Objectives: The endoplasmic reticulum aminopeptidase () haplotype encodes for a variant allotype of the endoplasmic reticulum (ER)-resident peptide-trimming aminopeptidase ERAP1 with low enzymatic activity. This haplotype recessively confers the highest risk for Behçet's diseases (BD) currently known, but only in carriers of , the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact.
Methods: We genotyped and immune phenotyped a cohort of 26 untreated Turkish BD subjects and 22 healthy donors, generated CRISPR-Cas9 KOs from LCL, analysed the HLA class I-bound peptidome for peptide length differences and assessed immunogenicity of genome-edited cells in CD8 T cell co-culture systems.
Results: Allele frequencies of were similar to previous studies. There were frequency shifts between antigen-experienced and naïve CD8 T cell populations of carriers and non-carriers of in an background. KO cells showed peptidomes with longer peptides above 9mer and significant differences in their ability to stimulate alloreactive CD8 T cells compared with wild-type control cells.
Conclusions: We demonstrate that hypoactive ERAP1 changes immunogenicity to CD8 T cells, mediated by an HLA class I peptidome with undertrimmed peptides. Naïve/effector CD8 T cell shifts in affected carriers provide evidence of the biological relevance of at the cellular level and point to an HLA-B51-restricted process. Our findings suggest that variant ERAP1-Hap10 partakes in BD pathogenesis by generating HLA-B51-restricted peptides, causing a change in immunodominance of the ensuing CD8 T cell response.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585993 | PMC |
http://dx.doi.org/10.1136/ard-2022-222277 | DOI Listing |
Inflammation
December 2024
Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
Endoplasmic reticulum stress (ERs) is implicated in antitumor immunity. However, the exact role of ERs in mediating the effects of dendritic cells (DCs) is not unclear. In this study, we explored the role of exosomes derived from ER-stressed hepatocellular carcinoma (HCC) cells in the antitumor effects of DCs and the precise underlying mechanism.
View Article and Find Full Text PDFImmunol Res
December 2024
Department of Respiratory Medicine, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
This study aims to characterize the majority of immune cell subsets in peripheral blood mononuclear cells in children with Mycoplasma pneumoniae pneumonia (MPP) by a 21-color flow cytometry panel. Patients who met the predetermined eligibility criteria for pneumonia diagnosis were recruited for the research study. Multi-color flow cytometry was conducted on the peripheral blood mononuclear cells of each patient group, which were then subjected to dimensionality reduction and cluster analysis.
View Article and Find Full Text PDFMol Neurobiol
December 2024
Department of Physical Therapy, School of Health and Social Services, Saitama Prefectural University, 820 San-Nomiya, Koshigaya-Shi, Saitama, 343-8540, Japan.
Accumulation of senescent neurons in the dorsal root ganglion (DRG) is an important tissue phenotype that causes age-related degeneration of peripheral sensory nerves. Senescent neurons are neurons with arrested cell cycle that have undergone cellular senescence but remain in the tissue and play various biological roles. To understand the accumulation of senescent neurons in the DRG during aging, we aimed to elucidate the mechanism that induces cellular senescence in DRG neurons and the role of senescent DRG neurons.
View Article and Find Full Text PDFmBio
December 2024
Center for Vaccine Innovation, La Jolla Institute for Immunology (LJI), La Jolla, California, USA.
Frequent recent spillovers of subtype H5N1 clade 2.3.4.
View Article and Find Full Text PDFAdv Mater
December 2024
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore.
The unprecedented success of mRNA vaccines against COVID-19 has inspired scientists to develop mRNA vaccines for cancer immunotherapy. However, using nucleoside modified mRNA as vaccine, though evading innate immune toxicity, diminishes its therapeutic efficacy for cancers. Here, we report a polyvalent stimulator of interferon genes (STING) activating polymer (termed as PD) to bolster the immunogenicity of mRNA vaccine.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!