How Does Eczema Affect The Immune System – Itching is often described as a hallmark of atopic dermatitis (AD), and nearly 100% of people with AD report pruritus as one of their main symptoms. Itching causes scratching, which can be very annoying and difficult to deal with. Itching and scratching have been shown to affect sleep, physical activity, daily functioning at work or school, social life and mental health (depression, anxiety, suicidal thoughts), resulting in an overall reduced quality of life.
Investigating itching is not easy. Dr. Gil Josipovich, a professor at the University of Miami and a renowned itch clinician and researcher, said, “In the beginning, the general understanding was that AD was an immune disease. We had a very limited understanding of the neural transmission mechanism of itch. Dr. Brian Kim, professor of dermatology at the University Mount Sinai, after saying: “People do not know that itching itself is a disease. It is very difficult to get money to support your research if no one believes that you are studying a real disease. .
- 1 How Does Eczema Affect The Immune System
- 2 Types Of Eczema: Symptoms And Causes
- 3 What Causes Eczema To Flare Up? Causes & Triggers
How Does Eczema Affect The Immune System
Despite the difficulties, some itch researchers have determined that there are multiple mechanisms underlying pruritus in AD, in which keratinocytes (i.e., the main structural cells of the skin), as well as various immune, nerve, and brain cells play a role. role. . How all these different cells and systems communicate and interact is still an active area of research, but it is becoming increasingly clear that all these systems talk to each other (Figure 1).
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Think about how the function of the skin has evolved significantly in recent years. “We used to think of the skin as just a brick-and-mortar structure that blocks environmental stimuli,” said Dr. Kim. “In recent years, we have realized that the skin itself is an immune system, part of the innate immune system.” Dr. Kim added that “the structure of the brick and mortar wall actually integrates directly with the immune system. The nerves quickly sense and modify specific responses to alert the body when something is wrong. The nerves interface and integrate with the immune system to create a fluid, sophisticated response. .The structure of the skin, the immune system and integrated neurons, do not spread.
Figure 1: Multiple systems underlying pruritus in AD. In AD, the structure of the skin is disrupted, resulting in a damaged skin barrier. Keratinocytes release active proteins (enzymes such as kallikrein (KLK)) and immune signals (cytokines and interleukins (IL)), which further disturb the skin structure and activate various cells of the immune system (shown in purple). Nerve fibers in the skin (shown in yellow) activate signals released by keratinocytes and immune cells, which then transmit messages through the spinal cord and into the brain. The brain receives this message as an unpleasant sensation and tells the hand to start scratching, which can activate the brain’s reward center, causing an itch/scratch cycle that can worsen AD symptoms and impair quality of life. Image adapted from ref 19 and generated using Biorender.com.
The axis of pruritus in AD involves the skin, nerve signals, and the brain and immune system
The skin is a sensory organ, and itching is one way the skin interacts with the environment.
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When the skin is healthy, the outer cells that form the skin’s barrier, called the stratum corneum, prevent foreign bodies from entering the skin – allergens and pathogens cannot enter the skin. Healthy skin also has nerve endings that terminate in the dermis, the layer of tissue below the epidermis.
However, when the skin barrier is disrupted (as in AD), allergens and pathogens can enter the skin, increasing inflammation.
Nerve fibers found in the skin are called pruriceptors, which act as “antennas” to continuously sample the environment and send signals along neurons to the spinal cord and brain for interpretation.
When there is an acute itch, such as an insect bite, mast cells release histamine, which can activate special nerve fibers (C nerve fibers), which then connect to the spinal nerves and up to the brain. For this type of itching, antihistamines can be used topically or used systemically to reduce itching. However, antihistamines usually do not relieve itching in AD
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Brain imaging has shown that brain regions involved in emotion, reward, and memory of negative experiences, as well as pain processing, are more active in itchy AD than healthy people.
Dr. Josipovic said: “Emotional states such as stress, anxiety and mood changes can affect the skin-inflammation-nerve-brain axis. For example, it can increase itching in AD by damaging the skin barrier, increasing inflammation and increasing nerve sensitivity.
Itching causes an urge to scratch, which can provide temporary relief from itching. However, the reward mechanism in the brain is activated by scratching, which can lead to the pleasure associated with scratching. This can lead to an “itch cycle” that can damage the skin and worsen AD symptoms. New research shows that when people itch and scratch their skin, two types of nerves are activated in the brain – the gamma-aminobutyric acid (GABA) nerve and the dopaminergic (DA) nerve.
GABA neurons are what tell the brain to process the disturbed sensations associated with itching, and DA neurons contribute to the pleasure associated with scratching. DA neurons are activated only after scratching, meaning that if the itchy person does not scratch, only the unpleasant itching sensation will be felt. Inhibition of DA nerve activation results in reduced scratching behavior in mice, suggesting that blocking these nerves therapeutically can reduce the itch cycle. GABA nerve block can also reduce the unpleasant sensation associated with itching and reduce the urge to scratch.
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Keratinocytes are also an active part of the immune system; they have the ability to release signaling molecules that talk to the immune and other nervous systems. AD has long been known to be caused by a damaged skin barrier and an enhanced immune response that is influenced by genetics, the environment, and the specific types of immune cells that are activated.
, but keratinocytes also play a direct role in itching. Keratinocytes secrete active proteins called enzymes, especially kallikrein (KLK), which break down other proteins. Under normal conditions, in healthy skin, KLK can remove the top layer of the skin to prevent the skin from thickening. However, some kallikreins, especially KLK7, KLK8, KLK10, and KLK11, are up-regulated in AD-injured skin.
, and by increasing the activation of KLK, excess cell depletion and the barrier decrease.
Interestingly, in a mouse model of AD lacking KLK7 expression, the mice still had AD and had an improved immune response, but the animals had a reduced scratch response. KLK7 itself was found to activate nerves that are itchy without involving the immune system.
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Dr. Kim is the author of the study and said, “The reduction of itching in mice is amazing, but we still don’t know exactly what KLK7 does. We are happy to continue this research because pharmaceutical companies are very interested in finding a way to selectively block KLK7, to reduce itch.
The main function of the skin is to protect the internal body from external attacks. Dr. Ethan Lerner of Massachusetts General Hospital believes that the sensation of itching is a switch to activate the immune system, thereby providing protection against foreign bodies and pathogens that enter the skin. She said, “Scratching is fun because it’s your body’s way of activating your immune system.” AD pruritus has been shown to be related to interactions between nerves and different types of immune cells.
Active neurons participate in the recruitment and activation of immune cells by releasing chemical messengers called neuropeptides and chemokines.
On the contrary, the immune cells release many signals that activate nerves to send itching sensations to the spinal cord and brain.
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Interleukin IL-31, first discovered in 2004, is the cytokine most directly involved in mediating itch. IL-31 is released by many types of immune cells, including T cells, mast cells, macrophages, basophils, eosinophils, and dendritic cells. Keratinocytes release IL-31, further demonstrating how keratinocytes are part of the immune system. Blockade of antibodies against IL-31 or its receptor rapidly reduces itching in mice, dogs, and humans.
Keratinocytes can also release interleukins and messengers called IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), all of which activate pruritic interleukins (IL-4, IL-13, and IL-31), which then act. . nerve fibers cause itching.
Exciting recent work has shown some significant differences in the immune response to acute AD flares, often triggered by allergen exposure, compared to the chronic pruritus associated with AD. Immune cells called basophils circulate more in the blood and are localized in the skin tissue of AD patients compared to healthy people.
Basophils localize along cutaneous nerve endings to transmit itch signals. AD patients have a subset of basophils that express high levels of the IgE receptor, which is a signal.
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