Cellular immune endophenotypes separating early and late-onset myasthenia gravis

Jakob Theorell; Nicolas Ruffin; Andrew Fower; Chiara Sorini; Philip Ambrose; Valentina Damato; Lahiru Handunnetthi; Isabel Leite; Sarosh R. Irani; Susanna Brauner; Adam E. Handel; Fredrik Piehl

doi:10.1172/jci.insight.199679

Cellular immune endophenotypes separating early and late-onset myasthenia gravis

Jakob Theorell,¹ Nicolas Ruffin,² Andrew Fower,³ Chiara Sorini,² Philip Ambrose,³ Valentina Damato,⁴ Lahiru Handunnetthi,⁵ Isabel Leite,³ Sarosh R. Irani,³ Susanna Brauner,⁶ Adam E. Handel,³ and Fredrik Piehl⁶

Published November 27, 2025 - More info

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Abstract

The two main subgroups of autoimmune myasthenia gravis, a neuromuscular junction disorder associated with muscle weakness, are the early and late-onset forms, defined by onset before or after 50 years of age. Both carry acetylcholine-receptor autoantibodies, but differ in sex ratios, genetics and occurrence of disease-specific thymus inflammation. By applying multimodal techniques, including deep spectral cytometric phenotyping and single cell sequencing to peripheral blood and thymic lymphocyte samples we explored the possibility to discriminate the two forms by cellular immune phenotyping. Analyzing two independent cohorts we identified distinct immunological differences driven by three main lymphocyte populations. Lower frequencies of mucosa-associated invariant T cells and naïve CD8 T cells were observed in late-onset myasthenia, suggesting enhanced immune senescence. Further, a highly differentiated, canonical natural killer cell population was reduced in early-onset myasthenia, which was negatively correlated with the degree of thymic inflammation. Using only the frequency of these three populations, correct myasthenia subgroup assignment could be predicted with an accuracy of 90%. The NK cell population negatively associated to early-onset disease had a similar association to thymic hyperlasia, whereas the two T-cell populations point to enhanced immune senescence in late-onset myasthenia gravis. These distinct immunocellular endophenotypes for early- and late onset disease suggest differences in the immunopathogenic processes. Together with demographic factors and other disease subgroup-specific features, the frequency of the identified cell subpopulations may improve clinical classification, in turn of relevance for channeling to interventions.

Cellular immune endophenotypes separating early and late-onset myasthenia gravis

Jakob Theorell,¹ Nicolas Ruffin,² Andrew Fower,³ Chiara Sorini,² Philip Ambrose,³ Valentina Damato,⁴ Lahiru Handunnetthi,⁵ Isabel Leite,³ Sarosh R. Irani,³ Susanna Brauner,⁶ Adam E. Handel,³ and Fredrik Piehl⁶

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Cellular immune endophenotypes separating early and late-onset myasthenia gravis

Jakob Theorell,1 Nicolas Ruffin,2 Andrew Fower,3 Chiara Sorini,2 Philip Ambrose,3 Valentina Damato,4 Lahiru Handunnetthi,5 Isabel Leite,3 Sarosh R. Irani,3 Susanna Brauner,6 Adam E. Handel,3 and Fredrik Piehl6

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Jakob Theorell,¹ Nicolas Ruffin,² Andrew Fower,³ Chiara Sorini,² Philip Ambrose,³ Valentina Damato,⁴ Lahiru Handunnetthi,⁵ Isabel Leite,³ Sarosh R. Irani,³ Susanna Brauner,⁶ Adam E. Handel,³ and Fredrik Piehl⁶