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1.
Arthritis Rheumatol ; 74(4): 692-699, 2022 04.
Article in English | MEDLINE | ID: mdl-34672126

ABSTRACT

OBJECTIVE: Autoinflammatory diseases are inherited disorders of innate immunity that usually start during childhood. However, several recent reports have described an increasing number of patients with autoinflammatory disease starting in adulthood. This study was undertaken to investigate the underlying cause of a case of late-onset uncharacterized autoinflammatory disease. METHODS: Genetics studies were performed using Sanger sequencing and next-generation sequencing (NGS) methods. In silico, in vitro, and ex vivo analyses were performed to determine the functional consequences of the detected variant. RESULTS: We studied a 57-year-old woman who at the age of 47 years began to have recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies, and systemic inflammation, which were relatively well controlled with anti-interleukin-1 (anti-IL-1) drugs. NGS analyses did not detect germline variants in any of the known autoinflammatory disease-associated genes, but they identified the p.Ser171Phe NLRC4 variant in unfractionated blood, with an allele fraction (2-4%) compatible with gene mosaicism. Structural modeling analyses suggested that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its propensity to oligomerize and activate the NLRC4 inflammasome, with subsequent overproduction of IL-18. CONCLUSION: Our findings indicate that the postzygotic p.Ser171Phe NLRC4 variant is a plausible cause of the disease in the enrolled patient. Functional and structural studies clearly support, for the first time, its gain-of-function behavior, consistent with previously reported NLRC4 pathogenic variants. These novel findings should be considered in the diagnostic evaluation of patients with adult-onset uncharacterized autoinflammatory disease.


Subject(s)
CARD Signaling Adaptor Proteins , Hereditary Autoinflammatory Diseases , CARD Signaling Adaptor Proteins/genetics , Calcium-Binding Proteins , Female , Hereditary Autoinflammatory Diseases/genetics , Humans , Inflammasomes , Late Onset Disorders , Middle Aged , Mosaicism
2.
Front Cell Dev Biol ; 8: 321, 2020.
Article in English | MEDLINE | ID: mdl-32582685

ABSTRACT

Experimental data demonstrated that the regenerative potential and immunomodulatory capacity of cardiosphere-derived cells (CDCs) is mediated by paracrine mechanisms. In this process, extracellular vesicles derived from CDCs (EV-CDCs) are key mediators of their therapeutic effect. Considering the future applicability of these vesicles in human diseases, an accurate preclinical-to-clinical translation is needed, as well as an exhaustive molecular characterization of animal-derived therapeutic products. Based on that, the main goal of this study was to perform a comprehensive characterization of proteins and miRNAs in extracellular vesicles from porcine CDCs as a clinically relevant animal model. The analysis was performed by identification and quantification of proteins and miRNA expression profiles. Our results revealed the presence of clusters of immune-related and cardiac-related molecular biomarkers in EV-CDCs. Additionally, considering that priming stem cells with inflammatory stimuli may increase the therapeutic potential of released vesicles, here we studied the dynamic changes that occur in the extracellular vesicles from IFNγ-primed CDCs. These analyses detected statistically significant changes in several miRNAs and proteins. Notably, the increase in interleukin 6 (IL6) protein, as well as the increase in mir-125b (that targets IL6 receptor) was especially relevant. These results suggest a potential involvement of EV-CDCs in the regulation of the IL6/IL6R axis, with implications in inflammatory-mediated diseases.

3.
Case Rep Med ; 2017: 2127167, 2017.
Article in English | MEDLINE | ID: mdl-28894468

ABSTRACT

BACKGROUND: Maltitol is a sugar alcohol that is frequently used as a noncaloric sweetener, although it is also used as an excipient, a plasticizer in gelatin capsules, and an emollient. It has not been previously described as an agent involved in immediate hypersensitivity reactions. METHODS: We report on an anaphylactoid reaction with pharyngeal occlusion suffered by a 60-year-old man after ingestion of a candy containing maltitol syrup. A prick-to-prick test was performed with the candy and maltitol powder. Other allergens were excluded as causative agents of the adverse reaction, although the patient refused to undergo an oral challenge test with the candy. A basophil activation test (BAT) was performed with maltitol powder, and a dose-response curve was generated. The test was also performed in 3 healthy controls. RESULTS: Both prick-to-prick tests were negative. The result of the BAT was positive at all the concentrations tested in the patient's blood and negative in all the controls. CONCLUSIONS: The BAT can help to clarify the agents implicated in an adverse reaction and can reduce the risk involved in diagnosis. The BAT can also prove useful in the study of reactions caused by low-molecular-weight antigens, for which routine diagnostic tests are not feasible.

4.
Allergy Asthma Immunol Res ; 8(5): 412-20, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27334779

ABSTRACT

PURPOSE: The basophil activation test (BAT) has been used to monitor venom immunotherapy (VIT) due to its high specificity. A previous study has reported a good correlation between a significant decrease in basophil activation during 5 years of VIT and clinical protection assessed by sting challenge. The following prospective study was performed to examine changes in basophil reactivity over a complete VIT period of 5 years. METHODS: BAT in a dose-response curve was studied prospectively in 10 hymenoptera venom-allergic patients over 5 years of VIT. BAT was performed at the time of diagnosis, 1 month after finishing the VIT build-up phase, and 3, 6, 12, 24, and 60 months after beginning treatment. The repeated measures ANOVA was applied to evaluate basophil activation changes throughout VIT. A cross-sectional study was also performed in 6 patients who received treatment for more than 3 years, and in another 12 patients who followed immunotherapy for at least 5 years. RESULTS: An early activation decrease was observed during the first 3 months of treatment, compared to pre-treatment values. This activation decrease was not maintained 6 to 18 months after treatment, but was observed again after 2 years of treatment, and maintained until the completion of the 5-year immunotherapy period. In cross-sectional analysis, the 6 patients who received treatment for 3 years, and 9 of the 12 patients who received treatment for 5 years, had negative BAT results. Three patients in this last group had positive BAT results and 2 patients had systemic reactions after field stings. CONCLUSIONS: BAT appears to be an optimal non-invasive test for close monitoring of VIT.

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