| 1. |
- Abolhassani, Hassan, et al.
(författare)
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Genetic and immunologic evaluation of children with inborn errors of immunity and severe or critical COVID-19
- 2022
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 150:5, s. 1059-1073
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals are asymptomatic or only exhibit mild disease. In about 10% of cases, the infection leads to hypoxemic pneumonia, although it is much more rare in children. Objective: We evaluated 31 young patients aged 0.5 to 19 years who had preexisting inborn errors of immunity (IEI) but lacked a molecular diagnosis and were later diagnosed with coronavirus disease 2019 (COVID-19) complications. Methods: Genetic evaluation by whole-exome sequencing was performed in all patients. SARS-CoV-2-specific antibodies, autoantibodies against type I IFN (IFN-I), and inflammatory factors in plasma were measured. We also reviewed COVID-19 disease severity/outcome in reported IEI patients. Results: A potential genetic cause of the IEI was identified in 28 patients (90.3%), including mutations that may affect IFN signaling, T- and B-cell function, the inflammasome, and the complement system. From tested patients 65.5% had detectable virus-specific antibodies, and 6.8% had autoantibodies neutralizing IFN-I. Five patients (16.1%) fulfilled the diagnostic criteria of multisystem inflammatory syndrome in children. Eleven patients (35.4%) died of COVID-19 complications. All together, at least 381 IEI children with COVID-19 have been reported in the literature to date. Although many patients with asymptomatic or mild disease may not have been reported, severe presentation of COVID-19 was observed in 23.6% of the published cases, and the mortality rate was 8.7%. Conclusions: Young patients with preexisting IEI may have higher mortality than children without IEI when infected with SARS-CoV-2. Elucidating the genetic basis of IEI patients with severe/critical COVID-19 may help to develop better strategies for prevention and treatment of severe COVID-19 disease and complications in pediatric patients.
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| 2. |
- 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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| 3. |
- Abolhassani, Hassan, et al.
(författare)
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X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia
- 2022
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Ingår i: Journal of Clinical Immunology. - : Springer Science and Business Media LLC. - 0271-9142 .- 1573-2592. ; 42:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Background Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk.Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI).Methods Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry.Results We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient.Conclusions We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.
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| 4. |
- Björkander, Sophia, et al.
(författare)
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SARS-CoV-2-specific B- and T-cell immunity in a population-based study of young Swedish adults
- 2022
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 149:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Background: Young adults are now considered major spreaders of coronavirus disease 2019 (COVID-19) disease. Although most young individuals experience mild to moderate disease, there are concerns of long-term adverse health effects. The impact of COVID-19 disease and to which extent population-level immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists in young adults remain unclear.Objective: We conducted a population-based study on humoral and cellular immunity to SARS-CoV-2 and explored COVID-19 disease characteristics in young adults.Methods: We invited participants from the Swedish BAMSE (Barn [Children], Allergy Milieu, Stockholm, Epidemiology) birth cohort (age 24-27 years) to take part in a COVID-19 followup. From 980 participants (October 2020 to June 2021), we here present data on SARS-CoV-2 receptor-binding domain-specific IgM, IgA, and IgG titers measured by ELISA and on symptoms and epidemiologic factors associated with seropositivity. Further, SARS-CoV-2-specific memory B-and T-cell responses were detected for a subpopulation (n 5 108) by ELISpot and FluoroSpot.Results: A total of 28.4% of subjects were seropositive, of whom 18.4% were IgM single positive. One in 7 seropositive subjects was asymptomatic. Seropositivity was associated with use of public transport, but not with sex, asthma, rhinitis, IgE sensitization, smoking, or body mass index. In a subset of representative samples, 20.7% and 35.0% had detectable SARSCoV-2 specific B-and T-cell responses, respectively. B-and T-cell memory responses were clearly associated with seropositivity, but T-cell responses were also detected in 17.2% of seronegative subjects.Conclusions: Assessment of IgM and T-cell responses may improve population-based estimations of SARS-CoV-2 infection. The pronounced surge of both symptomatic and asymptomatic infections among young adults indicates that the large-scale vaccination campaign should be continued. (J Allergy Clin Immunol 2022;149:65-75.)
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| 5. |
- Björkman, Andrea, et al.
(författare)
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Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells.
- 2015
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 112:7, s. 2157-2162
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1's function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.
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| 6. |
- Chan, Yi-Hao, et al.
(författare)
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SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
- 2024
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Ingår i: The Journal of experimental medicine. - 1540-9538. ; 221:9
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Tidskriftsartikel (refereegranskat)abstract
- Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
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| 7. |
- Du, Likun, et al.
(författare)
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Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis
- 2012
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 209:2, s. 291-305
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Tidskriftsartikel (refereegranskat)abstract
- Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.
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| 8. |
- Du, Likun
(författare)
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Role of DNA repair in class switch recombination and somatic hypermutation
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Class switch recombination (CSR) and somatic hypermutation (SHM), occurring in the germinal center, are two important processes for B cell development. Both are initiated by activation-induced cytidine deaminase (AID), through deamination of the C residues in the variable and switch regions of the immunoglobulin locus, resulting in either in single stranded or double stranded DNA breaks. At least three pathways (nonhomologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR)) have been implicated in processing, repair and ligation of the DNA breaks during CSR and SHM. However, the way in which these pathways are regulated and coordinated to mediate CSR and/or SHM is still not well understood. To explore the potential role of several proteins in CSR and SHM, including Ataxia- telangiectasia and Rad3-related (ATR), Artemis, Cernunnos and the Mre11-Rad50-NBS1 (MRN) complex, CSR junctions and SHM patterns in the immunoglobulin variable region gene were analyzed in patients with deficiency in these factors. We first studied the role of ATR during CSR and SHM. CSR junctions obtained from ATR deficiency (ATRD) patients showed significantly increased usage of microhomology, but impaired end joining with partially complementary (1-3 bp) DNA ends. The SHM pattern was also altered, with fewer mutations occurring at A but more at T residues, representing a loss of strand bias in targeting A/T pairs within certain hotspots. The function of ATR and ATM in CSR and SHM was also compared. Our data suggest that the role of ATR is partially overlapping with ATM, whereas ATR is also endowed with unique functional properties in the repair processes during CSR and SHM. We further studied the CSR junctions in Artemis deficient patients. A significantly increased usage of microhomology of ≥10 bp and an absolute absence of blunt-end joining were observed in Sμ-Sα junctions in the patients. However, the Sμ-Sγ junctions obtained from a patient who carried “hypomorphic” mutations appeared to be largely normal in their usage of microhomology, although an unusual type of sequential switching was observed more frequently than expected. These findings suggest that varying modes of CSR junction resolution were used for different S regions, when the function of Artemis is impaired. The altered pattern of CSR junctions also strongly link Artemis to the predominant NHEJ pathway during CSR. CSR junctions were also studied in B cells from Cernunnos deficient patients. These junctions were characterized by a significantly increased usage of microhomology of ≥10 bp and a significantly decreased usage of “direct end joining”. This pattern has previously been observed in B cells deficient for DNA Ligase IV (Lig4), XRCC4, Artemis and ATM, suggesting that Cernunnos is likely to be involved in the DNA Lig4 dependent NHEJ pathway during CSR. One somatically acquired missense mutation (p.Q227R) was also observed in the Cernunnos encoding gene in a germinal B cell like (GCB) diffuse large B cell lymphoma (DLBCL) sample. Two types of translocations (IGH/BCL2 and MYC/IGH) were detected in this tumor sample and one of the switch γ regions appeared to be disrupted during translocation. Clonal-like, dynamic IgA switching activities were also observed, suggesting a link between defects in the Cernunnos dependent NHEJ pathway and aberrant CSR/switch translocations during the development of B cell malignancies. Mutations in Mre11 and NBS1 gene can cause Ataxia-telangiectasia-like disorder (ATLD) and Nijmegen breakage syndrome (NBS) respectively. SHM patterns in cells from these patients were furthermore analyzed. The frequency and distribution of mutations obtained from both patient groups were largely similar to that observed in controls. The mutation pattern from ATLD patients was only slightly changed, with a small increase of the frequency of A to C transversions, suggesting that Mre11 is unlikely to be the major nuclease involved in cleavage of the abasic sites during SHM. The mutation pattern from NBS patients was however, altered with a significantly increased number of G transversions (G→C and G→T), which mainly occurred in AID and/or SHM hotspot motifs. NBS1 might thus have a specific role in regulating the strand-biased repair during phase Ib mutagenesis.
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| 9. |
- Hueting, David A., et al.
(författare)
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Design, structure and plasma binding of ancestral β-CoV scaffold antigens
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- We report the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interact with plasma of patients recovered from COVID-19 but do not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yield high resolution structures (2.6–2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. The structures reveal an intricate hydrogen-bonding network mediated by well-resolved loops, both within and across monomers, tethering the N-terminal domain and RBD together. We show that AnSA-5 can induce and boost a broad-spectrum immune response against the wild-type RBD as well as circulating variants of concern in an immune organoid model derived from tonsils. Finally, we highlight how AnSAs are potent scaffolds by replacing the ancestral RBD with the wild-type sequence, which restores ACE2 binding and increases the interaction with convalescent plasma.
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| 10. |
- Marcotte, Harold, et al.
(författare)
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Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents Infection of Omicron lineages
- 2024
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 121:3
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Tidskriftsartikel (refereegranskat)abstract
- The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previ- ously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot suffi- ciently boost the mucosal secretory IgA response in uninfected individuals, particu- larly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgAl antibodies derived from four neutralizing IgG monoclonal antibodies (mAbs 01A05, rmAb23, DXP-604, and XG014) targeting the receptor-binding domain of the spike protein. Compared to their parental IgG antibod- ies, dimeric and secretory IgAl antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgAl form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2, and BA.4/5 with a 25- to 75-fold increase in potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Thus, dimeric or secre- tory IgA delivered by nasal administration may potentially be exploited for the treatment Iand prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.
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| 11. |
- Marcotte, Harold, et al.
(författare)
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Immunity to SARS-CoV-2 up to 15 months after infection
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:2
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Tidskriftsartikel (refereegranskat)abstract
- Information concerning the longevity of immunity to SARS-CoV-2 following natural infection may have considerable implications for durability of immunity induced by vaccines. Here, we monitored the SARS-CoV-2 specific immune response in COVID-19 patients followed up to 15 months after symptoms onset. Following a peak at day 15-28 postinfection, the IgG antibody response and plasma neutralizing titers gradually decreased over time but stabilized after 6 months. Compared to G614, plasma neutralizing titers were more than 8-fold lower against variants Beta, Gamma, and Delta. SARS-CoV-2-specific memory B and T cells persisted in the majority of patients up to 15 months although a significant decrease in specific T cells, but not B cells, was observed between 6 and 15 months. Antiviral specific immunity, especially memory B cells in COVID-19 convalescent patients, is long-lasting, but some variants of concern may at least partially escape the neutralizing activity of plasma antibodies.
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| 12. |
- Mogensen, Ida, et al.
(författare)
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Lung function before and after COVID-19 in young adults : A population-based study.
- 2022
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Ingår i: The journal of allergy and clinical immunology. Global. - : University of Wisconsin Press. - 2772-8293. ; 1:2, s. 37-42
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is limited evidence on the long-term impact of mild-to-moderate coronavirus disease 2019 (COVID-19) on lung function among young adults.OBJECTIVES: We aimed to assess whether COVID-19 has a negative impact on lung function in young adults and whether asthma, allergic sensitization, or use of inhaled corticosteroids (ICSs) modifies a potential association.METHODS: Participants from the population-based BAMSE (Barn, Allergi, Miljö, Stockholm, Epidemiologi) cohort with spirometry assessed before (2016-2019) and after onset of the COVID-19 pandemic (2020-2021) were included. Serum levels of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain-specific IgG, IgM, and/or IgA (determined with ELISA) defined seropositivity. Mean change in lung function (ie, change in FEV1, forced vital capacity [FVC], and FEV1/FVC ratio expressed as percent of predicted [pp]) from before to after onset of the pandemic were compared between the seronegative and seropositive participants. In seropositive participants, change in lung function was assessed in relation to allergic sensitization and self-reported ICS use.RESULTS: Of the 853 included participants, 29% (n = 243) were seropositive. There were no differences in change in lung function between the seronegative and seropositive participants (for mean change in FEV1 pp [SD], seropositivity = 0.87% [4.79%] and seronegativity = 1.03% (4.76%) [P = .66] for difference using a t test; FVC pp (SD), seropositivity = 1.34% (4.44%) and seronegativity = 1.29% (4.27%) [P = .87]; and for FEV1/FVC pp (SD), seropositivity = -0.25% (3.13%) and seronegativity = -0.13% (3.15%) [P = .61]). Similar results were observed among participants with asthma (n = 147 [17%]). Among seropositive participants, allergic sensitization or ICS use did not influence lung function.CONCLUSION: We found no evidence of mild-to-moderate COVID-19 affecting lung function long term in a population-based cohort of young adults. Moreover, neither asthma nor allergic sensitization nor ICS use affected the results.
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| 13. |
- Nie, Man, et al.
(författare)
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The dual role of CD70 in B‐cell lymphomagenesis
- 2022
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Ingår i: Clinical and Translational Medicine. - : John Wiley & Sons. - 2001-1326. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T-cell-mediated immunity. However, the role of CD70 in B-cell malignancies remains controversial.MethodsWe investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B-cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD-L1 inhibitor in a murine lymphoma model.ResultsWe showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over-expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high-expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD-L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells.ConclusionsOur findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno-therapeutic strategies.
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| 14. |
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| 15. |
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| 16. |
- Sherina, Natalia, et al.
(författare)
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Persistence of SARS-CoV-2-specific B and T cell responses in convalescent COVID-19 patients 6-8 months after the infection
- 2021
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Ingår i: Med. - : Elsevier BV. - 2666-6340. ; 2:3, s. 281-295
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Tidskriftsartikel (refereegranskat)abstract
- Background: Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody (Ab) levels and specific memory B and T cell responses in convalescent coronavirus disease 2019 (COVID-19) patients.Methods: A total of 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain Ab levels over a period of 8 months. In addition, the levels of SARS-CoV-2 neutralizing Abs and specific memory B and T cell responses were tested in a subset of samples.Findings: Anti-SARS-CoV-2 Abs were present in 85% of the samples collected within 4 weeks after the onset of symptoms in COVID-19 patients. Levels of specific immunoglobulin M (IgM)/IgA Abs declined after 1 month, while levels of specific IgG Abs and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG Abs were still present, although at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B and T cell responses developed with time and were persistent in all of the patients followed up for 6-8 months.Conclusions: Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 may persist for at least 6-8 months, regardless of disease severity. Development of medium- or long-term protective immunity through vaccination may thus be possible.
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| 17. |
- Syrén, Per-Olof, et al.
(författare)
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Design, structure and plasma binding of ancestral β-CoV scaffold antigens
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The pandemic caused by Severe acute respiratory syndrome coronavirus 2 has had devastating consequences on global health and economy. Despite the success of vaccination campaigns emerging variants are of concern and novel viruses with the potential to drive future pandemics are circulating in nature. Development of vaccines can be challenging, as key viral protein antigens can be unstable or aggregate. In this study, we present the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interacted with plasma of patients recovered from COVID-19 but did not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yielded high resolution structures (2.6-2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. This captured closed state is stabilised by an intricate hydrogen‑bonding network mediated by well-resolved loops, both within and across monomers, tethering the N‑terminal domain and RBD together, which determines their relative spatial orientation. Finally, we show how AnSAs are potent scaffolds by replacing the ancestral RBD with the Wuhan wild-type sequence, which restored ACE2 binding and increased the interaction with convalescent plasma. In contrast to rational antigen design depending on prior structural knowledge, our work highlights how stable and potentially interesting antigens can be generated using exclusively available sequence information.
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| 18. |
- Zuo, Fanglei, et al.
(författare)
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Heterologous immunization with inactivated vaccine followed by mRNA-booster elicits strong immunity against SARS-CoV-2 Omicron variant
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.
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