Endogenous self-peptides guard immune privilege of the central nervous system, 2024, Kim et al.

Endogenous self-peptides guard immune privilege of the central nervous system
Kim, Min Woo; Gao, Wenqing; Lichti, Cheryl F.; Gu, Xingxing; Dykstra, Taitea; Cao, Jay; Smirnov, Igor; Boskovic, Pavle; Kleverov, Denis; Salvador, Andrea F. M.; Drieu, Antoine; Kim, Kyungdeok; Blackburn, Susan; Crewe, Clair; Artyomov, Maxim N.; Unanue, Emil R.; Kipnis, Jonathan

Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system. In fact, it remains physically connected to, and can be influenced by, the peripheral immune system. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding question.

Here, in searching for molecular cues that derive from the CNS and enable its direct communication with the immune system, we identified an endogenous repertoire of CNS-derived regulatory self-peptides presented on major histocompatibility complex class II (MHC-II) molecules in the CNS and at its borders. During homeostasis, these regulatory self-peptides were found to be bound to MHC-II molecules throughout the path of lymphatic drainage from the brain to its surrounding meninges and its draining cervical lymph nodes.

However, in neuroinflammatory disease, the presentation of regulatory self-peptides diminished. After boosting the presentation of these regulatory self-peptides, a population of suppressor CD4+ T cells was expanded, controlling CNS autoimmunity in a CTLA-4-and TGFβ-dependent manner. CNS-derived regulatory self-peptides may be the molecular key to ensuring a continuous dialogue between the CNS and the immune system while balancing overt autoreactivity.

This sheds light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases.

Link | PDF (Nature) [Open Access]

 

It sounds as if they are just tracking the artefacts of immune diseases in mice that probably bear no relation to human disease.

I find this sort of research very distasteful.

 

No, you have it right but this is the same old cross-reactivity story that has been around since Robin Coombs in 1960 for rheumatic fever that by and large has turned out to have nothing to do with human disease. It is a bit going on prospecting for gold in a limestone escarpment when we have come to know that gold deposits do not occur in limestone escarpments.

If the system doesn't work when there is an immune challenge from infection then it isn't a protective system. So what are they going on about? This sort of stuff is always completely out of perspective.

What regulatory peptides? Where is the evidence for these being 'regulatory'. Cells with MHC Class 2 will present peptides in any tissue. I have no idea what they think they are hypothesising. Peptides in mice and humans will be broadly similar but also have significant differences but that is irrelevant I think. What they are arguing from is a pattern of cell behaviour in the context of an experimental disease in animals that bears no relation to any human disease we know. Everyone thinks that inflammatory diseases in animals triggered by injection of antigens with adjuvants mimic human autoimmunity but, as I say, the evidence over fifty years is that they have nothing in common other than that the organ gets nadgered.

It seems very difficult to help these sort of people to understand!! And they jolly well ought to if they are spending public money on submitting animals to excruciating illness.