Connections of Immune system to Central Nervous System

Last blog, we had written about how the brain is actually connected to the immune system. In this blog, we have presented how the immune system which was thought to be a closed system actually gives information about the immune response to the brain and also how the component of immune system are in close proximity of the brain.

It was observed that the electrical and chemical activity of the brain changes during immune responses. For example, hypothalamic neural activity increases at the time of peak B-cell proliferation to an administered antigen. Similarly, neurotransmitters in the hypothalamus, such as norepinephrine, also show profound changes at this time.

Later in one of the experiment using a harmless non-pathogenic protein as antigen, it was seen that that this protein resulted in changes in the brain activity hence leading to the conclusion that the progress and course of an immune response resulted in the changes in the activity of the brain and not the illness.

The cells of the immune system were considered to be the ones to cause these changes. However, the cells of the immune system, such as T cells, B cells, have limited access to the brain, because of the bloodbrain barrier.

It was then proposed that cytokines (Greek words: cyto- cell, kinos- movement) which are the messengers between cells of the immune system, could also converse with the nervous system. The cytokines are soluble proteins released by immune cells, during the course of the immune response. Most foreign proteins, many allergens, malignant cells, dying tissue and injury stimulate cytokine production. The immune cytokines are called interleukins, interferons and Tumor necrosis factor (TNF), lymphotoxin and the colony stimulating factors. IL1, IL2, IL6, TNF and the three interferons are been investigated for their ability to communicate with the brain. Receptors for IL1, IL2, IL6 and a few other cytokines were discovered throughout the brain.

Example of Mechanism of interleukin-1 (IL-1):

IL-1 is synthesized and secreted by a number of different cells. However, activated macrophages are the major source of IL-1 during the specific immune response. Macrophages are activated either by engulfing antigen or by a number of chemical signals that bind to surface receptors on the macrophage. Activation of macrophages with virus or bacterial endotoxin causes release of IL-1. This results in a subsequent alteration in the electrical activity of the brain , as well as metabolism of the neurotransmitters norepinephrine, serotonin, and dopamine in a number of discrete brain regions. Thus IL-l and other cytokines may be the communicators between the immune system and the brain, with potent effects on neural activity.

However, IL-1 are large lipophobic proteins and are therefore unlikely to readily cross the blood-brain barrier. Several possibilities have been proposed with regard to how cytokines could then alter neural activity.

There is an active transport mechanism to carry IL- 1 across the barrier.
IL-1 is able to cross the vascular endothelium in regions of the brain where the barrier is weak or absent, such as in the organum vasculosum lateralis terminalis.
IL-1 can stimulate peripheral nerves that send afferent input to the brain.

Many peripheral nerves have receptors for cytokines. In animal experiments, IL1 activates peripheral nerves, thereby forcing the nerves to send messages directly to the brain. These cytokine experiments indicate that activated immune cells in the skin, stomach, throat or any other site, can send urgent, powerful messages to the brain by secreting cytokines into the blood or into tissue spaces near certain peripheral nerves. Therefore an infection or other pathology in the body can profoundly affect brain function and behavior. Any pathology that activates the immune system can affect brain function and behavior.

The Immune System as a Sensory Organ

Therefore, the communications pathway is bi-directional. The immune system can be considered as a sensory organ. Immune cells are constantly on alert to detect dangerous bacteria, viruses, fungi, foreign proteins, antigens, harmful chemicals, poisons, malignant cells, damaged tissue, dying cells and abnormal cells. Therefore, the immune system is constantly ‘sensing’ for danger at the chemical and cellular level. When immune cells sense danger, they become activated and start secreting various cytokines to inform neighboring cells about the danger. Nearby peripheral nerves, if they have cytokine receptors, will carry the cytokine message to the brain. In addition, if enough cytokine is secreted to spill into the blood, then every tissue and organ in the body, including the brain, will be directly informed of the danger.

Further Evidence For Immune-Brain Connection

Monocytes and macrophages

Monocytes are inflammatory, phagocytic cells of the immune system. They are made in the bone marrow, released into the blood where they circulate for several days. After a few days, monocytes invade tissues and then transform into larger, more complex cells called macrophages (big eater). Blood monocytes can pass through a healthy blood-brain barrier. It was observed in the animals with brain tumors that the activated blood monocytes readily passed through the blood-brain barrier and then began attacking the brain tumor. Activated macrophages in the brain secrete cytokines, including IL1, IL6 and TNF, directly into the brain. Cytokines secreted into the brain are fundamental players in most, brain diseases, such as Alzheimer’s Disease, Parkinson’s Disease and multiple sclerosis.

Microglia

These are the resident macrophages in the brain. The microglia appear to help destroy excessive nerve cells produced during early brain development. The network of layered microglia may be in contact with every nerve cell in the brain. The intimate relationship between microglia and neurons in the brain is an extrordinary example of the profound connection between the immune system and the brain. Under normal conditions microglia are in a resting state and become activated during pathological conditions in the brain. For example, if the brain is injured, then microglia near the injury site become activated and begin secreting cytokines. These cytokines have intense effects on brain and immune system function.

Astrocytes

They are considered as the care-givers for nerve cells, providing nutrients, growth factors and clean-up service when excessive chemicals are present. Astrocytes have receptors for IL1, TNF and the neurotransmitter norepinephrine. Both IL1 and TNF induce astrocytes to produce the powerful immune cytokine IL6. In addition, norepinephrine, which is only secreted by nerve cells, induces astrocytes to release IL6. This means astrocytes can receive messages from the nervous system (via norepinephrine) and the immune system (via IL1 and TNF) and astrocytes can send messages via IL6 to the immune system and the nervous system. This is another example of a powerful but complex communication link between the immune system and the brain.

Lymphocytes

They are found in the blood, lymph, lymph glands and major immune organs like the spleen, thymus and intestine, but they do not normally reside in the brain. Resting lymphocytes are blocked from going into the brain by the blood-brain barrier. Nevertheless, activated T-lymphocytes can readily pass through the blood-brain barrier and then roam around the brain searching for problems. T-lymphocytes can secrete a variety of cytokines if required. If they don’t encounter any difficulties needing their attention, then they exit the brain and return to the blood. Activated lymphocytes are another example of a powerful, complex communication link between the immune system and the brain.

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