Peripheral neuropathy in scleroderma Corbo, M; Nemni, R; Iannaccone, S ...
Clinical neuropathology,
03/1993, Letnik:
12, Številka:
2
Journal Article
Recenzirano
Nervous system involvement is rare in progressive systemic sclerosis (PSS). We present a clinical pathological and immunological study of two patients with peripheral sensory motor neuropathy and ...PSS. In both, the sural nerve biopsies showed axonal degeneration with increased endoneurial connective tissue. There were also clusters of myelinated fibres indicating axonal regeneration. Only mild microangiopathic changes were evident in the endo, peri and epineurial vessels. By Western immunoblots, patients' sera contained a band of reactivity to a protein from peripheral nerve identified as collagen type I. Primary involvement of the peripheral nerves during PSS is very unusual. Abnormal production of collagen tissue and presence of microvascular disease are considered to be two possible causes of neuropathy. We think that our results suggest the important role of the connective tissue proliferation in the pathogenesis of PSS neuropathy.
Several integrins recognize as ligands proteins containing the Arg-Gly-Asp (RGD) sequence, such as fibronectin, vitronectin, and laminin. It has been previously demonstrated that oligopeptides ...containing the RGD sequence competitively inhibit both the adhesion of hamster and human sperm to zona-free hamster eggs and their subsequent penetration. In addition, the appearance of fibronectin on the surface of living human spermatozoa after capacitation has been demonstrated. In this work, it is shown that spermatozoa incubated overnight under capacitating conditions, but not fresh spermatozoa, also display the RGD-containing proteins vitronectin and laminin. Whereas the expression of fibronectin does not appear to be localized to any specific region of the sperm surface, laminin is present solely on the sperm tail, and vitronectin was detected mostly as an equatorial band on the sperm head. The percent of capacitated spermatozoa within each ejaculate reacting with antivitronectin antibodies (51% to 94%) was similar to that observed with antifibronectin antibodies (72% to 100%) in a series of fertile donors, and in a series of infertile men (7% to 98% for vitronectin versus 5% to 100% for fibronectin). In contrast, the percent of spermatozoa displaying laminin was lower, ranging from 2% to 42% for fertile donors and from 5% to 34% for infertile donors, and was unrelated to the expression of fibronectin or vitronectin. The time of appearance of both fibronectin and vitronectin when spermatozoa were incubated under capacitating conditions varied for different sperm donors, suggesting a difference in the process of their expression between different men. The specificity of antivitronectin antibody binding to human spermatozoa was demonstrated by competitive inhibition with purified human vitronectin. That there was no immunologic reaction between the antivitronectin antibodies used and fibronectin was demonstrated both by the failure of free fibronectin to inhibit antivitronectin antibody binding to spermatozoa, and by Dot blot analysis. A partial cross-reaction of the polyclonal antivitronectin antibody with fibronectin was shown by Western blot analysis, but this phenomenon was not present when the monoclonal antivitronectin antibody was used. In addition, both fibronectin and vitronectin could be extracted from capacitated spermatozoa solubilized in Chaps buffer, as shown by Dot blot and Western blot analysis. These observations suggest that vitronectin and fibronectin expressed on the surface of capacitated human spermatozoa could act as a ligand for specific receptors on the egg, and play a role in sperm-oolemmal adhesion.
A method has been developed to establish lines of transformed lymphocytes able to produce in vitro the same anti-sperm antibodies as those naturally occurring in immuno-infertile individuals. We ...utilized lymphocytes from a male donor whose serum contained anti-sperm antibodies of the IgG class up to the dilution 1:10 000, as detected by means of immunobead binding. T lymphocytes were separated from B lymphocytes using magnetic beads coated with anti-T antibody. B lymphocytes were then placed at a concentration of 5 × 10
6/ml in a 96-well plate, stimulated with phytohaemagglutinin (PHA) and transformed with Epstein-Barr virus. After a few days, only transformed cells continued growing and these were collected. The supernatant was tested for production of anti-sperm antibodies and those transformed lymphocytes shown to be synthesising antibodies directed against the sperm head and the tail were cloned. We obtained a clone of cells producing antibodies of the IgG1 class directed against the head of the spermatozoon. This oligoclonal antibody (F6) recognized a 58-kDa band from a lysate of sperm membranes and was able to reduce the penetration of zona-free hamster oocytes by capacitated spermatozoa.
Increased titers of IgM anti-GM1 antibodies are present in some patients with Lower Motor Neuron Disease (LMND) or Motor Neuropathy (MN), but their pathogenic role and the mechanism of action are ...unclear. Previous studies have shown that the B subunit of Cholera Toxin (CT), which binds and crosslinks ganglioside GM1, modulate intracellular calcium in murine neuroblastoma cells via the activation of L-type voltage-dependent calcium channels (VGCC). Therefore, using a fluorimetric approach, we have examined the hypothesis that the pentameric IgM anti-GM1 antibodies, could similarly alter calcium concentration in N18 neuroblastoma cells. Sera with human IgM anti-GM1 antibodies were obtained from 5 patients with LMND and 2 patients with MN. Human IgG anti-GM1, IgM anti-Myelin Associated Glycoprotein (MAG), IgM anti-sulfatide antibodies and lectin peanut agglutinin (PNA), that recognizes specifically the Gal(βl-3)GalNAc epitope, were used as control sera. Direct application of either human IgM anti-GM1 antibodies or the B subunit of CT to N18 neuroblastoma cells induced a sustained influx of manganese ions, as indicated by a quench of the intracellular fura-2 fluorescence. Furthermore, the dihydropyridine L-type channel antagonists completely inhibited the manganese influx, suggesting that it is due to activation of an L-type VGCC. The magnitude of the influx was correlated with antibody titers. None of human IgG anti-GM1, IgM anti-MAG, IgM anti-sulfatide antibodies or PNA induce an ion influx, pointing to the selective participation of the pentameric IgM isotype of anti-GM1 in the modulation of L-type calcium channels opening. Given that L-type calcium channels are present on motor neurons, the modulation of L-type calcium channels by IgM GM1 antisera may have important implications in diseases such as LMND and MN.
We have observed 9 patients (8 men and 1 woman), 58 to 77 years of age with neuropathy with only sensory symptoms and insidious onset. Five of them (4 men and 1 woman) aged 65 to 77 years, had normal ...serum electrophoretic profiles, while the others (all men), 58 to 74 years, had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinical data were consistent with a sensory neuropathy affecting predominantly the kinesthetic sense (position and vibration sensation). The electrophysiological data indicated predominant sensory axonal neuropathy. Morphological data confirmed the primary axonal damage. Western immunoblot showed that the IgG from a patient without MGUS reacted with a 55 kD protein of dorsal root ganglion homogenate. Three of four patients with IgM MGUS were serum reactive against chondroitin sulfate C (ChS-C) in double immunodiffusion. After absorption with ChS-C the monoclonal peak completely disappeared from two patients and was decreased in the third patient. Our data indicate that immunological abnormalities are part of the pathogenesis for a subgroup of chronic neuropathy with only sensory symptoms.
We have studied the pharmacokinetics of an anti transferrin receptor immunotoxin following intrathecal (i.t.) and intravenous (i.v.) bolus inoculation in healthy rats. After i.t. inoculation of 4.9 ...μg transferrin-ricin A-chain (Tfn-RTA) we have measured the immunotoxin concentration in the cerebrospinal fluid (CSF), in the brain tissue and in the peripheral blood. After i.v. administration of 4.9 μg Tfn-RTA the concentration of Tfn-RTA immunotoxin was evaluated in the peripheral blood. We found that the clearance of Tfn-RTA from the CSF is rapid (9.1 μLmin
−1), the immunotoxin then diffuses into the brain tissue and in the peripheral blood where it reaches concentrations below the MTC
50 (Minimum Toxin Concentration 50%). The rate of immunotoxin elimination from the peripheral blood following either i.v. or i.t. administration are similar (k
el = 0.0021 min
−1 vs. 0.0025 min
−1). Thus, in the healthy rat the immunotoxin does not accumulate following i.t. inoculation, reaching non toxic concentrations in the brain tissue and in the peripheral blood, whereas in the CSF as well as at the interface CSF/brain tissue the immunotoxin may reach potentially therapeutic concentrations. In conclusion we believe that the i.t. inoculation of an immunotoxin could be considered a potentially useful route of administration in the treatment of leptomeningeal carcinomatosis.
Sera from eight of 25 patients with chronic sensory neuropathy had high titers of antibodies to sulfatide and chondroitin sulfate C or both. Preclearing of patients' sera with either sulfatide or ...chondroitin sulfate C revealed that in four patients the antisulfatide antibodies crossreacted with chondroitin sulfate C. By indirect immunohistochemistry sera reactive to sulfatide only had a different staining pattern from those reactive to both sulfatide and chondroitin sulfate C. By direct immunohistochemistry we found immunoglobulins bound to nerve fibers only in patients with serum antibodies against both sulfatide and chondroitin sulfate C. Our study provides evidence that antibodies to sulfatide and to chondroitin sulfate C differ in their fine specificity and are present in 30% of patients with chronic sensory neuropathy.
We describe three patients with a sensorimotor axonal polyneuropathy and an IgG M-protein that binds to a 68 kDa axonal protein identified as the low molecular weight neurofilament protein (NF-L). ...The immunological studies revealed that the M-proteins have different target epitopes: one is phosphorylated and the other two are nonphosphorylated. One of the nonphosphorylated epitopes is common to other intermediate filaments, such as desmin and vimentin.
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