Abstract:
:Background: Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries. Methods: Demographic, clinical, and laboratory data were collected from RAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay. Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID (n = 20), OS (n = 37), and LS/CID (n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n = 47) of patients with RAG1 variants carried p.K86Vfs*33 (c.256_257delAA) allele, either in homozygous (n = 18, 27%) or in compound heterozygous (n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs*33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs*33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion: We propose that RAG1 p.K86Vfs*33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival.
journal_name
Front Immunoljournal_title
Frontiers in immunologyauthors
Sharapova SO,Skomska-Pawliszak M,Rodina YA,Wolska-Kuśnierz B,Dabrowska-Leonik N,Mikołuć B,Pashchenko OE,Pasic S,Freiberger T,Milota T,Formánková R,Szaflarska A,Siedlar M,Avčin T,Markelj G,Ciznar P,Kalwak K,Kołtan S,Jadoi
10.3389/fimmu.2020.00900subject
Has Abstractpub_date
2020-06-10 00:00:00pages
900issn
1664-3224journal_volume
11pub_type
杂志文章abstract::We have developed a therapeutic vaccine consisting of a mixture of lethally-irradiated allogeneic cutaneous melanoma cell lines with BCG and GM-CSF as adjuvants. The CSF-470 vaccine is currently being assayed in a Phase II-III trial against medium-dose IFN-α2b. All vaccinated patients immunized intradermally developed...
journal_title:Frontiers in immunology
pub_type: 杂志文章
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abstract::[This corrects the article on p. 998 in vol. 9, PMID: 29867975.]. ...
journal_title:Frontiers in immunology
pub_type: 杂志文章,已发布勘误
doi:10.3389/fimmu.2018.01343
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abstract::A wide variety of biomaterials have been developed as both stabilizing structures for the injured bone and inducers of bone neoformation. They differ in chemical composition, shape, porosity, and mechanical properties. The most extensively employed and studied subset of bioceramics are calcium phosphate materials (CaP...
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pub_type: 杂志文章,评审
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更新日期:2018-08-07 00:00:00
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pub_type: 临床试验,杂志文章
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更新日期:2018-03-14 00:00:00
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pub_type: 杂志文章,评审
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pub_type: 杂志文章,评审
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2016.00597
更新日期:2016-12-12 00:00:00
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2020.01069
更新日期:2020-06-23 00:00:00
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2020.01967
更新日期:2020-09-03 00:00:00
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2018.01182
更新日期:2018-05-29 00:00:00
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journal_title:Frontiers in immunology
pub_type: 杂志文章,评审
doi:10.3389/fimmu.2017.01695
更新日期:2017-11-29 00:00:00
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2020.00544
更新日期:2020-03-31 00:00:00
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2020.00106
更新日期:2020-02-11 00:00:00
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journal_title:Frontiers in immunology
pub_type: 杂志文章,评审
doi:10.3389/fimmu.2019.02278
更新日期:2019-09-24 00:00:00
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pub_type: 杂志文章,评审
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pub_type: 杂志文章,评审
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journal_title:Frontiers in immunology
pub_type: 杂志文章,评审
doi:10.3389/fimmu.2017.01024
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journal_title:Frontiers in immunology
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2011.00030
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abstract::The onset of hepatic disorders in patients with systemic lupus erythematosus (SLE) is frequent; however, the etiology and liver pathogenesis of SLE remain unknown. In the present study, the role of hepatic deposited immunoglobulin G (IgG) in SLE-derived liver damage was investigated. From a retrospective analysis of t...
journal_title:Frontiers in immunology
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abstract::Intravenous IgG (IVIg) contains polyclonal immunoglobulin G (IgG) from thousands of donors. It is administered at a low dose at regular intervals as antibody replacement therapy and at a higher dose as immunomodulatory treatment in various auto-immune or auto-inflammatory diseases. The working mechanism of immunomodul...
journal_title:Frontiers in immunology
pub_type: 杂志文章,评审
doi:10.3389/fimmu.2014.00674
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