State of the Art

State of the Art

Rationale

Tolerance to self is tightly regulated. The autoantibodies (auto-Abs) underlying the clinical symptoms are usually known, but their root cause remains a mystery for most conditions, despite continual increases in the prevalence of autoimmunity.

Myasthenia gravis (MG) is a rare (0.2-20/1,000,000 individuals) autoimmune disease first described in 1959-19601. It manifests as general muscle weakness and can be fatal if it affects the respiratory muscles. Its clinical symptoms are caused by auto-Abs targeting the transmitters at neuron-muscle junctions.

Epidemiologically, MG affects all age groups, but it appears to be more common in young women and elderly men. Patients of African origin may also be more frequently affected. The autoantibodies mostly target the acetylcholine receptor (RACh), the muscle-specific kinase receptors (MuSK) or LRP43. The presence of thymic tumors or dysplasia (thymoma in 10-15%, thymic hyperplasia in 65% of patients) suggests a thymic origin4. Furthermore, thymectomy has historically been used to treat MG.

There are several lines of evidence suggesting that MG has a genetic basis: (i) multiplex families (ii) a family history, and (iii) GWAS studies. However, the mechanism and genetic cause of MG remain elusive.

The work described in this proposal aims to fill the knowledge gap by deciphering the clinical, immunological, and genetic characteristics of MG patients, with the hypothesis that it will reveal general mechanisms of tolerance.

I will tackle this question with a three-fold approach combining

(i) clinical and thymic evaluation;

(ii) immunological studies including broad auto-Ab profiling,

(iii) unbiased searches for monogenic lesions

with the aim of discovering and characterizing new mechanisms of thymic tolerance.

References

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