A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome
Background: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resultin...
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MDPI AG
2022-01-01
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| Series: | Life |
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| Online Access: | https://www.mdpi.com/2075-1729/12/2/149 |
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| author | Daniel D. Reiff Mingce Zhang Emily A. Smitherman Melissa L. Mannion Matthew L. Stoll Peter Weiser Randy Q. Cron |
| author_facet | Daniel D. Reiff Mingce Zhang Emily A. Smitherman Melissa L. Mannion Matthew L. Stoll Peter Weiser Randy Q. Cron |
| author_sort | Daniel D. Reiff |
| collection | DOAJ |
| description | Background: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene <i>STXBP2</i>, and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo. Methods: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient’s <i>STXBP2</i> mutation and wild-type (WT) <i>STXBP2</i> were separately transduced into the NK-92 human NK cell line. The WT and mutant <i>STXBP2</i> transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively. Results: Compared to WT <i>STXBP2,</i> the patient’s <i>STXBP2</i> mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro. Conclusion: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19. |
| first_indexed | 2024-03-09T21:35:34Z |
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| institution | Directory Open Access Journal |
| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-09T21:35:34Z |
| publishDate | 2022-01-01 |
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| spelling | doaj.art-9e9b5cf68fe344fead5d3eb27129b7da2023-11-23T20:44:52ZengMDPI AGLife2075-17292022-01-0112214910.3390/life12020149A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm SyndromeDaniel D. Reiff0Mingce Zhang1Emily A. Smitherman2Melissa L. Mannion3Matthew L. Stoll4Peter Weiser5Randy Q. Cron6Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USADepartment of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USADepartment of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USADepartment of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USADepartment of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USADepartment of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USADepartment of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USABackground: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene <i>STXBP2</i>, and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo. Methods: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient’s <i>STXBP2</i> mutation and wild-type (WT) <i>STXBP2</i> were separately transduced into the NK-92 human NK cell line. The WT and mutant <i>STXBP2</i> transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively. Results: Compared to WT <i>STXBP2,</i> the patient’s <i>STXBP2</i> mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro. Conclusion: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19.https://www.mdpi.com/2075-1729/12/2/149hemophagocytic lymphohistiocytosismacrophage activation syndromecytokine storm syndromeCOVID-19geneticsmutation |
| spellingShingle | Daniel D. Reiff Mingce Zhang Emily A. Smitherman Melissa L. Mannion Matthew L. Stoll Peter Weiser Randy Q. Cron A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome Life hemophagocytic lymphohistiocytosis macrophage activation syndrome cytokine storm syndrome COVID-19 genetics mutation |
| title | A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome |
| title_full | A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome |
| title_fullStr | A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome |
| title_full_unstemmed | A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome |
| title_short | A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome |
| title_sort | rare stxbp2 mutation in severe covid 19 and secondary cytokine storm syndrome |
| topic | hemophagocytic lymphohistiocytosis macrophage activation syndrome cytokine storm syndrome COVID-19 genetics mutation |
| url | https://www.mdpi.com/2075-1729/12/2/149 |
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