What Is OTULIN?
OTULIN is a gene that provides necessary information and instructions for making a protein called ubiquitin. This protein helps in the regulation of inflammation which is part of the body's early immune response to foreign bodies. Inflammation occurs when the immune system sends white blood cells and signaling molecules toward the site of injury. These molecules and white blood cells initiate tissue repair and inflammation at the site of injury. The process via the information starts is called ubiquitination. In this process, the molecule called ubiquitin gets attached to specific proteins and initiates the process of inflammation.
As soon as the foreign invaders are recognized, ubiquitin molecules get linked to each other, called linear ubiquitin chains, and then get attached to particular proteins. The addition of these chains initiates signaling pathways that lead to inflammation. And hence when the infection is under control, the body stops the inflammatory process to prevent damage to its own cells and tissues. The OTULIN protein controls inflammation by removing linear ubiquitin chains. In addition to the information process, the OTULIN routine is also involved in regulating the development before birth and controlling cell death.
What Is OTULIN Deficiency?
The normal mechanism of inflammation is carried out by OTULIN. Activation of various immune receptors triggers the assembly of Met1-Ub by LUBAC. This carries out inflammation under normal conditions and is counterbalanced by other DUB OTULIN. But in cases of loss of function in OTULIN accumulation of Met1-Ub occurs independently of receptor activation. This develops a severe auto-inflammatory condition called OTULIN-related autoinflammation syndrome (ORAS).
What Is an Auto-Inflammatory Disease?
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The immune system is made up of a network of cells and tissues throughout the body that works together to defend against bacteria, viruses, and infection. The immune system comprises acquired and innate immunity.
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An autoinflammatory disorder implies difficulty with innate immune system reactions. The cells target the healthy tissues of the body. This leads to episodes of inflammation that result in a fever, skin rash, or joint swelling.
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The other symptoms include inflammation of the connective tissue, bone pain, swelling of bone tissue, recurrent infections, and delay in development. Autoinflammatory diseases are rare and are characterized by unprovoked episodes of fever and inflammation. Since the episodes of inflammation and fever occur regularly the disease is also called periodic fever syndrome. Autoinflammatory responses are different from autoimmune responses due to the dysfunction of the adaptive immune system. Examples of autoinflammatory disease or familial mediterranean fever (FMF), deficiency of interleukin-1 receptor antagonist (DIRA), hyper immunoglobulin D syndrome (HIDS), and cryopyrin-associated periodic syndromes (CAPS).
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The main reason behind auto-inflammatory disease is their inheritance from parents to the children leading to multiple cases of the disease in the extended family.
What Is an OTULIN-Related Autoinflammatory syndrome?
The OTULIN-related auto-inflammatory syndrome is the result of the autoinflammatory response of the body. The auto-inflammatory mechanism occurs due to a mutation in the gene OTULIN. The symptoms include fever, joint pain, skin rash, arthritis, and recurrent infection. The mutation causes changes in fibroblasts and monocytes. Both fibroblast and OTULIN-deficient monocytes are sensitive to certain types of tumor necrosis factor-induced death and apoptotic cell death. The OTULIN deficiency impairs the function of fibroblasts and monocytes. This impairment leads to an abnormal response to tumor necrosing factors. The OTULIN-deficient fibroblast and monocyte are sensitized to tumor necrosis factor-induced death and apoptotic cells. This results in various skin lesions. The only treatment is the transplantation of hematopoietic stem cells for complete resolution of inflammatory response. The transplantation also reserves other symptoms like periodic fever, inflammation of the subcutaneous fat, and diarrhea.
What Are the Symptoms of OTULIN-Related Autoinflammatory syndrome?
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Recurrent Fever - Mutations in the genes lead to disturbances in the inflammation mechanism causing fever, diarrhea, skin rash, and joint pain.
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Leukocytosis - Leukocytosis is an increase in the number of white blood cells.
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Increase in Blood Entities - Abnormal mechanism in inflammation leads to an increase in various blood entities like c-reactive protein, blood ferritin, and interleukin-6.
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Otulipenia - It is the condition seen in babies with at least three mutations in the OTULIN gene. The affected babies have episodes of fever, skin rashes, diarrhea, and painful joints. The excessive inflammation that results due to OTULIN gene mutation causes symptoms of otulipenia.
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Other Conditions - The other conditions that result from OTULIN deficiency are diarrhea, panniculitis (inflammation of the subcutaneous fat), and arthritis.
How Is OTULIN Deficiency Diagnosed?
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Physical Examination - The physician checks all the signs and symptoms related to auto-inflammatory diseases like skin and joint problems. Skin problems are significant in helping with early diagnosis and effective treatment plans.
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Family Medical History - A family history of the autoinflammatory disorder increases the risk of developing the same kind of disorders in future progeny. The disorder is inherited from parents to the children and is passed on in extended families too. Genetic screening is very essential to rule out these hereditary disorders.
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Blood Examination - Blood examination shows elevated levels of interleukin-6, c-reactive protein, blood ferritin, and white blood cells. These are the markers of inflammation.
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Genetic Testing - Genetic screening helps in determining mutation in a specific gene causing an autoinflammatory response.
How to Treat OTULIN Deficiency?
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Hematopoietic Stem Cell Transplantation - Transplantation of stem cells leads to complete resolution of the inflammatory response, including diarrhea, fever, and panniculitis. Therefore, transplantation of hematopoietic stem cells is very necessary as the pathogenesis of ORAS involves hyperinflammatory immune cells and tumor necrosis factor-induced death of leukocytes and non-hematopoietic cells.
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Anti-tumor Necrosis Factor (TNF) Therapy - Anti-TNF therapy is used to treat various types of auto-inflammatory diseases. It works by blocking a protein called interleukin-1.
Conclusion :
OTULIN deficiency occurs as a result of a mutation in the gene OTULIN. The deficiency results in an abnormal mechanism of inflammation. The deficiency of OTULIN in humans causes an auto-inflammatory process and the syndrome related is called OTULIN-related auto-inflammatory syndrome. The symptoms include swelling, arthritis, fever, skin rash, joint pain, and inflammation of the subcutaneous fat (panniculitis). The treatment is done by transplantation of hematopoietic stem cells that reduce the hyperinflammatory response of the immune cells.
