Myasthenia Gravis pathophysiology in adults
Myasthenia Gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by weakness in the voluntary muscles. In adults, MG presents a complex pathophysiology that involves an interplay between immune system dysregulation and neuromuscular junction dysfunction. Understanding these mechanisms provides insight into the clinical features and guides therapeutic strategies.
At the core of MG’s pathophysiology is the immune system’s production of abnormal antibodies that target components of the neuromuscular junction (NMJ). The most common target is the acetylcholine receptor (AChR), found on the postsynaptic membrane of muscle cells. These autoantibodies are produced by activated B cells, often facilitated by aberrant T-cell responses. When these antibodies bind to AChRs, they interfere with normal neurotransmission in multiple ways: they block the receptor sites, induce receptor internalization and degradation, and activate the complement system, leading to damage of the postsynaptic membrane. This damage results in a decreased number of functioning receptors, impairing the muscle’s ability to respond to nerve stimuli.
The reduction in functional AChRs diminishes the efficacy of neuromuscular transmission, which is normally achieved when acetylcholine, released from the nerve terminal, binds to these receptors to trigger muscle contraction. In MG, the compromised receptor availability means that even when acetylcholine is released in adequate amounts, the muscle response is insufficient, leading to muscle weakness and fatigability. The hallmark of this process is that muscle weakness worsens with activity and improves with rest, reflecting the depletion of available neurotransmitter-receptor complexes during exertion.
Another important aspect of MG involves the thymus gland. Many adults with MG exhibit thymic abnormalities such as hyperplasia or thymomas. The thymus is thought to play a role in the pathogenesis by abnormal T-cell education, which promotes the production of pathogenic autoantibodies. Thymic epithelial cells may present self-antigens that stimulate autoreactive T cells, perpetuating the autoimmune response.
In some cases, MG is associated with antibodies against other components of the NMJ, such as muscle-specific kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4). These variants tend to have different immunopathological mechanisms but similarly result in impaired neuromuscular transmission.
Finally, the clinical manifestation of MG reflects this disrupted transmission, presenting as fluctuating muscle weakness, often affecting the eyelids (ptosis), extraocular muscles (ophthalmoplegia), facial muscles, and, in more severe cases, bulbar and limb muscles. The episodic nature of symptoms and their variability are characteristic features stemming from the underlying immunological and structural alterations at the neuromuscular junction.
In summary, adult myasthenia gravis results from autoimmune-mediated destruction or blockade of acetylcholine receptors or related components, leading to impaired neuromuscular transmission. The immune system’s aberrant production of pathogenic antibodies, thymic abnormalities, and subsequent complement activation culminate in the hallmark muscle weakness that defines this condition.
