Immunomodulation

I wrote this for a group of physicians, so it’s heavy on the science. BUT I think everyone can benefit from understanding the difference between the sympathetic nervous system and the parasympathetic. Also, we can survive without the sympathetic but not without the parasympathetic.

My essay yesterday was about antibodies to tubulin, what tubulin is and how antibodies work. This doesn’t seem very useful if the only thing we can do about the antibodies is remove them by theraputic plasma exchange or give anti-inflammatories. However, there are other approaches. As a rural Family Physician, I have an ever expanding toolbox that I learn from multiple specialties and patients. Mothers of children with PANS/PANDAS may already have figured out many of these techniques.

Our bodies have two basic modes for the nervous system. The well known mode is the sympathetic nervous system. This is the amped up fight or flight system. When we have a very activated sympathetic nervous system, we make less thyroid hormone and less sex hormones and switch production to more cortisol and adrenaline. This helped me to understand adult patients who say they are constantly tired, don’t want sex, they keep getting sick and they also have trouble sleeping. Borderline low thyroid, low sex hormones, elevated cortisol and elevated adrenaline, though it may be at the upper range of normal. The sympathetic nervous system readies muscles for flight or flight, turns digestion to low, reduces secretions everywhere (eyes, salivary glands, stomach, gall bladder, urine, etc) and tightens fascia around the muscles. Blood pressure and heart rate rise. High cortisol over time is not good for the immune system.

The other mode is the parasympathetic nervous system. This is the relaxed system. Digestion and urination works well, muscles relax, cortisol and adrenaline come down, thyroid and sex hormones are manufactured. Blood pressure is lower and heart rate is lower.

The first technique I use to change from sympathetic to parasympathetic is breathing. Swedish hospital is teaching the anxious patients, chronic pain patients and veterans slow breathing. Five seconds in and five seconds out. They recommend building up to 20 minutes over time. If done for 20 minutes, they said that almost everyone calms from sympathetic to parasympathetic. Some people endorse square breathing: in, hold, out, hold, in. I did daily Zen Buddhist meditation facing a wall for 40 minutes during college. This also works and some children might find it an enjoyable challenge. I find Zen meditation easier in a group than alone. I asked a 30 year veteran of the Special Forces to try the 5 in and 5 out breathing because he would find his muscles tight just watching television. He was reluctant, but he returned and said that he is surprised that it works. He also said that he is not used to the relaxed feeling and it feels weird.

Other ways of activating the parasympathetic nervous system for adults include walking, rocking, laughing, magazines seem to love hot baths, anything that relaxes. Playgrounds include places to climb, spin, swing and hang upside down, for children to get a break and play. Again, different people find different things relaxing. During my second strep A pneumonia, an antibody titer came back at 600 with normal being 200 and below. I have read that children can have titers of 2000. I could barely function with a titrer of 600 (off work, obviously) and thought that if my titer was 2000 I would hide under my bed and not come out. I would like input from child psychiatry on downregulating the sympathetic nervous system to parasympathetic in children, but my guess would be that a safe place is very important. Where is that safe place for each child and when they are not having a flare, can they practice going to it in their minds?

Another helpful parasympathetic activity is games or puzzles. My father died leaving an out of date will and a difficult estate. For the year that I worked on it, I did a suduko every day. I could not solve the estate quickly but I could solve the number puzzle every day and that gave me a small window of feeling good and relaxation. Board games or puzzles could work as well. I am less certain about computer games: my understanding is that the visual cortex is activated along with other parts of the brain. This seems more sympathetic than parasympathetic but I could be wrong. The familiarity of a video game may feel very safe and more predictable than the illness. Old movies and reading beloved books is parasympathetic for me. Oddly, sex is parasympathetic in women but both sympathetic and parasympathetic in men. Music can relax many people, and repeating the same music or album over and over. Comics and silly cat videos are parasympathetic.

As a physician, I often acted in a high sympathetic nervous system. A friend of my son’s said, “Your mother is crazy.” My son replied, “No, she’s just intense. About EVERYTHING.” I had to learn not to be intense about everything. We can model relaxation and parasympathetic activity and slowing down for our children, but we may have to set more boundaries at work.

Here is the best write up I have found on the internet about the parasympathetic nervous system: http://www.wisebrain.org/ParasympatheticNS.pdf. They have a great explanation as well as exercises to calm to parasympathetic.

Covid-19, Long Haul and the immune system

“Whether immune-mediated secondary OCD could also develop as a consequence of COVID-19 poses a highly relevant research question to be elucidated in the near future [35, 36]. The first studies of their kind have demonstrated infection-triggered neuronal antibody production against various antigens in COVID-19 patients who were presenting with unexplained neurological symptoms [37].” from https://www.nature.com/articles/s41398-021-01700-4

Um, yes. It is looking highly likely that chronic fatigue, fibromyalgia, and Long Haul Covid-19 are all immune system responses. They are not simple at all. They can involve antibodies, cytokines and killer T cells and probably other things.

Antibodies: the difficulty here is that we all make different antibodies. It’s all very well to say that people with PANDAS and PANS make antibodies to Dopamine 1 and 2 receptors, tubulin receptors and lysoganglioside receptors, but people each make different antibodies. The antibodies can attach and block the receptor or can attach to the receptor and turn the key: act like dopamine, for example. Dopamine makes people tachycardic, a fast heart rate. If dopamine receptors are blocked, that could be a source for “brain fog” and feeling down.

Cytokines: I worked at the National Institutes of Health back in the 1980s before medical school. We were studying interleukin 2 and tumor necrosis factor for cancer treatment. Building 10 had mice on the north south axis and human patients on the east west. It was fascinating. Now I am reading a current book on the immune system. There has been a lot of research since 1988. Cytokines are released by cells and are immunodulating agents. They are a form of communication in the immune system.

Killer T cells: When antibodies coat a cell, there are immune system cells that kill and/or eat the coated cells. This is good if it is an infectious bacteria or a cell infected with virus, but it is bad if it is your own joint cells or your heart cells or, horrors, brain cells. In rheumatic fever, antibodies to strep A attack the patient’s own cells as well as the strep A cells. This is called “pseudo autoimmune” but I am starting to suspect that all the autoimmune disorders are responses to stress or infection or both.

So if you are still reading, you are saying wait, this is awful, what can we do about it?

Our understanding of the immune system is better than 1988 however… it still has a ways to go. I think that Covid-19 and Long Haul Covid are going to seriously accelerate the research in this area. Meanwhile there are some things people can do to “down regulate” or quiet down the immune system.

If antibodies are causing some of the problem, we need to quiet them down. With severe PANDAS in children, plasmapheresis filters the blood and filters out antibodies. However, the body keeps making them. Infection must be treated first, but then the initial antibody response lasts for 6-8 weeks. Then the body makes memory antibodies and cells to remember. With reinfection, the response lasts for 2-4 months and then subsides if the infection is gone.

Treat infection first. Then treat urgent symptoms, including urgent psychiatric symptoms. Then work can start on the sympathetic nervous system, quieting down to the parasympathetic state. This is not easy with Long Haul Covid-19 or chronic fatigue or fibromyalgia because people are afraid, confused, in pain, exhausted. I have written about the sympathetic and parasympathetic nervous systems here and here. Start with slow breathing, four seconds in and four seconds out. It takes practice.

I have been getting feedback at the pulmonary rehab. When I arrive, they take my pulse, 02 saturation and blood pressure. They put the pulse oximeter on and often I am up in the 90s. I slow my breathing and watch my pulse drop. One day I came in relaxed and my initial pulse was 71. When I was a little late, it started at 99 and came down. The therapist took it off when I got my pulse down to 90. We can check our own pulse, the number of heart beats in one minute, or a small pulse oximeter is about $30.

We can’t really “fix” the immune system with drugs. Steroids can quiet inflammation but they make us more susceptible to infection and raise blood sugar and cause multiple problems when used chronically, like osteoporosis. Plasmapheresis is expensive and requires specially trained nurses. Doesn’t a breathing exercise sound a lot more DIY and cheaper too? You got this. Practice, practice, practice.

Are our immune systems failing because of isolation? No, and here is why.

A friend quotes her son, who says that our immune systems are failing because we have been in isolation. I respond that it’s not isolation: it is stress. Anyone who is not stressed by the addition of war to a pandemic needs to have their head examined. Why does stress mess up our immune systems?

We have two main systemic states: sympathetic and parasympathetic. Sympathetic is the high stress, fight or flight, muscles fired up, gut on hold, and unfortunately we have a pretty sympathetic state culture. Add a pandemic on top of that and then a war and no wonder everyone is flipping out. Parasympathetic is the one we don’t hear about: the happy, relaxed one that likes stupid cat videos and laughter.

Without the sympathetic nervous system, we can survive. Without the parasympathetic, we die.

I have written about how we metabolize cholesterol, depending on whether we are in a sympathetic or parasympathetic state. When we are relaxed, or less stressed, we make more sex hormones and thyroid hormone. That is parasympathetic.

When we are in a crisis, or more stressed, we make more adrenaline and cortisol. That is in the sympathetic nervous system arousal state.

A pain conference I went to at Swedish Hospital took this a step further. They said that chronic pain and PTSD patients are in a high sympathetic nervous system state. The sympathetic nervous system is the fight or flight state. It’s great for emergencies: increases heart rate, dilates air passages in the lungs, dilates pupils, reduces gut mobility, increases blood glucose, and tightens the fascia in the muscles so that you can fight or run. But…. what if you are in a sympathetic nervous system state all the time? Fatigue, decreased sex drive, insomnia and agitated or anxious. And remember the tightened fascia? Muscle pain. The high cortisol level also is not good for the immune system, so we are more likely to get sick. High cortisol also raises blood sugar and the immune system is hyperalert. We are more likely to develop autoimmune disorders.

When we are relaxed, the parasympathetic system is in charge. Digesting food, resting, sexual arousal, salivation, lacrimation, urination, and defecation. So saliva, tears, urine, and bowel movements, not to mention digesting food and interest in sex. And muscles relax.

If the sympathetic nervous system is in overdrive, how do we shut it off? I had an interesting conversation with a person with PTSD , where he said that he finds that all his muscles are tight when he is watching television. He can consciously relax them.

“Do they stay relaxed?” I asked.

“I don’t know.” he replies, “but my normal is the hyperalert state.”

“Maybe the hyperalert state, the sympathetic state, is what you are used to, rather than being your normal.”

He sat and stared at me. A different idea….

So HOW do we switch over from the sympathetic to the parasympathetic state?

Swedish taught a breathing technique.

Twenty minutes. Six breaths per minute, either 5 seconds in and 5 seconds out, or 6 in and 4 out. Your preference. And they said that after 15 minutes, people switch from the sympathetic to the parasympathetic state.

Does this work for everyone? Is it always at 15 minutes? I don’t know yet. But now I am thinking hard about different ways to switch the sympathetic to parasympathetic.

Meditation.
Slow walking outside. No headphones! We need to listen to the birds and wind, watch the trees, really look at nature. All of the new sensory input relaxes us.
Rocking: a rocking chair or glider.
Breathing exercises: 5 seconds in and 5 seconds out. Work up to 20 minutes.
Massage: but not for people who fear being touched. One study of a one hour massage showed cortisol dropping by 50% on average in blood levels. That is huge.
Playing: (one site says especially with children and animals. But it also says we are intelligently designed).
Yoga, tai chi, and chi kung.
Whatever relaxes YOU: knitting, singing, working on cars, carving, puttering, soduku, jigsaw puzzles, word searches, making bean pictures or macaroni pictures, coloring, a purring cat, throwing a ball for a dog…..and I’ll bet the stupid pet photos and videos help too….

My patient took my diagrams and notes written on the exam table paper home. He is thinking about the parasympathetic state: about getting to know it and deliberately exploring it.

More ideas: http://www.wisebrain.org/ParasympatheticNS.pdf