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Anti-pentraxin 3 (PTX3) antibodies were associated with the absence of lupus glomerulonephritis in humans.To explore the effects of anti-PTX3 antibodies in New Zealand Black/White (NZB/NZW F1) mice and their inherent mechanisms of action.30 NZB/NZW F1 mice were subdivided into 3 groups of 10 mice each and subcutaneously injected with PTX3, alum and PBS (group 1), alum and PBS (group 2) or PBS alone (group 3), 3 times 3 weeks apart, before development of renal disease. Mice were followed until natural death. Histological analysis and immunohistochemistry were performed on harvested kidneys. Effects of anti-PTX3 antibodies on C1q binding to immobilized PTX3-anti-PTX3 immune complexes were evaluated in vitro using human SLE sera. Qualitative characterization of human IgG anti-PTX3 was performed.Only group 1 mice developed anti-PTX3 antibodies. Anti-dsDNA and anti-C1q antibodies appeared significantly later and at lower levels in group 1 mice vs. controls (p 0.0001). Proteinuria-free and overall survival were significantly increased in group 1 mice vs. controls (p 0.05 and p = 0.03, respectively). Histopathological analysis showed that glomerular and tubular PTX3 staining and renal lesions were increased in controls compared with immunized mice. Addition of human SLE sera positive for anti-PTX3 antibodies to C1q and fixed PTX3 interfered with C1q binding to PTX3-anti-PTX3 immune complexes. Qualitative characterization of human IgG anti-PTX3 showed an increased proportion of IgG4.Anti-PTX3 antibodies delay lupus-like nephritis and prolong survival of NZB/NZW F1 mice. In vitro observations suggest anti-PTX3 antibodies may dampen complement activation via their Fc fragment, likely hindering renal inflammation.

Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell–cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte–macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases.

The aim of our study was to analyze olfactory function in patients with idiopathic inflammatory myopathies (IIM). We performed a case–control study on 60 IIM patients (48 females and 12 males) and 60 healthy controls (HC) recruited by the best friend method, matched for age, sex and lifestyle. Olfactory function was analyzed by “Sniffin’ sticks test” and expressed through a score (TDI), indicating normosmia (TDI > 30), hyposmia (TDI 15–30) and anosmia (TDI

Serine protease inhibitors (serpins) are evolutionary old, structurally conserved molecules which encompass nearly all branches of life. More than 1,000 serpins were characterized to date which are subdivided into 16 subgroups (A-P) according to their common ancestry; among them, 37 are found in humans. Serpins were termed after their capability to inhibit serine proteases, but mounting evidence suggests that they may achieve a greater deal of functions, ranging from embryological growth to synaptic plasticity, development of both myeloid and lymphoid immune cells, and modulation of apoptosis. Serpins are mainly extracellular molecules, although some of them (namely, ov-serpins or clade B serpins) mostly act inside the cells, being either ubiquitously or tissue-specifically expressed. Among newly characterized serpin functions, regulation of cellular proliferation through apoptosis modulation and proteasome disturbance seems to play a major role. Accordingly, several serpins were found to be hyperexpressed in tumor cells. Indeed, apoptosis dysregulation is likely to be a cornerstone in both tumorigenesis and autoimmunity, since uncontrolled cellular viability results in tumor proliferation, while inefficient disposal of apoptotic debris may favor the rescue of autoreactive immune cells. Such a process was widely documented in systemic lupus erythematosus (SLE). Interestingly, alterations in the expression of some serpins, e.g., the ov-serpin SERPINB3, are being unraveled in patients affected with SLE and other autoimmune disorders, suggesting that a failure in serpin function might affect immune homeostasis and self-tolerance, thereby contributing to autoimmunity. Here, we provide an overview of serpin origin, function, and dysfunction, focusing on human serpins and ov-serpins, with a hub on SERPINB3.

Introduction Myositis specific autoantibodies (MSAs) are useful in the diagnosis of idiopathic inflammatory myopathies and in the definition of disease subsets. The aim of this study was to set up an unlabelled protein immunoprecipitation technique for MSA identification in the sera of myositis patients, in order to identify and investigate new antibody reactivity, undetectable by currently used methods. Methods Sera of 183 patients with connective tissue diseases (75 adult dermatomyositis, 12 juvenile dermatomyositis, 43 polymyositis, 53 other connective tissue diseases) and 30 healthy controls were screened by an in-house procedure of unlabelled protein immunoprecipitation. In the same sera MSAs and myositis associated antibodies were determined by immunoblotting and immunoprecipitation for RNA. Results The analytical specificity of unlabelled protein immunoprecipitation was demonstrated by testing reference sera with known antibody reactivity. Sera from five patients, affected with dermatomyositis (5/75 = 7%), immunoprecipitated two proteins of 40 and 90 kDa apparent molecular weights respectively, consistent with the subunits of the small ubiquitin like modifier activating enzyme heterodimer (SAE1/SAE2). The identity of putative SAE immunoprecipitated proteins was confirmed by immunoblotting on immunoprecipitates using commercial monospecific antibodies to SAE1 and SAE2. Major clinical features were compared between anti-SAE positive and negative patients. Interestingly, anti-SAE positive patients had mainly skin and muscle manifestations while dysphagia, interstitial lung disease, arthritis and constitutional symptoms were absent. Conclusions Unlabelled protein immunoprecipitation is a specific analytical approach, appropriate for the identification of the recently described anti-SAE autoantibody. We confirmed the role of anti-SAE antibody as marker of dermatomyositis.

Adjuvants, commonly used in vaccines, may be responsible for inducing autoimmunity and autoimmune diseases, both in humans and mice. The so-called ‘ASIA’ (Autoimmune/inflammatory Syndrome Induced by Adjuvants) syndrome has been recently described, which is caused by the exposure to a component reproducing the effect of adjuvants. The aim of our study was to evaluate the effect of injection of complete Freund’s adjuvant (CFA) in NZB/NZWF1 mice, a lupus-prone murine model. We injected 10 NZB/NZWF1 mice with CFA/PBS and 10 with PBS, three times, 3 weeks apart, and followed-up until natural death. CFA-injected mice developed both anti-double-stranded DNA and proteinuria earlier and at higher levels than the control group. Proteinuria-free survival rate and survival rate were significantly lower in CFA-treated mice than in the control mice ( p = 0.002 and p = 0.001, respectively). Histological analyses showed a more severe glomerulonephritis in CFA-injected mice compared with the control mice. In addition, lymphoid hyperplasia in spleen and lungs, myocarditis, and vasculitis were observed in the former, but not in the latter group. In conclusion, the injection of CFA in NZB/NZWF1 mice accelerated autoimmune manifestations resembling ‘ASIA’ syndrome in humans.

Around 1980 antinuclear antibody testing became widely used in routine laboratory practice leading to a tapering in the lag time between SLE onset and diagnosis. Since then nothing relevant has been introduced which could help us in making the diagnosis of SLE earlier than now. Notably, there is increasing evidence that early diagnosis and treatment could increase SLE remission rate and improve patient prognosis. Although it has been shown that autoantibodies appear before clinical manifestations in SLE patients, currently we cannot predict which autoantibody positive subjects will eventually develop the disease. Thus, great effort should be made in order to identify new biomarkers able to improve our diagnostic potential. B lymphocyte stimulator (BLyS), anti-ribosomal P protein and anti-C1q antibodies are among the most promising. In recent years, some therapeutic options have emerged as appropriate interventions for early SLE treatment, including antimalarials, vitamin D, statins and vaccination with self-derived peptides. All these immune modulators seem to be particularly useful when introduced in an early stage of the disease.

Impairment of the clearance of apoptotic material seems to contribute to autoantigen exposure, which can initiate or maintain an autoimmune response in predisposed individuals. Complement component C1q, Creactive protein (CRP), serum amyloid P (SAP), mannose-binding lectin (MBL), apolipoprotein A-1 (Apo A-1) and long pentraxin 3 (PTX3) are molecules involved in the removal of apoptotic bodies and pathogens, and in other antiinflammatory pathways. For this reason they have been called “protective” molecules. C1q has a key role in the activation of the complement cascade and acts as a bridging molecule between apoptotic bodies and macrophages favouring phagocytosis. In addition to other functions, CRP, SAP and MBL bind to the surface of numerous pathogens as well as cellular debris and activate the complement cascade, thus stimulating their clearance by immune cells. The role of PTX3 is more controversial. In fact, PTX also promotes the clearance of microorganisms, but the activation of the complement cascade through C1q and removal of apoptotic material can be either stimulated or inhibited by this molecule. Antibodies against protective molecules have been recently reported in systemic lupus erythematosus and other autoimmune rheumatic diseases. Some of them seem to be pathogenetic and others protective. Thus, protective molecules and their cognate antibodies may constitute a regulatory network involved in autoimmunity. Dysregulation of this system might contribute to the development of autoimmune diseases in predisposed individuals.

To evaluate the prevalence and correlates of anti-pentraxin 3 (PTX3) antibodies in systemic lupus erythematosus (SLE).Serum samples from 130 patients with SLE, 130 age- and sex-matched healthy subjects and 130 patients with other autoimmune rheumatic diseases (oARD) were analysed by home-made ELISAs using as substrate human recombinant PTX3 and two peptides, PTX3_1 and PTX3_2, obtained from the complete protein, identified as potential antigenic sites using the Lasergene DNA program (DNA Star). Inhibition tests were performed to evaluate potential interferences between bovine serum albumin or C-reactive protein and anti-PTX3 or anti-PTX3 peptides, and between antigens and antibodies. Statistical analysis was performed using receiving operating characteristics curves, the Fisher exact test, two-tailed t test and Pearson correlations.Patients with SLE had higher levels and prevalence of anti-PTX3, anti-PTX3_1 and anti-PTX3_2 antibodies than patients with oARD or healthy controls (p0.001 for all). No differences were observed between patients with oARD and healthy controls. A correlation was found between anti-PTX3 and anti-PTX3_2 antibodies (r=0.615, p0.001). No association was observed between these antibodies and disease activity. Univariate and multivariate analyses showed that anti-PTX3 and anti-PTX3_2 antibody levels and prevalence were higher in patients without glomerulonephritis and in patients positive for antiphospholipid antibody. All inhibition tests were negative apart from PTX3 against anti-PTX3 antibody or, to a lesser extent, against anti-PTX3_2 antibody, and PTX3_2 against anti-PTX3_2 antibody, all in a dose-dependent manner.Anti-PTX3 antibodies are significantly prevalent in patients with SLE where they might provide protection from renal involvement. The antigenic properties of PTX3_2 peptide are similar to those of PTX3, suggesting its potential use in further analyses.

This study aimed to determine the influence of autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen (HLA) class II genes on age at chronic fatigue syndrome (CFS) onset and symptoms. Eighty-one CFS patients were enrolled, and clinical data were recorded. Autoantibodies to different components of the central nervous system were tested. Polymorphisms in the promoter of the serotonin transporter gene (l/s) and a single nucleotide polymorphism in the serotonin receptor-2A gene (A/G) as well as HLA class II alleles were determined. Multivariate logistic-regression analyses were carried out. The mean age at CFS onset +/- SD was 33.5 +/- 12.5 years. An age at CFS onset (ACFSO) during the third decade of life was associated with the serotonin receptor AA genotype and the HLA-DRB1*03 allele. An ACFSO during the fourth decade of life was associated with the HLA-DRB1*07 allele, whereas an ACFSO > or = 43 years was associated with having at least one copy of the serotonin G allele. Concerning CFS symptoms, the serotonin AG genotype was protective against depressive symptoms. Although having at least one copy of the serotonin A allele and being female were associated with risk for arthralgia, the presence of antineuronal cell antibodies was protective against this. Episodes of unexplained fever were associated with the HLA-DRB1*11 allele. None of the genetic or serological features was associated with myalgia. None of the antibodies determined correlated with any ACFSO or other symptoms. Our results reveal that in CFS, like other autoimmune diseases, different genetic features are related to age at CFS onset and symptoms.

A growing body of experimental and clinical evidence supports the pivotal role of infections in the induction or exacerbation of systemic lupus erythematosus (SLE). Infections can be responsible for aberrant immune response leading to a loss of tolerance towards native proteins. Molecular mimicry, especially between Sm or Ro autoantigens and EBV Nuclear Antigen-1 response, as well as the over-expression of type 1 INF genes are among the major contributors to SLE development. On the other hand infections are very common in SLE patients, where they are responsible for 30-50% of morbidity and mortality. Several factors, either genetic, including complement deficiencies or mannose-binding lectin deficiency or acquired such as severe disease manifestations or immunosuppressant use, predispose SLE patients to infections. All types of infections, including bacterial, viral and opportunistic infections, have been reported and the most frequently involved sites of infections are the same as those observed in the general population, including respiratory, skin, and urinary tract infections. Some preventive measures could be adopted in order to reduce the rate of infections in SLE patients: i.e. screening for Mycobacterium tuberculosis and for some chronic viral infections before immunosuppressive treatment; adequate prophylaxes or drug adjustments when indicated, and pneumococcal and influenza vaccinations in patients with stable disease.

Pentraxin 3 (PTX3) is an acute-phase protein involved in C1q clearance. The presence of anti-C1q and the absence of anti-PTX3 antibodies were associated with lupus glomerulonephritis (LGLN). Our aim was to assess soluble and kidney-expressed PTX3 and their relationships with anti-C1q and anti-PTX3 antibodies in LGLN. Serum PTX3, anti-C1q, anti-dsDNA, and anti-PTX3 antibodies were tested in 130 systemic lupus erythematosus (SLE) patients, 130 healthy and 127 disease controls. Twenty-nine renal biopsies from SLE patients were analyzed and PTX3 immunostaining was quantified by morphometric analysis. Parametric and nonparametric statistics were performed. PTX3 serum levels were lower in SLE versus controls, but they were correlated with proteinuria in LGLN patients (p = 0.001). LGLN patients had higher anti-C1q and lower anti-PTX3 antibody levels than those without (p

Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects fertile women, suggesting sex hormones are involved in disease pathogenesis. B lymphocyte stimulator (BLyS) has been found to be elevated in SLE patients and to drive a lupus-like syndrome in transgenic mice. Our aim was to evaluate the effects of estrogen administration on BLyS and nephritogenic anti-C1q and anti-dsDNA antibodies in lupus-prone NZB/WF1 mice. We implanted pellets releasing 17-β-estradiol (18.8 µg/day) on the back side the ear of 10 NZB/WF1 mice (group 1), and compared them with 10 mice intraperitoneally injected with PBS 200 μl twice a week (group 2), as controls. We evaluated BLyS, anti-dsDNA and anti-C1q serum levels starting one week after pellet implantation. We also analyzed time to proteinuria onset, proteinuria-free survival and overall survival. Kidneys, spleen, liver and lungs were harvested for histological analysis. Mice were bred until natural death. BLyS serum levels were higher in group 1 than in group 2 mice at each evaluation. Group 1 mice developed nephritogenic antibodies and proteinuria significantly earlier and at higher levels than controls. Direct correlation between BLyS and anti-C1q ( R2 = 0.6962, p 2 = 0.5953, p 2 = 0.5615, p Estrogen administration is associated with increased levels of BLyS as well as of anti-C1q and anti-dsDNA antibodies, leading to accelerated glomerulonephritis and disease progression in NZB/WF1 mice.

High levels of oxidized low-density liprotein/beta2 glycoprotein 1 (oxLDL/β2GPI) complexes and anti-complex IgG as well as IgM have been reported in SLE. We analysed this complex and Ab against the complex in SLE patients and evaluated their relationship with clinical and serological findings, traditional risk factors for atherosclerosis, and subclinical atherosclerosis. The prevalence and the levels of the complex and of anti-complex Ab were significantly higher in systemic lupus erythematosus (SLE) patients than in normal healthy donors (NHD). The titers of oxLDL/β2GPI were significantly higher in patients with renal involvement and previous thromboembolic episodes and were correlated with the number of risk factors for atherosclerosis, whereas they were significantly lower in patients with neurological involvement. Both IgG and IgM anti-complex Ab were associated with antiphospholipid (APL). In conclusion, the oxLDL/β2GPI complex as well as Ab against the complex are prevalent in SLE where they seem to...

The aim of this study was to identify specific biomarkers that could be used to screen for psoriatic arthritis (PsA), as well as to assess disease activity and treatment outcome in affected patients. Forty-three outpatients considered eligible for anti-TNF-α treatment (etanercept 50 mg/week) were enrolled. Serum samples of vascular endothelial growth factor (VEGF), metalloproteinase-3 (MMP3), pentraxin 3 (PTX3), and high-sensitive C-reactive protein (hs-CRP) were collected at baseline (t0) and after 6 (t6), 12 (t12), and 24 months (t24) of treatment. Baseline values were compared with those of a group of healthy controls matched for age and sex. Disease activity scores and functional tests (DAS28, BASDAI, PASI, BASFI, HAQ, VAS pain, and VAS patient global disease activity) after treatment were found to be significantly different from baseline values. At baseline, MMP3, hs-CRP and VEGF values in the PsA-patients were found to be significantly higher with respect to levels in the controls. There were no differences in the PTX3 values. MMP3 was significantly lower at t6 ( P MMP3, hs-CRP, and VEGF appear to be useful for the early detection of PsA and to monitor disease progression. The rise in PTX3 did not appear to be linked to the inflammatory state of the disease but might be an expression of the atherosclerotic process frequently observed in PsA.

Inflammatory myopathies are a group of acquired diseases, characterized by immunoflogistic processes primarily involving the skeletal muscle. According to recent classification criteria, four major diseases have been identified: polymyositis (PM), dermatomyositis (DM), sporadic inclusion body myositis (IBM), and necrotizing autoimmune myositis (NAM). Autoantibodies can be found in the sera of most patients with myositis. Myositis-specific autoantibodies (MSAs) are markers of very specific disease entities within the spectrum of myositis, and target proteins involved in key processes of protein synthesis. Myositis autoantigens comprise the well-defined aminoacyl-tRNA synthetases, the Mi-2 helicase/histone deacetylase protein complex, and the signal recognition particle (SRP) ribonucleoprotein, together with novel targets such as TIF1-γ, MDA5, NXP2, SAE, and HMGCR. Recent studies suggest that autoantigens drive a B cell antigen-specific immune response in muscles. Interestingly, an increased expression of Jo-1 and Mi-2 in regenerating fibers in muscle biopsies from PM and DM patients compared to normal was demonstrated. Myositis autoantigen up-regulation was observed in neoplastic tissues, thus representing a potential link between cancer and autoimmunity in myositis. Non-immunological mechanisms seem to participate to the pathogenesis of inflammatory myopathies; induction of endoplasmic reticulum stress response in response to abnormal muscle regeneration and inflammation has recently been reported in patients with myositis. This review article provides an update of new emerging insights about the clinical and pathophysiologic role of principal autoantibodies in myositis.

OBJECTIVES: To evaluate the role of serum IgG, IgM and IgA anti-dsDNA antibody isotypes in the diagnosis of systemic lupus erythematosus (SLE), and their association with clinical features and disease activity, in a large cohort of SLE patients. METHODS: Sera of 200 SLE patients (mean age 34±10.3 years; 26 male and 174 female; median duration of disease 115 months, range 7-378), and of 206 controls, including 19 Sjögren's syndrome, 27 rheumatoid arthritis, 26 psoriatic arthritis, 15 idiopathic inflammatory myopathies (IIM), 13 systemic sclerosis, 49 infectious diseases and 57 healthy subjects, were tested for anti-dsDNA IgG, IgM and IgA isotypes. RESULTS: Selecting a cutoff corresponding to 95% specificity, the sensitivity of IgG, IgM and IgA anti-dsDNA antibodies in SLE was 55%, 30% and 49%, respectively; 12.5%, 1% and 7.5% of SLE patients had positive IgG, IgM or IgA isotype alone, respectively. SLE patients with glomerulonephritis showed higher levels of IgA anti-dsDNA (p = 0.0002), anti-dsDNA IgG/IgM (p = 0.001) and IgA/IgM (p4). CONCLUSIONS: The detection of IgA anti-dsDNA autoantibodies seems to improve our ability to diagnose SLE and to define lupus nephritis phenotype and active disease. By contrast, IgM anti-dsDNA antibodies might be protective for renal involvement. These data support the hypothesis that anti-dsDNA antibody class clustering may help to refine SLE diagnosis and prognosis.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving many organ systems. Glomerulonephritis (GLN) is one of the major causes of morbidity and mortality in SLE. It has recently been demonstrated that adjuvants of vaccines could cause the so called ASIA syndrome. The study aimed to assess the effects of Complete Freund's Adjuvant (CFA) vs alum injections in NZB/NZWF1 mice. Mice (n=10 each group) were injected with a total volume of 200 μL of: CFA in PBS (group 1), alum in PBS (group 2), PBS (group 3) as controls, PTX3/CFA (group 4), PTX3/alum (group 5), 3 times, 3 weeks apart /given in each injection, three weeks apart from ten weeks of age. Urine samples were collected weekly to evaluate proteinuria. Blood samples were collected before every injection, at 21 weeks of age, and at death to evaluate levels of anti-PTX3 and anti-dsDNA. Proteinuria free survival and survival rates were analyzed by the Kaplan-Meier method using Mantel-Cox's test for comparisons. CFA-treated mice developed both anti-dsDNA antibodies and proteinuria earlier and at higher levels than alumtreated and PBS-injected mice, starting from 13 weeks of age. Proteinuria free survival rates (proteinuria ≥ 300 mg/dL) and survival rates were lower in CFA-treated mice than those treated with alum or injected with PBS (P

Systemic lupus erythematosus (SLE) is a multisystemic, autoimmune disease, encompassing either mild or severe manifestations. SLE was originally labeled as being an immune complex-mediated disease, but further knowledge suggested its pathogenesis is motlier than that, involving complex interactions between predisposed individuals and their environment. People affected with SLE have their immune system skewed toward aberrant self-recognition usually after encountering a triggering agent. Defeats in early and late immune checkpoints contribute to tolerance breakdown and further generation and expansion of autoreactive cell-clones. B and T cells play a master role in SLE, however clues are emerging about other cell types and new light is being shed on SLE autoantibodies, since some of them display really harmful potential (pathogenic antibodies), while others are just connected with disease development (pathological antibodies) and may even be protective. Autoantibody generation is elicited by abnormal apoptosis and inefficient clearance of cellular debris causing intracellular autoantigens (e.g. nucleosomes) to persist in the extracellular environment, being further recognized by autoreactive cells. Here we explore the complexity of SLE pathogenesis through five core issues, i.e. genetic predisposition, B and T cell abnormalities, abnormal autoantigen availability, autoantibody generation and organ damage, relying on current knowledge and recent insights into SLE development.

As soon as autoinflammatory diseases (AIDs) emerged as new entities, they have been linked to the well known world of autoimmunity. In fact, AIDs and systemic autoimmune diseases (ADs), share some characteristics: they start with the prefix "auto" to define a pathological process directed against self; they are systemic diseases, frequently involving musculoskeletal system; both include monogenic and polygenic diseases. From the pathogenetic point of view, they are characterized by a chronic activation of immune system, which eventually leads to tissue inflammation in genetically predisposed individuals. Nevertheless, the specific effectors of the damage are different in the two groups of diseases: in AIDs the innate immune system directly causes tissue inflammation, whereas in ADs the innate immune system activates the adaptive immune system which, in turn, is responsible for the inflammatory process. Mutations in inflammasome-related proteins, particularly in NOD-like receptor (NLR) genes, have been strongly associated to the occurrence of AIDs, whereas the link between inflammasome and ADs is less clear. However, a role for this multiprotein-complex in some ADs can be postulated, since a wide spectrum of endogenous danger signals can activate NLRs and inflammasome products, including IL-1ß, can activate adaptive immunity. An association between single nucleotide polymorphisms (SNPs) localized in the inflammasome gene NLRP1 and systemic lupus erythematosus has recently been reported. AIDs and ADs are currently subdivided into two different groups, but looking at their similarities they might be considered as a single group of diseases with a large immune pathological and clinical spectrum which includes at one end pure ADs and at the other end pure AIDs.

The relationship between infections and autoimmunity as well as the risk of infections due to antirheumatic agents, including corticosteroids, immunosuppressants and biologics, are discussed. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. This review focuses on the pivotal role of infection in the induction of autoimmune disorders. Although the development of autoimmune phenomena linked to infections is a common finding, the onset of autoimmune diseases is a rare event, arising from a combination of genetic susceptibility and environmental factors. There are several mechanisms through which pathogens can initiate or perpetuate autoimmunity. Some of them are antigen-specific, including molecular mimicry, expression of modified, cryptic, or new antigenic determinants, and superantigens. Others are nonspecific and collectively known as “bystander activation.” They include enhanced processing and presentation of self-antigens, immune cell activation, cytokine release, and cell apoptosis/necrosis. Infections may also trigger organ-specific autoimmune diseases, but studies carried out until now have provided conflicting and inconclusive results regarding the role of viral and bacterial agents. Infections and autoimmune diseases have multifaceted and multidirectional relationships. It has been suggested recently that infections cannot only induce or precipitate autoimmune diseases, but they may also protect from autoimmunity or even abrogate an ongoing autoimmune process depending on the interaction between microorganisms and host. Therefore, we should look at microorganisms, not only as causes of infections but also as potential agents able to modulate the immune system. On the other hand, numerous evidences have emerged regarding the higher susceptibility of autoimmune patients to infections, possibly as a result of immunosuppressive therapy and treatment with biologic agents.

Commercial blot assays are advanced applications of immunoblotting or dot immunobinding methodologies for the detection of specific autoantibodies in autoimmune diseases. Line(Dot) blots in particular have cost-effectively optimized a sort of multiparametric assay for simultaneous determination of several autoantibody reactivities. Efficient and wide-spectrum potentialities of recombinant DNA technology and proteomics are fruitfully employed by manufacturers in order to obtain highly purified antigens or novel targets to be spotted on blot matrices thus continuously implementing their multianalytic platforms. At present most widely used commercial blot assays for the diagnosis of connective tissue diseases can detect autoantibodies to several Extractable Nuclear Antigens or myositis and/or scleroderma associated autoantigens. They actually represent an important step-forward in the methodological panorama designed for the autoimmunity laboratory. However continuous effort in order to validate and improve clinical reliability of commercially available blot assays should be carried out. In this short review, our preliminary contribution on the validation of a commercial line blot assay for the laboratory diagnosis of autoimmune myositis is briefly reported.

Atherosclerosis is a disease of the vascular wall, which predominantly affects large and medium-sized arteries. It represents a leading cause of morbidity and mortality in the Western world. In the last few decades, it has been clearly shown that immune system plays a relevant role in atherogenesis. The effectors of both innate and adaptive immunity, including immune cells, cell or soluble receptors, cytokines, chemokines, complement components or coagulation systems, and autoantibodies are able to modulate atherosclerosis. Among proteins belonging to innate immunity, the highly conserved pentraxin family, which encompass C-reactive protein (CRP), serum amyloid P (SAP), and the long pentraxin 3 (PTX3) seems to be directly involved in the induction and progression of atherosclerosis. By immunohistochemical staining, pentraxins were found within the atherosclerotic plaques where they could play a key role interacting with atherogenic-modified lipoproteins, favoring the formation of foam cells, and exerting a proinflammatory action. Pentraxin serum levels have been shown to be associated with clinical and subclinical atherosclerosis in general population. Antibodies against pentraxins have been demonstrated in patients with autoimmune diseases, but their role in atherogenesis is still controversial.

Objective Serum IgG antibodies (Abs) to phosphorylated ribosomal (P ribosomal) proteins have been inconsistently associated with neuropsychiatric manifestations in systemic lupus erythematosus (SLE). Our aim was to assess whether serum IgG Abs to ribosomal P proteins are associated with neuropsychiatric SLE. Patients and methods We examined an inception cohort of 219 SLE patients. Neuropsychiatric SLE manifestations were characterized using the American College of Rheumatology (ACR) definition. Serum Abs to P ribosomal proteins were searched for by immunoblotting. In a subgroup of patients, Abs were investigated also in cerebrospinal fluid (CSF). Results Abs to P ribosomal proteins were detected in 45 (21%) patients, 23 of whom (51%) with neuropsychiatric involvement. Abs to P ribosomal protein were present both in serum and CSF. Abs to P ribosomal proteins significantly correlated with psychosis (p = 0.017), mononeuropathy multiplex (p = 0.040), malar rash (p = 0.004), serum anti-Sm Abs (p = 0.042), and lupus anticoagulant (p = 0.036). SLE onset age was significantly younger in patients with Abs to P ribosomal proteins. Logistic regression analysis confirmed the relationship between Abs to P ribosomal proteins and psychosis, malar rash, SLE onset age and lupus anticoagulant. Conclusions Abs to ribosomal P proteins are associated with psychosis and might be associated with peripheral nervous system complications.

Chronic fatigue syndrome is a heterogeneous disorder with unknown pathogenesis and etiology, characterized by disabling fatigue, difficulty in concentration and memory, and concomitant skeletal and muscular pain. Several mechanisms have been suggested to play a role in CFS, such as excessive oxidative stress following exertion, immune imbalance characterized by decreased natural killer cell and macrophage activity, immunoglobulin G subclass deficiencies (IgG1, IgG3) and decreased serum concentrations of complement component. Autoantibodies were also suggested as a possible factor in the pathogenesis of CFS. Recent studies indicate that anti-serotonin, anti-microtubule-associated protein 2 and anti-muscarinic cholinergic receptor 1 may play a role in the pathogenesis of CFS. It has been demonstrated that impairment in vasoactive neuropeptide metabolism may explain the symptoms of CFS.

Antisense-mediated exon skipping holds great potential for the treatment of DMD. In mdx mice, functional recovery of skeletal muscle has been obtained upon systemic delivery of ‘‘naked” oligonucleotides or viral vectors encoding for antisense snRNAs. However, amongst the studies reported so far, which used either neonatal or young adult animals – only one achieved dystrophin restoration in cardiac muscle, using an adeno-associated vector. Here we report the in vivo delivery of morpholino oligos in aged mdx mice, both in skeletal muscle, via intra-arterial injection, and in cardiac muscle, via intra-muscular injection. Localized intra-arterial delivery yielded high levels of dystrophin restoration and just two doses of 100 lg each resulted into detectable force recovery in the EDL muscles of treated limbs. On the other hand, upon intra-cardiac injections in the left ventricle wall the skipping effect was much lower than what obtained in tibialis anterior muscles injected with comparable amounts of oligos. This latter finding suggests that even upon direct delivery antisensemediated dystrophin restoration in cardiac muscle might suffer from limitations that do not exist in skeletal muscle. 2008 Elsevier B.V. All rights reserved.

Objectives: To review the physiological and physiopathological roles of pentraxin 3 (PTX3), focusing on autoimmunity and vascular pathology. Methods: A systematic literature review using the keywords 'pentraxin 3,' 'innate immunity,' 'apoptosis,' 'autoimmunity,' and 'endothelial dysfunction' from 1990 to 2007 was performed. All relevant articles and pertinent secondary references in English were reviewed. Results: PTX3 has a large number of multiple functions in different contexts. PTX3 plays an important role in innate immunity, inflammation, vascular integrity, fertility, pregnancy, and also in the central nervous system. In innate immunity, its normal function is to increase the immune response to selected pathogens while also exerting control over potential autoimmune reactions. It maintains a tightly homeostatic equilibrium in the local immune microenvironment by avoiding an exaggerated immune response and controlling peripheral tolerance to self-antigens. In contrast, in some autoimmune diseases, PTX3 appears to be involved in the development of autoimmune phenomena. A possible explanation for these apparent paradoxical functions may be related to the highly polymorphic PTX3 gene. Conclusion: PTX3 is physiologically a protective molecule. However, in several autoimmune diseases PTX3 appears to facilitate the development of autoimmunity. The PTX3 gene could influence the development of autoimmune reactions and vascular involvement in human pathology. © 2008 Elsevier Inc. All rights reserved.

It has been demonstrated that atherosclerosis (ATS) is enhanced in autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). The reason for this accelerated process is still debatable and, although traditional risk factors are more prevalent in SLE patients than in general population, they do not seem to fully explain the enhanced risk. ATS has the characteristics of an autoimmune chronic disease, involving both the innate and the adaptive immunity. Moreover, it satisfies the four criteria defining an autoimmune disease, proposed by Witebsky and Rose. It has been shown that some autoantibodies, including anti-oxLDL, anti-beta(2)GPI, anti-HSP60/65, and more recently anti-oxLDL/beta(2)GPI, play a key role in the pathogenesis of ATS. However the role of these autoantibodies in accelerated ATS in SLE patients is still controversial. In fact, some of them seem to be proatherogenic and other protective; moreover, it has been demonstrated that induced oral tolerance has a protective role against ATS. We have recently observed that the levels of oxLDL/beta(2)GPI antigenic complexes and their antibodies were higher in patients with SLE than in healthy subjects, but we did not find a clear association between oxLDL/beta(2)GPI complexes and IgG or IgM anti-oxLDL/beta(2)GPI autoantibodies and subclinical ATS in SLE patients. Many other studies are required to explain the role of autoantibodies in the pathogenesis of ATS in SLE patients, because the characteristics of SLE seem to mask their effects for atherogenesis.

Systemic autoimmune diseases are characterized by the presence in patient sera of high titers of autoantibodies directed against self-antigens. The characterization of specific autoantigen-autoantibody system is very important for research as well as for diagnostic tools and several techniques can be employed in such immunological studies. In this review an overview of the different biochemical methods of antigen preparation and the specific methodological applications is given, also describing potential critical aspects and benefits of the different protocols.

Analysis of the transport sector in Italy gives evidence of infrastructure scarcity, management and organisational problems and, more generally, of poor quality and competitiveness of the services. At the end of 2005 the Italian Ministry of Infrastructures and Trasport established the UIRNet Company to create a computer platform for integrated logistics at the national level. Such platform was created to make more efficient, secure and safe the national logistics system by means of localisation and communication services. This paper describes the flexible and modular architecture of such platform and the services it provides. The UIRNet computer platform is based on the use of web-oriented data exchange solutions and allows the full integration with other external systems, such as, e.g., legacy platforms for fleet management, intelligent transport systems. Furthermore, the platform is accessible to the institutions and flexible in order to interface with other platforms. Its functionalities are fully accessible by mobile or fixed terminals, and via web through the internet.

Objective Serological testing for myositis-specific or associated autoantibodies [myositis-specific antibody (MSA) and myositis-associated antibody (MAA)] is useful for the diagnosis of idiopathic inflammatory myopathies (IIMs). However, available assays are neither standardized nor validated. The objective is to evaluate the accuracy of a commercial line blot assay for myositis diagnosis. Methods IgG antibodies against Jo-1, PL-7, PL-12, PM/Scl, Ku, Mi-2 and Ro52 antigens were detected by a line blot and in-house RNA immunoprecipitation or immunoblot. We tested sera from 208 IIM patients, 50 healthy subjects and 180 control patients (11 non-autoimmune myopathy, 23 muscular dystrophy, 11 UCTD, 68 SLE, 36 SSc, 22 SS and 9 arthropathy). Results MSAs or MAAs were detected in 98 (47%) out of the 208 IIM patients by line blot: anti-Jo-1 in 43 (21%), anti-PL-7 or anti-PL-12 in 8 (4%), anti-Mi-2 in 9 (4%), anti-PM/Scl in 9 (4%), anti-Ku in 10 (5%) and anti-Ro52 in 49 (24%). Overall specificity was: 100% for anti-Jo-1, anti-PL-7 or PL-12 and anti-PM/Scl; 96% for anti-Ku; 98% for anti-Mi-2; and 76% for anti-Ro52. In-house testing confirmed line blot results regarding anti-Jo-1, anti-PM/Scl and anti-Ku, while it was more accurate than line blot in detecting anti-Mi-2 (7 vs 4% sensitivity, 100 vs 98% specificity), and anti-aminoacyl-tRNA synthetase (anti-ARS) non-Jo-1 antibodies (11 vs 4% sensitivity, 97 vs 99% specificity). Conclusions Line blot could be a suitable serological test in the diagnostic workup for myositis, and it represents a reliable alternative to more time-consuming procedures. Continuous effort is recommended in order to improve its accuracy.

Anti-prothrombin (anti-PT) antibodies are recently identified antibodies directed toward a phospholipid-binding protein (prothrombin), which deserve attention for the reported clinical and pathogenic relevance in antiphospholipid syndrome and systemic lupus erythematosus (SLE). We have recently carried out a longitudinal study on the predictive value of anti-PT antibodies in SLE showing that they have a higher diagnostic accuracy for thrombosis than anti-beta(2)-GPI and anticardiolipin antibodies, and, along with LAC activity, are the best predictors of thromboembolic events in SLE patients.

Public passenger transport services are particularly significant examples of public services due to their status within the European and national legal orders. This essay briefly describes the ongoing evolution of the relevant legal framework and analyses its underlying principles and their current implementation. The Authors conclude by indicating a management system functioning on a competitive basis and mostly liberalised as a possible development in the public transport sector.

The publication explores the impact of the global financial crisis and of the European sovereign debt crisis on democratic principles in Europe. They have been democracy as much as financial crises. They not only emerged in democratic countries – first in the United States than in European countries – but caused the worst consequences on other democratic countries, where they had an impact on democratic governance. The two crises produced a number of institutional changes in Europe, which will be explored in the following paragraphs. Some patterns will appear as we go through this list of institutional novelties: first of all, the expanding role of the top political bodies (European Council, Eurozone Summit) and of the technocratic ones (IMF, European Commission, ECB, EMS). This evolution was legitimated by the circumstances, in particular by a sense of urgency, that limited the debate – and the time-consuming parliamentarism – and validated «technical» solutions. Such trends go hand in hand with technocratic solutions used as recipes for recovery, like the preference for regulatory solutions or the extensive use of the conditionality mechanism. As we will explain, the approach inspired by austerity is nothing but a natural consequence. After a comprehensive examination, a fact crops out: there has been a compression of democratic governance at national level through decisions stemming from less than democratic procedures represented to citizens as the only possible way out of the crisis. The scenario might look gloomy, but the goal of this analysis is to prove that the current crisis opened up a window of opportunity not only to address the original flaws of the EMU’s institutional frame as well as the limits of crisis management mechanisms but also to increase European citizens’ awareness and their demand for a more democratic governance.