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Urticaria and Angioedema
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Jenny M Stitt, Stephen C Dreskin
In patients with physical urticarias, systemic disorders must be further considered. For example, solar urticaria must be distinguished from other light-sensitive disorders including solar dermatitis, lupus, porphyria and photsensitivity reactions to medications (Dice 2004). Cold urticaria must be distinguished from the Familial Cold Autoinflammatory Syndrome (FCAS), an autosomal dominant disease (Wanderer 2004). Following cold exposure, individuals with FCAS experience papular dermatitis (not urticaria) with fever, chills, headache, arthralgia and myalgia and leukocytosis. Symptoms occurred at an average of 2.5 hours after cold exposure with average episodes lasting 12 hours (Hiragun et al. 2013). FCAS is a form of periodic fever with cold intolerance due to a defect in either of two genes, NLRPS or NLRP12 that regulate the inflammatory process (Hiragun et al. 2013).
Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Studies on NLRP6 predominate in the published literature. NLRP6 null mice develop more severe inflammation in DSS colitis, as do mice deficient in ASC. It was claimed that the altered microbiota seen in these null mice could transfer increased susceptibility to colitis to wild-type mice. NLRP null mice are also more susceptible to C. rodentium infection, attributable to changes in colonic goblet cells. Subsequent studies, however, cast doubt on some of these results. NRLP6 null mice and their control littermates (rather than co-housed mice) show no change in the microbiota or susceptibility to DSS colitis. This does not appear to be the case with NLRP12 null mice, since null littermates have a less diverse microbiota than their wild-type littermates.
Preterm labor and birth
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Vincenzo Berghella, Eduardo da Fonseca
There are several recent studies and reviews on possible genetic etiologies, or at least associations, with PTB (3–5). These in general confirm the different pathways associated so far with PTB and risk factors. For example, a recent review highlighted genetic variants detected by whole exome (or genome in some cases) sequencing (WES) pointing to the negative regulation (dampening) of the innate immune response (e.g., CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (e.g., DEFB1, MBL2) associated with PTB (3). These genetic associations support the concept that PTB, at least in part, has an inflammatory etiology, which can be induced either by pathogens (i.e., intra-amniotic infection) or “danger signals” (e.g., alarmins) released during cellular stress or necrosis (i.e., sterile intra-amniotic inflammation) (3). PTB has a polygenic basis that involves mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. WES is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous PTB (3).
Clinical phenotypes and genetic analyses for diagnosis of systemic autoinflammatory diseases in adult patients with unexplained fever
Published in Modern Rheumatology, 2021
Yukiko Hidaka, Kyoko Fujimoto, Norikazu Matsuo, Takuma Koga, Shinjiro Kaieda, Satoshi Yamasaki, Munetoshi Nakashima, Kiyoshi Migita, Manabu Nakayama, Osamu Ohara, Tomoaki Hoshino, Ryuta Nishikomori, Hiroaki Ida
We analyzed 179 cases for variants in 10 SAID genes other than the MEFV gene. Among the 176 cases (excluding 2 cases of TRAPS and one case of PAPA syndrome that met the diagnostic criteria), we detected rare variants, namely less than 1% of allele frequency of ExAC Browser in TNFRSF1A, NLRP3, NOD2, NLRP12, PSTPIP1, PSMB8, NLRC4, PLCG2, MVK, and IL1RN in 2, 14, 7, 17, 2, 2, 7, 6, 0, and 0 cases, respectively. Almost all of gene substitution was missense variants as shown in Table 4. Splicing variant of NLRP12 was found in one case. Finally, 53 cases (30.1%) exhibited variants in 10 SAID genes other than the MEFV gene when duplicate cases were considered. No variants were found in MVK and IL1RN genes. Cases with gene variants in NLRP3 and NLRP12 exhibited abdominal pain and arthralgia, and cases with gene variants in NOD2 tended to have myalgia (Table 4). Furthermore, we examined whether these cases were actually diagnosed as FMF on the basis of Tel Hashomer criteria [10]. Patients with NLRP3, NOD2, NLRP12, and PSMB8 variants were diagnosed with FMF in 3 out of 14 cases (21.4%), 2 out of 7 cases (28.6%), 3 out of 17 cases (17.6%), and 1 out of 2 cases (50.0%), respectively. Patients with NLRC4 and PLCG2 variants were not diagnosed with FMF. Nine out of 57 cases (15.8%) with variants in 10 genes other than MEFV were clinically diagnosed as FMF.
NLRP3 inflammasome contributes to neurovascular unit damage in stroke
Published in Journal of Drug Targeting, 2019
Jing Sun, Lumei Chi, Zhidong He, Yu Gao, Yufen Gao, Yujing Huang, Guangxian Nan
There has been considerable interest in the recently discovered inflammasome, a large molecular platform composed of an NLRP scaffold, the ASC adaptor and pro-caspase-1 [24,25]. The inflammasome-forming NLRs consist of many members such as NLRP1, NLRP3, NLRC4, NLRC5, NLRP6, NLRP7, NLRP12 and AIM2 [26]. NLRP3, also known as Nalp3 or cryopyrin, is encoded by the cold-induced autoinflammatory syndrome-1 gene and is expressed abundantly in the brain and in immune cells. Structurally, the NLRP3 protein, along with all other NLR family members, comprises three major domains: an N-terminal pyrin domain (PYD), a central nucleotide-binding and oligomerization domain (NACHT) and a C-terminal leucine-rich repeat (LRR) domain [27]. The PYD allows homotypic interactions with bipartite adapter ASC, which then subsequently recruits pro-caspase-1 to form the active inflammasome through caspase recruitment domain (CARD) interactions [28,29]. Pro-caspase-1 recruitment causes proximity-induced caspase-1 oligomerization and autocatalysis, leading to the release of the active caspase-1 fragments. Subsequently, active caspase-1 promotes the cleaving of pro-IL-1β and pro-IL-18 into their mature and active forms, which leads to the recruitment and activation of other immune cells, such as neutrophils [30,31].
Retinal Ganglion Cell Death in Glaucoma: Advances and Caveats
Published in Current Eye Research, 2023
Pyroptosis is a lytic cell death form that is characterized by cell swelling, the formation of plasma membrane pores, and cell rupture, accompanied by the release of IL-1beta and IL-18 in a caspase-1-dependent manner.37 In addition to caspase-1, caspases-4 and 5 in humans or caspase-11 in rodents also participate in the inflammatory process.46 It has been well-summarized that many stimuli (also known as damage-associated molecular patterns), such as extracellular ATP, heat shock protein, and double-stranded DNA, can activate pattern recognition receptors (PRRs, including NLRP1, NLRP3, AIM2, and PYRIN), and further activate caspase 1.47 Activated caspase-1 can specifically cleave the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains of gasdermin D (GSDMD) and thus relieve the intrinsic inhibition of GADMD.48 GSDMD has been identified as the effector of pyroptosis, performing the pore-formation function in pyroptosis.48 Dr. Wei Chi claimed that caspase-8 promotes NLRP1/3 inflammasome activation and IL-1beta secretion in animals with acute IOP elevation.49 Recently, the new-discovered NLRP12 was proven to collaborate with NLRP3 and NLR family CARD domain-containing protein 4 (NLRC4), functioning downstream of the CASP8-HIF1-alpha axis and participating in the formation of inflammasomes, to trigger pyroptosis in acute glaucoma.50 The knockdown of Nlrc4 protects RGCs by inhibiting IL-1beta release caused by acute IOP elevation.51 The connection between caspase and pyroptosis is summarized in Figure 3.