Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that affects about 2.8 million people worldwide; almost 130,000 are in Italy alone. In MS, certain cells of the immune system, called T lymphocytes, are abnormally activated and thus damage the tissues of the central nervous system. This activation occurs because the T lymphocytes recognise not only antigens derived from the neuronal tissue itself, but also other antigens that remain hidden under normal conditions, only to reveal themselves under tissue stress, and are therefore defined as 'cryptic'. These can be revealed, for example, during the apoptotic process of T lymphocytes, i.e. when these cells undergo programmed death (apoptosis) at the end of their functions. 

As demonstrated in a study by Vincenzo Barnaba's research group, from the Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences at Sapienza University, the immune response to cryptic antigens derived from apoptosis correlates with the severity of the disease. This is why in patients with multiple sclerosis, apoptotic T cells increase and, in parallel, the T cells that recognise cryptic antigens released during the death process also increase. 

In the new paper published in the journal Cell Death & Disease, the research team coordinated by Vincenzo Barnaba and Silvia Piconese of Sapienza University of Rome observed the role of the immune response also in an experimental mouse model, showing how the administration of cryptic antigens worsens the course of the disease, demonstrating the unfavourable role of this response in autoimmune damage.

The research was funded by the Italian Multiple Sclerosis Society (AISM); various Italian and foreign organisations and universities, such as the Carlo Besta Neurological Institute in Milan, La Jolla Institute for Immunology in San Diego (USA), Federico II University in Naples, CNR Institute for Endocrinology and Oncology in Naples, Irccs Santa Lucia and Pasteur Italia-Fondazione Cenci Bolognetti Institute in Rome have collaborated. 

The study showed that after disease induction, T cells specific for cryptic antigens accumulate in the central nervous system and exhibit an effector phenotype, i.e. they can perform their functions without the need for co-stimulatory signals. These cells also exist in healthy animals but are not activated in response to conventional immunisation, probably because they are controlled by immunosuppression mechanisms. Instead, they are activated and migrate into the central nervous system when the disease is induced, probably because it subverts all protective mechanisms.

"In this study, we explored the development and function of the immune response to apoptosis-associated cryptic antigens in a well-established mouse model of the disease, experimental autoimmune encephalomyelitis," says Vincenzo Barnaba of Sapienza, corresponding author of the study, "and we confirmed on this model the main results we observed previously both in patients with multiple sclerosis and in patients with different forms of chronic inflammation, such as in patients with AIDS, with chronic hepatitis B or C virus, or rheumatoid arthritis. In other words, immune responses against cryptic antigens derived from apoptotic cells represent a general mechanism of exacerbation of chronic inflammatory diseases."

"Interestingly, we found that T cells (CD8+) specific for cryptic antigens were also present in the lymphoid organs of unprimed mice, i.e. mice not induced to the disease," concludes Silvia Piconese, co-corresponding author of the study. "However, these cells failed to respond to peptide immunisation in vivo, suggesting, in this case, a physiological control of the response."

These observations show that the autoimmune response in MS is very complex and that even physiological phenomena such as apoptosis can become pathological in the context of chronic inflammation.

References:

CD8+T cells specific for cryptic apoptosis-associated epitopes exacerbate experimental autoimmune encephalomyelitis - Neda Feizi, Chiara Focaccetti, Ilenia Pacella, Gloria Tucci, Alessandra Rossi, Massimo Costanza, Rosetta Pedotti, John Sidney, Alessandro Sette, Claudia La Rocca, Claudio Procaccini, Giuseppe Matarese, Vincenzo Barnaba & Silvia Piconese – Cell Death & Disease 2021. DOI: https://doi.org/10.1038/s41419-021-04310-6 

Further Information

Vincenzo Barnaba
Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences 
vincenzo.barnaba@uniroma1.it

Silvia Piconese
Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences 
silvia.piconese@uniroma1.it