Immune Dysregulation

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 pathogeneses of autoimmune diseases and some cancers, to the extent that the pathophysiology is understood to date. 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.

IPEX syndrome

IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is a syndrome caused by a genetic mutation in the FOXP3 gene, 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. 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.

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.

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

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.

T-cell immunodefficiency

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.

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.

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. 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.

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 weaker NK cell response, but also by impaired activation and proliferation of T and B lymphocytes. B cells also have a weaker production of antibodies. As a result of aging, there is an increase in the production of proinflammatory mediators such as IL-6. After immunization (vaccination), elderly individuals have less responsiveness and reduced production of antibodies to antigens. Also, in old age, the wound healing process slows down, which leads to a greater susceptibility to infections at the wound site. The aging of the immune system is also supported by chronic stress.

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. 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.