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Activation of the NLRP3 inflammasome leads to cleavage of pro-IL-1b, by caspase-1, into the mature IL-1b
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The concept of autoinflammatory disease as a new disease classification has resulted in a paradigm shift in our understanding of the the broad spectrum of immunological diseases. The effectiveness of interleukin-1 blockade in a variety of disorders has resulted in a marked reduction in suffering for many of these patients.
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... NLRP3 mutations cause spontaneous activation of the inflammasome complex, leading to excessive inter- leukin (IL)-1b secretion (Figure 1). This excessive secretion is responsible for the clinical manifestations of CAPS, as well as playing a role in a number of other autoinflammatory diseases, including FMF and TRAPS. ...
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Mutations in the adaptor protein PSTPIP1 cause a spectrum of autoinflammatory diseases, including PAPA and PAMI; however, the mechanism underlying these diseases remains unknown. Most of these mutations lie in PSTPIP1 F-BAR domain, which binds to LYP, a protein tyrosine phosphatase associated with arthritis and lupus. To shed light on the mechanism...
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... Common features in CAPS patients include fever, urticaria-like skin rash, arthralgia, conjunctivitis and sensorineural hearing loss. In addition, severe headache, meningitis, mental retardation, and bony overgrowth occur in CINCA/NOMID [77][78][79][80][81]. CAPS are also characterized by dysregulated inflammation with a remarkable increase in acute phase reactants levels, mainly ESR (Erythrocyte sedimentation rate), CRP (C-reactive protein) and SAA (Serum Amyloid A), which are reduced or normalized in remission periods. ...
... In the last two years there has been the identification of genes for six monogenic autoinflammatory diseases. In addition, certain polygenic diseases previously considered as autoimmune are now being considered for reclassification as autoinflammatory , for example Behçet's disease, systemic juvenile idiopathic arthritis (sJIA), ankylosing spondylitis, Crohn's disease, psoriasis and more [4]. With the exception of the cryopyrinopathies, where IL-1 blockade has revolutionised treatment, and FMF where colchicine is a safe and effective treatment for most, there is no ideal consensus treatment for many emerging new autoinflammatory diseases. ...
Steady progress in our understanding of the genetic basis of autoinflammatory diseases has been made over the past 16 years. Since the discovery of the familial Mediterranean fever gene MEFV (also known as marenostrin) in 1997, 18 other genes responsible for monogenic autoinflammatory diseases have been identified to date. The discovery of these genes was made through the utilisation of many genetic mapping techniques, including next generation sequencing platforms. This review article clearly describes the gene hunting approaches, methods of data analysis and the technological platforms used, which has relevance to all those working within the field of gene discovery for Mendelian disorders.
... Hereditary PFSs encompass a rare group of diseases that share lifelong recurrent episodes of inflammatory symptoms and an acute phase response. Periodic fevers are typically present in the pediatric population, but a disease onset in adult age is not a rare occurrence for some conditions [10]. ...
Periodic fever syndromes (PFSs) are a wide group of autoinflammatory diseases. Due to some clinical overlap between different PFSs, differential diagnosis can be a difficult challenge. Nowadays, there are no universally agreed recommendations for most PFSs, and near half of patients may remain without a genetic diagnosis even after performing multiple-gene analyses. Molecular analysis of periodic fevers' causative genes can improve patient quality of life by providing early and accurate diagnosis and allowing the administration of appropriate treatment. In this paper we focus our discussion on effective usefulness of genetic diagnosis of PFSs. The aim of this paper is to establish how much can the diagnostic system improve, in order to increase the success of PFS diagnosis. The mayor expectation in the near future will be addressed to the so-called next generation sequencing approach. Although the application of bioinformatics to high-throughput genetic analysis could allow the identification of complex genotypes, the complexity of this definition will hardly result in a clear contribution for the physician. In our opinion, however, to obtain the best from this new development a rule should always be kept well in mind: use genetics only to answer specific clinical questions.
... Inflammasome activation and the continuum of diseases caused by immune-mediated inflammation against self Diseases classified by excessive or chronic activation of the immune system can be placed in a disease continuum, with autoinflammatory disorders at one end of the spectrum and autoimmune diseases at the other end of the spectrum [7]. Autoinflammatory diseases are clinical disorders that present with recurrent inflammation and unexplained fevers as part of their phenotype, due to abnormally increased inflammation mediated by cells of the innate immune system [8]. In autoinflammatory disorders, tissue damage results from self-directed inflammation, due to activation of innate immune cells, including macrophages and neutrophils. ...
The NOD-like receptor (NLR) family members are cytosolic sensors of microbial components and danger signals. A subset of NLRs control inflammasome assembly that results in caspase-1 activation and, in turn, IL-1β and IL-18 production. Excessive inflammasome activation can cause autoinflammatory disorders, including the hereditary periodic fevers. Autoinflammatory and autoimmune diseases form a disease spectrum of aberrant, immune-mediated inflammation against self, through innate and adaptive immunity. However, the role of inflammasomes in autoimmune disease is less clear than in autoinflammation, despite the numerous effects IL-1β and IL-18 can have on shaping adaptive immunity. We summarize the role of inflammasomes in autoimmune disorders, highlight the need for a better understanding of inflammasomes in these conditions and offer suggestions for future research directions.
The mitochondrion has been known for a long time to exert a central and vital role in the aerobic metabolism of eukaryotic cells. More recently, this organelle has been receiving substantial attention as a potential target for therapeutics, especially for cancer treatment. The knowledge of key structural and functional features of mitochondria allows scientists to develop several mitochondria-targeted drugs, from mitochondria-directed conventional drugs to nanoplatforms conjugated to mitochondria-targeted molecules and photosensitizers. Furthermore, multifunctional nanoplatforms targeting mitochondria and simultaneously eliciting immune responses have been explored as potential immunomodulators to be developed as vaccines or vaccine adjuvants. In this chapter, we present a brief overview of mitochondria and immunity focusing on the recent development of nanoparticle-based mitochondrial-targeted drugs.
The second affiliation of the corresponding author Eda Tahir Turanlı was incorrectly published as İstanbul Medeniyet University instead of Istanbul Technical University.
Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle–Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.
Autoinflammatory diseases were initially assigned to the hereditary recurrent fevers that were characterized by unprovoked episodes of inflammation without anti-gen-specific T cells or high titers of auto-antibodies, in contrast to the autoimmune dis-eases in which acquired immunity played an essential role. Except for Blau syndrome and early-onset sarcoidosis that are associated with granuloma due to NOD2 mutations and classified as NF-κB activation disorders, the major types of autoinflammatory dis-eases are defined as IL-1β activating disorders or inflammasomopathies. This is based on accumulating evidence for the efficacy of anti-IL-1 therapy. These diseases include intrinsic cryopyrin-associated periodic syndrome (CAPS), extrinsic familial Mediterra-nean fever, hyper IgD syndrome, pyogenic sterile arthritis pyoderma gangrenosum and acne syndrome, and deficiency of an IL-1 receptor antagonist. Knowledge obtained from these autoinflammatory disorders should also be pertinent to a number of common disorders. For example, neutrophil migration is observed in autoinflammatory CAPS and common inflammatory keratoses represented by psoriasis. Abnormal regulation of the innate immune response and Th17 cell differentiation via IL-1 signaling may be associated with the molecular pathogenesis of these conditions.
Inflammasomes are multi-protein complexes that sense microbial molecules and endogenous danger signals in intracellular compartments. Inflammasome assembly results in caspase-1 activation, which in turn drives maturation and secretion of the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18, and induces pyroptosis to eliminate the infectious agent. The importance of inflammasomes in regulating immune responses was recognized with the discovery of polymorphisms in genes encoding inflammasome components and their linkage to aberrant production of IL-1β and IL-18 in autoimmune and hereditary periodic fevers syndromes. We review the current knowledge on the role of inflammasomes in regulating innate and adaptive immune responses with an emphasis on the role of these immune complexes in autoinflammatory disorders and autoimmune diseases such as colitis, type I diabetes, multiple sclerosis and vitiligo.
