CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity? (65/830)

For most autoimmune disorders, the pattern of inheritance is very complex. The major histocompatibility complex (MHC) gene complex has been implicated as the major genetic component in the predisposition to these diseases but other genes are likely to be involved. Based on function and experimental data, the gene encoding cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. In this review, we critically evaluate the evidence for pathogenetical involvement of CTLA-4 in the different autoimmune diseases with focus on the possible role of genetic variation of the CTLA4 locus.  (+info)

Rapidly progressive polymyositis with elevated antiacetylcholine receptor antibody activity. (66/830)

We report a 51-year-old woman with polymyositis accompanied by a high titer of antiacetylcholine receptor antibody. The patient presented with weakness of grip strength followed by rapidly progressive dyspnea, which required mechanical ventilation. She was treated with a glucocorticoid and came off the respirator one week later. Antiacetylcholine receptor antibody activity was elevated in the acute phase and decreased during recovery, although other signs of myasthenia gravis were negative. This patient suggested that in cases of rapidly progressive bulbar palsy and limb muscle weakness, it is necessary to include polymyositis associated with elevated antiacetylcholine receptor antibody activity in the differential diagnosis.  (+info)

Tumours of the thymic region. Symptomatology, diagnosis, treatment, and prognosis. (67/830)

Fifty-three patients operated on between 1952 and 1971 were originally diagnosed as having thymoma. Re-examination of the material shows that only half of these tumours were true thymomas. The rest were classified as malignant lymphomas, primary and secondary carcinomas, and a few haemangiomas. Half of the patients had symptoms at the time of diagnosis. However, in half of the asymptomatic cases the tumours had penetrated the capsule. Decisive in prognosis are the macroscopic findings around the capsule. Of 33 patients with infiltration of the capsule, 30 had died at the time of investigation. Twenty-five patients died within two years of operation, Twenty-five patients had thymomas, of which 14 were well defined. Twelve patients with thymomas suffered from myasthenia gravis. The treatment of choice of thymoma is total excision, if necessary enbloc, and if there is penetration of the capsule, radiotherapy should be given. None of the patients with a well-defined thymoma had died from their tumour while only two patients with infiltrating thymomas are still alive, Of eight patients with Hodgkin's disease located in the thymus, six had penetration of the capsule, and of these only one patient is still alive. Two patients with well-defined tumours are both alive. The treatment of localized Hodgkin's disease is excision and irradiation. The prognosis for patients with other malignant tumours was bad, the mean time of survival being less than six months.  (+info)

Myasthenia gravis associated with penicillamine treatment for rheumatoid arthritis. (68/830)

Four patients with rheumatoid arthritis (R.A.) developed myasthenia gravis after taking penicillamine. In one patient withdrawal of the drug was followed by spontaneous remission of the myasthenia, and in two the dose of anticholinesterase was subsequently reduced. In the fourth patient continuing penicillamine treatment was associated with increasingly severe myasthenic features, but on withdrawal of the drug these resolved. As myasthenia gravis rarely complicates R.A. its onset in these patients shortly after the start of penicillamine treatment suggested that penicillamine may have precipitated this condition.  (+info)

Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs. (69/830)

Immunization of animals with acetylcholine receptor (AChR) protein from the electric organs of Electrophorus electricus and Torpedo californica induces an autoimmune response to the AChR of mammalian skeletal muscle. Rats and guinea pigs develop experimental autoimmune myasthenia gravis (EAMG) after a single inoculation with small quantities of AChR and adjuvant. The indicence and severity of disease appears to depend on the dose of AChR and stability of the emulsion. EAMG is strikingly similar to myasthenia gravis (MG) of man in its clinical picture and its electrophysiological abnormalities. The presence of antibodies to syngeneic rat muscle AChR in the serum of rats with EAMG documents the existence of autoimmunity in the experimental disease. A common immunopathogenesis is suggested for both EAMG and mg.  (+info)

Transgenic expression of IL-10 in T cells facilitates development of experimental myasthenia gravis. (70/830)

Ab to the acetylcholine receptor (AChR) cause experimental myasthenia gravis (EMG). Th1 cytokines facilitate EMG, whereas Th2 cytokines might be protective. IL-10 inhibits Th1 responses but facilitates B cell proliferation and Ig production. We examined the role of IL-10 in EMG by using wild-type (WT) C57BL/6 mice and transgenic (TG) C57BL/6 mice that express IL-10 under control of the IL-2 promoter. We immunized the mice with doses of AChR that cause EMG in WT mice or with low doses ineffective at causing EMG in WT mice. After low-dose AChR immunization, WT mice did not develop EMG and had very little anti-AChR serum Ab, which were mainly IgG1, whereas TG mice developed EMG and had higher levels of anti-AChR serum Ab, which were mainly IgG2, in addition to IgG1. At the higher doses, TG mice developed EMG earlier and more frequently than WT mice and had more serum anti-AChR Ab. Both strains had similar relative serum concentrations of anti-AChR IgG subclasses and IgG and complement at the muscle synapses. CD8(+)-depleted splenocytes from all AChR-immunized mice proliferated in the presence of AChR and recognized a similar epitope repertoire. CD8(+)-depleted splenocytes from AChR-immunized TG mice stimulated in vitro with AChR secreted significantly more IL-10, but less of the prototypic Th1 cytokine IFN-gamma, than those from WT mice. They secreted comparable amounts of IL-4 and slightly but not significantly reduced amounts of IL-2. This suggests that TG mice had reduced activation of anti-Torpedo AChR Th1 cells, but increased anti-AChR Ab synthesis, that likely resulted from IL-10-mediated stimulation of anti-AChR B cells. Thus, EMG development is not strictly dependent on Th1 cell activity.  (+info)

Anti-CTLA-4 antibody treatment triggers determinant spreading and enhances murine myasthenia gravis. (71/830)

CTLA-4 appears to be a negative regulator of T cell activation and is implicated in T cell-mediated autoimmune diseases. Experimental autoimmune myasthenia gravis (EAMG), induced by immunization of C57BL/6 mice with acetylcholine receptor (AChR) in adjuvant, is an autoantibody-mediated disease model for human myasthenia gravis (MG). The production of anti-AChR Abs in MG and EAMG is T cell dependent. In the present study, we demonstrate that anti-CTLA-4 Ab treatment enhances T cell responses to AChR, increases anti-AChR Ab production, and provokes a rapid onset and severe EAMG. To address possible mechanisms underlying the enhanced autoreactive T cell responses after anti-CTLA-4 Ab treatment, mice were immunized with the immunodominant peptide alpha(146-162) representing an extracellular sequence of the ACHR: Anti-CTLA-4 Ab, but not control Ab, treatment subsequent to peptide immunization results in clinical EAMG with diversification of the autoantibody repertoire as well as enhanced T cell proliferation against not only the immunizing alpha(146-162) peptide, but also against other subdominant epitopes. Thus, treatment with anti-CTLA-4 Ab appears to induce determinant spreading, diversify the autoantibody repertoire, and enhance B cell-mediated autoimmune disease in this murine model of MG.  (+info)

Oesophageal foreign bodies. (72/830)

Impaction of foreign bodies in the oesophagus was analysed in 54 patients, 45 of whom were children. Of the 45 children 28 were aged 2-4 years. Coins were the most common foreign body in children (27 cases) while in adults a bolus of meat was most common (nine cases). In 41 children there was no predisposing factor, but an underlying mechanism was detected in 88% of the adults. The mechanisms were of three types: oesophageal (stricture), neuromuscular (myasthenia gravis), and extrinsic and mechanical (ankylosing spondylitis). In children most of the foreign bodies were impacted in the upper oesophagus at the cricopharyngeal junction, which is the narrowest part of the oesophagus, while in adults the foreign body was usually impacted at the site of the predisposing lesion or in the lower oesophagus. In all patients oesophagoscopy was performed under general anaesthesia to remove the impacted foreign body. Complications were more frequent in adults, mainly owing to the underlying condition.  (+info)