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Titin antibodies in “seronegative” myasthenia gravis — A new role for an old antigen

      Highlights

      • We screened 667 MG sera from 13 countries with a sensitive RIPA for the detection of titin Abs.
      • Titin Abs were detected in 13.4% (50/372) of seronegative patients by RIPA vs 4.5% by the current ELISA.
      • Titin Abs were found in only 3.6% (7/193) of OND and none of the 121 healthy or 90 muscle disease controls.
      • The presence of RIPA-detected Abs did not correlate with thymoma or more severe symptoms.
      • Detection of titin Abs by RIPA in seronegative MG could serve as a valuable diagnostic marker.

      Abstract

      Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients.

      Graphical abstract

      Abbreviations:

      AChR (acetylcholine receptor), AChR+ (AChR antibody positive sera), LRP4 (low-density lipoprotein receptor-related protein 4), LRP4+ (LRP4 antibody positive sera), MG (myasthenia gravis), EOMG (early-onset MG), LOMG (late-onset MG), MGT30 (titin main immunogenic region), MuSK (muscle specific kinase), MuSK+ (MuSK antibody positive sera), OND (other neurological diseases), RIPA (radioimmunoprecipitation assay), tSN-MG (triple-seronegative-MG)

      Keywords

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