Chapter 146
Defeating Infectious Agents — 10
Autoimmunity to the central nervous system—brain and spinal cord—and reactive inflammation to the specific attack on myelin, the fatty tissue that insulates neurons, produced by oligodendrocytes, leads to cell destruction and tissue damage. The course of the disease in an individual is generally either a relapsing-remitting form, which usually responds well to current therapies, or the less common progressive form, in 15 percent of patients. The latter, far more aggressive type has been characterized using single-cell sequencing and spatiotemporal mapping, defining the four stages of lesion formation.
Depletion of B cells with ocrelizumab, a monoclonal antibody directed against CD20 surface receptor, steroids, and other immunosuppressive agents, is the most common treatment prescribed. But engineered T cells, including targeting CD19 (as previously reviewed for lupus and other autoimmune diseases in chapter 9), conjugated antibodies, and stem cell treatments are in clinical trials, as are various ways to manipulate the gut microbiome, which has been implicated in multiple studies.
Establishing Epstein-Barr as the most common cause of MS prompted initiatives to develop a vaccine. In the mouse experimental model of autoimmune encephalomyelitis, which mimics human MS, a vaccine that promotes immune tolerance by blocking self-directed T cell response has suppressed the disease. But the main pathway for vaccines has been to target glycoprotein 350 (gp 350), which enables the entry of Epstein-Barr into B cells, and in the case of related cancers, epithelial cells. Another such viral protein (gH/gL/gp 42) has also been targeted for a bivalent (both proteins) vaccine and exhibited strong efficacy in the mouse model. A vaccine study in mice that targeted both gp350 and a multiprotein strategy induced strong antibody and cellular immunity.
Those are some examples being tested in animal models, but two vaccines are already into clinical programs. Both target gp350. The Moderna program is testing the vaccine in healthy adults aged eighteen to thirty years who are Epstein-Barr negative by blood testing. The National Institutes of Health vaccine uses an iron nanoparticle and is a three-dose strategy in participants testing positive or negative.
These trials are intended to demonstrate the inability of the virus to get into B cells as well as the safety of the vaccines. That’s altogether different from preventing MS. Since MS is uncommon in people newly infected with Epstein-Barr, and since MS takes years to develop, it will take a long time and very large clinical trials to determine preventive efficacy.
That’s where all the progress on genetic susceptibility can come into play. Certain immune system genetic markers are linked to an increased risk of MS, such as HLA-DRB1*15:01, which denotes a greater than threefold risk in whites, as do other HLA markers in African American and Asian populations. Genetic susceptibility has been studied extensively with development of a polygenic risk score based on hundreds of both common and rare genomic variants. Individuals in the highest polygenic risk quartile have about a 40 percent chance of being diagnosed with MS compared with less than 5 percent in the lowest quartile. The list of genomic variants linked to MS keeps growing, such as those responsible for binding in the vitamin D receptor. With extensive assessment of immune markers and cell function, people with up to 260-fold increased risk of developing MS could be identified. A panel of autoantibodies can be used to identify high-risk individuals years before a first attack. Multimodal AI, with inclusion of all electronic health records, labs, images, unstructured notes, autoantibodies, gut microbiome, and environmental and lifestyle+ factors, has begun to unravel MS risk and its arc of progression.