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Biomedical subjects

N Goebels

Publications and source records attributed to N Goebels.

At least 19 recordsLinked to original sources
PubMed2004

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Clinical Trials as Topic↗
PubMed2002

[Multiple sclerosis. Therapeutic nihilism is the wrong approach here].

The standard treatment for acute multiple sclerosis relapses continues to be the intravenous administration of high-dose methylprednisolone. For prophylactic purposes, immunomodulatory therapy with interferon beta or glatiramer acetate, immunoglobulins or azathioprine. Studies have shown that interferon beta not only reduces the frequency of relapses by one-third, but also significantly delays the second relapse, provided it is administrated early, that is, immediately following the first relapse. The reduction in the patient's quality of life caused by the illness can be appreciably improved by a whole series of symptomatic treatments. The ideal situation is a cooperative effort by an interdisciplinary team.

Clinical Trials as Topic↗
PubMed2001

Extensive myelitis associated with Mycoplasma pneumoniae infection: magnetic resonance imaging and clinical long-term follow-up.

Myelitis is a severe neurological complication associated with Mycoplasma pneumoniae infections. Little is known about the extent and the reversibility of this myelitis, and reports on the value of spinal imaging are inconclusive. To obtain more information on the diagnostic and prognostic value of spinal magnetic resonance imaging (MRI) we studied the clinical course and MRI long-term follow-up of two patients with extensive myelitis associated with M. pneumoniae infection. The neuroradiological findings were correlated with the clinical extent of the spinal syndrome, but their reversibility preceded clinical improvement. These preliminary findings indicate that follow-up spinal MRI may give valuable prognostic information in cases of M. pneumoniae associated myelitis and warrant further more systematic studies to ascertain the relationship between spinal MRI findings and prognosis.

Adult↗
PubMed2001

Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response.

Chronic intrathecal immunoglobulin (Ig) production is a hallmark of multiple sclerosis characterized by the presence of oligoclonal IgGs and, in addition, polyspecific recognition of different pathogens such as measles, rubella and herpes zoster virus. While the antigen specificity of the oligoclonal IgGs in multiple sclerosis is largely unknown, the oligoclonal IgGs arising during CNS infectious diseases are reactive against the specific pathogen. Recently, a link between Chlamydia pneumoniae and multiple sclerosis has been claimed. To test the possible role of C. pneumoniae in multiple sclerosis, we analysed (i) whether there is intrathecal IgG production against C. pneumoniae in multiple sclerosis and (ii) if the oligoclonal IgGs in the CSF of multiple sclerosis patients recognize C. pneumoniae. By studying paired serum-CSF samples from 120 subjects (definite multiple sclerosis, 46; probable multiple sclerosis, 12; other inflammatory neurological diseases, 35; other neurological diseases, 27) by enzyme-linked immunosorbent assay, we found that 24% of all patients with definite multiple sclerosis, but only 5% of patients with other inflammatory or non-inflammatory diseases, produced IgGs specific for C. pneumoniae intrathecally (definite multiple sclerosis versus other inflammatory neurological diseases: P = 0.027). The presence of intrathecal IgGs to C. pneumoniae was independent of the duration of disease and relatively stable over time. The major CSF oligoclonal IgG bands from multiple sclerosis patients with an intrathecal Ig production to C. pneumoniae did not react towards purified elementary bodies and reticulate bodies of C. pneumoniae on affinity-mediated immunoblot following isoelectric focusing (IEF-western blots). In contrast, the IgGs in the CSF of control patients with neuroborreliosis strongly reacted with their specific pathogen, Borrelia burgdorferi, by IEF-western blot analysis. Concomitant analysis of the CSF of 23 patients with a nested polymerase chain reaction for C. pneumoniae was negative in all cases. Together, our findings strongly suggest that the immune response to C. pneumoniae is part of a polyspecific intrathecal Ig production, as is commonly observed with other pathogens. This argues against a specific role for C. pneumoniae in multiple sclerosis.

Animals↗
PubMed2000

Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction.

Clonal composition and T cell receptor (TCR) repertoire of CD4(+) and CD8(+) T cells infiltrating actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented resolution at the level of single cells. Individual CD4(+) or CD8(+) T cells were isolated from frozen sections of lesional tissue by micromanipulation and subjected to single target amplification of TCR-beta gene rearrangements. This strategy allows the assignment of a TCR variable region (V region) sequence to the particular T cell from which it was amplified. Sequence analysis revealed that in both cases investigated, the majority of CD8(+) T cells belonged to few clones. One of these clones accounted for 35% of CD8(+) T cells in case 1. V region sequence comparison revealed signs of selection for common peptide specificities for some of the CD8(+) T cells in case 1. In both cases, the CD4(+) T cell population was more heterogeneous. Most CD4(+) and CD8(+) clones were represented in perivascular infiltrates as well as among parenchymal T cells. In case 2, two of the CD8(+) clones identified in brain tissue were also detected in peripheral blood. Investigation of the antigenic specificities of expanded clones may help to elucidate their functional properties.

Adult↗
PubMed2000

Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: epitope spreading versus clonal persistence.

Autoantigen-specific T-lymphocytes are present in patients with autoimmune disease and in normal subjects. Little is currently known about the temporal variation (dynamics) of the immune repertoire of these autoreactive T cells. We analysed the long-term variation of the immune repertoire of T cells specific for myelin basic protein (MBP) in five untreated patients with multiple sclerosis and four normal control subjects over a mean observation period of 6 years. MBP-specific CD4(+) T-cell lines were selected with purified human MBP, and their epitope specificity was mapped with overlapping synthetic peptides. Three distinct patterns of repertoire development were observed. (i) Two patients and three control subjects maintained a broad epitope response with fluctuations over time. (ii) Two patients initially showed a focused response that broadened over the course of 6 years; this finding could be described as intramolecular epitope spreading. (iii) In one patient and one control subject, a strikingly focused response, which was directed to a cluster of nested epitopes in the MBP region 83-102, persisted over time. T-cell receptor Vbeta sequence analysis allowed us to trace individual clones of MBP-specific T cells for up to 7 years in the peripheral circulation in four of the five patients and three of the four controls, suggesting that the long-term persistence of MBP-specific T-cell clones is a common feature of the T-cell repertoire not unique to multiple sclerosis. The persisting MBP-specific T-cell clones were not detectable in the blood of one of the patients by complementarity-determining region (CDR)-3 spectratyping, indicating that their frequency does not exceed 1 in 5000 T cells. The temporal characteristics of the MBP-specific T-cell repertoire described here are relevant to therapeutic strategies targeting autoantigen-specific T cells in multiple sclerosis and other autoimmune diseases.

Adult↗
PubMed2000

Dementia associated with vitamin B(12) deficiency: presentation of two cases and review of the literature.

Vitamin B(12) deficiency has long been associated with a wide variety of hematological, neurological, and psychiatric disorders. The role of vitamin B(12) deficiency as one of the few treatable causes of dementia, however, is still controversial. The authors report on 2 elderly patients suffering from cognitive impairment and psychotic symptomatology probably related to cobalamin deficiency, who showed improvement after parenteral vitamin B(12) substitution. The literature concerning the pathophysiology and the diagnostic and therapeutic aspects of cobalamin deficiency is reviewed.

Aged↗
PubMed1999

[Interferon beta-1b for treatment of secondary chronic progressive multiple sclerosis].

Several phase III studies have proven that the beta-interferons have positive effects on the number and severity of acute exacerbations of relapsing remitting multiple sclerosis. Recently the first study on the effectiveness of interferon beta-1b in secondary progressive multiple sclerosis was published. In a multicenter, double-blind, randomized, Placebo-controlled study 718 patients with secondary progressive multiple sclerosis and an expanded disability status scale (EDSS) value between 3.0 and 6.5 were treated with either 8 Mio.interferon beta-1b or Placebo subcutaneously every second day for two to three years. The primary study end-point was the time until confirmed progression of the disease as signified by a one point increase of the EDSS value (for initial EDSS values between 3.0 and 5.5) or 0.5 point increase when the initial EDSS value was between 6.0 and 6.5. After two years an interim analysis showed a highly significant difference in delay of disease progression by nine to twelve months for the treatment group (p = 0.0008). This means that interferon beta-1b is the first recombinant beta-interferon to be shown effective in the treatment of secondary progressive multiple sclerosis.

Adjuvants, Immunologic↗
PubMed1999

[Intima media thickness in patients with vertebrobasilar and carotid stenosis/occlusions].

AIM: The purpose of this study was to investigate the degree of atherosclerosis in patients with stenoses or occlusions in the vertebrobasilar system (VBS) and the carotid system (CS). METHOD: The Intima-Media-Thickness (IMT) and the diameter of the common carotid artery (CCA) (as parameters of the proliferative and dilatative form of atherosclerosis) were measured on both sides on areas of vessel wall without stenoses and plaques. We examined of the neck 134 people, including 32 normal healthy counds, 57 patients with stenoses or occlusions in the CS and 16 patients with macroangiopathy exclusively in the VBS (following doppler- and duplex sonographical criteria). RESULTS: In control persons, a IMT of 0.67 +/- 0.2 mm and a CCA-diameter of 5.8 +/- 1.2 mm was found. Patients with CS-macroangiopathy exhibited a statistically significant increase in IMT with 0.97 +/- 0.2 mm (p < 0.001) and dilatation of the CCA (6.6 +/- 1.2 mm, p < 0.01). In comparison to the controls we also found a significant increase in IMT (0.86 +/- 0.2 mm, p < 0.001) and in diameter (6.8 +/- 0.9 mm, p < 0.01) in patients with VBS-macroangiopathy. There was no significant difference between both groups, despite a tendency of less severe changes in patients suffering from VBS-macroangiopathy. Patients with diabetes (1.1 +/- 0.2 mm, p < 0.001), with hypertension (0.99 +/- 0.2 mm, p < 0.05) and with coronary heart disease (0.96 +/- 0.2 mm, p < 0.05) showed a significant increase in IMT. CONCLUSION: Parameters of generalized atherosclerosis do not significantly differ between patients with stenoses or occlusions in the VBS and patients with changes in the CS and are correlated to the classical risk factors.

Aged↗
PubMed1998

Human muscle cells express a functional costimulatory molecule distinct from B7.1 (CD80) and B7.2 (CD86) in vitro and in inflammatory lesions.

The B7 family of costimulatory molecules likely includes members distinct from B7.1 (CD80) and B7.2 (CD86). After stimulation with IFN-gamma or TNF-alpha, human myoblasts selectively express BB-1, but not B7.1 or B7.2. BB-1 is detected by anti-BB-1, a mAb cross-reacting with B7.1 (but not B7.2) and an as yet undefined costimulatory molecule. The absence of B7.1 and B7.2 in BB-1-positive myoblasts was confirmed by RT-PCR. The molecule detected by anti-BB-1 is functional, because anti-BB-1 mAb and CTLA4Ig (but not anti-B7.1- or anti-B7.2-specific mAbs) completely inhibit Ag presentation by cytokine-induced myoblasts to HLA-DR-matched Ag-specific CD4+ T cell lines. Stimulation of myoblasts with IL-4 induces B7.1 and B7.2, as well as BB-1, but with different time kinetics. Stimulation of CD40-positive myoblasts with anti-CD40 mAb selectively induces BB-1, whereas stimulation with CD40L-transfected mouse L cells induces BB-1 and B7.1, with different kinetics. To assess whether BB-1 is expressed in muscle tissue, we investigated 23 muscle biopsy specimens from patients with polymyositis, dermatomyositis, inclusion body myositis, Duchenne muscular dystrophy, and nonmyopathic controls by immunohistochemistry and confocal laser microscopy. We found that, in all inflammatory myopathy cases, but not in normal muscle, many muscle fibers strongly react with anti-BB-1. In contrast, muscle fibers did not react with B7.1- or B7.2-monospecific mAbs in any of the pathologic specimens or in normal muscle. Our results demonstrate that human muscle cells can be induced to selectively express BB-1, a functional costimulatory molecule distinct from B7.1 and B7.2. This molecule may play an important role in the immunobiology of muscle.

Abatacept↗
PubMed1997

Cellular immune mechanisms in inflammatory myopathies.

The inflammatory myopathies include dermatomyositis, polymyositis, and inclusion body myositis. In dermatomyositis, muscle fiber injury is secondary to an antibody- or immune-complex-mediated immune response against a vascular-endothelial component. In polymyositis and inclusion body myositis, CD8+ T cells and macrophages invade and eventually destroy initially nonnecrotic muscle fibers. The autoaggressive T cells have the phenotype of activated (HLA-DR+) memory (CD45RO+) cells. T-cell receptor analyses indicate that the autoaggressive T cells are oligoclonal. In inflammatory lesions, muscle fibers express various cytoplasmic and surface molecules that are not detectable in normal fibers. These molecules, which include HLA class I antigens, heat-shock proteins, adhesion molecules, and Fas, are probably induced by locally secreted cytokines. The autoaggressive CD8+ T cells harbor granules containing perforin that aggregate near the contact zone with the target muscle fiber. This is consistent with a perforin- and secretion-dependent mechanism of muscle fiber injury. Many invaded muscle fibers also express the Fas "death receptor," but signs of apoptosis are absent.

Cell Adhesion Molecules↗
PubMed1996

Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.

Polymyositis (PM) and dermatomyositis (DM) are the prototypical inflammatory diseases of skeletal muscle. In PM, CD8+ T cells invade and destroy muscle fibers, whereas humoral effector mechanisms prevail in DM. We studied the expression of the cytotoxic mediator perforin in inflammatory cells in PM and DM muscle by semiquantitative PCR, immunohistochemistry and confocal laser microscopy. Similar levels of perforin mRNA were expressed in PM and DM, and abundant perforin-expressing CD3+CD8+ and CD3+ CD4+ T cells were observed in both diseases. However, there was a striking difference in the intracellular localization of perforin. In DM, perforin was distributed randomly in the cytoplasm of the inflammatory T cells. In contrast, 43% of the CD8+ T cells that contacted a muscle fiber in PM showed perforin located vectorially towards the target muscle fiber. The results suggest (a) that the random distribution of perforin in the cytoplasm of muscle-infiltrating T cells observed in DM reflects nonspecific activation, and (b) that the vectorial orientation observed only in PM reflects the specific recognition via the T cell receptor of an antigen on the muscle fiber surface, pointing to a perforin- and secretion-dependent mechanism of muscle fiber injury.

Base Sequence↗
PubMed1995

[Effect of muscular work on the myosonogram].

AIM: The purpose of this study was to examine quantitatively the change of muscle thickness and echo intensity caused by muscle exercise in healthy persons. METHOD: 16 healthy volunteers (7 women, 9 men), aged 23 to 37 years, underwent static exercises of the rectus abdominis, rectus femoris/vastus intermedius, and tibialis anterior muscles. In addition, the rectus femoris/vastus intermedius muscles were exercised dynamically. Thicknesses of these muscles were measured before and during/after exercise using the electronic caliper and computer-assisted gray-scale analysis of the echo signals. RESULTS: Short, maximal isometric contraction resulted in an increase of thickness by 5 to 18% depending on the examined muscle (p < 0.01). The echo intensity of the rectus femoris and vastus intermedius muscles decreased significantly (-8% and -26%, p < 0.01). The increase of muscle thickness immediately after isometric exercise for up to 90 s was significantly correlated to the duration of contraction (r = 0.26 to 0.49, p < 0.05). Muscle echo intensities did not significantly correlate with the duration of the contraction. After dynamic exercise on a bicycle ergometer both thickness of the rectus femoris/vastus intermedius muscles (+12.5%, p < 0.01) and echo intensity of the vastus intermedius muscle increased (+19.5%, p < 0.01). The change of echo intensity of the vastus intermedius muscle after static and dynamic exercise was significantly different (-26% vs. +18%, p < 0.001). CONCLUSION: Muscle thickness increases during and after static as well as dynamic exercise. Echo intensity may be unchanged, decreased or increased, depending on the exercised muscle and mode of exercise.

Adult↗
PubMed1995

The role of autoimmune T lymphocytes in the pathogenesis of multiple sclerosis.

Autoimmune T cells play a key role as regulators and effectors of autoimmune disease. In multiple sclerosis (MS), activated T cells specific for myelin components or other locally expressed autoantigens enter the CNS and recognize their antigen(s) on local antigen-presenting cells. After local stimulation, the T cells produce a plethora of cytokines and inflammatory mediators that have profound effects on the local cellular environment, induce and recruit additional inflammatory cells, and contribute to myelin damage. An increasingly detailed knowledge of these processes will greatly facilitate the development of new immunotherapies. This article focuses on the role of T cells in MS. We provide a brief overview of the principles of T-cell immunology, discuss the experimental techniques available for studying T cells, address the role of T cells in the pathogenesis of MS, and highlight modern concepts for immunotherapy.

Amino Acid Sequence↗
PubMed1993

Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones.

The human T cell response to the myelin basic protein (MBP) has been studied with respect to T cell receptor (TCR) usage, HLA class II restriction elements, and epitope specificity using a total of 215 long-term MBP-specific T cell lines (TCL) isolated from the peripheral blood of 13 patients with multiple sclerosis (MS) and 10 healthy donors. In most donors, the anti-MBP response was exceedingly heterogeneous. Using a panel of overlapping synthetic peptides spanning the entire length of human MBP, at least 26 epitopes recognized by human TCL could be distinguished. The MBP domain most commonly recognized was sequence 80-105 (31% of MS TCL, and 24% of control TCL). Sequence 29-48 was recognized more frequently by control-derived TCL (24%) than by TCL from MS patients (5%). The MBP epitopes were recognized in the context of DRB1 *0101, DRB5*0101, DRB1*1501, DRB1*0301, DRB1*0401, DRB1*1402, and DRB3*0102, as demonstrated using a panel of DR gene-transfected L cells. The TCR gene usage was also heterogeneous. V beta 5.2, a peptide of which is currently being used in a clinical trial for treatment of MS patients, was expressed by only one of our TCL. However, within this complex pattern of MBP-specific T cell responses, a minority of MS patients were found to exhibit a more restricted response with respect to their TCL epitope specificity. In these patients 75-87% of the TCL responded to a single, patient-specific cluster of immunodominant T cell epitopes located within a small (20-amino acid) domain of MBP. These nested clusters of immunodominant epitopes were noted within the amino acids 80-105, 108-131, and 131-153. The T cell response to the immunodominant epitopes was not monoclonal, but heterogeneous, with respect to fine specificity, TCR usage, and even HLA restriction. In one patient (H.K.), this restricted epitope profile remained stable for > 2 yr. The TCR beta chain sequences of TCL specific for the immunodominant region of HK are consistent with an oligoclonal response against the epitopes of this region (80-105). Further, two pairs of identical sequences were established from TCL generated from this patient at different times (June 1990 and June 1991), suggesting that some TCL specific for the immunodominant region persisted in the peripheral repertoire. The possible role of persistent immunodominant epitope clusters in the pathogenesis of MS remains to be established.

Adult↗
PubMed1993

Cellular mechanisms in inflammatory myopathies.

Cell-mediated immune mechanisms play a prominent role in inclusion body myositis (IBM) and polymyositis (PM). In both IBM and PM, CD8+ cytotoxic T cells expressing the alpha/beta receptor surround and focally invade non-necrotic muscle fibres. This lesion can be considered the hallmark of cell-mediated myocytotoxicity. Essentially the same type of lesion is observed in a variant form of PM, in which CD4-CD8- T cells bearing the gamma/delta receptor surround and invade non-necrotic muscle fibres. In both IBM and PM, all of the invaded and some of the non-invaded muscle fibres strongly express HLA class I molecules. This is consistent with the hypothesis that the CD8+ autoinvasive cytotoxic T cells recognize antigenic peptide(s) bound to HLA class I molecules on the muscle fibre surface. According to the rules of antigen processing, these peptides derive from proteins synthesized in the muscle fibre. Theoretically, the proteins could be viral components or self proteins that resemble viral components. Most attempts to demonstrate viral antigens or genome in muscle fibres have failed. On the other hand, the majority of HLA class I molecules expressed on the surface of any cell are loaded with endogenous self peptides. It seems plausible that muscle-specific autoantigen(s) could be recognized by autoaggressive T cells in the inflammatory myopathies, but the precise reasons for the recognition event remains elusive. Recently, it has become possible to study the interactions of muscle cells and cytotoxic effector cells in vitro. Myoblasts and myotubes can be induced to express a variety of immunologically relevant histocompatibility and cell adhesion molecules. Myotubes are highly susceptible to lysis by allogeneic CD8+ cytotoxic T cells sensitized against HLA class I alloantigens. Interestingly, cultured myotubes are also susceptible to lysis by antigen-nonspecific natural killer cells. Further, myoblasts stimulated by IFN gamma express HLA class II and acquire the full potential to process and present complex protein antigens to CD4+ T cells. This may indicate that myoblasts can actively participate in local immune reactions by presenting (auto) antigens to helper/inducer T cells. In different inflammatory myopathies, CD8+ T cells have been expanded directly from muscle and their interactions with autologous myotubes have been investigated in vitro. In several cases, a low but significant autoreactive cytotoxic effect was observed. This is consistent with the hypothesis that some cytotoxic effector T cells recognize an autoantigen on myotubes. One of the major goals for future studies is to define the autoantigens that are relevant in the pathogenesis of the inflammatory myopathies.

Antibody-Dependent Cell Cytotoxicity↗