonuclease. The titration of anti‐β2‐GPI antibodies was detected by ELISA. The results showed significantly higher frequencies of the V‐encoding allele and the homozygous VV genotype in patients with APS than in control subjects (OR = 1.781, P= 0.0068; and OR = 6.413, P < 0.0001, respectively). The frequency of this genotype was also significantly higher in patients with arterial and venous thrombosis than in the control group (52% and 44%, respectively, versus 13%). Anti‐β2‐GPI‐positive patients had significantly higher frequencies of the VV genotype than the controls subjects (OR = 8.179, P < 0.0001). These results suggest that the V‐encoding allele and the homozygous VV genotype at position 247 of the β2‐GPI gene may play a role in the generation of anomalous β2‐GPI, with consequent auto‐antibody production, and in phenotype expression of arterial and venous thrombosis in APS patients.
The IgM Response to Modified LDL in Experimental Atherosclerosis
Authors: Van Leeuwen Marcella , Damoiseaux Jan , Duijvestijn Adriaan , Heeringa Peter , Gijbels Marion , De Winther Menno , Tervaert Jan Willem Cohen
Published: September 2009

Introduction:
It is hypothesized that IgM antibodies to oxidized LDL are anti‐atherogenic. Myeloperoxidase from plaque‐infiltrating neutrophils catalyzes the production of hypochlorite (HOCl), which oxidizes LDL. Here we study the IgM response to HOCl‐modified LDL in comparison to titers of T15 clonotypic natural antibodies. Methods: Plasma of LDLR−/− mice fed a normal chow or high‐fat diet was obtained after 6 and 16 weeks. The IgM responses to HOCl‐modified LDL and T15 clonotypic natural IgM antibodies were measured by ELISA. Results: The IgM levels in response to HOCl‐modified LDL increased dramatically in the atherosclerotic group after introduction of the high‐fat diet, but not in mice on normal chow. The natural IgM T15 clonotypic antibody titers revealed a more moderate increase during atherogenesis. Conclusion: Our results show that during atherogenesis there is a strong induction of IgM antibodies to HOCl‐modified LDL particles. Whether these induced IgM antibodies are pro‐ or anti‐atherogenic remains to be established.
Accuracy of the First Fully Automated Method for Anti‐cardiolipin and Anti‐β2 Glycoprotein I Antibody Detection for the Diagnosis of Antiphospholipid Syndrome
Authors: Villalta D. , Alessio M.G. , Tampoia M. , Da Re A. , Stella S. , Da Re M. , Tozzoli R. , Bizzaro N.
Published: September 2009

In this study we evaluated the diagnostic accuracy for antiphospholipid syndrome (APS) of new fully automated immunoassays for anticardiolipin (aCL) and anti‐β2 glycoprotein I (anti‐β2‐GPI) auto‐antibody detection (EliA‐Phadia), and compared the results with those obtained with Orgentec and Inova ELISA methods. Sixty‐two APS patients and 123 controls (20 syphilis, 33 Lyme disease, 30 HCV infection and cryoglobulinemia, 40 healthy subjects) were studied. Using the 99th percentile cutoff, the sensitivity and specificity of EliA aCL IgG, aCL IgM, anti‐β2‐GPI IgG, and anti‐β2‐GPI IgM were 69.4% and 81.9%, 64.5% and 86.7%, 64.5% and 98.8%, and 53.2% and 92.8%, respectively. Using the Sydney criteria cutoff (>40 GPL/MPL units), sensitivity and specificity of EliA aCL IgG and aCL IgM were 45.2% and 98.8%, and 35.5% and 97.5%, respectively. The best diagnostic efficiency was obtained combining the aCL tests (>40 GPL/MPL units) with the anti‐β2‐GPI tests (sensitivity 85.7%, specificity 90.4%). The area under the ROC curves for EliA, Orgentec, and Inova methods were 0.870, 0.940, and 0.850 for aCL IgG; 0.820, 0.820, and 0.820 for aCL IgM; 0.910, 0.960, and 0.920 for anti‐β2‐GPI IgG; 0.840, 0.840, and 0.820 for anti‐β2‐GPI IgM, respectively. Finally, the overall agreement between EliA assays and the other two ELISA methods ranged from moderate (anti‐β2‐GPI IgG EliA versus Orgentec: Cohen's k= 0.426) to good (anti‐β2‐GPI IgM EliA vs. Inova: k= 0.841). In conclusion, newly developed EliA methods for antiphospholipid antibody detection perform similarly to other ELISA assays and represent a useful tool for APS laboratory diagnosis in daily practice.
Preventing Viral‐induced Type 1 Diabetes
Authors: Richer Martin Joseph , Horwitz Marc Steven
Published: September 2009

The development of type 1 diabetes is, in part, dictated by the failure of regulatory T cells to maintain peripheral tolerance. As such, therapies aimed at correcting the declining function of regulatory T cells have been the subject of intense investigation. In this review, we discuss the potential of regulatory T cells to suppress autoreactive responses and prevent type 1 diabetes induced by viral infection while maintaining protective antiviral immunity.
Proliferation Signal Inhibitors for the Treatment of Refractory Autoimmune Rheumatic Diseases
Authors: Yoon Kam Hon
Published: September 2009

Sirolimus and everolimus belong to the novel class of immunosuppressant agents known as proliferation signal inhibitors (PSIs). They act by preventing antigen‐driven T cell proliferation. While PSIs are widely used in transplantation, there are few reports of PSI usage in the treatment of autoimmune rheumatic diseases. The author has presented a series in the APLAR 2006 conference. This report summarizes the clinical experience with PSIs in the treatment of resistant or relapsed rheumatic diseases where conventional immunosuppressive agents have failed. This is a retrospective review of patients with various autoimmune rheumatic diseases who had sirolimus and everolimus treatment from the rheumatological clinics of Changi Hospital or the Arthritis and Rheumatism Specialist Medical Centre. The period of review was from April 2006 to April 2008. A total of 46 patients were reviewed, 39 females and 7 males. The racial distribution was 33 Chinese, 7 Malays, and 6 Indians. Their disease conditions were as follows: 26 (57%) rheumatoid arthritis, 7 psoriatic arthritis, 4 systemic lupus erythematosus, 3 scleroderma, 2 anti‐Jo‐1 syndrome, 2 spondyloarthropathy, 1 MCTD, and 1 vasculitis. All patients had failed at least three DMARDs or immunosuppressants. Twenty‐eight patients received sirolimus and 28 patients received everolimus. Overall positive response rate was 48.2%. Twenty‐seven percent had adverse events. 20% had no response. 7% relapsed after initial response. PSIs, namely sirolimus and everolimus, are a novel class of immunosuppressants that can be added to the armamentarium of rheumatologists for the treatment of patients with refractory autoimmune rheumatic diseases.
Clonal CD27+ CD19+ B Cell Expansion through Inhibition of FCγIIR in HCV+ Cryoglobulinemic Patients
Authors: De Re Valli , Pavan Alessandro , Sansonno Silvia , Sansonno Domenico , Racanelli Vito
Published: September 2009

Persistent HCV infection may be associated with extrahepatic manifestations such as type II mixed cryoglobulinemia (II‐MC), a clonal B cell proliferative disorder. In persistent HCV infection without II‐MC, an increase in serum immunoglobulins (Ig) is commonly observed. This increase is polyclonal and is determined primarily by increased levels of IgG which include both HCV‐specific and nonspecific antibodies. Nonetheless, memory CD27+ B cells do not accumulate. This paradoxical phenomenon depends on heightened sensitivity of memory B cells to BCR‐independent noncognate T cell help, which speeds up their terminal differentiation into antibody‐secreting cells and makes them more prone to apoptosis. In persistent HCV infection with II‐MC, serum Ig elevation is also a general occurrence, and characteristically includes IgM antibodies with rheumatoid factor activity, which are essential for the development of circulating, cryoprecipitable immune complexes. Hypergammaglobulinemia is sustained by a peripheral expansion of IgM+k+IgDlow/negCD21lowCD27+ B cells. These cells exhibit marked VH, JH, and VK gene segment usage restriction, indicating that a limited number of antigens drive their proliferation through BCR interaction. Recently, two epitopes, one of the human IgG and the second of the HCVNS3 protein, had been identified and demonstrated able to link the BCR exposed on II‐MC subjects. Based on the above findings, we propose a model whereby BCR binding the IgM/IgG/HCVNS3 immune complexes deprives FcγIIR of its natural ligand. This takes the brake off RF+CD27+ B cell proliferation and promotes their selective accumulation, which is otherwise prevented by increased apoptosis susceptibility in persistent HCV infection without II‐MC.
Predictors of Damage Progression in Portuguese Patients with Systemic Lupus Erythematosus
Authors: Santos Maria José , Vinagre Filipe , Nero Patrícia , Barcelos Filipe , Barcelos Anabela , Rodrigues Ana Maria , De Matos António Alves , Silva Cândida , Miranda Luis , Capela Susana , Marques Aurora , Branco Jaime , Da Silva José Canas
Published: September 2009

Patients with systemic lupus erythematosus (SLE) have a longer life expectancy. The occurrence of irreversible damage has become a major concern. The present study assessed damage progression in patients with SLE over a 2‐year period and identified baseline features associated with damage accrual. Two hundred and twenty‐one patients that fulfilled criteria for SLE and had a follow‐up longer than 6 months were enrolled. Demographic, clinical, and immunological data were collected at baseline. Accumulated organ damage was scored using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Patients were prospectively followed and SDI assessment repeated at 2 years. At baseline 72 patients (33%) presented some irreversible damage, and after 2 years 53 had accrued new damage. The mean SDI for the whole cohort increased from 0.582 to 0.980. Damage progression was higher in ocular, cardiovascular, and musculoskeletal systems. Older age [OR = 1.045; 95% confidence interval (CI) 1.021–1.069; P= 0.03], presence of antiphospholipid antibodies (OR = 3.047; 95% CI 1.169–7.941; P= 0.02), steroid use (OR = 6.401; 95% CI 1.601–25.210; P= 0.008), azathioprine use (OR = 3.501; CI 1.224–10.012; P= 0.01), and hypertension (OR = 3.825; 95% CI 1.490–9.820; P= 0.005) were predictors of damage progression in multivariate analysis. Overall SDI increased over time, with some systems being affected more frequently. Demographic and clinical characteristics, co‐morbidity, and treatment options may contribute to irreversible damage. It is necessary to determine whether the control of modifiable factors (e.g., hypertension and judicious use of medications) might prevent damage progression in SLE patients.
Anti‐C1q Antibodies in Juvenile‐Onset Systemic Lupus Erythematosus
Authors: Jesus A.A. , Silva C.A. , Carneiro‐Sampaio M. , Sheinberg M. , Mangueira C.L. , Marie S.K. , Liphaus B.L.
Published: September 2009

The objective of this study was to evaluate the presence of anti‐C1q antibodies Hospital Israelita Albert Einstein Research Institute, São Paulo, Brazil in 67 juvenile systemic lupus erythematosus (JSLE) patients and 26 healthy controls and to assess the association of these antibodies with disease activity, nephritis, and presence of anti‐double‐stranded (ds)DNA. Anti‐C1q antibodies were detected by ELISA. A higher frequency of anti‐C1q antibodies was observed in JSLE patients compared to controls (20% vs. 0%, P= 0.016). Specificity of these antibodies was 100%[95% confidence interval (CI) 86.7–100%] and sensitivity was 19.4% (95% CI 10.7–30.8%) for a lupus diagnosis. The median anti‐C1q antibodies was higher in JSLE patients compared to controls [median (range) 9.4 (5.5–127) vs. 7.3 (5–20) units, P= 0.004]. Remarkably, a positive Spearman's coefficient was found between anti‐dsDNA and anti‐C1q units (r= 0.42, P= 0.0004, 95% CI 0.19–0.60). Our results confirm a low frequency of anti‐C1q antibody in our lupus populations, but the presence of anti‐Clq antibodies appears to be a good marker for JSLE diagnosis.
Autoimmune Bullous Dermatoses: A Review
Authors: Patrício Patrícia , Ferreira Carlos , Gomes Manuel Marques , Filipe Paulo
Published: September 2009

Bullous dermatoses are a variety of autoimmune skin diseases that are characterized by the presence of bullae or blisters. Most of these diseases are associated with substantial morbidity, and a few may result in death. Although most general approaches to the treatment and diagnosis of these entities are similar, the diagnosis of the specific disease is important, because the most appropriate dosage and timing of some commonly used medications vary considerably. The review covers the management of main autoimmune bullous dermatoses, including bullous pemphigoid and pemphigus vulgaris, linear IgA dermatosis, dermatitis herpetiformis, and bullous systemic lupus erythematosus.
Sugar‐free Antibodies—The Bacterial Solution to Autoimmunity?
Authors: Allhorn Maria , Collin Mattias
Published: September 2009

The enzyme EndoS from Streptococcus pyogenes is an immunomodulatory molecule hydrolyzing the conserved glycans in the effector part of immunoglobulin G (IgG). EndoS is remarkably specific for IgG, and hydrolysis has profound effects on IgG effector functions. EndoS pretreatment of IgG, or direct administration to animals with experimental antibody‐mediated autoimmune diseases, inhibits development of disease or cures animals from established disease. The properties of EndoS make it a unique experimental tool and an attractive alternative to current therapies of conditions involving pathogenic antibodies. This review describes the discovery of EndoS, the effects of EndoS on IgG effector functions in vitro and in vivo, the biotechnological potential of EndoS, and the outcomes of EndoS treatment in animal models of autoimmunity.
The Role of iNKT Cells in the Immunopathology of Systemic Lupus Erythematosus
Authors: Gabriel Luisa , Morley Bernard J. , Rogers Nicola J.
Published: September 2009

An increasing body of evidence suggests that CD1d‐restricted invariant natural killer T (iNKT) cells play an important immunoregulatory role in a variety of autoimmune diseases in both humans and mouse models. Their role in systemic lupus erythematosus (SLE), however, is not fully determined, as SLE mouse models have yielded conflicting results demonstrating both a protective function and a pathogenic role. The reduced frequency of iNKT cells in peripheral blood of lupus patients supports the idea of a protective role for these cells in the immunopathology of SLE. Therapeutic approaches using glycolipids provide a promising tool to correct numerical iNKT cell deficiencies and to modulate their function. This review highlights the potential role of iNKT cells in lupus immunopathology and summarizes recent studies concerning iNKT cells in SLE patients, lupus‐prone murine models and glycolipid therapy.
Relevance of Anti‐C1q Autoantibodies to Lupus Nephritis
Authors: Tsirogianni Alexandra , Pipi Elena , Soufleros Kostantinos
Published: September 2009

The first component of the classical pathway of the complement system (C1q) is considered to have a crucial role in the clearance of immune complexes (ICs) as well as in the removal of waste material originating from apoptotic cells. A prolonged exposure of C1q epitopes to the immune system could eventually lead to an autoimmune response against itself. Although autoantibodies against C1q are found in several diseases, their clinical interest originates from their strong association to active lupus nephritis (LN). Several studies indicate that anti‐C1q autoantibodies could serve as a reliable serologic marker in the assessment of LN activity compared to other immunological tests. Additionally, it was suggested that anti‐C1q autoantibodies could play a role in LN pathogenesis. Their potential pathogenic actions likely depend on genetic background, titers, Ig classes and subclasses, and specific epitopes of anti‐C1q autoantibodies as well as C1q availability and allocation. It is still unclear which different types of anti‐C1q autoantibodies dominate in each case and if their upregulation is pathogenic, an epiphenomenon of aberrant tissue damage, or compensatory to an uncontrolled immune response.
Do We Need Autoimmune Disease Units in Hospitals?
Authors: Vasconcelos Carlos
Published: September 2009

Autoimmune diseases are increasing worldwide, and associated morbidity, mortality, and health care costs are high. Biological therapies, however, have brought physicians an extraordinary opportunity to change natural disease history, although these therapies can also have high associated iatrogenic costs. These factors point to the necessity of having physicians that are dedicated to autoimmunology. The question regarding the creation of a new specialty, the autoimmunologist, should be addressed after an inquiry into the current practice in this field of medicine. This includes many classical specialties, such as internal medicine, rheumatology, and neurology, as well as clinical immunology. In clinical immunology, not counting the specialists in allergology and clinical immunology that mainly work only with allergies, heterogeneity is high in clinical practice, as the European Union of Medical Specialists documented some years ago. I am, at least for now, in favor of the creation of a transversal competency to which the different physicians working in the area could apply to in order to standardize the clinical practice in autoimmunology. It will be necessary to define a core curriculum, and in the end we shall have classical specialists and clinical immunologists with or without the competency of autoimmunology. Of utmost importance is that this new field of medicine should not be translated, as in the past happened with other areas, by walls between medical specialties. Instead it should help standardize and harmonize clinical practice. The time for autoimmunology is now, and, indeed, hospitals must have autoimmune disease units.
Exposure to Epstein–Barr Virus Infection Is Associated with Mild Systemic Lupus Erythematosus Disease
Authors: Zandman‐Goddard Gisele , Berkun Yackov , Barzilai Ori , Boaz Mona , Blank Miri , Ram Maya , Sherer Yaniv , Anaya Juan Manuel , Shoenfeld Yehuda
Published: September 2009

Infections may act as environmental triggers for the induction of systemic lupus erythematosus (SLE). In this study, we determine the relationship between disease manifestations of SLE patients and the titers of five Epstein–Barr virus (EBV) Abs. We evaluated the titers of early antigen IgG (EAG), nuclear antigen IgG, viral capsid antigen (VCA) IgG and IgM, and heterophile IgM, using the BioPlex 2200 multiplexed immunoassay method in 260 sera (120 SLE patients and 140 controls). EAG titers were significantly elevated (P < 0.024) in patients with cutaneous symptoms and increased anti‐Ro antibody titers (P < 0.005). VCA IgG titers were significantly elevated (P < 0.003) in patients with joint involvement. None of the titers differed by central nervous system or renal involvement or antiphospholipid syndrome. We conclude that exposure to EBV infection may predict a disease phenotype of mild SLE disease with cutaneous and joint manifestations and elevated titers of anti‐Ro Abs.
The Incidence of Celiac Disease Antibodies in Plasma Specimens with Low Hemoglobin Levels
Authors: Alexander Thomas S. , Oshilaja Olaronke , Define Linda
Published: September 2009

Antibodies to gliadin and tissue transglutaminase (TTG) are associated with celiac disease. Celiac patients often present with low hemoglobin levels; however, the incidence of celiac disease in patients with low hemoglobin levels is unknown. We investigated the incidence of celiac disease–associated antibodies in plasma obtained from individuals with low and normal hemoglobin levels. Our objective was to determine if antigliadin and anti‐TTG antibodies are more prevalent in individuals with low hemoglobin levels than in control subjects with normal hemoglobin levels. Following IRB approval, we obtained 86 plasma specimens with hemoglobin levels less than or equal to 10 g/dL and 88 plasma specimens from individuals with hemoglobin levels greater than or equal to 13 g/dL. IgA and IgG antibodies to gliadin and TTG were determined by ELISA assays provided by BioRad, Inc. IgG antigliadin Ab was present in 6 out of 86 low hemoglobin specimens and in two of the normal hemoglobin specimens. The IgA antigliadin ELISA assay was positive in 19 out of 86 low hemoglobin specimens and in 21 out of 88 normal hemoglobin specimens. IgA anti‐TTG was detected in 9 out of 86 low hemoglobin specimens and in 3 out of 88 normal hemoglobin specimens. IgG anti‐TTG was not present in any of the specimens. IgA antibodies to TTG were more prevalent in individuals with low hemoglobin levels. The incidence of IgG anti‐TTG and IgG and IgA antibodies to gliadin was not related to plasma hemoglobin levels in our sample.
HLA‐B27 Transgenic Rat
Authors: Milia Anna Franca , Ibba‐Manneschi Lidia , Manetti Mirko , Benelli Gemma , Messerini Luca , Matucci‐Cerinic Marco
Published: September 2009

The HLA‐B27 gene is strongly associated with the spondyloarthropathies (SpA), a group of chronic inflammatory diseases affecting the bowel, the joints, and the axial skeleton. Yet the basis for this association remains unknown, despite extensive study in the past years. The HLA‐B27 transgenic rat spontaneously develops a disease that strikingly resembles human SpA. The purpose of this article is to review the contribution of studies on the HLA‐B27 transgenic rat model aimed to elucidate the intimate relationship between gut and joint involvement in SpA.