E1021K Homozygous Mutation in PIK3CD Leads to Activated PI3K-Delta Syndrome 1

Background Ulcerative colitis (UC) is a form of chronic inflammatory bowel disease of nonspecific origin. This study used an RNA-Sequencing (RNA-Seq) approach to evaluate the transcriptomic landscape of a well-stratified treatment-naïve pediatric UC patient population by comparing them with healthy control children. The data were analyzed to evaluate the mechanisms driving UC-related intestinal inflammation and fibrosis. Methods Intestinal mucosal samples from five pediatric UC patients and five healthy controls were analyzed by RNA-Seq, and results were verified by qPCR. A CRISPR/Cas9 approach was used to knock out the expression of HLA-DRB5, and molecular biology techniques were used for additional mechanistic studies. Results In these analyses, 2290 genes were found to be differentially expressed between the UC and control samples, of which 1258 and 1032 were upregulated and downregulated, respectively. Gene Ontology analysis showed that these genes were enriched in extracellular matrix (ECM)-related processes and that 7 of 8 differentially expressed genes of interest (PIK3CD, IL1β, IL1α, TIMP1, MMP1, MMP12, COL6A3, and HLADRB5) were upregulated and involved in ECM-receptor interaction and inflammatory bowel disease-related pathways. Increased HLA-DRB5 expression driven by intestinal bacteria was found to promote IL-1α secretion, leading to intestinal inflammation and fibrosis, suggesting a possible target for the treatment of UC. Conclusion These data suggest that intestinal inflammation is present in pediatric UC patients for extended periods before the onset of symptoms, and intestinal fibrosis begins even during the early stages of UC. Intestinal bacteria were also found to trigger intestinal inflammation and fibrosis, with HLA-DRB5 playing a central role in this process.

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“…4). Nevertheless, both up-and downregulation are indicative of altered immune functionality [21][22][23].…”

Section: Kegg Pathway Enrichment Analysismentioning

confidence: 99%

Transcriptomic analyses of treatment-naïve pediatric ulcerative colitis patients and exploration of underlying disease pathogenesis

Pang

Song

et al. 2023

J Transl Med

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“…GOF mutations in the PI3K genes PIK3CD (p110δ) and PIK3R1 (p85α) cause a combined immunodeficiency syndrome called APDS 38 . TRECs levels and CD4 naïve T cell numbers were suppressed significantly in those with APDS 39 . The PI3K-AKT pathway is crucial for transition of intermediate single positive thymocytes to double positive thymocytes 40 .…”

Section: Discussionmentioning

confidence: 94%

Trends in TRECs values according to age and gender in Chinese children, and their clinical application

Zhao

2021

Preprint

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T cell receptor excision circles (TRECs) are small circularized DNA elements produced during rearrangement of T cell receptor (TCR) genes. Because TRECS are fairly stable, do not replicate during mitosis, and are not diluted during division of naïve T cells1, they are suitable for assessing the number of newly formed T cells 2. In this study, we detected TRECs in 475 healthy Chinese children aged 0–18 years in different clinical settings. We found a strong correlation between TRECs levels and peripheral CD4 naïve T cell numbers, but not between TRECs levels and effector or memory CD4 and CD8 T cell numbers. TRECs levels fell significantly compared with normal controls in patients with severe combined immunodeficiencies (SCID) (n=7), wiskott-aldrich syndrome (WAS) (n=22), or activated PI3Kδ syndrome (APDS) (n=5). TRECs levels in those with signal transducer and activator of transcription 1 (STAT1) deficiency (n=8) decreased or did not change significantly, a finding consistent with that for CD4 naïve T cells. We also measured TRECs levels in seven PIDs after hematopoietic stem cell transplantation (HSCT) (WAS=5; chronic granulomatous disease (CGD)=2), and found the complications after HSCT may reduce TRECs levels by interfering with production of naïve T cells. In conclusion, we established reference values for TRECs, which can be used to screen for primary immunodeficiency diseases (PIDs) during early life and track immune reconstitution after HSCT.

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“…Severe Combined ImmunoDeficiency (SCID) CD45 311 Combined ImmunoDeficiency (CID) LCK 312 Severe Combined ImmunoDeficiency (SCID) ADA 313 CARD9 deficiency CARD9 290 IRF4 deficiency IRF4 314 LRBA deficiency LRBA 315 Activated PI3K-Delta Syndrome 1 PIK3CD 316 Chédiak-Higashi Syndrome LYST 317 Schimke immuno-osseous dysplasia SMARCAL1 318 Wiskott-Aldrich syndrome WAS 319 CNV X-linked agammaglobulinemia with neurologic impairment and sensorineural deafness BTK 320 Atypical SCID IL7R 321,322 Very early onset-inflammatory bowel disease (VEO-IBD) XIAP 323 Ataxia-telangiectasia ATM 324 Mendelian susceptibility to mycobacterial disease (MSMD) IFNGR1 325 Severe Combined ImmunoDeficiency (SCID) DCLRE1C 326 Williams-Beuren syndrome and Chronic Granulomatous Disease (CGD) NCF1 327 DOCK8 deficiency DOCK8 328 CTLA-4 deficiency CTLA4 329 Allelic imbalance Combined immunodeficiency (Artemis CID) DCLRE1C 330 CARD9 deficiency CARD9 31 Skewed X lyonization Wiskott-Aldrich syndrome WAS 319,[331][332][333][334][335][336][337][338] X-linked hyper-IgM CD40LG 339 Chronic Granulomatous Diseases CYBB [340][341][342] Mosaicism Germline mosaicism X-linked SCID IL2RG [343][344][345] Wiskott-Aldrich syndrome WAS 346 Several disorders…”

Section: G Enomi C Ba S E S Of Ieimentioning

confidence: 99%

From Mendel to mycoses: Immuno‐genomic warfare at the human–fungus interface

Vinh

2023

Immunological Reviews

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SummaryFungi are opportunists: They particularly require a defect of immunity to cause severe or disseminated disease. While often secondary to an apparent iatrogenic cause, fungal diseases do occur in the absence of one, albeit infrequently. These rare cases may be due to an underlying genetic immunodeficiency that can present variably in age of onset, severity, or other infections, and in the absence of a family history of disease. They may also be due to anti‐cytokine autoantibodies. This review provides a background on how human genetics or autoantibodies underlie cases of susceptibility to severe or disseminated fungal disease. Subsequently, the lessons learned from these inborn errors of immunity marked by fungal disease (IEI‐FD) provide a framework to begin to mechanistically decipher fungal syndromes, potentially paving the way for precision therapy of the mycoses.

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E1021K Homozygous Mutation in PIK3CD Leads to Activated PI3K-Delta Syndrome 1

Cited by 12 publications

References 25 publications

Transcriptomic analyses of treatment-naïve pediatric ulcerative colitis patients and exploration of underlying disease pathogenesis

Transcriptomic analyses of treatment-naïve pediatric ulcerative colitis patients and exploration of underlying disease pathogenesis

Trends in TRECs values according to age and gender in Chinese children, and their clinical application

From Mendel to mycoses: Immuno‐genomic warfare at the human–fungus interface

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