Health & Wellness

Relapse and the Immune System: What’s Really Going on?

By Ben Thrower, M.D.

“Relapse” is an important concept to understand in multiple sclerosis. Most people know the basics:  A relapse (also known as an exacerbation or attack) is defined as a new or worsened neurological symptom(s) persisting for at least 24 hours with no better explanation. When diagnosed, 85 percent of people with multiple sclerosis will have a relapsing- remitting form of the disease. With each MS relapse, there is always the potential that the person does not return to their previous baseline and therefore, a new level of disability. One of the goals of treating multiple sclerosis with any of the available disease-modifying therapies is the prevention of relapses. What is actually going on, however, during an MS relapse in terms of the immune system?
The human immune system is incredibly complex. It is made up of both cells and chemical messengers (cytokines) that allow for communication between immune cells. When working appropriately, the immune system is highly regulated and has a balance between inflammatory and anti-inflammatory actions. The human central nervous system is selective about what immune cells can traffic in an area. The blood-brain barrier helps protect the human brain from potentially damaging inflammatory cells, chemicals, and other substances.
During an MS relapse, inflammatory cells from the human immune system cross the blood-brain barrier into the brain and spinal cord, resulting in damage to myelin and nerve fibers (axons). It’s thought that cells in the central nervous system, called glia, become activated and secrete cytokines that serve as sort of a homing signal for inflammatory cells. The blood-brain barrier is less effective in the person with multiple sclerosis at keeping these inflammatory cells out. What we don’t know at this point is what turns on these glial cells in the first place.
Some of the cells involved in the immune attack of a relapse include T-cells, B-cells and macrophages. T-cells can be further divided into classes called CD4 and CD8 cells. CD4 cells can be further divided into cells called Th1, Th17 and Th2. The Th1 and Th17 cells are felt to be inflammatory in nature and are relatively overrepresented in people with MS. During a relapse, Th1 and Th17 cells may be moving across the blood-brain barrier more easily, resulting in myelin/axon damage. Speaking of the blood-brain barrier, we can actually see this “leaky” blood-brain barrier on MRI. When we give dye by vein during an MRI, if the blood-brain barrier is leaky, the dye crosses it and results in MS lesions that “enhance.” This enhancement typically lasts for four to six weeks and then resolves.
B-cells are cells of the immune system that have two major roles in inflammation. B-cells can become plasma cells, which produce antibodies. Antibodies are crucial in protecting us from foreign invaders like bacteria, but can also be problematic in autoimmune diseases like MS. Interesting, a class of antibodies called monoclonal antibodies are also used to treat MS and include Tysabri (natalizumab), Lemtrada (alemtuzumab), Ocrevus (ocrelizumab) and Zinbryta (daclizumab).
Finally, macrophages also play a role in the inflammatory damage of an MS relapse. Macrophage comes from the Greek words “makro” meaning big and “phagein” meaning to eat. So, macrophages are big eaters. Think of them as like a  little Pac-Man, gobbling up bacteria or other undesirable things in your body. Again, in the setting of an autoimmune disease, this normally helpful cell can be turned against healthy tissue, such as myelin.
Fortunately, the human immune system can eventually turn off the immune attack of an MS relapse. Many people recover naturally and completely from an MS relapse. Steroid treatment may speed up the recovery process. Unfortunately, some relapses are not associated with a complete recovery and may lead to a new level of permanent disability. The number of relapses in the first two years after the diagnosis of MS is also important. More relapses in the first two years of MS are associated with a higher risk of needing a cane to walk sooner.
Recovery from a relapse also involves the myelin and axons themselves. As humans, we do have some ability to make new myelin after it has been damaged. The new myelin tends to be thinner than the original equipment and may be more prone to damage from another attack. Even if new myelin is not made, electrical conduction can be re-established across a demyelinated axon. This is done by spreading out sodium channels across the naked nerve fiber. While this does re-establish electrical signaling, this way of repairing the damage may lead to “conduction block” or “nerve fiber fatigue.” In everyday life, this means weakness, visual loss, sensory symptoms or other symptoms that happen with exertion or fatigue. It’s important to remember that you are not causing any new damage if you overheat or exert yourself too much. You are simply draining the battery. Once you rest and cool off, things should be back to baseline.
In terms of managing relapses, the best treatment is prevention. That’s the goal of any of the 16 available FDA-approved disease modifying therapies. If you do experience a relapse, decisions will need to be made about treating it with steroids or not, and whether any changes are warranted to your existing long-term therapy. In general, there are not many lifestyle factors that we think are associated with a higher risk of a relapse. Let’s look at a few though:
• Stress – Many people with MS will experience a temporary increase in symptoms when they are stressed. This is usually not a true relapse, however.

• Infections – Infections may be associated with pseudorelapses. These may walk and talk like a relapse, but are being driven by the underlying infection. Urinary tract infections and upper respiratory infections are the most common culprits. (See Megan Weigel’s article on page 16 to learn more about pseudorelapses.)

• Tobacco smoking – Several studies have shown that tobacco smoking may be associated with more severe and more frequent MS relapses.

• Vitamin D – Research is increasingly showing that vitamin D is important in MS. Having 25 hydroxy vitamin D levels above 50 has been associated with fewer MS relapses and MRI lesions. Don’t overdo it though. Excessive vitamin D can be harmful to your health. It’s best to base vitamin D dosing on blood levels, so work closely with your doctor.
Understanding relapses is crucial in MS. There’s a lot going on with our complex
immune system during an attack. While this presents challenges on one hand, it also means there are many opportunities for science to prevent relapses and move one step closer to a cure.