Traditionally, we have understood the immune system and the nervous system as two distinct and unrelated entities. The former fights disease by responding to pathogens and stimulating inflammation and other responses. The latter directs sensation, movement, cognition and the functions of the internal organs. For some, therefore, the recent discovery that left-sided brain lesions correlate with an increased rate of hospital infections is difficult to understand. However, other recent research into the extremely close relationship between these two systems makes this finding comprehensible.
A study, published in the March 2013 issue of Archives of Physical Medicine and Rehabilitation, looked at more than 2,000 hospital patients with brain lesions from either stroke or traumatic brain injury. They looked at how many of these brain-injured patients contracted infections within 2 to 3 days of admission. Of those patients who developed infections, 60% had left-sided lesions. The authors concluded that an unknown left-sided brain/immune network might influence infections. But why would the left side of the brain affect immunity?
The nervous and immune systems are quite different in their speed and mode of action. The two major immune systems, innate and adaptive, are both wireless—they communicate through cell-to-cell contact, secreted signals, and antigen-antibody reactions. The innate system is the first responder, followed by the slower adaptive response. The nervous system, on the other hand, is wired for much more rapid communication throughout the body. It turns out that the two work surprisingly closely together.
The Brain Helps Immune Function
One example of cooperation between the immune and nervous systems is inflammation. Of the four signs of inflammation—pain, heat, redness, and swelling—it has been thought that only pain is mediated through the nervous system. Recently, however, it has been shown that all aspects of the immune process are in some ways modulated or directly meditated by the nervous system.
Only quite recently was it learned that neurons could directly stimulate the immune mast and dendritic cells into action against pathogens. Also, neuropeptides secreted by neurons often function directly as an antibiotic. A surprising new finding is that pain fibers send signals in the direction opposite to their usual sensory function, and directly alter the immune response by stimulating white blood cells and changing the flow of blood.
Direct links between the two systems have now been found in which neurons also affect the three hallmarks of inflammation other than pain—heat, swelling and redness. The first response to danger comes from nerves in the skin, lining of the lungs, and digestive and urinary tracts. Neuronal signals related to noxious stimuli, trauma, toxins, and microbes use more than a dozen recently discovered neurotransmitters to directly change blood flow, which increases heat, swelling and redness and attracts local immune cells. Another finding consistent with this is that severing a nerve lowers inflammation in patients with arthritis.
Many of the complex feedback loops between immune cells and neurons are just being discovered. For example, lymphocytes, whose behavior is now known to be affected by dopamine, also secrete dopamine. In this elaborate communication circuit, lymphocytes are affected by neuronal secretion of dopamine and then use dopamine to pass signals to other immune cells.
The Immune System Helps the Nervous System
Just as neurons are using their hard-wired, speedy connections to perform functions previously thought to be specific to the immune system, so too are immune cells performing tasks thought to be in the purview of the nervous system.
It is critical to avoid damage in the brain from immune reactions. The brain is the only region of the body where intrusion of ordinary immune cells is rare and can be devastating, causing much of the damage associated with illnesses such as meningitis and encephalitis. Microglia are specialized brain-based immune cells, part of the glia family, that protect against intruders near the blood brain barrier. They also watch for microbes near another less well-known protective barrier in the brain, made up of a dense web of astrocytes, another type of glial cell. When there is an intruder, microglia send warning signals to the neurons and other glia cells, triggering a rapid response. In this response, microglia can identify microbes and toxins, and can provide antigens related to these microbes to immune cells. Immune cells, such as macrophages, dendritic cells, and T cells, are waiting in the blood vessels nearby to help.
But immune cells do much more than just protecting the brain from intruders. In the peripheral nervous system, immune cells help rebuild axons that have been damaged. Immune cells are also critical to the very important synapse-pruning process that occurs on a daily basis to update connections and eliminate unnecessary and unused synapses between neurons. One major way that synapses are pruned is with the help of the complement cascade, a very elaborate component of the immune system that “complements” the use of antibodies to kill pathogens. In fact, when a fetus is being pruned of the 900 billion extra neurons not being maintained through experience, there is a very high amount of complement protein present in the fetus. Finally, molecules involved in the immune antigen reactions, such as immunoglobulin, sit on the surface of neurons as adhesion molecules. These adhesion molecules guide neuron migration, as well as the long voyage of the axon to make a synapse, where one neuron meets another neuron that has on its surface a protein molecule from the complement cascade.
A very surprising recent finding goes even further. It has been discovered that microglia control production of neurons from stem cells as the brain develops. These brain-based immune cells remove healthy neural progenitor cells through phagocytosis to control the over-production of neurons.
Immune System and Behavior
There are very close ties between the immune system and human behavior. One example is the influence of interleukin 6, a very important cytokine signal from immune cells, which has been tied to hunger and the ability to burn fat and lose weight. Another very familiar behavior triggered by the immune system is the “sick feeling” that includes fatigue, pain, and lack of interest. The sick feeling is triggered by microglia in the brain, but through a surprising and complex route. When microbes trigger lymphocytes in the body, the lymphocytes secrete cytokine signal molecules, such as interleukin 1 or 6. These cytokines activate the vagus nerve to send a signal backwards from the body to the brain, which triggers the microglia to send yet another signal that triggers the sick feeling. The sick feeling modifies our behavior by causing us to slow down and rest, thus providing more energy for the body to fight the infection.
So, we really have one brain with two branches—a wireless branch that can travel to hard-to-reach places and a hard-wired branch that provides very fast communication throughout the body—both constantly working together. Knowing that the brain influences the immune reaction to infection and that some brain functions tend to be lateralized, it is certainly reasonable to consider the possibility that the left side of the brain helps defend against infections. This recent research finding poses new questions and new directions for future medical innovations. Will we be able to help fight infections in the future with medications, procedures, or other techniques that affect the brain?
1. Pasquale G. Frisina, Ann M. Kutlik, Anna M. Barrett. Left-Sided Brain Injury Associated With More Hospital-Acquired Infections During Inpatient Rehabilitation. Archives of Physical Medicine and Rehabilitation, 2013; 94 (3): 516 DOI: 10.1016/j.apmr.2012.10.012
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