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Overview of genes linked to early and late onset myasthenia gravis

Myasthenia gravis is a debilitating autoimmune disorder that manifests clinically as muscle weakness and fatigability. Early and late onset forms of myasthenia gravis have distinct epidemiological and pathological characteristics. However, little is known about the immunological mechanisms that lead to the development of autoantibodies against the acetylcholine receptor in the majority of these patients.

In a new study led by Dr Lahiru Handunnetthi (Academic Clinical Lecturer at NDCN), a team of researchers used cutting-edge genomic methodology to identify disease-relevant genes. The methodology integrated genome-wide study findings with cell-type-specific information such as gene expression patterns and promotor-enhancer interactions. This approach shed light on the underlying mechanisms for early and late forms of myasthenia gravis.

The genes prioritised in this study highlight several key differences in the immunological pathways between early and late onset myasthenia gravis. The researchers identified a unique role for the innate immune system in early onset disease, whereas they found multiple layers of evidence for T-cell pathways in late onset disease. Furthermore, the researchers demonstrated for the first time that causal genetic variants linked to late onset disease result in low expression of CTLA4 in CD4+ T-cells.

The disease-relevant genes identified in this study are a unique resource for clinicians, scientists and the pharmaceutical industry. The distinct immunological pathways linked to early and late onset myasthenia gravis carry important implications for repurposing existing drugs, and for future drug development.

The researchers plan to carry out further studies at single cell level with the help of funding from the Human Immune Discovery Initiative. They are also working towards early preclinical studies to help target existing and novel therapeutic agents for early and late forms of myasthenia gravis. 

This work was carried out in collaboration with Professor Julian Knight at the Wellcome Centre for Human Genetics and Professor Sarosh Irani from NDCN as well as others from the Wellcome Sanger Institute and Estonian Genome Centre.

Read the full paper in Annals of Neurology

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