Introduction:
Autoimmune diseases occur when the body's defense system cannot identify the difference between its cells and outside or foreign cells. This makes the immune system mistakenly attack the normal cells of the body. It affects a lot of body parts, causing morbidity and mortality all over the world.
NF-kB, or nuclear factor kappa B, is a protein complex that regulates immunity, inflammation, cancer, and the nervous system. It is present in most of the cells in the body. It is associated with the cellular response to various stimuli like stress, the presence of microbes, free radicals, exposure to ultraviolet radiation, etc. NF-kB regulates a large group of genes that play a significant role in regulating immunity and inflammatory response. This protein complex comprises five members, including NF-kB1, NF-kB2, RelA, RelB, and c-Rel. Inaccurate regulation of NF-kB is associated with cancer, inflammatory diseases, autoimmune diseases, septic shock, and viral infection.
Over five percent of the Western population is affected by some autoimmune disease with improper activation of the nuclear factor NF-kB. The treatment for autoimmune diseases has improved to a great extent over the years.
What Causes The Activation of NF-kB?
There are two separate pathways involved in the activation of NF-kB:
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Canonical or the Classical Pathway- This involves the NF-kB dimers (a group of molecules linked together) and regulating NF-kB activity, creating an autoregulatory feedback loop. Following the activation of NF-kB, the newly synthesized proteins move to the nucleus (the center of the cell), where it binds to the NF-kB molecules, blocking their DNA (hereditary material in organisms) binding ability, thus limiting the duration of NF-kB-dependent responses.
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Noncanonical Pathway- This pathway controls the genes important for regulating homeostatic processes such as lymphoid organogenesis, metabolism of bone, and survival of B cells (the cells of the immune system that develop from the bone marrow). This pathway is triggered by the members of the tumor necrosis factor receptor. Tumor necrosis factor is a cellular toxin substance produced by the immune cells. Activation of the noncanonical pathway is usually slower than the classical pathway.
NF-kB activation has been found in patients with rheumatoid arthritis and plays an important role in expressing proinflammatory genes. Improper NF-kB activation has also been found in biopsy specimens of individuals with Crohn's disease and ulcerative colitis, known as inflammatory bowel diseases. This activation of NF-kB leads to the production of proinflammatory mediators, with a few of these mediators further activating the NF-kB protein complex, thus leading to an autoregulatory circle and the continuation of the disease. The abnormal expression of NF-kB does not always increase the activity of the complex.
What Mechanisms Cause NF-kB Activation?
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NF-kB as a Mediator of Pro-inflammatory Gene Trigger -
Inflammation is the body's response to infections and tissue damage. It is characterized by widening the blood vessels, redness, and transport of the immune cells and certain proteins to the site of injury or infection. Inflammation is a beneficial response, but long-term inflammation can cause tissue damage leading to the development of acute or chronic inflammatory diseases.
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The Function of NF-kB in Innate Immune Cells -
The innate immune system is the first line of immunity against pathogens. The cells of innate immunity express a certain class of receptors that recognize pathogens and damaged cells. The canonical NF-kB pathway activates these receptors to induce inflammatory mediators in various types of innate immune cells. These inflammatory mediators can directly take part in inflammatory processes or indirectly act via T cells (cells of the immune system formed in the bone marrow).
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The Function of NF-kB in T Cells -
The canonical pathway has a pivotal role in T cell activation. Deregulation of NF-kB activation causes changes in T cell activation, which is associated with autoimmune and inflammatory responses.
NF-kB Is Associated With Which Inflammatory Diseases?
NF-kB has been associated with several inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, systemic lupus erythematosus, type 1 diabetes, chronic obstructive pulmonary disease, and asthma. NF-kB plays an important role in various diseases.
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Rheumatoid Arthritis - Rheumatoid arthritis is a chronic inflammatory disease characterized by the infiltration of immune cells into the lining of the joints causing chronic inflammation and destruction of bone and cartilage. NF-kB is an important mediator of rheumatoid arthritis. NF-kB triggers the proinflammatory cells. Many of these cells further trigger additional inflammatory cells leading to a cycle of inflammation. This also leads to inflammatory bone loss in rheumatoid arthritis.
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Inflammatory Bowel Disease - This includes diseases like Crohn's disease and ulcerative colitis. They are inflammatory disorders of the gastrointestinal tract that results from an improper inflammatory response to microbes. NF-kB has been involved in the pathogenesis of IBD and has been found in the colon tissues of such patients.
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Multiple Sclerosis - It is an inflammatory condition of the nervous system. Both the canonical and noncanonical pathways play an important role in the pathogenesis of multiple sclerosis. NF-kB also regulates neuroinflammation in the central nervous system.
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Atherosclerosis - Atherosclerosis is the inflammation of the walls of the blood vessels characterized by the deposition of cholesterol particles and immune cells. NF-kB is associated with a large group of genes involved in various pathological processes of atherosclerosis. In the cells of the blood vessels, NF-kB induces proinflammatory cells, thereby causing disease progression. NF-kB also causes the myeloid cells (bone marrow cells) to enhance inflammatory gene expression.
Conclusion:
It is concluded that NF-kB is a central inflammatory mediator that responds to many immune receptors. Deregulated NF-kB activation has been associated with several inflammatory diseases, so targeting the NF-kB pathway opens an opportunity for anti-inflammatory therapies. Various inhibitors have been developed to block the different pathways of NF-kB signaling. Important progress has been made in designs approaching the inhibition of NF-kB.
The development of clinically available NF-kB-based drugs is still a far-fetched dream. NF-kB inhibition could be beneficial in treating inflammatory diseases. Still, the fact that NF-kB function is also needed for maintaining normal immune response and survival of cells raises the question of balance between efficacy and safety. Furthermore, many studies suggest that inhibiting NF-kB signaling may lead to severe side effects. Therefore a better knowledge of the underlying mechanism of the pathological activation of NF-kB in inflammatory diseases is important for preparing specific and effective drugs for treating several inflammatory diseases.
