Altered intrathymic T-cell repertoire in human myasthenia gravis.

Abstract

In myasthenia gravis, the thymus is thought to be the primary site of autosensitization. We investigated the V beta T-cell repertoire at different intrathymic differentiation stages in 17 patients with myasthenia gravis and 8 age-matched control subjects by tricolor immunofluorescence, using a panel of six anti-V beta antibodies. We observed an increased expression of V beta 5.1 and V beta 8 subfamilies in the patients compared to the control subjects. These increases were observed not only in mature cells but also in the latest thymic precursors of mature cells (double-positive CD3 high), while there was no change in intermediate precursors (double-positive CD3 low), pointing to biased selection during intrathymic differentiation. In addition, there was a strong correlation between the percentage of V beta 5.1+ and V beta 8+ cells among both the CD4 and CD8 subsets in the patients, but not in control subjects, suggesting that thymic events relevant to the disease lead to these selected populations. Finally, location studies of V beta 5.1+ cells on thymic sections indicated that these cells were overrepresented both in the core of germinal centers and in perifollicular areas of hyperplastic thymuses, suggesting a role in the autoimmune response. Taken together, these findings are compatible with the hypothesis of a biased intrathymic selection in myasthenia gravis.