"Greater understanding of immune system function is increasingly important in the era of viral pandemics, because we need to think about how to target the non-immune aspects of MS, especially for the many years that people live with this disease."

—Peter A. Calabresi, MD

Whitaker Lecture: Immune Responses in Multiple Sclerosis Have New Relevance in the COVID-19 Era

Peter Calabresi, MD, highlighted immune responses in progressive multiple sclerosis in his Whitaker Lecture for the CMSC's 2020 virtual annual meeting, but did not ignore COVID-19 immune responses relevant in the current pandemic.The Consortium of Multiple Sclerosis Centers (CMSC) kicked off its 2020 Annual Meeting this year using a virtual online format due to COVID-19 precautions. CMSC CEO June Halper opened the meeting noting that while this is an unprecedented situation for such gatherings, she was grateful to the many supporters, faculty, and staff for pulling together to deliver an outstanding online educational program. Each day's activities included 4 to 5 didactic sessions from multiple sclerosis (MS) experts and an independently supported symposium.

This year's Whitaker Lecture was delivered by Peter A. Calabresi, MD, Professor of Neurology and Neuroscience Director, Division of Neuroimmunology and Co‐Director of Precision Medicine at the MS Center of Excellence at Johns Hopkins University School of Medicine. Dr. Calabresi focused on new and rapidly evolving developments in the understanding of immune processes that underlie progressive MS (PMS).

"Persistent demyelination rendering the axons susceptible to degeneration occurs through a variety of pathways," Dr. Calabresi explained. "These mechanisms are there for a reason—they are programmed to respond to injury, and their short-term response may be beneficial, but sometimes the compensatory mechanisms that ensue after chronic injury result in neurodegeneration and the ultimate demise of the system resulting in permanent disability. By understanding the details that underlie this process, we hope to identify targets that could translate into new therapies for progressive MS."

Some cases of progressive MS do have an underlying inflammatory component, with microscopic peripheral immune-mediated inflammation causing damage to oligodendrocytes and axons. Dr. Calabresi acknowledged. "We need better ways to determine if this is predominant enough to justify treating PMS patients using higher efficacy, immune modulating therapies," he said. "We know from experience in clinical trials that many of our highly effective monoclonal antibody therapies don't have the same benefit in many patients with PMS."

Compensatory mechanisms preserve axons and allow remyelination for a time, he said, but multiple mechanisms eventually lead to loss of trophic support to the axons and ultimately energy failure that results in death of the cell. The glia, which are normally homeostatic and provide support under chronic inflammatory conditions, become neurotoxic. "Perhaps there is an opportunity to intervene, either through remyelination or interfering with energy failure pathways, or by understanding the mechanisms by which glia neurotoxically kill neurons and oligodendrocytes."

Newer research is looking further into loss of synapses and connectivity between neural circuits in the brain. "There's emerging evidence of synaptic degeneration from imaging and pathology, but how and why it's happening is just starting to be unraveled," Dr. Calabresi noted. This, too, may be amenable to therapeutic intervention.

Degenerative processes and immune responses are highly variable among individuals, creating challenges that may eventually warrant a focused, personalized approach to treatment. "Of course, we're not inbred strains of mice, so genetic and environmental influences are likely impacting the outcomes of our patients," he commented. "We know that infections can activate immune cell, microbial pathogens in the gut directly interact with immune cells and influence immune responses. There are likely environmental toxins that impact the health of our nervous system and immune cells. And of course, dietary factors are directly related to metabolism and energy. Metabolic syndrome leads to obesity and propensity to type 2 diabetes, hypertension, hyperlipidemia, and these factors have been well described to influence vascular health, but are increasingly being linked to increased susceptibility to neurodegeneration."

The need for better understanding of immune system function is heightened in the current era of a viral pandemic, Dr. Calabresi said. He reviewed the current and rapidly evolving research on COVID-19, and how drugs that alter immune system function might interfere with viral entry into the cells, viral replication, and cytokine response. "So far, no one has figured out a way to my knowledge of interfering with viral entry into the cell. Interfering with antigen presentation may be one way. "This is one of the putative mechanisms of hydroxychloroquine, but it turns out this might be a bad thing because you actually want the immune system to target and kill virally infected cells," he said. "You would not want to block antigen presentation of viral antigen in the context of a severe viral infection."

Much interest has focused on cytokine response in COVID-19, he said. The question is still open as to whether cytokine response in this infection is appropriate for the amount of virus colonizing the lungs, or whether it is an inappropriate response that should be dampened by immunosuppressant drugs. "It would be important to learn whether the immune response is commensurate with the degree of virus and just trying desperately to kill the virus, or whether it's an excessive immune response that would be successfully amenable to dampening without rendering the host susceptible to more viral replication and perpetuating the process."


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