Intravenous IgG has been adopted as treatment for various immune-related diseases, including immune thrombocytopenic purpura, autoimmune neuropathies, systemic lupus erythematosus, Guillain-Barré syndrome, myasthenia gravis, Kawasaki disease, skin blistering diseases. The intravenous administration of exogenously pooled human immunoglobulin was originally licensed as antibody replacement therapy in patients with primary immunodeficiencies, but in the last thirty years, despite a current lack of institutional approval, off-label IVIgG treatment of a consistent number of disorders has shown to be a useful approach with good clinical results. The mechanism of action of IVIgG is complex and is not fully understood. The current understanding and development in the immune modulant action of IVIgG has three basic mechanisms: 1) F(ab')2 mediated actions; 2) interaction of IgGFc molecule with Fc receptors (FcgammaR); 3) actions mediated by complement fractions binding within the Fc molecular structure. The mode of action of IVIgG involves expression and function of Fc receptors, idiotype network, complement and cytokine network, T and B cell differentiation, modulation of antigen-presenting cells (APC). The therapeutic action of IVIgG is also related to natural antibodies in maintaining immune homeostasis. In addition, IVIgG interaction through V regions with complementary V regions of antibodies may provide a rational basis for selection of various immune repertoires. Since there is a significant gap between the institutional approval and the use of IVIgG in various clinical conditions, for which there is no adequate testing or for which a small number of records does not allow a rigorous statistical approach, several public and private institutions (mostly insurance companies) and research centres have developed guidelines for evaluating a rational and deontological approach in various pathological situations where IVIgG is used. Mathematical models based on non-linear differential equations may represent another potentially useful system to better understand an IVIgG targeted use in individual subjects.
IL-33, a member of IL-1 family, induces the differentiation of T-cells (depending on the phosphorylation of MAPKs and NF-kB) and is involved in T-cell mediated immune responses. IL-33 is also involved in the production of IL-5, IL-4 and IL-13 and several chemokines. In this editorial we show the importance of IL-33 in allergic diseases and its role as an inflammatory cytokine. In addition, the induction of certain chemokines by IL-33 may candidate this new cytokine as a mediator in inflammatory and autoimmune diseases and may prove to be a therapeutic target for the prevention of these diseases.
Human beings must adapt both to novel, unfavourable conditions and to circumstances of physical or psychological isolation. The initial response to stress depends fundamentally on the activation of the HPA axis. In regaining homeostatic equilibrium, melatonin plays a role due to its synchronising and anti-stress properties. To study the role of melatonin and the pineal gland in the organic and/or behavioural response to acute or chronic stress, 311 children were divided into two large groups: 1) Control Group - 121 healthy children classified, in turn, into 4 control subgroups, one for each pathology being studied; 2) Problem Groups, classified as traumatic stress (n=58), surgical stress (n=38), psychic stress (n=64) and febrile stress (n=30), according to pre-established clinical criteria. These groups were sub-classified according to the degree (low or high) and duration (acute or chronic) of the stress. This study used a case controlled, cross sectional design. Serum melatonin was measured by radioimmunoassay (RIA). In all the situations of acute stress, melatonin increased at a rate directly proportional to the severity and/or duration of the stress-causing stimulus. In contrast, in chronic stress, i.e. the Affective Deprivation Syndrome (or Psychological Dwarfism) with or without non-organic failure to thrive, resulted in the opposite response with a significant reduction of melatonin. In conclusion, in acute stress an increase in the bioavailability of melatonin could contribute to maintaining homeostatic balance. The lack of an appropriate response to acute stress could make some groups of patients (Affective deprivation syndrome with or without growth failure) predisposed to suffer depressive symptoms associated with a wide range of neurological, endocrinological or immunological consequences.
The aim of our study is to evaluate in Systemic Sclerosis (SSc) male patients the tadalafil effects on Raynaud's phenomenon and on AM and ET-1 plasma levels. In an open-label study 20 consecutive male patients with SSc were enrolled and received 10 mg of tadalafil daily for 12 weeks. The primary endpoint was the subjective reduction of frequency and duration of Raynaud's attacks measured with a 10-point Raynaud's Condition Score; the secondary aim was to modify Adrenomedullin (AM) and Endothelin-1 (ET-1) plasma levels. After the treatment Raynaud's phenomenon was improved by once-daily tadalafil (decrease of mean number of Raynaud's attacks and of Raynaud's Condition Score) and plasma AM and ET-1 levels decreased. The results of our study lead us to postulate the beneficial effect of adding long term inhibition of Phosphodiesterase type 5 to Systemic Sclerosis' therapy.
Nasal obstruction is a leading symptom in patients with allergic rhinitis and depends on inflammation characterized by Th2 polarization. Thus, IFN-gamma is typically deficient in allergic patients. It has been previously reported that ebastine is able to reduce Th2-dependent cytokines. The aim of this study is to preliminarily evaluate IFN-gamma production by peripheral blood mononuclear cells (PBMNC) and clinical changes after a treatment with lyophilized ebastine in patients with persistent allergic rhinitis (PER). Ten patients with PER were evaluated, 7 males and 3 females (mean age 32.4 +/- 6.2 years), all of whom received lyophilized ebastine (20 mg/daily) for 3 weeks. Total nasal symptom score (TSS), subjective evaluation score by visual analogue scale (VAS), and rhinomanometry were evaluated in all subjects before and after treatment. IFN-gamma production by peripheral blood mononuclear cells (PBMNC) was evaluated using different stimuli, in un-treated and ebastine-treated allergic patients by ELISPOT. Ebastine treatment induced significant increase of IFN-gamma production stimulated by grasses (p<0.0001) and Dermatophagoides farinae (p=0.0015). This effect was significantly related with TSS and VAS improvement after treatment (p=0.0038 and 0.004 respectively). In conclusion, this preliminary study demonstrates the effectiveness of ebastine treatment in increasing IFN-gamma production. The clinical relevance of this study is that the clinical improvement is related to the immunologic activity.
The IgG response to allergens is well-known, however few studies have investigated IgG and IgG4 production in normal subjects. Therefore, total IgG and IgG4 serum levels specific for 6 common inhalant allergens were measured in 282 non-allergic subjects to establish reference values at different ages and sex. Thus, 282 subjects were studied (141 female and 141 male) ranging from pre-school to adult age, all living in Northern Italy at the time of the study. Family history of first degree relatives and personal history were negative for allergic diseases. The findings obtained in this study indicate that: i) reference values for specific IgG4 and IgG levels against the allergen studied should take into account both the sex and age of the subject evaluated; ii) there is a difference in trend for age between seasonal and perennial allergens and iii) the relationships between age and specific IgG4 and IgG levels have different slopes. In conclusion, relevant differences exist in the distribution of IgG and IgG4 levels in normal subjects.
Rat myocardial fiber development and formation is a complex event which begins in the early stages of fetal life and continues until the end of the first month of life. In fact, a progressive morphological structure arrangement is observed until the 22nd day of life. These modifications are based on biochemical events which are switched on at plasma membrane level and then transduced into the nucleus. Since the presence of Protein Kinase C (PKC) inside the nucleus could allow the enzyme to phosphorylate also proteins located on chromatin, on nuclear matrix and speckles, in this study attention was paid to the role played by phospho-Protein Kinase C-alpha (p-PKCalpha) in regulating the activation of SC-35 splicing factor which leads to the occurrence of morphological modifications during post-natal rat heart development. Besides the parallel increase of the expression of both proteins up to 4/8 days of life, firstly p-PKCalpha and SC-35 co-localize at nuclear level at day 1 after birth, thus suggesting a main role of p-PKCalpha in modulating the early transcription of components related to post-natal rat heart development.
Sarcopenia is the physiological age-related reduction of muscle mass and strength. Considering that life span is correlated with metabolic rate and mitochondria are the site of oxygen consumption, muscle mitochondria volume densities were determined by morphometric analysis. We found a tight correlation between aging and hypoxia with decrease in muscle total mitochondria volume. Therefore, hypoxia and aging seem to share some common pathways, allowing hypoxic models to be used for the study of the aging processes. Additional research will be required to fully elucidate the correlations among aging, sarcopenia and hypoxia, but these findings provide a starting point for such investigations.