Introduction:
The immune system of the body is a complex system that does the work of protecting the body from infections and can also attack the own cells of the body. In situations where the immune system is not able to protect the body, it is considered deficient. When the immune system incorrectly attacks the own tissues of the body, cells are termed autoimmunity. The term immune dysregulation is used for individuals with both these conditions. Therefore immune dysregulation disorders are usually associated with immunodeficiency disorders and other autoimmune diseases.
How Does the Immune System Work?
The prime function of the immune system is to identify foreign invaders such as bacteria, viruses, fungi, and parasites and then eradicate them from the body. The cells of the immune system can move around all over the body and help fight or remove harmful objects. These cells are abundant in the liver, bone marrow, thymus, tonsils, lymph nodes, blood, and spleen. These are where immune system cells are formed, stored, and transported to all body parts wherever there is infection. The primary cells and proteins of the immune system include:
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B-cells (also called B-lymphocytes).
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Plasma cells (antibodies made by certain B-cells).
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T-cells (also called T-lymphocytes).
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Phagocytes.
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Complement system.
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Antigen-presenting cells.
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Natural killer cells.
What Are the Potential Reasons for Immune System Dysregulation?
The immune system can malfunction due to some of the following reasons, which include:
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Over-reaction to any harmless stimulus reading to problems like sneezing or itching.
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Attacking the healthy cells and tissues of the body is termed autoimmunity.
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Not able to detoxify or eliminate the harmful substances that enter the body.
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Not able to combat the harmful pathogens such as bacteria, viruses, or parasites that invade the body and cause infections.
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Keeping the body in a heightened state of “attack” causes inflammation and oxidative stress, which can disrupt cellular functions and operations.
What Are the Types of Immunodeficiency Disorders?
The immune dysregulated or immune deficiency syndrome can lead to frequent and recurrent infections of varying severity. The disorder that occurs due to an underlying medical condition is secondary (acquired) immunodeficiency disorder. This is a more common type and is one reason for adult recurrent infections. The primary (congenital) immunodeficiency disorder is a less common type, usually present in infants.
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Primary Immunodeficiency - This type of immunity disorder is usually present during birth due to genetic abnormalities of the immune system. This can cause problems with the cells of the immune system, such as T-cells, B-cells, phagocytic cells, or the complement system. Research shows more than 430 children are born with primary immunodeficiency yearly. Most of these primary immunodeficiency disorders are run within families, including X-linked agammaglobulinemia (XLA), severe combined immunodeficiency (SCID), and DiGeorge syndrome.
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Acquired Immunodeficiency - This occurs when the immune system cannot function properly due to a secondary underlying infection in the body or due to medications or any surgical procedure. It is more common than primary immunodeficiency, and the following conditions can lead to secondary immunodeficiency, which includes -
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Leukemia or multiple myeloma.
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Medicines used in chemotherapy or immunosuppressant drugs such as Cyclophosphamide, Mycophenolate mofetil, Azathioprine, and Rituximab.
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Chronic infections such as acquired immune deficiency syndrome (AIDS) are caused by the human immunodeficiency virus (HIV).
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Radiation and burns can also result in immune deficiency.
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Surgical procedures such as the removal of the spleen (splenectomy).
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Each of these immune system disorders differs from the others and needs to be treated differently. Therefore a complete understanding of the disease is required to understand the symptoms and manage them following a specific treatment plan.
What Are the Symptoms of Immune Dysregulated Disorders?
The most obvious sign of immune dysregulated disorders includes frequent or unusual infections. In addition, the dysregulated immune system cannot protect the body from harmful invaders, which leads to harmful effects on the body itself, causing inflammatory or gastrointestinal symptoms.
In the case of children, various types of chronic infections of the ears, sinuses, and gastrointestinal system can be seen as their immune systems are dysregulated or do not function properly. Some of the following symptoms in children may indicate that the immune system is not functioning properly which include the following:
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Recurrent ear infections.
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Chronic or recurrent sinus infections.
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Swollen lymph nodes.
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Chronic vaginal infections or urinary tract infections.
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Chronic runny nose or cough.
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Chronic athlete's foot, ringworm, or other fungal skin infections.
In adults, some of the following symptoms can be seen, which include the following:
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Two or more new ear infections within a year.
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Two or more new sinus infections within a year.
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Chronic diarrhea with weight loss.
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Recurrent viral infections include the common cold, herpes, warts, and condyloma.
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Recurrent requirement for intravenous antibiotics to clear infections.
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Recurrent, deep abscesses of the skin, lymph nodes, or internal organs.
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Persistent thrush or fungal infections on the skin or elsewhere.
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Infections with tuberculosis-like bacteria.
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A family history of primary immunodeficiency.
What Are the Various Dysregulated Immune Disorders?
The different types of dysregulated immune disorders include:
1. Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX), and IPEX-like Conditions - This genetic disorder affects the function of a type of white blood cell that regulates the immune system of the body. This leads to harming the healthy cells of the body by the immune system. This can cause other infections which may be difficult to treat, such as inflammatory bowel disease (IBD), resulting in diarrhea and failure to thrive, severe eczema, and autoimmune endocrinopathies such as Type 1 diabetes. The genetic mutation in gene FOXP3 causes IPEX. In addition, certain conditions affect T-cell tolerance, activation, and proliferation resulting in similar clinical manifestations, which are referred to as IPEX-like conditions.
2. Autoimmune Lymphoproliferative Syndrome (ALPS) and ALPS-Like Conditions - This condition is usually linked to underlying immune regulatory disorders. Patients with this condition are referred to as ALPS-like, and it can also occur due to genetic mutations in genes STAT3, CTLA-4, LRBA, and PIK3CD. Genetic testing can identify genetic abnormalities in these patients, and appropriate therapeutic interventions can be used, including drugs like Sirolimus, Abatacept, Tocilizumab, and Ruxolitinib.
3. Common Variable Immune Deficiency (CVID) - This disorder is associated with low immunoglobulin levels that can lead to recurrent lung and sinus infections. While some patients develop infectious complications of their immune deficiency, and others may develop non-infectious inflammatory disease and immune dysregulation, which can lead to a shortened lifespan.
4. PLCG2-Associated Antibody Deficiency and Immune Dysregulation (PLAID) - This disorder occurs due to a mutation in phospholipase C Gamma-2 (PLCG2). This mutation leads to impaired B cell receptor signaling and impaired signaling through natural killer cell activating receptors. Patients with these conditions have antibody deficiencies and autoimmune disorders, including vitiligo, autoimmune thyroiditis, inflammatory arthritis, and connective tissue diseases.
5. Hemophagocytic Lymphohistiocytosis (HLH) - This disorder is a serious condition that can be fatal if not treated or diagnosed early. It is caused due to defects in T cells and natural killer cells of the immune system. This is commonly seen in patients with conditions like Epstein-Barr virus (EBV), underlying malignancy, and systemic rheumatological conditions.
6. Very Early Onset Inflammatory Bowel Disease (IBD) and Treatment-Refractory IBD - This disorder is usually found in patients younger than five and has an underlying immune and genetic defect.
7. Periodic Fever Syndromes and Autoinflammatory Syndromes - This is seen in patients with unexplained recurrent fevers without any infections and may need to check for underlying periodic fever syndrome and autoinflammatory syndromes.
How to Diagnose Dysregulated Immune Disorders?
The initial step in diagnosing the dysregulated immune disorder is the physical examination followed by multiple tests, which include the following:
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Detailed medical history, including detailed family medical history.
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Physical exam.
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Blood tests.
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Vaccines to test the immune response.
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Genetic testing.
What Is the Treatment for Dysregulated Immune Disorder?
The treatment of dysregulated immune disorders depends upon the type and severity of the condition. The medications that can be prescribed may include the following:
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Antimicrobial therapy to fight and prevent infections.
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Immune globulin replacement therapy.
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Vaccinations.
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Specialized immune globulins.
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Hematopoietic cell transplant.
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Enzyme replacement therapy.
Conclusion:
Dysregulated immune disorders are commonly seen in patients with primary immunodeficiency diseases. Early diagnosis and treatment of these conditions are critical to have a good and quality life and decrease the associated complications. Patients and their care providers should be aware of the signs and symptoms that may indicate these disorders.
