NEW AUTOANTIGENS AND NEW METHODOLOGIES FOR MYASTHENIA GRAVIS DIAGNOSIS, SHRINK SERONEGATIVE MYASTHENIA

Abstract

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease which is mainly due to loss of functional nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. This loss of functional AChRs, which disturbs muscle contraction, is usually due to autoantibodies against AChR or against proteins necessary for proper AChR functioning. The latter proteins include the postsynaptic membrane proteins MuSK and LRP4 and the agrin which is secreted by the nerve terminal. Agrin binds to LRP4 and then the LRP4-agrin complex binds and activates MuSK. The activated MuSK causes, via other proteins, AChR clustering in the postsynaptic membrane, necessary for proper AChR function.
An invaluable tool in the diagnosis of MG is the detection of autoantibodies against the above proteins in patients’ sera. With the use of radioimmunoassays, AChR autoantibodies are detected in ~80% of MG patients, while MuSK autoantibodies are detected in about 20-40% of the remaining patients. Symptoms in “MuSK-MG” often differ from those in “AChR-MG” and the recommended treatment differs significantly between the two groups of patients.Although several MG patients remain until today “seronegative”, recently there has been considerable progress towards the reduction of “seronegative” MG. With new techniques (cell-based assays, CBA), more AChR and MuSK antibodies are now detected, undetectable by the classical techniques. Furthermore, the last two years we have shown that ~19% of “seronegative” MG patients have autoantibodies to the new autoantigen, LRP4. The onset of the disease in “LRP4MG “ is usually milder than in the other two MG groups, but in double-positive MG (anti-LRP4/anti-AChR or anti-LRP4/anti-MuSK), symptoms are considerably more severe than in any single-positive MG group. Antibodies to LRP4, like those to AChR and MuSK, can induce experimental MG in experimental animals. More recently, antibodies against additional proteins of the neuromuscular junction have been discovered in MG sera, such as antibodies to agrin. Finally, by a new technique, we can now detect antibodies against titin (a protein of the muscle cell) in ~13% of the “seronegative” MG patients, in addition to their known presence in many AChR-MG sera, further reducing the “seronegative” MG.