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Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo.

ABSTRACT: Changes in miRNA expression glomerular of capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes. A better understanding could lead to novel diagnostic tools and reveal novel therapeutic targets. We explored deregulated miRNAs in an glomeruloendothelial in vitro model of ABMR due to class I human leukocyte antigen (HLA) with and without complement activation. We studied a set of 16 promising candidate miRNAs in microdissected glomeruli a confirmation set of 20 human transplant biopsies (DSA+) compared to 10 matched controls without evidence for ABMR. Twelve out of these 16 glomerulocapillary miRNAs could successfully be confirmed as dysregulated in vivo with 10 upregulated (let-7c-5p, miR-28-3p, miR-30d-5p, miR-99b-5p, miR-125a-5p, miR-195-5p, miR-374b-3p, miR-484, miR-501-3p, miR-520e) and 2 downregulated (miR29b-3p, miR-885-5p) in DSA+ vs. CONTROLS:A random forest analysis based on glomerular miRNAs identified 18/20 DSA+ and 8/10 controls correctly. This glomerulocapillary miRNA signature associated with HLA class I-DSA could improve our understanding of ABMR and be useful for diagnostic or therapeutic purposes.

SUBMITTER: Heinemann FM

PROVIDER: S-EPMC5673998 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aim: The objective of this study was to evaluate the association of the human leukocyte antigen (HLA) class II genes HLA-DRB1, HLA-DPB1, and HLA-DQB1 with the humoral immune response elicited by inactivated Japanese encephalitis (JE) vaccine (IJEV). Methods: A total of 373 individuals aged 3-12 years in the Inner Mongolia Autonomous Region in China, who received two doses of IJEV at 0 and 7 days, were enrolled in the current study. Based on the individuals' specific JE virus (JEV)-neutralizing antibodies (NAbs), they were divided into a seropositive and a seronegative group. HLA-DRB1, HLA-DPB1, and HLA-DQB1 were genotyped using a sequencing-based typing method. Next, the association of the HLA class II genes and their haplotypes with antibody response was evaluated. Results: Based on NAbs, a total of 161 individuals were classified as seropositive and 212 as seronegative. DQB1 * 02:01 was significantly associated with JEV seropositivity (P < 0.001, OR = 0.364, 95% CI: 0.221-0.600), while DQB1 * 02:02 was significantly associated with JEV seronegativity (P = 5.03 × 10-6, OR = 7.341, 95% CI: 2.876-18.736). The haplotypes DRB1 * 07:01-DPB1 * 04:01-DQB1 * 02:01, DRB1 * 15:01-DPB1 * 02:01-DQB1 * 06:02, DRB1 * 07:01-DQB1 * 02:01, and DPB1 * 02:01-DQB1 * 06:02 were very frequent in the seropositive group, while DRB1 * 07:01-DPB1 * 17:01-DQB1 * 02:02, DRB1 * 07:01-DQB1 * 02:02, and DPB1 * 17:01-DQB1 * 02:02 were very frequent in the seronegative group. The presence of DRB1 * 01:01, DRB1 * 04:05, DRB1 * 09:01, DRB1 * 12:02, DRB1 * 13:02, and DRB1 * 14:01 was associated with a higher geometric mean titer (GMT) of NAbs than that of DRB1 * 11:01 at the DRB1 locus (P < 0.05). At the DPB1 locus, the presence of DPB1 * 05:01 was associated with higher GMTs than that of DPB1 * 02:01 and DPB1 * 13:01 (P < 0.05), and the presence of DPB1 * 04:01 and DPB1 * 09:01 was associated with higher GMTs than that of DPB1 * 13:01 (P < 0.05). Conclusions: The present study suggests that HLA class II genes may influence the antibody response to IJEV.

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Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo.

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