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Hal M. Hoffman, MD, Lori Broderick, MD, PhD 

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1 The role of the inflammasome in patients with autoinflammatory diseases 
Hal M. Hoffman, MD, Lori Broderick, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 138, Issue 1, Pages 3-14 (July 2016) DOI: /j.jaci Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 General inflammasome structure and function. Inflammasomes are multimeric protein complexes consisting of a sensor, an effector, and usually an adaptor protein. Oligomerization is triggered by danger-associated molecular patterns (DAMPs) or PAMPs, resulting in effector activation and leading to maturation of procytokines and pyroptosis, a form of inflammatory cell death. Journal of Allergy and Clinical Immunology  , 3-14DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Specific inflammasome structure and triggers. Sensor proteins known to form inflammasomes include NLRP1, NLRP3, NLRC4, AIM2, and pyrin. Although most inflammasomes are triggered by specific pathogen-associated molecules, the NLRP3 inflammasome is activated by a variety of danger signals, as well as some pathogens. Inflammasome component proteins consist of shared domains that mediate protein-protein interactions, including pyrin domains (PYD) and caspase activation and recruitment domains (CARD). Domains observed in some component proteins include leucine-rich repeat (LRR) domains, NACHT, BIR, HIN, Bbox, B30.2, and FIIND domains. Caspase-1 (CASP1) contains p20 and p10 subunits that are cleaved when activated. Journal of Allergy and Clinical Immunology  , 3-14DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Inhibitors of the IL-1 pathway. There are 3 approved drugs that block IL-1–mediated inflammation by preventing IL-1β from binding to the IL-1 receptor. Anakinra is a recombinant form of the natural IL-1 inhibitor IL-1RA, which binds to the IL-1 receptor. Rilonacept is a fusion protein, and canakinumab is an mAb that binds IL-1β. Journal of Allergy and Clinical Immunology  , 3-14DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Targeting the inflammasome pathway. Treatment strategies for blocking the inflammasome pathway include targeting upstream activators of the inflammasome or specific inflammasome component proteins. Inhibitors of caspase-1 activation or IL-1 receptor signaling are additional therapeutic approaches. cAMP, Cyclic AMP; ROS, reactive oxygen species. Journal of Allergy and Clinical Immunology  , 3-14DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions


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