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Theorell J, Ruffin N, Fower A, Sorini C, Ambrose P, Damato V, Handunnetthi L, Leite I, Irani SR, Brauner S, Handel AE, Piehl F
JCI Insight 11 (1) - [2026-01-09; online 2025-11-27]
The 2 main subgroups of autoimmune myasthenia gravis, a neuromuscular junction disorder associated with muscle weakness, are 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. To distinguish the 2 forms by cellular immune phenotyping, we applied multimodal techniques, including deep spectral cytometric phenotyping and single-cell sequencing. Analysis of 2 independent cohorts identified immunological differences driven by 3 main lymphocyte populations. Lower frequencies of mucosa-associated invariant T cells and naive CD8+ T cells were observed in late-onset myasthenia, suggesting enhanced immune senescence. A highly differentiated, canonical NK cell population was reduced in early-onset myasthenia and negatively correlated with the degree of thymic hyperplasia. Using only the frequency of these 3 populations, correct myasthenia subgroup assignment could be predicted with 90% accuracy. These distinct immunocellular endophenotypes for early- and late-onset disease suggest differences in immunopathogenic processes. Along with demographic factors and other disease subgroup-specific features, the frequency of the identified cell subpopulations may improve clinical classification.
NGI Stockholm (Genomics Applications) [Service]
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 41307955
DOI 10.1172/jci.insight.199679
Crossref 10.1172/jci.insight.199679
pmc: PMC12890496
pii: 199679