Eosinophils are a crucial component in understanding Churg-Strauss Syndrome (CSS), also known as Eosinophilic Granulomatosis with Polyangiitis (EGPA). These white blood cells, typically associated with allergic reactions and the immune response to parasites, play a central role in the disease. In CSS/EGPA, eosinophils are overproduced and accumulate in tissues, leading to inflammation, damage, and a wide range of symptoms.
To understand the role of eosinophils in CSS, it's essential to explore their normal function, how they contribute to the disease's pathology, and the mechanisms through which they cause tissue damage.
Eosinophils are a type of white blood cell, part of the body's immune system, and make up about 1–6% of the white blood cells in a healthy person. They are produced in the bone marrow and then released into the bloodstream, where they circulate for a short period before moving into tissues.
The primary function of eosinophils is to defend the body against parasitic infections and to play a role in allergic reactions. They do this by releasing toxic substances, such as enzymes and proteins, that can kill pathogens or modulate immune responses. These substances are stored in granules inside the eosinophils and are released when the eosinophils are activated.
While eosinophils are essential for protecting the body, an excessive or inappropriate activation of eosinophils can lead to damage. In diseases like CSS/EGPA, eosinophils become overactive, leading to inflammation and tissue injury in various organs.
In Churg-Strauss Syndrome, eosinophils play a critical role in the disease's progression, from early symptoms of asthma to the later stages involving vasculitis and organ damage. The disease typically progresses through three phases, with eosinophils being a prominent feature throughout.
The first phase of CSS often involves allergic symptoms, most notably asthma and allergic rhinitis (hay fever). Eosinophils are heavily involved in the allergic response, particularly in asthma, where they contribute to airway inflammation.
In this phase, eosinophils are activated by cytokines, signaling molecules that mediate immune responses. In particular, interleukin-5 (IL-5), a cytokine that promotes the growth and activation of eosinophils, plays a key role in eosinophil proliferation and recruitment to the airways. As eosinophils accumulate in the lungs, they release substances that cause inflammation, contributing to asthma symptoms like wheezing, coughing, and shortness of breath.
Asthma is one of the earliest and most common symptoms of CSS/EGPA, often appearing years before other signs of the disease emerge. The persistence of asthma, particularly if it worsens or becomes difficult to control, may be a warning sign that eosinophils are beginning to play a larger role in the body's immune response.
The second phase of CSS is characterized by eosinophilia, or an abnormally high number of eosinophils in the blood and tissues. This phase is where eosinophils begin to invade various organs, causing damage due to the toxic substances they release. The blood count of eosinophils can rise dramatically, often exceeding 10% of the total white blood cell count, which is far higher than normal levels.
During the eosinophilic phase, eosinophils infiltrate tissues such as the lungs, gastrointestinal tract, and skin. In the lungs, eosinophilic pneumonia may develop, leading to symptoms such as coughing, wheezing, and difficulty breathing. The accumulation of eosinophils in the gastrointestinal tract can cause abdominal pain, diarrhea, and gastrointestinal bleeding. Skin involvement may present as rashes, nodules, or hives.
This phase is particularly damaging because the toxic substances released by eosinophils, such as major basic protein and eosinophil cationic protein, cause inflammation and tissue injury. These proteins can directly damage cells and contribute to the formation of granulomas, small areas of inflammation that characterize CSS/EGPA.
In the final phase of CSS, eosinophils contribute to vasculitis, or inflammation of the blood vessels. This phase is the most dangerous, as vasculitis can lead to severe complications affecting multiple organs, including the heart, kidneys, and nervous system.
The exact mechanisms through which eosinophils contribute to vasculitis are not fully understood, but it is believed that their toxic granule proteins and cytokines induce inflammation in the blood vessel walls. This inflammation can cause the blood vessels to become narrowed or blocked, reducing blood flow to vital organs. The result is tissue damage or even tissue death due to lack of oxygen and nutrients.
Vasculitis in CSS can affect blood vessels of various sizes, from small capillaries to larger arteries. The heart is one of the most commonly affected organs in this phase, with eosinophilic myocarditis (inflammation of the heart muscle) being a major complication. Eosinophils can invade the heart tissue, causing inflammation, scarring, and weakening of the heart muscle. This can lead to heart failure if left untreated.
Eosinophils contribute to tissue damage in CSS/EGPA through several mechanisms:
Degranulation: Eosinophils release toxic granules containing proteins like major basic protein, eosinophil cationic protein, and eosinophil peroxidase. These proteins can kill parasites, but inappropriately high levels can also damage healthy tissues. They cause inflammation, damage to the blood vessel walls, and promote the formation of granulomas.
Cytokine Production: Eosinophils release cytokines such as interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), which amplify the inflammatory response. IL-5, in particular, promotes the proliferation and activation of eosinophils, creating a cycle of increasing eosinophilic activity and inflammation.
Recruitment of Other Immune Cells: Eosinophils attract other immune cells, such as neutrophils and lymphocytes, to the site of inflammation. This can lead to a cascade of immune reactions, further contributing to tissue injury.
Granuloma Formation: Eosinophils play a role in the formation of granulomas, small areas of chronic inflammation that are a hallmark of CSS/EGPA. Granulomas form when the immune system attempts to wall off foreign substances that it cannot eliminate. In CSS/EGPA, granulomas often form around blood vessels, contributing to vasculitis.
Given the central role that eosinophils play in CSS/EGPA, targeting these cells is a key strategy in the treatment of the disease. Treatments aim to reduce eosinophil numbers and activity, thereby limiting tissue damage and controlling inflammation.
Corticosteroids, such as prednisone, are the cornerstone of treatment for CSS/EGPA. These drugs suppress the immune system and reduce eosinophil levels in the blood and tissues. Corticosteroids can help control inflammation, relieve symptoms, and prevent further organ damage.
In recent years, biologic therapies that specifically target eosinophils have shown promise in treating CSS/EGPA. One such drug is mepolizumab, a monoclonal antibody that targets IL-5, the cytokine responsible for eosinophil activation and proliferation. By blocking IL-5, mepolizumab reduces the number of eosinophils in the blood and tissues, helping to control the disease.
Other biologic therapies, such as benralizumab and reslizumab, also target IL-5 or its receptor, providing alternative options for patients who do not respond to standard treatments.
Eosinophils are essential immune cells that protect the body from infections and play a role in allergic reactions. However, in Churg-Strauss Syndrome/Eosinophilic Granulomatosis with Polyangiitis, eosinophils become overactive and cause significant tissue damage.
Their involvement in the disease spans all phases of CSS/EGPA, from the allergic and eosinophilic stages to the final vasculitic stage, where they contribute to life-threatening complications. Understanding the role of eosinophils in this disease has led to more targeted therapies, offering hope for better management and improved outcomes for patients.