L. Fontana

Deficiency of natural killer activity, but not of natural killer binding, in patients with lymphoadenopathy syndrome positive for antibodies to HTLV-III

Blood lymphocytes (BL) of eleven patients with lymphoadenopathy syndrome (LAS) were studied for natural killer (NK) activity against the K562 cell line (using both the standard 51Cr release assay and the single-cell cytotoxicity assay on poly-L-lysine-coated coverslips) and for surface phenotype (employing OKT4, OKT8 and Leu7 monoclonal antibodies). A significant reduction in NK activity and in NK active cells was detected, while the percentage of target binding cells was not affected. Furthermore, the OKT4/OKT8 ratio was found to be inverted, and the Leu7+ subpopulation expanded. The patients had high titers of anti-HTLV-III antibodies. This study indicates that defective NK activity in LAS is secondary to an abnormality in the lytic event itself and not in target binding.

Cyclosporin A (CyA) reduces sCD30 serum levels in atopic dermatitis: a possible new immune intervention

Atopic dermatitis (AD) is a chronic inflammatory skin disease frequently associated with asthma, rhinitis, and food allergy. Lymphocytes producing Th2‐type cytokines (such as interleukin [IL]‐3, IL‐4, and IL‐5) have been thought to have a key role in the pathogenesis of the disease. We have recently demonstrated that elevated serum levels of the soluble form of CD30 (sCD30), an activation marker of Th2‐cell clones, correlates with disease activity in pediatric patients suffering from AD. Clinical trials have demonstrated that cyclosporin A (CyA) treatment resulted in significant improvement of clinical symptoms in patients affected with AD. In this study, we evaluated the role of CyA in modulating sCD30 release in a group of adult patients affected by severe AD treated with CyA at the dosage of 3.5 mg/kg body weight for 12 weeks. Our results demonstrated, in parallel with an improvement of clinical symptoms, a significant reduction of serum levels of both IL‐4 and sCD30, thus suggesting that CyA can prevent the activation of Th2 cells observed in AD.

Complement, complement activation and anaphylatoxins in human ovarian follicular fluid

Functionally active complement was sought and detected in human follicular fluids obtained during the pre‐ovulatory period. All the functional complement activities tested, including total haemolytic complement, classical pathway activity and alternative pathway activity were present in nine fluids from four different donors with values within the normal serum range. The immunochemical analysis demonstrated the presence of complement factors from C1 to C9, of B and of C1 INH, H, I. Complement anaphylatoxins were found employing RIA techniques in amounts significantly higher than in human plasma, thus demonstrating that follicular fluid complement, at least during the preovulatory period, is partially activated. A possible role for urokinase‐like substances in such an activation was indicated by further in vitro experiments. The presence of active complement in follicular fluid can be relevant for the function of the enzymatic multi‐factorial mechanism of ovulation.

Cystic ovaries in women affected with hereditary angioedema.

Polycystic ovary (PCO) syndrome is biochemically characterized by abnormal gonadotropin secretion and polycystic ovaries associated with increase in size and functional activity of stromal tissue; multifollicular ovaries (MFO) are defined by the presence of multiple cysts with no increase in stromal tissue. A central (hypothalamic‐pituitary) abnormality, including high plasma /?‐endorphin (BE) concentrations without simultaneous elevation of ACTH, was reported for subjects with PCO syndrome. Since we have found the presence of high plasma BE concentrations in hereditary angioedema (H ANE) during attacks as well as during symptom‐free periods, we studied, by means of pelvic ultrasound scanning employed to determine the prevalence of PCO and of MFO, 13 women of reproductive age affected with HAN E who were not on oral contraceptives. We have found PCO in 5/ 13 (38.4%) and MFO in 7/13 (53.8%) HANE patients. Nine patients had oligomenorrhoea (five with PCO, three with MFO, one with normal ovaries), five (three with PCO, two with MFO) were hirsute and only one (with MFO) had weight loss. No patient was obese. Mean plasma LH, testosterone, prolactin, cortisol and ACTH concentrations were normal, while FSH was significantly reduced and LH/FSH ratio increased. BE concentrations were significantly high in all the patients studied. Our results clearly demonstrate that women with HANE frequently have cystic ovaries (polycystic or multifollicular) in the presence of high BE concentrations.

Deficiency of lymphocyte lectin-dependent cytotoxicity in myelodysplastic syndromes.

We studied a group of patients with myelodysplastic syndromes (MDS) for surface markers and cytotoxic activities of peripheral blood mononuclear cells (PBMNC). The results indicate a significant increase in the total count of CD11b+, Leu7+ and CD16+ with a percent reduction in CD4+. A reduction in PHA-induced cellular cytotoxicity (PHA-ICC) and NK activity were found. A similar phenotype was found both in refractory anemia (RA) and (RA) with excess of blasts (RAEB/RAEB-t). However, the functional activities reached the normal level only in RA patients; while in RAEB/RAEB-t patients a significant reduction was detected in PHA-ICC and NK activity.

Endothelial dysfunction in rheumatoid arthritis is improved by anti-tumor necrosis factorα treatment

Rheumatoid arthritis (RA) is associated with excess cardiovascular morbidity and mortality. TNFα plays a pivotal role in causing both RA synovial damage and atherosclerosis, also by inducing endothelial dysfunction. The aim of the present study was to assess the occurrence of endothelial dysfunction and the effects of anti-TNFα antagonism on endothelial function in RA. Ten RA women with Disease Activity Score (DAS) ≥ 3.7 despite treatment with at least two disease-modifying antirheumatic drugs for 4 months underwent anti-TNFα treatment with infliximab or etanercept. Endothelium-dependent vasodilation was significantly lower than normal (3.8±3.7 % vs. 13.7 ±5.1, p≤0.05), thus demonstrating the presence of endothelial dysfunction in our RA patient population. Anti-TNF- treatment significantly improved flow-mediated vasodilation, which increased from baseline values of 3.8±3.7% to 10.9±6.6% (p<0.05) at day 1, to 13.4±5.4 % (p < 0.05) at week 1, to 12.7±5.3 % (p<0.05) at week 2 and to 15.5±5.2 % at week 6 (p≤0.05). There was no significant difference between two anti-TNFα treatments regarding mean percentage increase of flow-mediated vasodilation during treatment. RA clinical improvement was demonstrated by a significant decrease in the DAS score (from 6.26±1.6 to 5.26 1.38, p < 0.05) associated to a marked decrease of acute phase reactants serum levels. The present study supports the hypothesis of the pivotal role for TNFα as a mediator of systemic and vascular wall inflammation in RA.

Generation and Neuronal Differentiation of hiPSCs from Patients with Myotonic Dystrophy Type 2

Human induced pluripotent stem cells (hiPSCs)-patient specific are an innovative tool to reproduce a model of disease in vitro and summarize the pathological phenotype and the disease etiopathology. Myotonic dystrophy type 2 (DM2) is caused by an unstable (CCTG)n expansion in intron 1 of the CNBP gene, leading to a progressive multisystemic disease with muscle, heart and central nervous dysfunctions. The pathogenesis of CNS involvement in DM2 is poorly understood since no cellular or animal models fully recapitulate the molecular and clinical neurodegenerative phenotype of patients. In this study, we generated for the first time, two DM2 and two wild type hiPSC lines from dermal fibroblasts by polycistronic lentiviral vector (hSTEMCCA-loxP) expressing OCT4, SOX2, KLF4, and cMYC genes and containing loxP-sites, excisable by Cre recombinase. Specific morphological, molecular and immunocytochemical markers have confirmed the stemness of DM2 and wild type-derived hiPSCs. These cells are able to differentiate into neuronal population (NP) expressing tissue specific markers. hiPSCs-derived NP cells maintain (CCTG)n repeat expansion and intranuclear RNA foci exhibiting sequestration of MBNL1 protein, which are pathognomonic of the disease. DM2 hiPSCs represent an important tool for the study of CNS pathogenesis in patients, opening new perspectives for the development of cell-based therapies in the field of personalized medicine and drug screening.

Churg-Strauss syndrome development during asthma therapy with leukotriene receptor antagonists: just a coincidental association?

A report on our clinical experience based on 3 male patients who developed Churg-Strauss syndrome (CSS) after standard oral montelukast use. All patients affected by moderate asthma and chronic hyperplastic rhinosinusitis were treated with inhaled corticosteroids and ß2 agonists. Systemic corticosteroid treatment consisted in oral daily prednisone in case 1, in short courses of oral betamethasone in case 2, and in remote and isolated administrations of oral betamethasone and intramuscular methylprednisolone in case 3. Because of the improvement of the asthma symptoms after montelukast use, patient 1 decided to take half the dose of prednisone for 10 days and patient 2 decided to discontinue systemic and inhaled corticosteroids for 45 days. Overt CSS was heralded by vasculitic skin lesions and developed in each patient with severe organ damage, consisting in renal, myocardial and gastrointestinal involvement. Remission was obtained by standard CSS therapy after montelukast withdrawal. According to the unmasking hypothesis, antileukotriene treatment, by enabling the reduction in systemic corticosteroid therapy in case 1 and its discontinuation in case 2, might have only permitted the precipitation of the vasculitis. However antileukotriene-associated CSS reportedly occurred in systemic corticosteroid-naïve patients and relapsed in one patient after antileukotriene treatment. These observations lend support to the concept that the precipitation of the vasculitic phase may be associated with leukotriene modifier deleterious effects. In conclusion there is not enough evidence to prove that antileukotriene treatment plays a direct causative role in the pathogenesis of CSS. Further clinical and experimental research is required to clarify the antileukotriene associated CSS controversy.

Squamous Cell Carcinoma Related Antigen (SCC-rAg), sICAM-1 and β 2Microglobulin are Usefull Markers of Disease Activity in Psoriasis

genes involved in glycide metabolism and a glucose transporter are located in this genomic area. Moreover, recent data suggest that Rh is also a transporter. ACPl is a highly polymorphic phosphotyrosine phosphatase (PTPase): it is composed by two distinct isoforms F and S and may have an important role in the modulation of the postreceptorial pathway of insulin action. The association of the two clusters with different ACPl isoforms represents a strong indication ofbiochemical heterogeneity ofneuropathic complications. In fact, F and S isoforms show different structure and biochemical properties and have probably different functions. On the other hand the association with RhE may represent the effect of complex haplotypes of genes located in the short arm of chromosome 1 involving glucose transport and metabolism.

Iatrogenic Modifications of the Complement System

controlled with monoclonal antibodies (AbMos) and peptides that prevent specific clonal activation of T cells. The initial immune response generates a process of inflammation and synovial proliferation. Some agents potentially capable of interrupting this phase would be: metalloprotease antagonists and cytokine inhibitors(AbMos anti-IL-l, antiTNFa). The anti-TNFa chimeric AbMos is well tolerated and improves clinical symptoms and serological markers of disease activity (5). In conclusion, it is not unreasonable to suggest that, in the future a combination therapy with DMARDs and various biological response modifiers, selectively administered during specific pathogenetic phases could modify the evolution and the outcome of the disease.