Myasthenia gravis remission and anti-AChR ab reduction after immunosuppressive and anti-neoplastic therapy in a patient with thymic Hodgkin's disease.
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Antineoplastic Agents↗
Biomedical subjects
R Mantegazza
Publications and source records attributed to R Mantegazza.
Sequential antibodies to potassium channels and glutamic acid decarboxylase in neuromyotonia.
A patient with thymoma-associated neuromyotonia and voltage-gated potassium channel (Kv1.2 and Kv1.6) antibodies by immunoprecipitation and rat brain immunolabeling was treated successfully with immunoadsorption and cyclophosphamide. Curiously, glutamic acid decarboxylase antibodies, absent at onset, appeared later. Stiff-person syndrome was absent, but fast blink reflex recovery suggested enhanced brainstem excitability. The range of antibodies produced in thymoma-associated neuromyotonia is richer, and the timing of antibody appearance more complex, than previously suspected.
Adult↗
Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement.
Rasmussen encephalitis (RE) is a rare but severe immune-mediated brain disorder leading to unilateral hemispheric atrophy, associated progressive neurological dysfunction and intractable seizures. Recent data on the pathogenesis of the disease, its clinical and paraclinical presentation, and therapeutic approaches are summarized. Based on these data, we propose formal diagnostic criteria and a therapeutic pathway for the management of RE patients.
Adolescent↗
Experience with immunomodulatory treatments in Rasmussen's encephalitis.
The authors investigated immunomodulatory treatments in 15 patients with Rasmussen encephalitis (RE) (14 with childhood and one with adolescent onset RE). Positive time-limited responses were obtained in 11 patients using variable combinations of corticosteroids, apheresis, and high-dose IV immunoglobulins. Although surgical exclusion of the affected hemisphere is the only treatment that halts disease progression, immunomodulation can be considered when early surgery is not feasible, in late-onset patients with slower disease progression, and in the few cases of bilateral disease.
Adolescent↗
Similar binding to glutamate receptors by Rasmussen and partial epilepsy patients' sera.
Immunoreactivity of sera from patients with Rasmussen encephalitis (RE) and patients with partial epilepsy (PE) was analyzed by immunohistoblot on rat brain sections and the staining pattern compared with that obtained with antibodies to a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and NMDA receptors. Staining for anti-glutamate receptor 3 (GluR3) was found in 82% of patients with RE and 64% of patients with PE. Histoblot analysis showed a positive staining in GluR3- and NMDA-specific regions of rat brain, providing a comprehensive CNS immunolocalization.
Animals↗
Analysis of antibody gene rearrangement, usage, and specificity in chronic focal encephalitis.
BACKGROUND: Autoantibodies have been implicated in the development of chronic focal encephalitis (CFE) or Rasmussen's disease, a progressive and intractable form of epilepsy characterized by uncontrollable unilateral focal seizures, brain atrophy, and inflammation. OBJECTIVE: To investigate the origin and characteristics of the B cell population that trigger or sustain brain inflammation in patients with CFE. METHODS: The authors used immunoglobulin (Ig) complementary determining region 3 (CDR3)-size spectratyping and DNA sequencing to examine the rearranged IgG heavy chain (IgGH) transcript repertoire in resected brain samples from four patients with CFE. They also performed Western blotting on human and rat brain homogenates and immunostaining on a human neuronal cell line to test the reactivity of sera from patients with CFE. RESULTS: The authors observed substantial perturbations from the normal, unstimulated repertoire of immunoglobulin genes. Sequencing of randomly selected clones confirmed the restricted profile and provided evidence for somatic mutation patterns characteristic of antigen-specific stimulation. They also observed IgGVH-CDR3 sequence diversity among patients. When sera were assayed from patients with CFE for specificity against rat and human brain homogenates, heterogeneous reactivity patterns were detected among patients. Immunostaining of postmitotic human neuronal cells demonstrated reactivity of some patients' sera against neural antigens. CONCLUSIONS: These findings support an important role for clonally expanded B lymphocytes in some forms of epilepsy, but also indicate a wide spectrum of reactivity characteristic of antigenic heterogeneity.
Animals↗
Is the CACNA1A gene involved in familial migraine with aura?
The discovery of mutations in the neural calcium channel (CACNA1A) gene in familial hemiplegic migraine (FHM), variant of migraine with aura, led to the suggestion that this gene might be involved in familial migraine with aura (FMA). We investigated whether the mutations in FHM are present in FMA patients, analyzing genomic DNA by PCR, single stranded conformation polymorphism, sequencing and restriction enzyme. No mutations were found. A known polymorphism (5682-14C>T) was found in exon 36. These findings suggest that the mutations found in FHM and the other known mutations of the CACNA1A gene are not the genetic basis of FMA. Genetic alterations in FMA patients may be localized on chromosome 19 but not in the CACNA1A exons we investigated.
Adult↗
GluR3 antibodies: prevalence in focal epilepsy but no specificity for Rasmussen's encephalitis.
Eight patients with Rasmussen's encephalitis, 40 patients with noninflammatory focal epilepsy, 104 patients with various neurologic diseases, and 16 healthy donors were tested for the prevalence of antibodies against the GluR3 receptor in serum and CSF. Reactivities against different peptides derived from various portions of this glutamate receptor subtype were detectable in a significantly higher number of patients with focal epilepsy than in those with other neurologic diseases, but they were not specific for the diagnosis of Rasmussen's encephalitis.
Adolescent↗
Labeling of rat neurons by anti-GluR3 IgG from patients with Rasmussen encephalitis.
The authors report the immunocytochemical localization in rat brain of affinity-purified anti-GluR3 (glutamate receptor) antibodies from two patients with Rasmussen encephalitis (RE) and from immunized rabbits. The distribution of immunolabeling was similar using antibodies from rabbits and patients with RE. No electrophysiologic responses were elicited from acutely dissociated kainate-responsive neurons isolated from rat brain when these antibodies were applied. These findings show that anti-GluR3 antibodies purified from patients with RE bind to specific regions of the CNS but do not act through an excitotoxic mechanism.
Animals↗
Anti-neuronal nicotinic receptor antibodies in MG patients with thymoma.
We tested 24 MG patients with thymoma (11 invasive) for the presence of anti-neuronal nicotinic receptor subtype antibodies and found that none had antibodies against the alpha 7-containing subtype, and only one (with invasive thymoma) had antibodies directed against the alpha 3-containing subtype. In this patient, the anti-alpha 3 antibodies recognized the extracellular part of the alpha 3 subunit. They developed later than the anti-alpha 1 muscle antibodies, with their titer increasing during the illness, while that of the anti-alpha1 muscle antibody decreased. Our data suggest that there is no correlation between the presence of anti-alpha 3 antibodies and thymoma.
Autoantibodies↗
Antibodies against neuronal nicotinic receptor subtypes in neurological disorders.
Patients with myasthenia gravis (MG) have antibodies to the muscle nicotinic acetylcholine receptor (mAChR) which are responsible for their muscle weakness: but some patients with MG and other neuroimmunological disorders have autonomic symptoms. We characterised the neuronal forms of AChRs (nAChRs) into two neuroblastoma cell lines and developed immunoprecipitation assays to test for antibodies to the alpha7- and alpha3-containing nAChR subtypes, present in the autonomic ganglia. We then tested 70 sera samples from MG patients, 38 from subjects with other neurological diseases, and 30 from healthy individuals, for antibodies to these two forms of neuronal AChR subtypes. We used the alpha7 subtype extracted from the human neuroblastoma IMR32 cell line labeled with 125IalphaBungarotoxin (alphaBgtx), and the alpha3-containing subtype extracted from the human neuroblastoma SY5Y cell line labeled with 3H-Epibatidine (Epi). Nine subjects (five MG, one GBS, one CIPD and two LEMS) were positive for the alpha7 subtype; and four for the alpha3-containing subtype (two MG patients, one LEMS and the same GBS patient). None of the MG patients with undetectable levels of antibodies against muscle AChR were positive. The patients with serum antibodies to alpha7 or alpha3-containing neuronal AChRs showed a range of clinical features including autonomic symptoms and thymoma in two MG patients. These results indicate that patients with MG and other immune-mediated disorders can have antibodies to neuronal AChRs, and that these may contribute to the clinical characteristics of the diseases.
Antibodies↗
Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation.
The idiopathic inflammatory myopathies are characterized by antibody- or cell-mediated immune response against unknown muscle tissue antigens. In these diseases a cellular infiltrate, composed of T and B lymphocytes, macrophages and NK cells, may invade muscle tissue with a gradient from the perivascular space to the endomysial compartment. Muscle cells may be actively involved in the processes of mononuclear cell recruitment and activation from the blood stream to the areas of inflammation. In order to verify this hypothesis, cultured human myoblasts were tested for their capacity to express different pro-inflammatory cytokines [IL-1alpha, IL-1beta, IL-6 and tumor necrosis factor (TNF)-alpha] and chemokines (IL-8, MCP-1 and RANTES) at the mRNA level and protein secretion, in the presence of the pro-inflammatory cytokines IFN-gamma and TNF-alpha alone or in combination. We confirmed that human myoblasts expressed IL-1alpha and IL-6 constitutively, while IL-1beta and TNF-alpha are detected only after treatment with pro-inflammatory cytokines; moreover, we observed that TNF-alpha was expressed on an autocrine fashion by myoblasts. IL-8 and RANTES were expressed constitutively while MCP-1 after proper induction. These molecular data were further confirmed by specific ELISA in the supernatant from cultured myoblasts. Our results underline the importance of human myoblasts in the recruitment of leukocytes from the blood stream and, most probably, in the cross-talk between infiltrating inflammatory cells and muscle cells, creating the conditions for a chronic inflammation. Moreover, the capacity of muscle cells to behave as cells of the immune system has to be kept in mind, also in view of i.m. vaccination and use of molecular engineered myoblasts as vehicles in gene therapy.
Cells, Cultured↗
Increased expression of beta-chemokines in muscle of patients with inflammatory myopathies.
Idiopathic inflammatory myopathies (IIM) are muscle diseases of autoimmune pathogenesis characterized by mononuclear cell infiltration within muscle tissue. Since immune cell homing and accumulation at the site of antigenic challenge is usually mediated by chemokines, we evaluated the expression of 2 beta-chemokines--monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha)--by immunohistochemistry and polymerase chain reaction in muscles of polymyositis, inclusion body myositis, and dermatomyositis patients, and related their expression to immunopathological alterations in muscle. MCP-1 and MIP-1alpha transcripts were detected by PCR in all IIM muscles, but not in controls. By immunohistochemistry, the chemokines were found in all IIM muscle sections located in infiltrating inflammatory cells and also in neighboring extracellular matrix. The extent to which extracellular matrix was filled by each chemokine differed in each disease. In view of the known ability of chemokines to bind extracellular matrix and their possible synthesis by extracellular matrix components, we suggest that chemokine storage in the extracellular matrix can act as a microenvironmental factor amplifying lymphocyte activation and migration, thereby maintaining the autoimmune attack against unknown muscle antigens.
Chemokine CCL2↗
Clinical features and anti-neural reactivity in neuropathy associated with IgG monoclonal gammopathy of undetermined significance.
Neuropathy has been frequently reported in patients with IgG monoclonal gammopathy of undetermined significance (MGUS) but it is still unclear whether this association has clinical or pathogenetic relevance. In order to clarify the possible role of IgG MGUS in the neuropathy we correlated the clinical and electrophysiological features of the neuropathy with the duration and anti-neural activity of the M-protein in 17 patients with neuropathy and IgG MGUS. Ten patients (59%) had a chronic demyelinating neuropathy clinically indistinguishable from chronic inflammatory demyelinating polyneuropathy (CIDP) while 7 (41%) had a predominantly sensory axonal or mixed neuropathy. In 80% of patients in the CIDP-like and 28% in the sensory group the IgG M-protein became manifest several months to years after onset of the neuropathy. Antibodies to one or more neural antigens (including tubulin, a 35KD P0-like nerve myelin glycoprotein, GD1a, GM1 and chondrotin sulfate C) were found in 40% of patients with CIDP-like and 43% with sensory neuropathy but also in 37% patients with IgG MGUS without neuropathy. Neuropathy associated with IgG MGUS is probably less heterogeneous than previously considered suggesting that this association may not be merely casual. The evidence for primary pathogenetic role of IgG M-proteins in the neuropathy remains however elusive.
Adult↗
Identification of three novel mutations in the major human skeletal muscle chloride channel gene (CLCN1), causing myotonia congenita.
Myotonia congenita (MC) is a genetic disease characterized by mutations in the CLCN1 gene (OMIM*118425) encoding the skeletal muscle voltage-gated chloride channel (ClC-1). Autosomal dominant and recessive forms are observed, characterized by impaired muscle relaxation after forceful contraction (myotonia), which is more pronounced after inactivity and improves with exercise. We report three novel and one known mutations of the CLCN1 gene in four unrelated MC families. In two families the mutations were missense: 803C>T (T268M) and 1272C>G (I424M) in exons 7 and 12, respectively. The third was a splice mutation in intron 5 (696+2T>A), which induced a frame shift with a stop codon in exon 6 (fs213X). In the fourth family the previously-reported missense mutation 689G>A (G230E) was found. We also report two known polymorphisms: 261C>T (T87T) and 2154T>C (D718D) in exons 2 and 17 of two MC families; also found in 14 (33%) and 28 (67%) of 42 healthy controls, respectively. These findings expand our knowledge of mutations responsible for myotonia congenita, reducing the proportion of MC patients in whom genetic alterations have not been found.
Chloride Channels↗
Transforming growth factor-beta1 and fibrosis in congenital muscular dystrophies.
We evaluated transforming growth factor-beta1 (TGF-beta1) expression in the muscle of four laminin alpha2-negative, four laminin alpha2-positive and seven partial laminin alpha2-deficient congenital muscular dystrophy (CMD) patients, and compared it to Duchenne muscular dystrophy (DMD) patients and controls. TGF-beta1 mRNA levels in skeletal muscle from laminin alpha2-negative and laminin alpha2-positive CMD patients were significantly greater than in controls (P < 0.05 and P < 0.005, respectively), while in partial laminin alpha2-deficient muscular dystrophy patients the amount was not significantly higher than in controls (P > 0.1). The TGF-beta1 values were lower than those found in DMD, although the extent of fibrosis was greater in CMD than in DMD and controls. Our findings suggest that TGF-beta1 is involved in CMD muscle fibrosis, but differently from what we observed in DMD muscles as it seems not to be the major player in connective tissue proliferation.
Adult↗
Oral administration of an immunodominant T-cell epitope downregulates Th1/Th2 cytokines and prevents experimental myasthenia gravis.
The mucosal administration of the native antigen or peptide fragments corresponding to immunodominant regions is effective in preventing or treating several T cell-dependent models of autoimmune disease. No data are yet available on oral tolerance with immunodominant T-cell peptides in experimental autoimmune myasthenia gravis (EAMG), an animal model of B cell-dependent disease. We report that oral administration of the T-cell epitope alpha146-162 of the Torpedo californica acetylcholine receptor (TAChR) alpha-subunit suppressed T-cell responses to AChR and ameliorated the disease in C57Bl/6 (B6) mice. Protection from EAMG was associated with reduced serum Ab's to mouse AChR and reduced AChR loss in muscle. The effect of Talpha146-162 feeding was specific; treatment with a control peptide did not affect EAMG manifestations. The protective effect induced by peptide Talpha146-162 was mediated by reduced production of IFN-gamma, IL-2, and IL-10 by TAChR-reactive cells, suggesting T-cell anergy. TGF-beta-secreting Th3 cells did not seem to be involved in tolerance induction. We therefore demonstrate that feeding a single immunodominant epitope can prevent an Ab-mediated experimental model of autoimmune disease.
Administration, Oral↗
Identification of a novel HLA class II association with DQB1*0502 in an Italian myasthenic population.
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Adult↗