Myasthenia gravis causes defects in cellular communication between nerve and muscle cells. Under normal circumstances, an impulse travels along a nerve to the nerve ending, and the nerve sends a messenger called acetylcholine to the muscle cell. Acetylcholine binds to the acetylcholine receptor on muscle cells, resulting in muscular contraction. In myasthenia gravis, the body produces antibodies against its own acetylcholine receptors and blocks them from binding acetylcholine. Individual receptors are also destroyed by antibodies, complement fixation, and by inducing the muscle cell to eliminate the receptors via endocytosis; this results in a decreased number of acetylcholine receptors. These phenomena lead to a reduced ability of the muscle cell to respond to nerve impulses (Jayam Trouth 2012; Howard 2006; NINDS 2012).
It is generally accepted that the thymus plays an important role in the development of myasthenia gravis, though the precise mechanism is still unclear. Over 50% of all people with myasthenia gravis have hyperplasia within the thymus and 10–15% of patients have a tumor of the thymus – called a thymoma (Meriggioli 2009; Meriggioli 2012a). The thymus produces different types of T cells that identify foreign invaders in the body and help eliminate them (Takahama 2006). Regulatory T cells (Treg) monitor the activity of other T cells. Treg maintain tolerance and prevent an autoimmune response as they have the ability to recognize proteins that are normally present in the cells of the body. T helper (TH) cells, on the other hand, help combat the attack of foreign pathogens by different mechanisms. There are several types of T helper cells; some of them produce proteins called cytokines, which regulate inflammation, while others communicate with other immune cells, including B cells, to participate in immune responses against various types of pathogens. B cells produce specific ‘antibodies,’ specialized molecules that target the specific pathogen or ‘antigen’ (NIAID 2014).
In myasthenia gravis, certain T helper cells begin to react against self-proteins and cause B cells to produce antibodies against self-proteins (Jayam Trouth 2012). Defects in T regulatory cells’ ability to recognize normal proteins in the body also play a role in this process (Thiruppathi, Rowin, Ganesh 2012). These combined events result in the circulation of self-reacting antibodies and an inflammatory environment.
The majority of patients with myasthenia gravis (about 85%) have antibodies against the acetylcholine receptor on muscle cells. In approximately 7–8% of patients, antibodies against muscle-specific tyrosine kinase (MuSK) are detected (Meriggioli 2012a). The remaining patients may have antibodies against lipoprotein-related protein 4 (LRP4) or other muscle-associated proteins (Zhang 2012; Meriggioli 2012a). Some patients may be considered seronegative (no detectable antibodies against acetylcholine receptors). Patients with no detectable antibodies to MuSK or acetylcholine receptors are referred to as ‘double seronegative.’ However, patients may be ‘falsely seronegative’ due to immunosuppression or if the test is performed early in the disease course. Furthermore, the number of ‘true seronegative’ patients may be very low due to a simple inability of currently available screening tests to detect levels of some antibodies (Meriggioli 2012a).
A theory published in 2012 suggested that an impaired ability of the immune system to control the Epstein-Barr virus (EBV) could be involved in producing autoantibodies that could be responsible for a number of autoimmune diseases, including myasthenia gravis. Based on this theory, B cells infected with EBV are not eliminated by the immune system. Under normal circumstances, when B cells become infected with EBV, they are killed by a type of T cells known as CD8+. However, since patients with myasthenia gravis (and other immune diseases) have low numbers of these CD8+ T cells, the EBV-infected B cells, instead of being destroyed by the immune system, multiply and enter the thymus where they produce antibodies against self-proteins (Pender 2012). Interestingly, females generally have lower numbers of CD8+ cells than males (Cavalcante 2011; Amadori 1995). Scientists have shown that levels of CD4+ and CD8+ T cells may be regulated by hormone levels — higher levels of serum estrogen correlate with an increase in the ratio of CD4+/CD8+ T cells (Ho 1991). This discovery may indicate why myasthenia gravis tends to affect women at a younger age than men: higher levels of estrogen in females under the age of 40 coupled with a higher ratio of CD4+/CD8+ T cells may predispose this population of women to the disease.
It is known that exposure to sunlight can increase the number of CD8+ cells (Hersey, Bradley, 1983; Hersey, Haran, 1983). Scientists believe that this may be due to the production of vitamin D, as vitamin D can increase the number of CD8+ T cells (Zofkova 1997), and people who are deficient in vitamin D have lower levels of CD8+ T cells (Pender 2012). Scientists have hypothesized that the high prevalence of autoimmune diseases in populations living at high latitudes may in part be due to lack of sunlight and vitamin D (Pender 2012).