Inflammasome regulation in Cryopyrin Associated Periodic Syndromes

  • Research type

    Research Study

  • Full title

    Understanding inflammasome over-activation in Cryopyrin Associated Periodic Syndrome patients.

  • IRAS ID

    171875

  • Contact name

    Gloria Lopez-Castejon

  • Contact email

    gloria.lopez-castejon@manchester.ac.uk

  • Sponsor organisation

    University of Manchester

  • Research summary

    Cryopyrin-Associated Periodic Syndromes (CAPS) are a group of rare, inherited, autoinflammatory diseases. These syndromes are not contagious, differ in the organs involved and in the severity of the disease. The major symptoms include fever, hive-like rash, joint pain and swelling, red eyes, hearing loss and central (brain) nerve problems.

    CAPS are generally caused by mutations of the NLRP3 (nucleotide-binding domain, leucine-rich family [NLR], pyrin domain containing 3) gene that results in alterations in the protein cryopyrin, which NLRP3 encodes and that is critical to the production of the inflammatory cytokine interleukin-1β (IL-1β). These genetic mutations lead to certain immune cells becoming overactive and producing too many chemical messengers, such as IL-1β overproduction, resulting in an inflammatory response and the symptoms of CAPS. Treatments that block IL-1β, such as Canakinumab, are very effective; they need to be administered every 8 weeks and long term effects of the treatment are still unknown. Canakinumab works by binding to IL-1β and preventing it from binding to inflammatory cells and increasing inflammation.

    However, and despite extensive research, the mechanisms by which mutations in the NLRP3 gene induce an overactivation of the inflammatory response are still poorly understood. The aim of this research is to investigate how this over activation occurs, identifying new players in this process. A better understanding of this process may lead to better treatments for CAPS but will also provide us with a better understanding of the NLRP3 function and regulation and hence benefit patients from other inflammatory conditions where this protein is involved such as arthritis, gout or diabetes.

    The main purpose of this proposal is to study biological samples from CAPS patients to better understand these syndromes. To achieve this, immune cells from CAPS patient’s blood will be used. Gene and protein expression levels will be assessed and compared to cells from healthy volunteers. We will also screen for drugs that can block the auto-activation of cryopyrin and asses how these affect cytokine production.

  • REC name

    East Midlands - Derby Research Ethics Committee

  • REC reference

    16/EM/0302

  • Date of REC Opinion

    4 Aug 2016

  • REC opinion

    Further Information Favourable Opinion