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      Identifying changes in immune cells and constructing prognostic models using immune-related genes in post-burn immunosuppression

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          Abstract

          Background

          Burn patients are prone to infection as well as immunosuppression, which is a significant cause of death. Currently, there is a lack of prognostic biomarkers for immunosuppression in burn patients. This study was conducted to identify immune-related genes that are prognosis biomarkers in post-burn immunosuppression and potential targets for immunotherapy.

          Methods

          We downloaded the gene expression profiles and clinical data of 213 burn patients and 79 healthy samples from the Gene Expression Omnibus (GEO) database. Immune infiltration analysis was used to identify the proportion of circulating immune cells. Functional enrichment analyses were carried out to identify immune-related genes that were used to build miRNA-mRNA networks to screen key genes. Next, we carried out correlation analysis between immune cells and key genes that were then used to construct logistic regression models in GSE77791 and were validated in GSE19743. Finally, we determined the expression of key genes in burn patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR).

          Results

          A total of 745 differently expressed genes were screened out: 299 were up-regulated and 446 were down-regulated. The number of Th-cells (CD4+) decreased while neutrophils increased in burn patients. The enrichment analysis showed that down-regulated genes were enriched in the T-cell activation pathway, while up-regulated genes were enriched in neutrophil activation response in burn patients. We screened out key genes ( NFATC2, RORA, and CAMK4) that could be regulated by miRNA. The expression of key genes was related to the proportion of Th-cells (CD4+) and survival, and was an excellent predictor of prognosis in burns with an area under the curve (AUC) value of 0.945. Finally, we determined that NFATC2, RORA, and CAMK4 were down-regulated in burn patients.

          Conclusion

          We found that NFATC2, RORA, and CAMK4 were likely prognostic biomarkers in post-burn immunosuppression and potential immunotherapeutic targets to convert Th-cell dysfunction.

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          Most cited references66

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          Robust enumeration of cell subsets from tissue expression profiles

          We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles. When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen, and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unknown mixture content, and closely related cell types. CIBERSORT should enable large-scale analysis of RNA mixtures for cellular biomarkers and therapeutic targets (http://cibersort.stanford.edu).
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            A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

            Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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              T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

              T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ Inc. (San Diego, USA )
                2167-8359
                13 January 2022
                2022
                : 10
                : e12680
                Affiliations
                [1 ]Department of Burns and Plastic & Wound Repair Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University , Xiamen, China
                [2 ]Department of Anesthesia Operation, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University , Xiamen, Fujian, China
                [3 ]Department of Burns and Plastic Surgery, Plastic Surgery Hospital, Xi’an International Medical Center , Xi’an, Shaanxi, China
                Author information
                http://orcid.org/0000-0002-1151-5603
                Article
                12680
                10.7717/peerj.12680
                8761370
                35070500
                dd2bfaa6-101c-480f-85f2-9b5c1a228ed2
                © 2022 Wang et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 10 June 2021
                : 2 December 2021
                Funding
                Funded by: Natural Science Foundation of Fujian Province of China
                Award ID: 2019J01011
                Funded by: Fujian Key Laboratory
                Award ID: XHZDSYS202004, XHZDSYS202005
                Funded by: Xiang’an Hospital of Xiamen University
                Award ID: PM201809170010
                The project was supported by the Natural Science Foundation of Fujian Province of China (No. 2019J01011); Opening Project of Fujian Key Laboratory (No. XHZDSYS202004, No. XHZDSYS202005); Starting Package of Xiang’an Hospital of Xiamen University (No. PM201809170010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Bioinformatics
                Molecular Biology
                Dermatology
                Immunology
                Medical Genetics

                post-burn immunosuppression,prognostic biomarkers,targets of immunotherapy,immune-related cell,mirna

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