Hi James, explaining why autoimmunity occurs is very complicated. In the case of MG, it frequently occurs as a neoplastic

syndrome in the context of a thymoma aka carcinoma of the thymus. Indeed, in many patients, removal of the affected thymus corrects the MG. For an understanding of neoplastic syndrome and thymoma, I would direct you to harrison's.

Hi James Doran

This is a recent 2021 article on MG. Hope you enjoy going through it.

https://pubmed.ncbi.nlm.nih.gov/32644757/

Take Care

Our immune system produces antibodies that block or destroy many of our muscles' receptor sites for a neurotransmitter called acetylcholine. With fewer receptor sites available, our muscles receive fewer nerve signals, resulting in weakness.

Friend Aroop Mohanty

Thank you for your answer about the root cause of MG. My question is deeper. WHY/HOW EXACTLY does our immune system produce the damaging antibodies that, as you say, "block or destroy many of our muscles' receptor sites" causing weakness? What makes the immune system misbehave in this way?

James

@AroopMohanty

My thanks to Professors Benoit and Ghelta for very useful pointers.

Has the following idea been explored (or considered and swiftly dismissed)?

IDEA --- May the adaptive immune system on some occasions correctly identify and go through its procedure to characterize antigen but overgeneralise the characterization it forms? (Consider the difference between "The alien is green and has five legs" and "The alien is green and has many legs".).

It seems to me that this kind of immune system error could lead to the phenomenon we see in MG where muscle receptor sites are attacked for no good reason. They are wrongly included in an antigen characterisation. Of course, this implies that there is, or has been, a "real" antigen involved, if only briefly.

So -- does the adaptive immune system sometimes overgeneralise?

HI James,

I dont think I would call it overgeneralizing. Central and peripheral tolerance is imperfect, especially for B cells. There is a concept of molecular mimicry that is relevant to your question though, for example, there can be an infection with pathogen X. A protein that is 95% identical to a host protein. In the resolution of the infection, T cell and B cells are expanded that can respond not just to the pathogen proteins, but which can cross react with the similar host proteins, leading to autoimmunity. In MG, for example, herpes simplex virus glycoprotein D appears to exhibit molecular mimicry to AhcR.

A further little question -- is the root cause of MG essentially the same as the root cause of MS?

Hi James,

In MS, inflammation of the meninges allows for immune cells and cytokines to breach the blood-brain-barrier and contact an immunoprivileged site -the CNS. Because the CNS is an immunopriviledged site, there has been no deletion of auto-reactive B cells and T cells during development, thus cells with the potential to react with CNS determinants are now allowed to do so, and this causes MS (short story, I hope I have not offended anyone with my brevity).

In MG, there is molecular mimicry and also in many cases, a very unique context of paraneoplastic syndrome secondary to carcinoma of the thymus. Thymus is where the T cells develop and undergo tolerance induction. This cancer allows for factors to be made that allow the developing T cells to evade tolerance and now react with AchR and other muscle related factors. The MG can be successfully eliminated by a thymectomy in most instances. So one of my former colleagues had a daughter with MG, there was no cancer, but interestingly, when they removed her thymus, her MG disappeared.

Kind regards, Lora

Is Janeway's Immuno-Biology still (9th ed) a reliable source for the Thymus and what is currently known or suspected of what should happen and yet can happen within it? Great complexity I know. Or is there a better alternative up to date textbook read? Your help is much appreciated!