Researchers have a revealed a new molecular mechanism that can determine the degree of severity during anaphylaxis.
Anaphylaxis
Anaphylaxis is a systemic allergic reaction that can affect several systems in the body, including the skin, the gastrointestinal tract, the respiratory system and the cardiovascular system. The most severe form of anaphylaxis is an anaphylactic shock, which results in hypotension and can lead to death. There are several causes of this reaction, including allergy to food, medicines or insect venom. In addition, mast cell are the known effector cells in anaphylaxis.
Unfortunately, within the last few decades, the incidence of anaphylaxis has risen at an alarming rate with the underlying molecular mechanisms responsible still largely unknown. Therefore, understanding the molecular basis of anaphylactic shock is important to develop new biomarkers and effective preventative measures and/or treatments.
Novel molecular mechanism
This study, published in the Journal of Allergy and Clinical Immunology, was based on a clinical case of a patient suffering from severe anaphylaxis to paper wasp venom. This patient had a mutation (P542R) in the KARS gene, which encodes lysyl-tRNA synthetase, a protein with functions in protein synthesis and mast cell activation. The aim of the study was to characterise this mutation at the molecular level. Specifically, the team carried out a range of biochemical, functional and structural characterisation approaches of the mutation in the KARS gene.
The team found that the mutation affects the location of the protein, moving the protein towards the nucleus and preventing its function in protein synthesis. It also activates the MITF transcription factor when there is a lack of stimuli; thereby, increasing the synthesis of proinflammatory mediators and activating mast cells. The team identified that the new mechanism, involving the signalling pathway IgE-LysRWS-MITF, can control the degree of severity in an anaphylactic reaction.
This study for the first time explains the switching mechanism from translation to transcription of LysRS at a molecular level and how specific mutations in the KARS gene regulate its function. This discovery will enable specialists to identify those at risk of severe anaphylaxis and set-in place the proper prophylactic measures.
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