Immune dysregulation

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Immune dysregulation is any proposed or confirmed breakdown or maladaptive change in molecular control of immune system processes. For example, dysregulation is a component in the pathogenesis of autoimmune diseases and some cancers. Immune system dysfunction, as seen in IPEX syndrome leads to immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX typically presents during the first few months of life with diabetes mellitus, intractable diarrhea, failure to thrive, eczema, and hemolytic anemia. unrestrained or unregulated immune response. [1]

Contents

IPEX syndrome

IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is a syndrome caused by a genetic mutation in the FOXP3 gene, [2] [3] [4] which encodes a major transcription factor of regulatory T cells (Tregs). Such a mutation leads to dysfunctional Tregs and, as a result, autoimmune diseases. The classic clinical manifestations are enteropathy, type I diabetes mellitus and eczema. Various other autoimmune diseases or hypersensitivity are common in other individuals with IPEX syndrome. [2] In addition to autoimmune diseases, individuals experience higher immune reactivity (e.g. chronic dermatitis) and susceptibility to infections. Individuals also develop autoimmune diseases at a young age. [4]

Other genetic syndromes associated with immune dysregulation

APECED

Autoimmune polyendocrinopathy-candidiasis-endodermal dystrophy (APECED) is a syndrome caused by a mutation in AIRE (autoimmune regulator). Typical manifestations of APECED are mucocutaneous candidiasis and multiple endocrine autoimmune diseases. APECED causes loss of central immune tolerance. [5]

Omenn syndrome

Omenn syndrome manifests as GVHD (graft versus host disease)-like autoimmune disease. Immune dysregulation is caused by increased IgE production. The syndrome is caused by mutations in the RAG1, RAG2, IL2RG, IL7RA or RMRP genes. The number of immune cells is usually normal in this syndrome, but functionality is reduced [6]

Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is caused by a mutation in the WAS gene. It manifests itself as a higher susceptibility to infections, eczema, more frequent development of autoimmune hemolytic anemia, neutropenia and arthritis. [6]

T-cell immunodeficiency

Partial T cell immunodeficiency is characterized by an incomplete reduction in T cell number or activity. In contrast to severe T cell immunodeficiency, some of T-cell ability to respond to infections can be maintained. T-cell immunodeficiencies tend to be associated with autoimmune diseases or hyperreactivity and increased IgE production. Mutations tend to be in genes for cytokines (such as IL-7), TCRs, or proteins important for somatic recombination and antigen presentation. [6]

Additional T cell-associated immune dysregulation may be due to a mutation in CTLA-4. CTLA-4 is essential for the negative regulation of the immune response and its loss leads to dysregulation and autoimmune diseases. The disease is characterized by hypogammaglobulinemia, frequent infections and the occurrence of autoimmune diseases. In individuals, the disease may manifest itself differently, with in some cases only a partial reduction in the number of Tregs, in others the ability to bind CTLA-4 ligand has been reduced, resulting in disruption homeostasis of effector T and B cells. The inheritance of this syndrome is autosomal dominant with incomplete penetration. [7]

Immune dysregulation associated with stress

Chronic stress at various stages of life can lead to chronic inflammation and immune dysregulation. Individuals with high stress in childhood (abuse, neglect, etc.) are at higher risk of cardiovascular disease, type II diabetes, osteoporosis, rheumatoid arthritis and other problems associated with immune dysregulation in adulthood. [8] [9] Overall, individuals with higher childhood stress increases the risk of chronic inflammation in adulthood. Higher levels of IL-6 and TNF-α are then noted in stressed individuals. Chronic stress in childhood also promotes the development of proinflammatory types of monocytes and macrophages and they also develop resistance to anti-inflammatory agent (e.g. cortisol). Traumatized individuals also have higher antibody titers to viruses such as Herpes simplex virus, Epstein–Barr virus, or Cytomegalovirus than individuals without chronic stress. [8] [10]

Aging of the immune system

Dysregulation of the immune system is also associated with immunosenescence, which arises due to aging. Immunosenescence is manifested by a decrease in reactivity to vaccination or infection, an impaired ability of T and B lymphocytes to activate and proliferate, or a lower ability of antigen presentation by dendritic cells. In immunosenescence, memory and effector T cells accumulate at the expense of naïve T cells. The lack of naïve T lymphocytes is the cause of low plasticity of the immune system in the elderly. [11] In aging of the immune system is also a decrease in central tolerance and an increase in the number of autoreactive T cells. [12] B cells also have a decreased repertoire of naïve cells and an increase in memory B cells. [13] They also have reduced the production of antibodies against antigens. In immunosenescence, here is a change in the individual subtypes of immunoglobulins. IgM and IgD levels decrease while IgG1, IgG2, and IgG3 levels increase. IgA is higher in the form of monomers in serum but lower as a dimer on the mucosal surface. [11] The overall accumulation of both effector T and B cells is due to the presence of chronic inflammation due to long-term exposure to antigens. In immunosenescence is also a reduced ability to apoptosis, which promotes the survival of memory cells. [11] In old age, innate immunity cells are also affected, when activated cells have a lower ability to return to a quiescent state, only effector functions decrease. [12] Elderly people show poor NK cell reactivity and impaired ability of antigen presentation by dendritic cells. [14] In macrophages, the ability of phagocytosis is reduced and the M2 phenotype of macrophages (alternatively activated) is promoted. [13] Immunosenescence also results in increased production of some immune mediators, such as proinflammatory IL-6 [14] or IL-1. There may also be higher production of anti-inflammatory IL-10 or IL-4. [12] In old age, the ability to heal wounds also decreases, leading to a susceptibility to further infections at the site of injury. [14] The aging of the immune system is also supported by chronic infections, oxidative stress, or the production and accumulation of reactive oxygen species (ROS). The increase in the proportion of memory cells is also affected by cytomegalovirus infection. [11] A chronic pro-inflammatory condition in an aging organism is also referred to as inflammaging. It is a long-term, low-grade systemic inflammation present without the presence of infection. [13]

Dysregulation of the immune system in response to toxins

Immune dysregulation can also be caused by toxins. For example, in environmental workers, increased exposure to pesticides (such as DDT, organophosphate, amides, phthalamides, etc.) disrupts immune system responses. The resulting damage depends on the individual's age, dose and time of toxin exposure. At a young age and in adolescents, there are significant negative effects even with a lower dose of toxins. However, the ability to break down toxic substances and the resulting impact on the organism is also related to the metabolism and genetic equipment of the individual. Toxins can act directly on the cellular component of immunity, or by their metabolites, or they can promote reactive oxygen species (ROS) in the body, or by depletion of antioxidants or oxidative stress. The most common clinical manifestations are immunosuppression, hypersensitivity, autoimmune diseases, but also support for the Th2 response and the development of allergies, or support for chronic inflammation. [15] Conventional toxins and irritants in the environment, such as saliva enzymes of blood-feeding parasites, insect poisons, or irritants in plants, can also cause allergic reactions. These substances can disrupt cell membranes, activate cell receptors, aggregate or degrade certain proteins, or disrupt the mucosal surface layer. The immune system often responds to these substances with reactions that lead to the removal of an irritant substance from the body, such as itching, coughing, sneezing, or vomiting. [16] Combining the action of several toxins at the same time can increase the negative effects, but in some cases the effects of the toxins can cancel each other out. [15]

Allergy

Allergic reactions are misdirected reactions of the immune system to substances commonly found in the environment. Allergens elicit a Th2 immune response, including the involvement of IgE, mast cells, Innate lymphoid cells 2 (ILC2), eosinophils, and basophils. Allergy symptoms are often related to the body's efforts to expel the allergen from the body and to protect it from further exposure to the allergen. [17] Allergic reactions increase the production of mucus by goblet cells on the mucosa. The production of mucus is promoted by IL-13 from ILC2 and Th2 cells. Higher mucus production then creates stronger barrier protection and supports runny nose, coughing, or sneezing. Removal of the allergen from the body by sneezing, coughing, vomiting, or diarrhea is enabled by the activation of peristalsis and contractions of the smooth muscles of the digestive and respiratory systems. Activation of smooth muscles occurs after the action of histamine, which is released by mast cells. Manifestations of allergies generally aim to eliminate the body's allergen. This is also related to hearing the flushing of antigens in the eyes or to attempts to achieve mechanical removal of the surface of the organism. [16]

Allergies can be caused by genetic and environmental factors. Some theories support the view that allergies enter as protection against environmental substances that can disrupt the body, such as insect venom. Another possibility of activating an allergic reaction is the similarity of some allergens to the molecular patterns of parasites against which the immune system also uses a type 2 immune response. [16] The hygiene hypothesis then relates to changes in lifetime exposure to pathogens in developed countries. In the case of insufficient exposure to pathogens and insufficient stimulation of the Th1 response during an individual's development, the balance between Th1 and Th2 type responses may predominate to proallergic Th2. The theory is supported by the more frequent occurrence of allergies in developed countries compared to developing countries, but also by the higher incidence of allergies in cities compared to villages, where individuals can meet with pathogens of farm animals. Children from small families are also more likely to have allergies than children from families with more children, where there is more frequent contact with pathogens from siblings. [17] Another environmental factor that may promote the predisposition to allergies is a reduction in the diversity of the microbiome – this affects the diet of individuals, but also the diet of the mother during pregnancy, method of delivery, breastfeeding, antibiotics, and the presence of domestic or farm animals in the normal life of individuals. [18]

Related Research Articles

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.

<span class="mw-page-title-main">Autoimmune polyendocrine syndrome</span> Medical condition

Autoimmune polyendocrine syndromes (APSs), also called polyglandular autoimmune syndromes (PGASs) or polyendocrine autoimmune syndromes (PASs), are a heterogeneous group of rare diseases characterized by autoimmune activity against more than one endocrine organ, although non-endocrine organs can be affected. There are three types of APS, and there are a number of other diseases which involve endocrine autoimmunity.

<span class="mw-page-title-main">FOXP3</span> Immune response protein

FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

Common variable immunodeficiency (CVID) is an inborn immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM, and IgA. Symptoms generally include high susceptibility to pathogens, chronic lung disease, as well as inflammation and infection of the gastrointestinal tract.

<span class="mw-page-title-main">IPEX syndrome</span> Medical condition

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is a rare autoimmune disease. It is one of the autoimmune polyendocrine syndromes. Most often, IPEX presents with autoimmune enteropathy, dermatitis (eczema), and autoimmune endocrinopathy, but other presentations exist.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

<span class="mw-page-title-main">Autoimmune regulator</span> Immune system protein

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. AIRE is a transcription factor expressed in the medulla of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:

<span class="mw-page-title-main">Autoimmune polyendocrine syndrome type 1</span> Autoimmune condition causing dysfunction of endocrine glands

Autoimmune polyendocrine syndrome type 1 (APS-1), is a subtype of autoimmune polyendocrine syndrome. It causes the dysfunction of multiple endocrine glands due to autoimmunity. It is a genetic disorder, inherited in autosomal recessive fashion due to a defect in the AIRE gene , which is located on chromosome 21 and normally confers immune tolerance.

The effects of parasitic worms, or helminths, on the immune system is a recently emerging topic of study among immunologists and other biologists. Experiments have involved a wide range of parasites, diseases, and hosts. The effects on humans have been of special interest. The tendency of many parasitic worms to pacify the host's immune response allows them to mollify some diseases, while worsening others.

<span class="mw-page-title-main">CD25 deficiency</span> Medical condition

CD25 deficiency or interleukin 2 receptor alpha deficiency is an immunodeficiency disorder associated with mutations in the interleukin 2 receptor alpha (CD25) (IL2RA) gene. The mutations cause expression of a defective α chain or complete absence thereof, an essential part of high-affinity interleukin-2 (IL-2) receptors. The result is a syndrome described as IPEX-like or a SCID.

<span class="mw-page-title-main">Autoimmune enteropathy</span> Medical condition

Autoimmune enteropathy is a rare autoimmune disorder characterized by weight loss from malabsorption, severe and protracted diarrhea, and autoimmune damage to the intestinal mucosa. Autoimmune enteropathy typically occurs in infants and younger children however, adult cases have been reported in literature. Autoimmune enteropathy was first described by Walker-Smith et al. in 1982.

<span class="mw-page-title-main">LRBA deficiency</span> Medical condition

LRBA deficiency is a rare genetic disorder of the immune system. This disorder is caused by a mutation in the gene LRBA. LRBA stands for “lipopolysaccharide (LPS)-responsive and beige-like anchor protein”. This condition is characterized by autoimmunity, lymphoproliferation, and immune deficiency. It was first described by Gabriela Lopez-Herrera from University College London in 2012. Investigators in the laboratory of Dr. Michael Lenardo at National Institute of Allergy and Infectious Diseases, the National Institutes of Health and Dr. Michael Jordan at Cincinnati Children’s Hospital Medical Center later described this condition and therapy in 2015.

<span class="mw-page-title-main">Intestinal mucosal barrier</span>

The intestinal mucosal barrier, also referred to as intestinal barrier, refers to the property of the intestinal mucosa that ensures adequate containment of undesirable luminal contents within the intestine while preserving the ability to absorb nutrients. The separation it provides between the body and the gut prevents the uncontrolled translocation of luminal contents into the body proper. Its role in protecting the mucosal tissues and circulatory system from exposure to pro-inflammatory molecules, such as microorganisms, toxins, and antigens is vital for the maintenance of health and well-being. Intestinal mucosal barrier dysfunction has been implicated in numerous health conditions such as: food allergies, microbial infections, irritable bowel syndrome, inflammatory bowel disease, celiac disease, metabolic syndrome, non-alcoholic fatty liver disease, diabetes, and septic shock.

References

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