Laboratory Investigation of Hybrid IgG4 k/λ in MuSK Positive Myasthenia Gravis

Myasthenia gravis with antibodies (Abs) against the muscle-specific tyrosine kinase (MuSK) is a rare autoimmune disorder (AD) of the neuromuscular junction (NMJ) and represents a prototype of AD with proven IgG4-mediated pathogenicity. Thanks to the mechanism of Fab-arm exchange (FAE) occurring in vivo, resulting MuSK IgG4 k/lambda Abs increase their interference on NMJ and pathogenicity. The characterization of hybrid MuSK IgG4 as a biomarker for MG management is poorly investigated. Here, we evaluated total IgG4, hybrid IgG4 k/lambda, and the hybrid/total ratio in 14 MuSK-MG sera in comparison with 24 from MG with Abs against acetylcholine receptor (AChR) that represents the not IgG4-mediated MG form. In both subtypes of MG, we found that the hybrid/total ratio reflects distribution reported in normal individuals; instead, when we correlated the hybrid/total ratio with specific immune-reactivity we found a positive correlation only with anti-MuSK titer, with a progressive increase of hybrid/total mean values with increasing disease severity, indirectly confirming that most part of hybrid IgG4 molecules are engaged in the anti-MuSK pathogenetic immune-reactivity. Further analysis is necessary to strengthen the significance of this less unknown biomarker, but we retain it is full of a diagnostic-prognostic powerful potential for the management of MuSK-MG.

Automated summary

The study found that in both MuSK-MG and AChR antibody-positive MG patients, the hybrid/total ratio is similar to the distribution in normal individuals, but it is only positively correlated with anti-MuSK titer in terms of specific immune reactivity. As disease severity increases, the hybrid/total ratio also gradually increases, indicating the involvement of hybrid IgG4 molecules in the pathogenic immune reactivity against MuSK. Further research is needed to strengthen the significance of this lesser-known biomarker, but it is believed to have diagnostic and prognostic potential for the management of MuSK-MG.