Science News: A Distinct Immunological Signature in Late-Onset Myasthenia Gravis: Insights from an Exploratory Proteomics Study

Edited by: Justin Willer, MD

Citation: Roy, B., Chen, J., Khani-Habibabadi, F., McLaren, N., Soliven, B.C., Juel, V.C., O’Connor, K.C., Nowak, R.J., Kusner, L.L. and Kaminski, H.J. (2025), A Distinct Immunological Signature in Late-Onset Myasthenia Gravis: Insights from an Exploratory Proteomics Study. Ann Neurol. https://doi.org/10.1002/ana.78017

Summary: Acetylcholine receptor positive myasthenia gravis shows a bimodal distribution of incidence with early onset (EOMG, onset <50) being predominantly female with thymic pathology and late onset (LOMG, onset >50) more likely to be male with greater treatment responsiveness. This prospective proteomics study using the BeatMG cohort evaluate for immunological differences in these distinct epidemiological groups.

A total of 49 samples myasthenia gravis samples from the BeatMG cohort were used as the study group with MG validation cohort from the MGNet biorepository and UK biobank. Most of the study samples were from men (53.1%).  The number of EOMG (average age of onset 29.5) and LOMG (average age of onset 64.1) were roughly equally represented in the samples. Patients in the EOMG group were more likely to be women, with a longer disease duration, and to have undergone thymectomy. Patients in the LOMG group were more likely to be men, with a shorter disease duration, and none had undergone thymectomies. Clinical measures (MG-ADL, QMG) and treatment parameters were similar between groups. Healthy control samples were gathered from George Washington and Yale University biobanks.

Following examination of various proteomics profiles were analyzed, pathway enrichment profiles were then tested. Of 730 proteins evaluated, 73 were difference between the EOMG and LOMG groups within the study cohort. Certain pathways (regulation of leukocyte differentiation, regulation of phagocytosis, regulation of IL-10 production, and myeloid leukocyte differentiation and migration) were overrepresented in the LOMG group.

Comments: This was a relatively small sample of patient samples and there was a heterogenous concurrent immunosuppressive treatment landscape in the patient population

The effect of thymectomy (54% EOMG, 0% LOMG) could be a confounding factor in this analysis though there was no difference in EOMG patients with versus without thymectomy. 

With the use of the validation cohorts, LOMG patients were found to have higher levels of IL18R1, IL17C, and CCL11 and lower levels of CXCL17.

This study suggests a differing immunologic mechanism may be at play between EOMG and LOMG. If these findings are confirmed in larger studies, this may ultimately inform different treatment choices between these epidemiologic groups. 

While the study cannot determine the clinical significance of the proteomic differences, this may suggest a different immunological pathophysiologic mechanism between EOMG and LOMG which could lead to better understanding of the disease and treatment approaches.