Sepsis and identification of reliable biomarkers for postoperative period prognosis.

Sepsis is currently defined as the presence of organ dysfunction occurring as the result of a disturbed host response to a serious infection. Sepsis is one of the most common diseases, which cause mortality and a considerable absorber of healthcare resources. Despite progress in technology and improving knowledge of pathophysiology, the disease mechanism is still poorly understood. At present, diagnosis is based on non-specific physiological criteria and on the late identification of the pathogen. For these reasons, the diagnosis may be uncertain, treatment delayed or an immunomodulatory therapy cannot be established. An early and reliable diagnosis is essential to achieve better outcomes on disease progression. The host response to infection involves hundreds of many mediators of which have been proposed as biomarkers. There is a need for new diagnostic approaches for sepsis, new sepsis biomarkers that can aid in diagnosis, therapeutic decision and monitoring of the response to therapy. The differentiation of sepsis from non-infectious systemic inflammatory response syndrome is difficult, and the search for a highly accurate biomarker of sepsis has become one important objective of the medicine. The goal of our review is to summarize the recent advances on the most commonly studied serum biomarkers, evaluated in clinical and experimental studies, for early diagnosis of sepsis and their informative value in diagnosis, prognosis, or response to therapy. In this context, we have tracked the clinical utility of measuring serum biomarkers, such as procalcitonin, pro- and anti-inflammatory cytokines, C-reactive protein, leptin and their combinations. Currently, has not been identified an ideal biomarker to aid in the diagnosis of sepsis. It is hoped that the discovery of new serum markers, as well as their combinations, will serve for the diagnosis and prognosis of sepsis.

The role of autoantibodies in health and disease.

Serum of healthy individuals contains antibodies that react with self and non-self antigens, generated in absence of external antigen stimulation. These antibodies, called natural antibodies, are particularly IgM isotype, are considered natural autoantibodies (NAA), displaying a moderate affinity for self-antigens. Although incidence of NAA in healthy individuals is not reported, it is established that autoreactive antibodies and B-cells, as well as autoreactive T-cells, are present in healthy persons. The functional abilities of NAA are not clear but is well accepted that they may participate in a variety of activities, such as maintenance of immune homeostasis, regulation of the immune response, resistance to infections, transport and functional modulation of biologically active molecules. On the other hand, specific adaptive immune responses through high-affinity, class-switched IgG autoantibodies, which bind self-proteins, can cause tissue damage or malfunctions, inducing autoimmune diseases. The new technology that allows for more autoantibody screening may further enhance the clinical utility of autoantibody tests, making it possible to diagnose autoimmune disease in its early stages and to intervene before installing injuries. The aim of this review paper is to succinctly analyze the progress in the physiological role and regulatory significance of natural autoantibodies in health and disease.

The Relationship of Cytokines IL-13 and IL-17 with Autoantibodies Profile in Early Rheumatoid Arthritis.

Aims. In the present study, we aimed to assess the concentrations of IL-13 and IL-17 in serum of patients with early rheumatoid arthritis (eRA), the investigation of correlation between the concentrations of these cytokines and disease activity score, and the concentration of some autoantibodies and the evaluation of the utility of IL-13 and -17 concentration measurements as markers of disease activity. Materials and Methods. Serum samples were collected from 30 patients and from 28 controls and analysed parameters. Results. The serum concentrations of IL-13, IL-17, anti-CCP, and IgM-RF were statistically significantly higher in patients with eRA, compared to the controls. IL-13 concentrations in the severe and moderate groups with eRA were statistically higher than in the mild and control groups. Also, in the case of IL-17, serum concentrations increased proportionally with the disease activity of eRA. We observe that concentrations of IL-13 and -17 did not correlate with autoantibodies. IL-17 concentration significantly positively correlated with CRP, while IL-13 concentration significantly negatively correlated with CRP. Disease activity score, DAS28, was strongly positively correlated with levels of ESR and weakly positively correlated with concentrations of anti-RA33 autoantibodies. IL-13 has a higher diagnostic utility than IL-17, CRP, ESR, IgM-RF, and anti-CCP as markers of disease activity. Conclusions. The presence of higher IL-13 and IL-17 serum levels in patients, compared with those of controls, confirms that these markers, found with high specificity, might be involved in the pathogenesis of eRA. IL-13 and IL-17 might be of better usefulness in the prediction of eRA activity status than IgM-RF and anti-CCP.

New Insights into Antisynthetase Syndrome.

Antisynthetase syndrome (ASS) is a rare chronic autoimmune disorder (2-3 times more common in women than in men), associated with interstitial lung disease (the most important feature), dermatomyositis (DM), and polymyositis (PM). The cause of ASS is unknown. Recent developments in immunology have improved our knowledge and it is now possible to classify ASS according to the presence of myositis specific autoantibodies. The hallmark of ASS is the presence of serum autoantibodies directed against aminoacyl-tRNA synthetases (anti-ARS involved in protein synthesis). ASS is due to IgG antibodies directed against the enzyme synthase. Antisynthetase antibodies (ASAb) include: anti-histidyl- (anti-Jo-1, being the best known), anti-threonyl- (anti-PL-7), anti-alanyl (anti-PL-12), anti-isoleucyl- (anti-OJ), anti-glycyl- (anti-EJ), anti-asparaginyl- (anti-KS), anti-Wa, anti-tyrosil- (anti-YRS), anti-phenylalanyl-transfer RNA synthetase (anti-Zo), and anti-signal recognition particle (anti-SRP). Anti-Jo-1 is the most common ASAb (in ~20-30% of PM/DM patients).

The immunoprofile of interstitial Cajal cells within adenomyosis/endometriosis lesions.

Adenomyosis and endometriosis are lesions which have aroused the interest for the investigation of antibodies specific to the structures from the composition, but also for the cause behind the appearance of these lesions in completely different structures. The impact they have on fertility is not known entirely, for they are difficult to diagnose. Endometriosis causes infertility and it is a hard to treat lesion. The research performed in the last years has been focused on the so-called linkage analysis, or reverse genetics. It refers to identifying the genes which are prone to developing this affection. We investigated clinically 40 female inpatients (n=40) who had underwent genital surgery and received a variegate diagnosis in the "Sf. Ioan" Emergency Hospital, Bucharest, Romania, between January-September 2014 and also their histopathology and immunohistochemistry. We proceeded with the histopathology examination in order to establish a diagnosis in respect to the admission diagnosis and then, using the ABC (Avidin-Biotin complex) method, we analyzed the immunohistochemistry of the following markers: S100 protein (for detection of ganglia and nerve cells), CD117÷c-kit (selective detection of interstitial Cajal cells - ICC), desmin and vimentin (intermediary filaments for detecting ICC-like cells, which cohabit with uterine myocytes and are not contractile cells) and CD10 (a sensitive and useful immunomarker in the diagnosis of endometrial stroma and, in some cases, of neoplasia). Our study, regarding the immunoprofile of some markers of adenomyosis÷endometriosis lesions, supports the hypothesis that the interstitial Cajal cells are non-reactive, they are not in relationship with investigated lesions, but CD10 is a very useful marker to highlight the endometrial stroma in query cases.

Significance of circulating and crevicular matrix metalloproteinase-9 in rheumatoid arthritis-chronic periodontitis association.

In the recent years, statistically significant associations between rheumatoid arthritis (RA) and periodontal disease have been identified. Emerging as a chronic inflammatory joint disease, RA displays various features and pathogenetic events similar to chronic periodontitis (CP). The purpose of this study was to evaluate the utility of determining systemic and crevicular levels of metalloproteinase-9 (MMP-9) as potential biomarkers for association between RA and CP. A total of fifty-six patients were included in the study. The subjects were categorized into four groups as follows: healthy-control (n = 21), active RA (n = 16), CP (n = 14), and RA-CP association (n = 12). Assessment of serum and crevicular concentrations of total MMP-9 (active and pro-MMP-9) was based on ELISA technique. The results of this study showed statistically significant differences of serum MMP-9 between patients groups and control. Serum levels of MMP-9 were similar in RA and RA-CP associated patients. Gingival crevicular fluid (GCF) recorded increased MMP-9 levels in RA-CP association subjects as compared to CP. Considering that RA-CP association is characterized by a disregulation of the inflammatory response, MMP-9 may play a role in the pathogenesis of RA-CP association. MMP-9 is therefore a sensitive tool in the diagnosis and management of patients affected by this binomial association.

Involvement of TSP1 and MMP9/NGAL in angiogenesis during orthodontic periodontal remodeling.

In the present study the aim was to measure the levels of Thrombospondin-1 (TSP1) and Lipocalin-2/matrix metalloproteinase 9 (MMP9/NGAL) complex in gingival crevicular fluid (GCF) at different time points of orthodontic treatment, to determine the relationship between these values and those of total-matrix metalloproteinase 9 (MMP9) and theirs implication in angiogenesis balance, in the situation of a good control of the bacterial plaque, emphasizing the role of TSP1 and MMP9/NGAL complex. GCF samples were collected from 16 young orthodontic patients requiring upper canine distalization (test tooth) with first premolar extraction. The contralateral canine (control tooth) was free from orthodontic force. For the orthodontic appliance, brackets Roth 0.018 inch with 0.012 inch NiTi archwire and a laceback were used. TSP1, MMP9/NGAL, and MMP9 increased from 1 hour before activation of orthodontic appliance to a maximum at 8 hours for MMP9 and 72 hours for MMP9/NGAL and TSP1. The results show a change in time of TSP1, MMP9/NGAL, and MMP9 levels in GCF of patients with this method of orthodontic treatment. The powerful correlation of MMP9/NGAL with TSP1 suggests their stronger involvement in angiogenesis processes in PDL during orthodontic periodontal remodeling, in the situation of a healthy periodontium and a good control of the bacterial plaque.

Peripheral nervous system manifestations in systemic autoimmune diseases.

The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord. Systemic autoimmune diseases can affect both the central and peripheral nervous systems in a myriad of ways and through a heterogeneous number of mechanisms leading to many different clinical manifestations. As a result, neurological complications of these disorders can result in significant morbidity and mortality. The most common complication of peripheral nervous system (PNS) involvement is peripheral neuropathy, with symptoms of numbness, sensory paresthesias, weakness, or gait imbalance. The neuropathy may be multifocal and asymmetric or, less frequently, distal and symmetric.

Matrix metalloproteinases (MMP-3 and MMP-9) implication in the pathogenesis of inflammatory bowel disease (IBD).

Inflammatory bowel disease is a chronic disease, with unknown etiology, characterized by a sustained inflammatory cascade that gives rise to the release of mediators, capable of degrading and modifying bowel wall structure. The present study investigated changes of circulating metalloproteinases (MMP-3, MMP-9) and CRP levels in patients with ulcerative colitis and Crohn's disease, in order to contribute to the elucidation of pathogenesis. We have studied serum samples of 67 patients, of which 46 with ulcerative colitis (mean age 44.8 years) and 21 affected by Crohn's diseases (mean age 39.52 years), who were hospitalized in the Clinic of Gastroenterology of the Emergency County Hospital of Craiova, Romania. For the quantitative determination of MMP-3, MMP-9 and CRP, the ELISA technique was used. Both patients, with Crohn's disease and ulcerative colitis, showed increased production of studied immunomarkers, which were correlated with some clinical stages, indicating their involvement in the disease activity.

Investigation of inflammatory activity in ulcerative colitis.

Inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn's disease are lifelong disorders, characterized by the chronic inflammation of all or part of our digestive tract. Cytokines have an essential role in the pathogenesis of IBDs, because they control the inflammatory response, and the disequilibrium of pro-inflammatory/anti-inflammatory cytokines may lead directly to tissue destruction. Histopathologically, these diseases are characterized by the extent and the distribution of mucosal architectural abnormality, the cellularity of the lamina propria and the present cell types, but these features frequently overlap. We performed a prospective study, which included 46 patients diagnosed with ulcerative colitis (UC) (gender ratio 25 males/21 females, mean age 44.8 years) and 30 subjects, with similar demographic characteristics, which were selected from the patients investigated for other digestive disorders, unaffected by UC. Serological investigations were performed by quantitative determination of IL-17, IL-13, and CRP using ELISA sandwich technique. We have achieved significantly higher concentrations of IL-13, IL-17 and CRP in the serum of patients with UC, compared to the control group. We have found in our study correlations between ulcerative colitis activity and serum levels of interleukins, IL-13 and IL-17. Because IL-17 serum levels were significantly correlated with the disease severity and only cytokine had a significantly statistic correlation with high serum levels of CRP in UC patients, IL-17 can be considered an important progress inflammation marker of this disease.

Role of leptin in autoimmune diseases.

Leptin represents a link between metabolism, nutritional status, and immune responses. Leptin is important for optimal functioning of the immune system. Leptin is a cytokine-like hormone with proinflammatory properties linked to autoimmune diseases. Moreover, there has been increasing evidence that leptin is involved in the pathogenesis of various autoimmune diseases. Leptin has been shown to enhance immune reactions in autoimmune diseases that are commonly associated with inflammatory responses. Both high and low levels of leptin might contribute to autoimmune diseases. Leptin has been explored as a potential target for therapeutic development in treating autoimmune diseases. In this review, we review here the most recent advances on the role of leptin in autoimmunity and in immune-rheumatological diseases.

Liver involvement in patients with systemic autoimmune diseases.

ABSTRACT: A wide variety of systemic autoimmune diseases (SAD) affects the liver, and various forms of hepatic involvement have been reported. Patients who have SAD, the abnormal liver function tests might be caused by SAD. In most of these patients, SAD should be treated primary. Liver involvement in SAD is a matter of great clinical challenge evoking several questions upon diagnostic criteria for liver diseases and the presence of overlap syndromes. This review will describe liver injury caused by various systemic autoimmune diseases.

Metabolic syndrome in rheumatoid arthritis.

Rheumatoid arthritis (RA) generally affects people between the ages of 20 and 50. Patients with RA have a significantly higher prevalence of the metabolic syndrome (MS) compared to the general population. The increased cardiovascular risk (CVR) associated with RA places this disease among the most widely studied. The duration of RA was associated with MS, implicating the role of inflammation in MS development. The presence of MS correlates with increased subclinical atherosclerosis. A positive correlation between prevalence of MS and worsening of functional status was found in patients with RA. Patients with rheumatoid arthritis have an increased risk and a higher mortality from cardiovascular diseases (CVD), the rheumatologist should be aware of those MS risk factors and attempt to modify them. This review summarizes recent advances in the field of MS in RA.

Associated pulmonary arterial hypertension in connective tissue diseases.

In recent years, major advances have been achieved in the understanding of pulmonary arterial hypertension (PAH) patho-physiology. Associated pulmonary arterial hypertension (APAH) can occur in a variety of other conditions and circumstances including a number of systemic autoimmune diseases. As with PAH in general, clinical symptoms of APAH in systemic autoimmune diseases are unspecific. In addition, there is a long standing association between autoimmunity and APAH. It has been postulated that autoimmunity may play a role in the pathogenesis of APAH. This argument has been based on frequent coexisting clinical and serological rheumatic findings. There is no experimental model of immune mechanism-dependent severe APAH. The loss of self-tolerance could initiate a process which ultimately results in APAH. It is possible that T-cell deficiencies (in either function or number) may contribute to pulmonary vascular injury or disease. These conditions are often associated with autoantibodies as well as defects in the CD4 T-cell compartiment. However, it remains uncertain how autoimmune mechanisms contribute to the pathogenesis of APAH. There are data that show a significant association between APAH and connective tissue diseases (CTD). In this regard, systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, dermato/polymyositis and primary Sjögren's syndrome are associated with APAH. The study of APAH in the systemic autoimmune diseases and its relation to basic immunologic disturbances may yet bring effective therapies in the future. APAH can be a severe complication attracting a high excess mortality in autoimmune diseases. The present review will focus on what is known about autoimmune phenomena in APAH patients.

Pulmonary manifestations of systemic autoimmune diseases.

Systemic autoimmune diseases (SAD) are a heterogeneous group of immunologically mediated inflammatory disorders including multiorgan involvement. As expected in a multisystem disease, the entire pulmonary system is vulnerable to injury. Any of its compartments may be independently or simultaneously affected. It is difficult to assess the true prevalence of lung disease in cases of SAD. In this article, we will review the pulmonary manifestations caused by systemic lupus erithematosus, rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, mixed connective tissue disease, Wegener's granulomatosis, Churg-Strauss syndrome, Goodpasture's syndrome, and ankylosing spondylitis.

Manifestations of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic, multifaceted autoimmune inflammatory disease that can affect any part of the body. SLE is a disease of unknown aetiology with a variety of presenting features and manifestations. Interest in the disease has been stimulated in recent years, and improved methods of diagnosis have resulted in a significant increase in the number of cases recognized. It is apparent that it can no longer be regarded as a rare disease. The majority of the pathology in SLE is related to deposits of immune complexes in various organs, which triggers complement and other mediators of inflammation. Symptoms vary from person to person, and may come and go, depend on what part of the body is affected, can be mild, moderate, or severe. Diagnosis can be difficult because lupus mimics many other diseases; it requires clinical and serologic criteria.

Lipoprotein-associated phospholipase A2 as a predictive biomarker of sub-clinical inflammation in cardiovascular diseases.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a predictor biomarker for incident atherosclerotic disease. Lp-PLA2 has been identified in atherosclerotic plaques, however, its role in atherosclerosis is still under investigation. Lp-PLA2 belongs to the superfamily of phospholipase A2 enzymes. It is produced by macrophages that appears to play a role in the atherosclerotic vessel wall. Emerging data seem to suggest that Lp-PLA2 may be proatherogenic, which is an effect thought to be mediated by lypophosphatidylcholine and oxidized nonesterified fatty acids, two mediators generated by Lp-PLA2. Phospholipase A2 plays an essential role in metabolism of membrane phospholipids, it is related to inflammatory reactions, secretion of amyloid precursor protein. Several studies have documented the strong association of Lp-PLA2 with coronary heart disease and stroke in the general population. Lp-PLA2 may be a stronger predictor of recurrent stroke risk. Inflammatory markers have been associated with ischemic stroke risk. Their relationship to prognosis after stroke is unsettled. The present review article focuses particularly on the characteristics of the Lp(a)-associated Lp-PLA2 and discusses the possible role of this enzyme in view of the new data.

Reactions of the immune system in epilepsy.

Epilepsy may present as a symptom of many neurological disorders and often an etiological explanation cannot be identified. There is growing evidence that autoimmune mechanisms might have a role in some patients. The evidence for immunological mechanisms in epilepsy can be examined within the following three main areas: the childhood epilepsy syndromes, epilepsy associated with other immunologically mediated diseases, and the more common unselected groups of patients with epilepsy. Autoimmunity was recently suspected to be involved in the pathology of certain human epilepsies. This includes numerous reports of the detection of theoretically relevant serum autoantibodies, experimental data showing that antibodies can be epileptogenic, and a response of some epilepsy syndromes to immunomodulation. The high prevalence of epilepsies in specific immune diseases suggests that immune system may play a role in the pathogenesis of epilepsy or might be associated with it. There is some evidence that immune mechanisms play a role in the pathogenesis of some epilepsy syndromes.

Extra-articular Manifestations in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose main characteristic is persistent joint inflammation that results in joint damage and loss of function.Although RA is more common in females, extra-articular manifestations of the disease are more common in males. The extra-articular manifestations of RA can occur at any age after onset. It is characterised by destructive polyarthritis and extra-articular organ involvement, including the skin, eye, heart, lung, renal, nervous and gastrointestinal systems. The frequence of extra-articular manifestations in RA differs from one country to another. Extra-articular organ involvement in RA is more frequently seen in patients with severe, active disease and is associated with increased mortality. Incidence and frequence figures for extra-articular RA vary according to study design. Extra-articular involvement is more likely in those who have RF and/or are HLA-DR4 positive. Occasionally, there are also systemic manifestations such as vasculitis, visceral nodules, Sjögren's syndrome, or pulmonary fibrosis present. Nodules are the most common extra-articular feature, and are present in up to 30%; many of the other classic features occur in 1% or less in normal clinic settings. Sjögren's syndrome, anaemia of chronic disease and pulmonary manifestations are relatively common - in 6-10%, are frequently present in early disease and are all related to worse outcomes measures of rheumatoid disease in particular functional impairment and mortality. The occurrence of these systemic manifestations is a major predictor of mortality in patients with RA.This paper focuses on extra-articular manifestations, defined as diseases and symptoms not directly related to the locomotor system.