50 research outputs found
Multiple sclerosis and human T-cell lymphotropic retroviruses: negative serological results in 135 German patients
No full textSpecificity of intrathecal IgG synthesis for HTLV-1 core and envelope proteins in HAM/TSP
No full textIn patients with human T-cell lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP), we investigated the significance of HTLV-1 specific antibodies in the cerebrospinal fluid (CSF)
Differential diagnosis of HTLV-I-associated myelopathy and multiple sclerosis in Iranian patients
No full textTwo Iranian patients with chronic progressive spastic paraparesis and urinary dysfunction were referred to our hospital with the presumptive diagnosis of multiple sclerosis (MS). Routine CSF analysis and magnetic resonance imaging of the two patients were only partially characteristic of MS. Testing for antibodies to human T-cell leukemia virus type I [HTLV-I] in serum using a radioimmune precipitation assay revealed antibodies to HTLV-I in both patients. The infection with HTLV-I was confirmed by polymerase chain reaction (PCR) and liquid hybridization analysis using primers to the tax/rex region and a corresponding probe, demonstrating proviral DNA in peripheral blood mononuclear cells of both patients. On the basis of these findings demonstrating the presence of proviral HTLV-I DNA in the two Iranian patients, the initial diagnosis of MS was corrected to that of HTLV-I-associated myelopathy (HAM). In contrast, several patients with definite MS (nine from Germany, two from Iran) with a relapsing and remitting form of the disease were tested for HTLV-I infection by enzyme-linked immunosorbent assay and PCR, which yielded negative results. However, the mother of one HAM patient was found to be infected with HTLV-I. To support an association between HTLV-I infection and CNS disease in the two HAM patients, we analyzed the production of specific IgG antibodies within the CNS based on a simple enzyme immunoassay for viral IgG antibodies in CSF and serum. In the two HAM patients there was significant intrathecal antibody production directed against HTLV-I, but this was not found in any of the samples from MS patients.(ABSTRACT TRUNCATED AT 250 WORDS
Immunoadsorption therapy in patients with multiple sclerosis with steroid-refractory optical neuritis
No full textBackground: In multiple sclerosis relapses refractory to intravenous corticosteroid therapy, plasma exchange is recommended. Immunoadsorption (IA) is regarded as an alternative therapy, but its efficacy and putative mechanism of action still needs to be established. Methods: We prospectively treated 11 patients with multiple sclerosis who had optical neuritis and fulfilled the indications for apheresis therapy (Trial registration DE/CA25/00007080-00). In total, five IA treatments were performed using tryptophan-IA. Clinical activity (visual acuity, Expanded Disability Status Scale, Incapacity Status Scale), laboratory values and visual evoked potentials were measured before, during and after IA, with a follow-up of six months. Moreover, proteomic analyses were performed to analyze column-bound proteins as well as corresponding changes in patients' sera. Results: After the third IA, we detected an improvement of vision in eight of eleven patients, whom we termed responders. Amongst these, the mean visual acuity improved from 0.15 +/- 0.12 at baseline to 0.47 +/- 0.32 after the third IA (P = 0.0252) up to 0.89 +/- 0.15 (P < 0.0001) at day 180 +/- 10 after IA. Soluble interleukin-2 receptor decreased in responders (P = 0.03), whereas in non-responders it did not. Proteomic analyses of proteins adsorbed to IA columns revealed that several significant immunological proteins as well as central nervous system protein fragments, including myelin basic protein, had been removed by IA. Conclusions: IA was effective in the treatment of corticosteroid-refractory optic neuritis. IA influenced the humoral immune response. Strikingly, however, we found strong evidence that demyelination products and immunological mediators were also cleared from plasma by IA.Open-Access-Publikationsfonds 201
The specificity of the systemic and intrathecal immune response against the human T-lymphotropic virus 1 (HTLV-1)
No full textDas Retrovirus HTLV-1 induziert eine Myelitis, die HTLV-1 assoziierte Myelopathie / tropische spastische Paraparese (HAM/TSP) genannt wird. Bei dieser chronisch entzündlichen Erkrankung des ZNS infiltrieren HTLV-1 infizierte CD4+ T-Lymphozyten das Rückenmark und exprimieren retrovirale Proteine. Bei HTLV-1 infizierten Patienten wurde die Spezifität der systemischen und intrathe-kalen Immunantwort gegen nicht denaturierte HTLV-1 Proteine untersucht. Durch die Anwendung eines Zell EIA in Kombination mit einem RIPA konnte gezeigt werden, daß bei HAM/TSP Patienten eine intrathekale Synthese gegen mehrere HTLV-1 ko-dierte Proteine vorliegt. An HTLV-1 Infizierten mit und ohne HAM/TSP aus Südjapan wurde die Feinspezifität der antiviralen IgG-Antikörpersynthese analysiert. Hier zeigte sich, daß das Auftreten der Erkrankung bei Virusträgern mit dem Nachweis multipler Antikörperspezifitäten korrellierte, d.h. erkrankte Individuen bildeten Antikörper gegen mehrere lineare B-Zell Epitope. Bei 16 ausgewählten synthetischen Peptiden, die immundominanten Epitopen von HTLV-1 gag und env entsprachen, zeigten HAM/TSP Patienten eine intrathekale Antikörpersynthese gegen durchschnittlich 3,6 Peptide, während nicht erkrankte HTLV-1 seropositive Individuen gegen 0,3 Peptide reagierten.Antikörperspezifitäten gegen ein einzelnes Epitop der HTLV-1 env oder gag Proteine waren nicht mit dem Auftreten der Erkrankung korreliert, sondern die Vielzahl der Spezifitäten. Auch die Analyse der Feinspezifität von IgG-Antikörpern gegen immundominante HTLV-1 tax und rex Sequenzen ergab kein einzelnes B-Zell Epitop, das bei allen HAM/TSP Patienten gefunden wurde. Es galt für HTLV-1 Infizierte mit und ohne HAM/TSP, daß die intrathekal gebildeten Antikörperspezifitäten eine Teilmenge der im Serum nachgewiesen Spezifitäten darstellten. Die HAM/TSP Patienten wiesen allerdings ein deutlich größeres Spektrum der Antikörperspezifitäten auf, sowohl systemisch als auch intrathekal. Bei dem Vergleich von intrathekaler Synthese und den Serumkonzentrationen von IgG-Antikörpern gegen einzelne immun-dominante Peptide zeigte sich ein signifikanter Zusammenhang zwischen der Quan-tität der Serumantikörper und dem Nachweis der intrathekalen Synthese nur bei 2 immundominanten B-Zell Epitopen des HTLV-1 gp21, nicht aber bei 14 anderen unter-suchten B-Zell Epitopen. Patienten mit sogenannten HAM/TSP assoziierten HLA Haplotypen wiesen eine humorale Immunantwort gegen eine größere Anzahl von B-Zell Epitopen auf als HAM/TSP Patienten ohne diese definierten HLA Haplotypen.Erstmals wurden HTLV-1 env gp21 spezifische, HLA DR1 restringierte CD4+ T-Zell Lymphozyten isoliert und charakterisiert. Die immundominanten CD4+ T-Zell Linien erkannten konservierte Sequenzen des HTLV-1 Transmembranglykoproteins gp21 und konnten durch Antigenkonzentrationen im nanomolaren Bereich aktiviert werden.Im Hinblick auf die Immunpathogenese von HAM/TSP zeigten diese Daten, daß sowohl die B-Zell als auch die T-Zell Immunantwort gegen mehrere Epitope gerichtet und daß die oligoklonale B-Zell Aktivierung mit dem Auftreten der Erkrankung assoziiert ist. CD4+ T-Zell Epitope des HTLV-1 gp21 wurden identifiziert, die im Vergleich zu den B-Zell Epitopen überlappende oder benachbarte Sequenzen darstellten. Aufgrund dieser Befunde wurde ein Modell der T-Zell / B-Zell Kooperation zur Aktivierung des Immunsystems bei niedrigen Antigenkonzentrationen vorge-schlagen, um die Persistenz der Immunantwort im ZNS im Verlauf von HAM/TSP zu erklären.The retrovirus HTLV-1 induces a myelitis called HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP). In this chronic inflammatory CNS disease, HTLV-1 infected CD4+ T-lymphocytes infiltrate into the spinal cord and express retroviral proteins.In HTLV-1 infected patients the specificity of the systemic and intrathecal immune response against non-denaturated HTLV-1 proteins was analyzed first. It was shown by using a cell-EIA combined with a RIPA that there is an intrathecal IgG synthesis against several HTLV-1 proteins in HAM/TSP. Second, in HTLV-1 infected humans with and without HAM/TSP the fine specificity of IgG antibodies was screened. Humans with HAM/TSP showed more antibody specificities compared to humans without disease. However, no single specificity was exclusively linked to the disease. Furthermore, immune reactivity to immunodominant tax and rex antibody epitopes was also diverse in HAM/TSP patients. The serum quantity and intrathecal synthesis of specific IgG antibodies did not correlate for 14 env and gag epitopes, however there was a strong correlation for 2 immunodominant env gp21 epitopes. HAM/TSP patients with disease-associated haplotypes showed a larger variety of antibody specificities than patients without.HTLV-1 gp21 specific HLA DR1 restricted CD4+ T-cell lines were isolated and characterized for the first time. Immunodominant helper T-cells recognized highly conserved sequences of the transmembrane protein gp21 in nanomolar concentrations.These data confirmed that the B-cell as well as the T-cell response in HTLV-1 infection is polyclonal. The intrathecal oligoclonal B-cell response however is associated with the disease HAM/TSP. B-cells and T-cells target sequences of HTLV-1 gp21 which are overlapping or close to each other. Following, a model of T-cell / B-cell cooperation is suggested to explain the immune activation at very low levels of antigen and the persistence of the immune response in the CNS in HAM/TSP
Interferon-beta-1b increases serum interleukin-12 p40 levels in primary progressive multiple sclerosis patients
No full textSerum levels of interleukin-12 heterodimer (IL-12p70) and its homodimeric subunit (IL-12p40) were analyzed by enzyme-linked immunosorbent assay in 18 patients with primary progressive multiple sclerosis (MS) during 3 months before and 3 months under treatment with interferon-beta-1b (IFNbeta-1b, Betaferon(TM), eight million units (MIU) every other day subcutaneously). Median IL-12p40 levels in MS patients before treatment (66.5 and 63.9 pg/ml) were not elevated compared to 18 healthy controls. IL-12p40 significantly increased during treatment (P < 0.0001, median 105.3 pg/ml after 1 month and 95.3 pg/ml after 3 months). Detectable serum levels of IL-12p70 before therapy were only found in one patient. IL-12p70 did not increase during treatment. These data show that immunological processes may also play a role in primary progressive MS and that IFNbeta-1b has an immunomodulating effect in this particular MS subtype. (C) 2002 Published by Elsevier Science Ireland Lt
