| 1. |
- Abolhassani, Hassan, et al.
(författare)
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Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome
- 2022
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Ingår i: Journal of Clinical Immunology. - : Springer Nature. - 0271-9142 .- 1573-2592. ; 42:3, s. 471-483
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Tidskriftsartikel (refereegranskat)abstract
- Background Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive. Objectives To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C. Methods Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured. Results We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency. Conclusions Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.
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| 2. |
- Bengnér, Malin, et al.
(författare)
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Independent skewing of the T cell and NK cell compartments associated with cytomegalovirus infection suggests division of labor between innate and adaptive immunity.
- 2014
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Ingår i: Age (Omaha). - : Springer Science and Business Media LLC. - 0161-9152 .- 1574-4647. ; 36:2, s. 571-582
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Tidskriftsartikel (refereegranskat)abstract
- Cytomegalovirus (CMV) infection induces profound changes in different subsets of the cellular immune system. We have previously identified an immune risk profile (IRP) where CMV-associated changes in the T cell compartment, defined as a CD4/CD8 ratio < 1, are associated with increased mortality in elderly people. Since natural killer (NK) cells have an important role in the defense against viral infections, we examined whether the expansion of CD8 + T cells seen in individuals with CD4/CD8 ratio < 1 is coupled to a parallel skewing of the NK cell compartment. A number of 151 subjects were examined with CMV serology and a flow cytometry panel for assessment of T cell and NK cell subsets. CMV-seropositive individuals had higher frequencies of CD57 + and NKG2C + NK cells and lower frequencies of NKG2A + NK cells, in line with a more differentiated NK cell compartment. Intriguingly, however, there was no correlation between CD4/CD8 ratio and NK cell repertoires among CMV-seropositive donors, despite the profound skewing of the T cell compartment in the group with CD4/CD8 ratio < 1. Conversely, donors with profound expansion of NK cells, defined as NKG2C + NK cells with high expression of CD57 and ILT-2, did not display more common changes in their T cell repertoire, suggesting that NK cell expansion is independent of the T cell-defined IRP. Altogether, these results indicate that the effect of CMV on CD8 T cells and NK cells is largely nonoverlapping and independent.
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| 3. |
- Beziat, Vivien, et al.
(författare)
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NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:14, s. 2678-2688
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Tidskriftsartikel (refereegranskat)abstract
- Human natural killer (NK) cells are functionally regulated by killer cell immunoglobulin-like receptors (KIRs) and their interactions with HLA class I molecules. As KIR expression in a given NK cell is genetically hard-wired, we hypothesized that KIR repertoire perturbations reflect expansions of unique NK-cell subsets and may be used to trace adaptation of the NK-cell compartment to virus infections. By determining the human KIR-ome at a single-cell level in more than 200 donors, we were able to analyze the magnitude of NK cell adaptation to virus infections in healthy individuals. Strikingly, infection with human cytomegalovirus (CMV), but not with other common herpesviruses, induced expansion and differentiation of KIR-expressing NK cells, visible as stable imprints in the repertoire. Education by inhibitory KIRs promoted the clonal-like expansion of NK cells, causing a bias for self-specific inhibitory KIRs. Furthermore, our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human NK cells. These results provide new insight into the diversity of KIR repertoire and its adaptation to virus infection, suggesting a role for both activating and inhibitory KIRs in immunity to CMV infection.
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| 4. |
- Lévy, Romain, et al.
(författare)
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Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
- 2023
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:2
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Tidskriftsartikel (refereegranskat)abstract
- Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.
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| 5. |
- Liu, Lisa L., et al.
(författare)
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Ex Vivo Expanded Adaptive NK Cells Effectively Kill Primary Acute Lymphoblastic Leukemia Cells
- 2017
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Ingår i: CANCER IMMUNOLOGY RESEARCH. - 2326-6066 .- 2326-6074. ; 5:8, s. 654-665
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Tidskriftsartikel (refereegranskat)abstract
- Manipulation of human natural killer (NK) cell repertoires promises more effective strategies for NK cell-based cancer immunotherapy. A subset of highly differentiated NK cells, termed adaptive NK cells, expands naturally in vivo in response to human cytomegalovirus (HCMV) infection, carries unique repertoires of inhibitory killer cell immunoglobulin-like receptors (KIR), and displays strong cytotoxicity against tumor cells. Here, we established a robust and scalable protocol for ex vivo generation and expansion of adaptive NK cells for cell therapy against pediatric acute lymphoblastic leukemia (ALL). Culture of polyclonal NK cells together with feeder cells expressing HLA-E, the ligand for the activating NKG2C receptor, led to selective expansion of adaptive NK cells with enhanced allor-eactivity against HLA-mismatched targets. The ex vivo expanded adaptive NK cells gradually obtained a more differentiated phenotype and were specific and highly efficient killers of allogeneic pediatric T-and precursor B-cell acute lymphoblastic leukemia (ALL) blasts, previously shown to be refractory to killing by autologous NK cells and the NK-cell line NK92 currently in clinical testing. Selective expansion of NK cells that express one single inhibitory KIR for self-HLA class I would allow exploitation of the full potential of NK-cell alloreactivity in cancer immunotherapy. In summary, our data suggest that adaptive NK cells may hold utility for therapy of refractory ALL, either as a bridge to transplant or for patients that lack stem cell donors.
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| 6. |
- Manry, Jérémy, et al.
(författare)
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:21
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
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| 7. |
- Trotta, Luca, et al.
(författare)
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Diagnostics of rare disorders : whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders
- 2018
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Ingår i: Orphanet Journal of Rare Diseases. - : BioMed Central (BMC). - 1750-1172. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKQ, the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.Methods: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.Results: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.Conclusions: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.
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