E. Morel

Neonatal myasthenia gravis A new clinical and immunologic appraisal on 30 cases

Anti-acetylcholine receptor (AChR) antibody titers, toxin binding blocking antibody, functional activity of serum on rat myotube cultures, IgG subclasses, and clinical data were studied in relation to the onset of neonatal myasthenia gravis (NMG) in 30 children of myasthenic mothers. Fourteen had NMG, including 4 atypical cases. Anti-AChR antibody titer was the best indication of NMG onset. NMG in a previous baby was also predictive. Pattern of IgG subclasses, presence of toxin-binding blocking antibodies, and serum functional activity were less predictive, but cast light on the mechanism of anti-AChR antibody pathogenicity.

Association of neonatal myasthenia gravis with antibodies against the fetal acetylcholine receptor.

The specificities of autoantibodies directed against the acetylcholine receptor (AChR) for embryonic and adult muscle AChR were studied in 22 mothers with myasthenia gravis (MG) and in their newborns using human fetus and normal adult muscle AChR preparations. 12 mothers had transmitted MG to their neonates with, in three cases, antenatal injury. A clear correlation was found between occurrence of neonatal MG (NMG) and the high overall level of anti-AChR antibodies (embryonic or adult muscle AChR). However, a strong correlation was also found between occurrence of NMG and the ratio of anti-embryonic AChR to anti-adult muscle (Te/Ta) AChR antibodies (P < 0.0002). Taken together, these data suggest that autoantibodies directed against the embryonic form of the AChR could play a predominant role in the pathogenesis of NMG. Paradoxically, the three cases with antenatal injury presumably the most severe form of NMG, were not associated with high Te/Ta. At the clinical level, these observations could prove helpful in the prediction of transmission of NMG.

The fetal/adult acetylcholine receptor antibody ratio in mothers with myasthenia gravis as a marker for transfer of the disease to the newborn

High anti-fetal/anti-adult muscle anti-acetylcholine receptor (AChR) antibody (Ab) titer ratio is predictive of the occurrence of neonatal myasthenia gravis in a first child. The aim of the present study was to determine whether the ratio between the levels of antibodies is an intrinsic property of the mothers sera or varies with physiologic status such as pregnancy. We performed a longitudinal study of the levels of Ab directed against both fetal and adult AChRs and the ratio between them in 11 mothers with myasthenia gravis (MG). Sera were taken during, before, and after pregnancy. Absolute levels of Ab varied considerably during the time of observation as indicated by analyzing the maximum change between any two sample times during the study (adult mean percentage change 45.9 +/- 26.4; fetal 42.51 +/- 22.05). In contrast to this, the anti-fetal/anti-adult muscle AChR Ab titer ratio was much less variable (mean percentage change 16.66 +/- 10.11; p < 0.0033). The levels of the two Ab types yielded a correlation coefficient of 0.918, consistent with the stability of the ratio between them. This stability of ratio has practical value in the management of pregnancy and infant care in mothers with MG because the ratio at any time, before or during pregnancy, will predict whether the child will contract neonatal MG. We determined this for the first child, but further studies are necessary to establish if this remains true for subsequent pregnancies. NEUROLOGY 1997;48: 50-54

Evidence for the presence of immunoreactive acetylcholine receptors on human thymus cells

Triton extracts from thymuses and thymomas from either normal subjects or MG patients specifically bind [125I] alpha-bungarotoxin (alpha Bgt). This binding is saturable (apparent Ks = 5.9 X 10(-9) M) and can be inhibited by cold alpha Bgt, acetylcholine or nicotinic agonists. These results demonstrate the presence on human thymus cells of acetylcholine receptor (ACh.R), 2.8% for normal human thymus in regard of ACh.R concentration in human muscle. Normal human thymic extracts were used as an antigen source in the radioimmunoassay for the detection of anti-ACh.R antibodies in positive MG patients sera. 72% of these sera were also positive with the thymic antigen. The demonstration of ACh.R in human thymus brings further support to the hypothesis of intrathymic autosensitivity against ACh.R as a major factor in MG pathogenesis.

Heterogeneity of antibodies directed against the α-bungarotoxin binding site on human acetylcholine receptor and severity of myasthenia gravis

A rapid and sensitive radioimmunological method is described, using decamethonium (DC), which revealed antibodies which blocked alpha-bungarotoxin (alpha-Bgt) binding to human acetylcholine receptor (AChR) in 98% of myasthenia gravis (MG) patients sera tested. These sera had anti-AChR antibody titres by the conventional assay. The titre of blocking antibodies (1 to 110 nM) could be measured and was found to produce from 1 to 54% inhibition of alpha-Bgt binding. No relationship was found between these titres and anti-AChR antibody titres. MG sera were divided into 2 major groups on the basis of their blocking effects, with and without DC, but there was no correlation between these and the clinical status, as defined by Ossermans classification. However, no sera from asymptomatic or ocular MG patients had the dual capacities of blocking alpha-Bgt binding, directly and in the presence of DC.

Neonatal myasthenia gravis: Anti-acetylcholine receptor antibodies in the amniotic fluid

Neonatal myasthenia gravis (NMG) with mild arthrogryposis was observed at birth in the newborn infant of a myasthenic mother. Anti-acetylcholine receptor (anti-AChR) antibodies were present in the serum of both mother and child, in umbilical cord serum and in the amniotic fluid. The presence of anti-AChR antibodies in the amniotic fluid may be one of the causes of the NMG.

Neonatal myasthenia gravis : antigenic specificities of antibodies in sera from mothers and their infants

Transient neonatal myasthenia gravis (MG) is a human model or passively transferred MG, In an effort to understand the characteristics of the most pathogenic antibodies in MG, we studied the fine antigenic specificities of anti‐AChR antibodies in sera from 21 MG mothers (nine of which had transiently transferred the disease) and 17 of their infants. Although in a few cases significant differences in antibody specificities were observed between mothers and infants, whether myasthenic or not, generally the antigenic specificities of the antibodies in sera from infants were very similar to those of their mothers. Furthermore, no characteristic differences were detected between the antibody repertoires of mothers who transferred the disease and those who did not.

Sesquiterpene quinones as immunomodulating agents

The influence of sesquiterpene quinones and of a sesquiterpene hydroquinone, isolated from the sponge Smenospongia sp. on normal and tumour cells, was investigated. Most showed cytotoxic effects on L1210 leukemia cells. However, their activity on normal cells, such as murine spleen lymphocytes and human peripheral lymphocytes, revealed different behaviours: some of them inhibited, while other enhanced mitogen-stimulated lymphocyte proliferation. These biological studies revealed products modulating immune responses.

High recombinant interleukin-2 sensitivity of peripheral blood lymphocytes from patients with Myasthenia Gravis: Correlations with clinical parameters

Myasthenia Gravis (MG) is an autoimmune disorder of neuromuscular transmission associated with antibodies (Ab) against acetylcholine receptor (AChR). Autoantibody production is a T-cell-dependent phenomenon perhaps caused by aberrant immunoregulation. So far, a possible role for immunoregulatory molecules has not been investigated in the pathogenesis of MG. Since interleukin-2 (IL-2) is able to induce peripheral blood mononuclear cell (PBMC) proliferation without a previous activating signal and to upregulate IL-2-receptor expression, we have evaluated the activation state of PBMC in patients with MG, by cytofluorographic analysis of CD25 expression and by testing their sensitivity to recombinant IL-2 (rIL-2) without any known previous stimulation. We found no significant difference in CD25 expression in a large group of patients compared to controls. However, proliferative responses to rIL-2 were significantly higher in MG patients than in controls. In MG, as in controls, this response was time- and dose-dependent, was inhibited by an anti-IL-2 receptor Ab and correlated with an increased percentage of CD25+ T cells after rIL-2 exposure. The response was greater in patients with a high anti-AChR Ab titer and a severe form of the disease, and in patients tested before thymectomy. Thus blood T cells in MG showed functional signs of preactivation (high sensitivity to rIL-2 alone) without detectable CD25 expression on fresh cells, raising the possibility of aberrant IL-2 receptor regulation and/or expression in MG T cells. Decreased sensitivity to rIL-2 after thymectomy, associated with general clinical improvement, suggests a role for activated cells originating from the thymus in the pathogenesis of MG, and is of clinical relevance in patient follow-up. Our findings also provide a new approach in the study of MG pathogenesis: the search for aberrant immunoregulation mechanisms linked to defects in lymphokine circuits.

Anti-acetylcholine receptor antibodies in neonatal myasthenia gravis: Heterogeneity and pathogenic significance

Precipitating, blocking and modulating anti-AChR antibodies and their capacity to recognize embryo or adult muscle were investigated in parallel in maternal and neonatal sera of fifty-two newborns and their myasthenic mothers. Twenty-four babies presented neonatal myasthenia gravis (NMG) with a common expression in twenty cases and foetal involvement in four cases. Occurrence of NMG was clearly related to levels of maternal precipitating, decamethonium blocking (DC blocking) and modulating antibodies (respectively P less than 0.001, P less than 0.02, P less than 0.01, Mann-Whitney test), these three parameters being interrelated. The only significant difference between mothers with severely affected babies and others with mild NMG newborns concerned DC blocking antibodies. Transfer fraction of DC blocking antibodies was significantly higher in NMG than in asymptomatic babies. Our data suggest that (1) the amount of anti-AChR antibodies, whatever the tested category, is involved in the pathogeny of NMG in a more direct manner than in adult MG where the correlation with their levels is poor, and (2) among antibodies, those with blocking effects could be preponderant for triggering NMG and be involved in the severity of the disease in the child.