Flora Ippoliti

Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus

BACKGROUND Several studies found a high incidence rate of neuro-psychiatric complications during long-term therapy with interferon alpha (IFNalpha), e.g. slowness, severe fatigue, hypersomnia, lethargy, depressed mood, mnemonic troubles, irritability, short temper, emotional lability, social withdrawal, and lack of concentration. The aim of this study was to examine the incidence of depressed mood and major depression in patients who were treated with IFNalpha. METHODS 30 patients, affected by chronic active C-hepatitis, have been evaluated at baseline and 3 months after IFNalpha treatment. The evaluation consisted of psychometric assessments employing the DSM-IV criteria and the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS At end-point, 40.7% of the patients suffered from a full blown major depression, according to the DSM-IV criteria for major depression. IFNalpha treatment induced a significant increase in the MADRS score from baseline to 3 months later. The MADRS items which were significantly increased at end-point were: expressed and unexpressed sadness; irritability; insomnia; loss of appetite; and asthenia. DISCUSSION The results show that prolonged IFNalpha treatment may induce depressive symptoms and major depression in a considerable number of subjects.

Immunomodulation during sublingual therapy in allergic children.

The clinical efficacy of sublingual immunotherapy (SLIT) has been demonstrated, but its mechanism of action is still controversial. The most recent experimental observations suggest that a critical role in the modulation of immune response is sustained by Th2 cytokines, such as interleukin‐4 (IL‐4), IL‐5 and IL‐13, by co‐stimulatory molecules, such as CD40 on B cells, and by hormones and neuropeptides. To better understand whether SLIT affects immune responses we used a double‐blind placebo‐controlled design. Eighty‐six children with mild asthma due to allergy to Dermatophagoides pteronyssinus (33 of whom also had rhinoconjunctivitis) were randomly assigned SLIT (n = 47) or placebo (n = 39). We assessed symptom scores using diary cards of each patient and determined the expression of CD40 on B cells and the serum concentration of ECP, IL‐13, prolactin (PRL) and ACTH at enrolment and after 6 months of therapy. We observed a significant reduction in asthma and rhinitis scores in the immunotherapy group compared with the placebo group, no variation in CD40 and ACTH, but a significant decrease in ECP, IL‐13 and PRL after 6 months of therapy (p <0.01). Our results confirm the efficacy and safety of SLIT, and lead us to believe that it could modulate the synthesis of Th2 cytokines, as revealed from the decrease of IL‐13. In addition, the reduction of PRL might be a signal of reduced activation of T lymphocytes.

Altered Cytokine and BDNF Levels in Autism Spectrum Disorder

The contribution of neuroimmune functioning and brain-derived neurotrophic factor (BDNF) to functional dysregulation in autism spectrum disorder was assessed in 29 patients under treatment in two specialized centers of Basilicata (Chiaromonte and Matera), Southern Italy, through analysis of serum levels of cytokines and BDNF. Elevated levels of the pro-inflammatory cytokine, including interleukin-1, interleukin-6, interleukin-12, interleukin-23, tumor necrosis factor-α and BDNF were observed, regardless of age and gender. Comparisons were made with age- and gender-related healthy controls. The present findings reinforce current notions regarding immunoexcitotoxic mechanisms contributing to the pathophysiology of autistic disorder.

Heat shock protein (HSP70) expression in septic patients

PURPOSE This study investigates heat shock protein 70 (HSP70) expression by peripheral blood mononuclear cells (PBMCs) of septic patients admitted to an intensive care unit and examines the possibility of a correlation between HSP70 levels and plasma tumor necrosis factor alpha (TNF-alpha) concentrations. Additionally, we evaluated whether the HSP70 production could be regarded as a prognostic factor for the development of septic shock as well as for patient survival. MATERIALS AND METHODS Blood samples of 29 patients were taken 24 hours after the diagnosis of sepsis. HSP70 expression and TNF-alpha level were measured using indirect immunofluorescent analysis and a commercially available enzyme-linked immunosorbent assay method, respectively. RESULTS PBMCs expressed significantly high levels of HSP70 (11.9 +/- 5.6 [sd]) compared with those of the healthy control group (3.2 +/- 2.1% positive cells). Such enhanced levels were correlated to plasma TNF-alpha concentrations (r = .99, P < .01). This study failed to demonstrate a relationship between HSP70 production and clinical outcome. CONCLUSION These findings give further evidence that also in humans, heat shock response is activated during sepsis. The correlation observed between HSP70 overproduction and TNF-alpha plasma concentrations suggests that HSP70 exerts a possible protective effect against TNF-alpha cytotoxicity. Such hypothesis has not been confirmed by our clinical data.

Stress-induced cytokines and neuronal dysfunction in Alzheimer's disease

Increasing evidence has been accumulating about the role of stress as an important challenge to the onset and progression of Alzheimers disease (AD). The hippocampus, one of the areas of the brain damaged during AD, was the first brain region, besides the hypothalamus, to be recognized as a target of stress hormones, including cortisol, sympathetic and parasympathetic transmitters, cytokines, and metabolic hormones. The present review aims at summarizing neuroinflammatory mechanisms induced by stress, resulting in neuronal dysfunction and impaired neurogenesis. Lifestyle and environmental factors related to metabolic and inflammatory alterations observed in stressed subjects and thought to favor AD development and progression, as well as the possible ways of prevention, are discussed.

Cellular and molecular players in the atherosclerotic plaque progression.

Atherosclerosis initiation and progression is controlled by inflammatory molecular and cellular mediators. Cells of innate immunity, stimulated by various endogenous molecules that have undergone a transformation following an oxidative stress or nonenzymatic glycation processes, activate cells of the adaptive immunity, found at the borders of atheromas. In this way, an immune response against endogenous modified antigens takes place and gives rise to chronic low‐level inflammation leading to the slow development of complex atherosclerotic plaques. These lesions will occasionally ulcerate, thus ending with fatal clinical events. Plaque macrophages represent the majority of leukocytes in the atherosclerotic lesions, and their secretory activity, including proinflammatory cytokines and matrix‐degrading proteases, may be related to the fragilization of the fibrous cap and then to the rupture of the plaque. A considerable amount of work is currently focused on the identification of locally released proinflammatory factors that influence the evolution of the plaque to an unstable phenotype. A better understanding of these molecular processes may contribute to new treatment strategies. Mediators released by the immune system and associated with the development of carotid atherosclerosis are discussed.

Alzheimer's Disease Promotion by Obesity: Induced Mechanisms—Molecular Links and Perspectives

The incidence of AD is increasing in parallel with the increase in life expectancy. At the same time the prevalence of metabolic syndrome and obesity is reaching epidemic proportions in western populations. Stress is one of the major inducers of visceral fat and obesity development, underlying accelerated aging processes. Adipose tissue is at present considered as an active endocrine organ, producing important mediators involved in metabolism regulation as well as in inflammatory mechanisms. Insulin and leptin resistance has been related to the dysregulation of energy balance and to the induction of a chronic inflammatory status which have been recognized as important cofactors in cognitive impairment and AD initiation and progression. The aim of this paper is to disclose the correlation between the onset and progression of AD and the stress-induced changes in lifestyle, leading to overnutrition and reduced physical activity, ending with metabolic syndrome and obesity. The involved molecular mechanisms will be briefly discussed, and advisable guide lines for the prevention of AD through lifestyle modifications will be proposed.

Stress and Obesity as Risk Factors in Cardiovascular Diseases: A Neuroimmune Perspective

Obesity is now growing at an alarming rate reaching epidemic proportions worldwide thus increasing morbidity and mortality rates for chronic disease. But although we have ample information on the complications associated with obesity, precisely what causes obesity remains poorly understood. Some evidence attributes a major role to a low-grade chronic inflammatory state (neurogenic inflammation) induced in obesity by inflammatory mediators produced and secreted within the expanded activated adipocyte pool. Adipose tissue is an endocrine organ that secretes numerous adipose tissue-specific or enriched hormones, known as adipokines, cytokine-like molecules thought to play a pathogenic role in cardiovascular diseases. The imbalance between increased inflammatory stimuli and decreased anti-inflammatory mechanisms may depend on chronic stress. Hence the positive correlation found between stress, obesity and cardiovascular diseases. The chronic inflammatory state associated with insulin resistance and endothelial dysfunction is highly deleterious for vascular function. This review focuses on the proposed neuroimmunodulatory mechanisms linking chronic (psychological) stress, obesity and cardiovascular diseases.

Psychological stress affects response to sublingual immunotherapy in asthmatic children allergic to house dust mite

While the clinical and immunologic efficacy of sublingual immunotherapy (SLIT) in allergic diseases has been extensively demonstrated, some patients display a poor clinical response. Psychological stress has been shown to play a role in atopy and also to affect response to immunomodulating therapies such as vaccination with microbial antigens. This study addresses the possibility of response to SLIT being affected by psychological stress. Forty children with mild asthma caused by allergy to Dermatophagoides pteronyssinus and farinae were subjected to SLIT and then divided after 6 months into two groups based on the results of the stress integrated measure (SIM) test: group 1 (24 stressed patients, mean SIM value of 60.1) and group 2 (16 non‐stressed patients, mean SIM value of 7.6). There was also a higher prevalence of psychosocial stressing factors (divorced/absent parents, low income households, non‐working parents) among stressed patients. The symptom score, peak expiratory flow (PEF), forced expiratory volume in 1 s (FEV1) and serum eosinophie cationic protein (ECP) concentration were evaluated at both times. The serum concentration of neuroendocrine parameters [prolactin, cortisol, adrenocorticotropic hormone (ACTH)] was also measured after 6 months of therapy. While all the clinical parameters and ECP concentration improved after SLIT, symptom score, PEF and ECP showed a significantly greater improvement in non‐stressed patients. The concentration of neuroendocrine parameters was significantly increased in stressed patients. Our findings show that psychological stress can affect response to SLIT also in allergic subjects and are consistent with data recently reported showing a correlation between stress and poor response to antimicrobial vaccines. Our data also suggest that stress evaluation may become a useful prognostic factor in immunotherapy.

Cell-Mediated Immunity Imbalance in Pregnancy-Induced Hypertension

Pregnancy is associated with modifications in the maternal immune system that may be involved in the absence of rejection of the fetoplacental graft characterized by the presence of paternal antigens. This active and specific tolerance towards the fetoplacental unit seems to be compromised in pregnancy-induced hypertension (PIH). To evaluate whether the immunological state in patients with PIH is altered with respect to normal pregnant women we studied 15 patients with PIH, 15 uncomplicated pregnant and 10 healthy nonpregnant women using monoclonal antibodies directed to specific lymphocyte antigen determinants, cytokines (TNF) and soluble molecules (sIL-2R, sCD8). The percentage of CD4 lymphocytes and of natural killer (NK) cells was significantly higher in PIH patients compared to controls (CD4: 42.9 +/- 10.5 vs. 32.7 +/- 12.5%; p < 0.05; NK: 14.7 +/- 6.3 vs. 8.3 +/- 3.4%; p < 0.01). However, these values did not differ when compared to normotensive nonpregnant controls (CD4: 53.1 +/- 5.9%; NK: 17.2 +/- 7.1%). In addition, the soluble IL-2 receptor (sIL-2R) was higher in PIH patients when compared to control patients (725.5 +/- 194.2 vs. 482.5 +/- 187.2 U/ml; p < 0.01). The immune response observed in normal pregnancies responsible for the tolerance towards the fetoplacental unit seems to be altered in PIH patients as suggested by higher levels of CD4 and NK cells, and sIL-2R. This may lead to a chronic rejection syndrome and be involved in the pathophysiology of PIH.