[Neurofibromatosis (NF1) and neuroleprosy: immunoreaction against pathologic Schwann-cells. Physiopathogenetic observations]. / Neurofibromatosi (NF1) e neurolebbra: immunoreazione verso cellule di Schwann patologiche. Considerazioni fisiopatogenetiche.

BACKGROUND: We reviewed the literature evaluating the immune reaction in neurofibromatosis (NF1) and neuroleprosy, so as to underline the immunopathegenetic parallelism and the possible therapeutic implications regarding the treatment of these two disorders. In particular we evaluated the systemic modifications and the local fibrotic events that lead to nerve damage in NF1 and complete neuronal destruction as in leprosy. METHODS: With the above aim in mind we studied the histology, histochemistry and immunohistochemistry (Schwann cells and immunoglobulins) of four plexiform neurofibroma, one common neurofibroma and one case of borderline neuroleprosy (BT). RESULTS: Two plexiform neurofibromas showed an evident immune reaction that was antibody mediated with numerous IgG; the remaining neurofibromas represented other stages of disease evolution and disease quiescence and thus showed a scarce immune reaction with a reduced presence of immunoglobulins. All the neurofibromas showed the presence of fibrous bundles. In the case of neuroleprosy (BT), the immune reaction was modest, immunoglobulins were present and fibrotic transformation on neuronal fibers was observed. CONCLUSIONS: Being that pathologic Schwann cell are the site of immune reactions that can become abnormal (at times with autoimmune reactions), clinical as well as biochemical surveillance of leprous neuropathy and NF1 could allow for a timely modification of the abnormal reaction with selective immunomodulators. The inactivation of the mycobacterial RNA polymerase or of the NF1 gene could offer hope for controlling disease activity and disease evolution of the two disorders.

Tumour suppressor genes, immunology and local manifestations of neurofibromatosis phenotypes.

Research on Neurofibromatosis (NF) has been directed at understanding what determines disease quiescence, exacerbation, and the possible malignant evolution. Studies on NF have examined the role of genetic oncosuppression in the evolution of the defence against the non-self. Paraffin fixed specimens of benign and malignant neoplasia, occurring in patients with NF1 and NF2, were tested for the presence of p53: a reliable marker of genetic oncosupression. The wild type variant of p53 is expressed in malignant neoplasia, and is usually not expressed in benign tumors. Contrariwise, an immune reaction it is seen in benign tumors and is practically absent in malignant tumors. Evidence of protein p53 in the various malignant neoplasias studied by our group seems to reflect the up-regulation on the oncosuppresive genetic potential that occurs while there is a lack of immunological defence. In the presence of an immunological defence, the expression p53 is normally not seen e.g. plexiform neurofibromas. The evolution of the various neoplastic types here reported was the same as that reported by current clinical and experimental models: the cell's defective genes are no longer suppressed and after activation the genes undergo initiation, promotion, and the cell sustains inflammatory-immune reactions that lead to fibrosis; what follows is a variable period of apparent quiescence. Severe pathogenic stimuli may act on predisposed cells and deteriorate pre-existing genetic damage, casting the cell into a phase of dysplastic or neoplastic proliferation that overcomes the body's defences. Hope for future therapy lies in the development of drugs that can either mimic the immune system or the proteins encoded by the oncosuppressor genes.

Inhibition of diamine oxidase activity by metronidazole.

Metronidazole was found to be a non-competitive inhibitor of man, rabbit and rat intestinal diamine oxidases with an inhibition constant value of approximately 10(-4) M. The purified bovine serum amine oxidase was not inhibited, whereas the purified swine kidney enzyme gave similar results. These findings suggest that metronidazole and similar compounds, used as antibacterial and antiprotozoal drugs, should be given under careful control, especially when administered for long times, because a decrease of intestinal diamine oxidase activity was proven to be a risk factor for several pathologies of this organ.

[The clinico-immunological surveillance of neurofibromatosis]. / La sorveglianza clinico-immunologica delle neurofibromatosi.

Considering the more recent physiopathogenetic advancements in neurofibromatosis (NF), we propose to employ novel instrumental and laboratory procedures for the immunological and clinical surveillance of NF. In NF the evolution of the non-self can lead to disease expansion, at times transforming into malignancy. Contemporarily, the resulting immunological reactivity can either lead to the type of fibrosis that one sees in paraneoplastic connective tissue disease or be deficient. Through interdisciplinary biohumoral analyses were carried out contemporarily so as to gain comparative insight into the eventual unfolding of immunological and fibrotic phenomena. The range of the clinical follow-up varied from one to four years with periodic day hospital admissions. We studied ten NF patients that originated from southern Italy and belonged to middle and lower middle class status; we also studied one healthy subject who had the same HLA haplotype as his NF affected twin. We performed biohumoral analyses in clinical stable patients and saw moderate variations in induces useful for monitoring the evolution of this dysplastic-neoplastic condition, e.g. procollagens, interleukin-2, NSE (assayed with radioimmunological methods) and complement these parameters proved to be of use in monitoring the fibrotic evolution of NF. The intent of our work was to complete the earlier studies on NF surveillance, especially during periods of disease evolution and immuno-fibrotic alteration.

Immunological and clinical surveillance in Recklinghausen's neurofibromatosis (NF1).

Neurofibromatosis evolution is described in relation to the factors that may favour its expansion and immune modifications. NF1 monitorization should employ periodic clinical and immune surveillance. Such an approach would allow the application of immunomodulating treatment (e.g. adapted therapy) only when indicated, thereby reducing its duration and potentiating its efficacy.

[Local immune response in neurofibromatosis type 1 and type 2]. / L'immunoreazione locale nelle neurofibromatosi di von Recklinghausen e del neurinoma bilaterale del nervo acustico.

Neurofibromatosis, in all its variant forms, is a hereditary disease characterized by dysplasia, neoplasia, and the tendency to expand and undergo malignant transformation. We underline the presence of chronic inflammation and of immunologic interdependency. The immune reactions against the non-self have been investigated histologically in light of the concepts of immunosurveillance and immunotolerance. Such investigations would ameliorate subsequent studies and favour the employment of immunomodulatory treatments.

Specific temperature dependence of diamine oxidase activity and its thermal stability in the presence of polyvinylalcohol.

An inflexion point on the dependence of the swine kidney diamine oxidase activity upon the temperature was found at 40-43 degrees C, suggesting a conformational transition. The activation energies with putrescine as substrate calculated from the Arrhenius plots were 38.23 kcal/mol for the temperature interval 25-40 degrees C and only 15.14 kcal/mol for the range 45-60 degrees C. These values suggest two different conformations, one corresponding to the interval below 40 degrees C and another one between 43-60 degrees C, with an intermediate transitory form corresponding to the inflexion point at 40-43 degrees C. For various temperature decades within 10-60 degrees C, peculiar Q10 values in the range 1.37-3.00 (differing from the usual value Q10 = 2), were obtained. The non-strictly Arrhenius curves, the activation energies and the inflexion point were quite similar with and without 0.05% polyvinylalcohol. This particular temperature effect found for swine kidney diamine oxidase is similar to the one reported for bovine serum amine oxidase. An increased enzyme thermal stability was obtained in the presence of high molecular weight polyvinylalcohol.

[Immune reaction in von Recklinghausen's neurofibromatosis]. / La reazione immunitaria nelle neurofibromatosi di von Recklinghausen.

A multidisciplinary study was performed on cases of neurofibromatosis to highlight the immunological reaction using broad-spectrum hematic tests and multiphase evaluation together with clinical and instrumental monitoring. The aim of the study was to focus attention on this rare disease and prompt further sequential immunological studies. A greater knowledge of the disease would allow the promising potential of new drugs to be exploited, in particular selective immunomodulatory drugs, in the hope of controlling the symptoms of disease (and overcoming further obstacles to the surgical removal of any neurofibromas that the patient wishes.

Studies on the effect of polyamines and their products on Ehrlich ascites tumours.

Immobilized diamine oxidase injected into the peritoneal cavity of Swiss male mice 24 h after the viable intraperitoneal transplantation of Ehrlich ascites cells inhibits tumour growth. This fact should be imputable to the oxidation of polyamines, originating from tumour cells, into aldehyde, the oxidation product.

The effect of azide on the spectral and catalytic properties of ascorbate oxidase.

(1) 45% of the total copper of green zucchini ascorbate oxidase is EPR-detectable. At least two species of copper are present, one with a small A parallel (Type 1) and one with a large A parallel (Type 2). Computer simulated spectra indicated 50% contribution by each type of copper. (2) Azide inhibited ascorbate oxidase activity by an uncompetitive mechanism. EPR and optical spectra performed on titration of ascorbate oxidase with azide indicated the formation of a copper-azide complex. The Type 2 copper appears to be the binding site of azide. The involvement of the EPR non-detectable copper as an anion binding site with high affinity toward azide can not be excluded.