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Published on: October 9, 2014
Significance of PD1 Alternative Splicing in Celiac Disease as a Novel Source for Diagnostic and Therapeutic Target
Candelaria Ponce de León1, Pedro Lorite1, Miguel Ángel López-Casado2
1Department of Experimental Biology, Faculty of Health Sciences, University of Jaén, Jaén, Spain.
Background:
We have focused on the alteration of the PD-1/PD-L1 pathway in celiac disease and discussed the roles of the PD1 pathway in regulating the immune response. We explored the idea that the altered mRNA splicing process in key regulatory proteins could represent a novel source to identify diagnostic, prognostic, and therapeutic targets in celiac disease.
Methods:
We characterized the PD1 mRNA variants' profile in CD patients and in response to gluten peptides' incubation after in vitro experiments. Total RNA from whole blood was isolated, and the coding region of the human PD-1 mRNA was amplified by cDNA PCR.
Results:
PCR amplification of the human PD-1 coding sequence revealed an association between the over-expression of the sPD-1 protein and the PD-1Δex3 transcript in celiac disease. Thus, we have found three novel alternative spliced isoforms, two of which result in a truncated protein and the other isoform with a loss of 14 aa of exon 2 and complete exon 3 (Δ3) which could encode a new soluble form of PD1 (sPD-1).
Conclusions:
Our study provides evidence that dietary gluten can modulate processes required for cell homeostasis through the splicing of pre-mRNAs encoding key regulatory proteins, which represents an adaptive mechanism in response to different nutritional conditions.
Insights
Altered mRNA splicing of the programmed cell death protein 1 (PD-1) pathway is linked to celiac disease. This discovery offers new diagnostic and therapeutic targets for immune regulation in celiac disease patients.
Area of Science:
- Immunology
- Molecular Biology
- Gastroenterology
Background:
- The programmed cell death protein 1 (PD-1)/PD-L1 pathway plays a crucial role in regulating immune responses.
- Alterations in this pathway are implicated in celiac disease pathogenesis.
- Altered mRNA splicing of regulatory proteins may offer novel targets for celiac disease.
Purpose of the Study:
- To investigate the PD-1 pathway's role in celiac disease.
- To characterize PD-1 mRNA variants in celiac disease patients.
- To explore the impact of gluten peptides on PD-1 mRNA splicing.
Main Methods:
- Characterization of PD-1 mRNA variants in celiac disease (CD) patients.
- In vitro incubation of immune cells with gluten peptides.
- Isolation of total RNA from whole blood and cDNA PCR amplification of the human PD-1 mRNA coding region.
Main Results:
- Over-expression of soluble PD-1 (sPD-1) protein and the PD-1Δex3 transcript are associated with celiac disease.
- Three novel alternative spliced isoforms of PD-1 were identified.
- One novel isoform (Δ3) may encode a new soluble form of PD-1 (sPD-1).
Conclusions:
- Dietary gluten modulates mRNA splicing of key regulatory proteins, including PD-1.
- This splicing modulation is an adaptive mechanism in response to nutritional conditions.
- Findings suggest potential diagnostic and therapeutic targets within the PD-1 pathway for celiac disease.
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