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Article ; Online: Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption.

Gröning, Remigius / Dernstedt, Andy / Ahlm, Clas / Normark, Johan / Sundström, Peter / Forsell, Mattias N E

2023 Volume 14, Page(s) 1219560

Abstract: Peripheral B cell ... ...

Abstract	Peripheral B cell depletion
MeSH term(s)	Humans ; BNT162 Vaccine ; Rituximab/therapeutic use ; SARS-CoV-2 ; Multiple Sclerosis/drug therapy ; COVID-19/prevention & control ; Vaccination ; Antibodies ; Immunity ; RNA, Messenger
Chemical Substances	BNT162 Vaccine ; Rituximab (4F4X42SYQ6) ; Antibodies ; RNA, Messenger
Language	English
Publishing date	2023-07-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1219560
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Article ; Online: Direct and indirect effects of Puumala hantavirus on platelet function.

Schrottmaier, Waltraud C / Schmuckenschlager, Anna / Thunberg, Therese / Wigren-Byström, Julia / Fors-Connolly, Anne-Marie / Assinger, Alice / Ahlm, Clas / Forsell, Mattias N E

Thrombosis research

2023 Volume 233, Page(s) 41–54

Abstract: Thrombocytopenia is a cardinal symptom of hantavirus-induced diseases including Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome (HFRS), which is associated with impaired platelet function, bleeding manifestations and augmented ... ...

Abstract	Thrombocytopenia is a cardinal symptom of hantavirus-induced diseases including Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome (HFRS), which is associated with impaired platelet function, bleeding manifestations and augmented thrombotic risk. However, the underlying mechanisms causing thrombocytopenia and platelet hypo-responsiveness are unknown. Thus, we investigated the direct and indirect impact of PUUV on platelet production, function and degradation. Analysis of PUUV-HFRS patient blood revealed that platelet hypo-responsiveness in PUUV infection was cell-intrinsic and accompanied by reduced platelet-leukocyte aggregates (PLAs) and upregulation of monocyte tissue factor (TF), whereas platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation was comparable to healthy controls. Plasma CXCL4 levels followed platelet count dynamics throughout disease course. PUUV activated both neutrophils and monocytes in vitro, but platelet desialylation, degranulation and GPIIb/IIIa activation as well as PLA formation and endothelial adhesion under flow remained unaltered in the presence of PUUV. Further, MEG-01 megakaryocytes infected with PUUV displayed unaltered polyploidization, expression of surface receptors and platelet production. However, infection of endothelial cells with PUUV significantly increased platelet sequestration. Our data thus demonstrate that although platelet production, activation or degradation are not directly modulated, PUUV indirectly fosters thrombocytopenia by sequestration of platelets to infected endothelium. Upregulation of immunothrombotic processes in PUUV-HFRS may further contribute to platelet dysfunction and consumption. Given the pathophysiologic similarities of hantavirus infections, our findings thus provide important insights into the mechanisms underlying thrombocytopenia and highlight immune-mediated coagulopathy as potential therapeutic target.
MeSH term(s)	Humans ; Puumala virus ; Hemorrhagic Fever with Renal Syndrome/diagnosis ; Hemorrhagic Fever with Renal Syndrome/therapy ; Endothelial Cells ; Orthohantavirus ; Thrombocytopenia
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	121852-9
ISSN	1879-2472 ; 0049-3848
ISSN (online)	1879-2472
ISSN	0049-3848
DOI	10.1016/j.thromres.2023.11.017
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Zs.A 863: Show issues

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Article ; Online: Hybrid capture-based next-generation sequencing of new and old world Orthohantavirus strains and wild-type Puumala isolates from humans and bank voles.

Rosenbaum, William / Bovinder Ylitalo, Erik / Castel, Guillaume / Sjödin, Andreas / Larsson, Pär / Wigren Byström, Julia / Forsell, Mattias N E / Ahlm, Clas / Pettersson, Lisa / Tuiskunen Bäck, Anne

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology

2024 Volume 172, Page(s) 105672

Abstract: Orthohantaviruses, transmitted primarily by rodents, cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in the Americas. These viruses, with documented human-to-human transmission, exhibit a wide case-fatality ...

Abstract	Orthohantaviruses, transmitted primarily by rodents, cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in the Americas. These viruses, with documented human-to-human transmission, exhibit a wide case-fatality rate, 0.5-40 %, depending on the virus species, and no vaccine or effective treatment for severe Orthohantavirus infections exists. In Europe, the Puumala virus (PUUV), carried by the bank vole Myodes glareolus, causes a milder form of HFRS. Despite the reliance on serology and PCR for diagnosis, the three genomic segments of Swedish wild-type PUUV have yet to be completely sequenced. We have developed a targeted hybrid-capture method aimed at comprehensive genomic sequencing of wild-type PUUV isolates and the identification of other Orthohantaviruses. Our custom-designed panel includes >11,200 probes covering the entire Orthohantavirus genus. Using this panel, we sequenced complete viral genomes from bank vole lung tissue, human plasma samples, and cell-cultured reference strains. Analysis revealed that Swedish PUUV isolates belong to the Northern Scandinavian lineage, with nucleotide diversity ranging from 2.8 % to 3.7 % among them. Notably, no significant genotypic differences were observed between the viral sequences from reservoirs and human cases except in the nonstructural protein. Despite the high endemicity of PUUV in Northern Sweden, these are the first complete Swedish wild-type PUUV genomes and substantially increase our understanding of PUUV evolution and epidemiology. The panel's sensitivity enables genomic sequencing of human samples with viral RNA levels reflecting the natural progression of infection and underscores our panel's diagnostic value, and could help to uncover novel Orthohantavirus transmission routes.
Language	English
Publishing date	2024-03-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1446080-4
ISSN	1873-5967 ; 1386-6532
ISSN (online)	1873-5967
ISSN	1386-6532
DOI	10.1016/j.jcv.2024.105672
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Zs.A 3790: Show issues

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Article ; Online: SARS-CoV-2-related mortality decrease in nursing home residents given multiple COVID-19 boosters.

Blom, Kim / Fjällström, Peter / Molnár, Christian / Åberg, Mikael / Vikström, Linnea / Wigren-Byström, Julia / Bennet, Louise / Widerström, Micael / Rasmussen, Gunlög / Klingström, Jonas / Forsell, Mattias N E / Johansson, Anders F

The Lancet. Infectious diseases

2023 Volume 23, Issue 10, Page(s) e393–e394

MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; Nursing Homes
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Letter
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(23)00548-0
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Zs.A 5743: Show issues

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Article ; Online: Recall of preexisting cross-reactive B cell memory after Omicron BA.1 breakthrough infection.

Kaku, Chengzi I / Bergeron, Alan J / Ahlm, Clas / Normark, Johan / Sakharkar, Mrunal / Forsell, Mattias N E / Walker, Laura M

Science immunology

2022 Volume 7, Issue 73, Page(s) eabq3511

Abstract: Understanding immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)-specific B cell responses after Omicron/BA.1 ...

Abstract	Understanding immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)-specific B cell responses after Omicron/BA.1 infection in messenger RNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells. BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit, which is highly conserved across SARS-CoV-2 variants of concern (VOCs), and toward the antigenically variable receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 VOCs. Together, these findings provide insights into the role of preexisting immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.
MeSH term(s)	Antibodies, Viral ; B-Lymphocytes/immunology ; COVID-19/immunology ; COVID-19 Vaccines/immunology ; Cross Reactions ; Humans ; Immunologic Memory ; Membrane Glycoproteins ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/genetics ; Viral Envelope Proteins
Chemical Substances	Antibodies, Viral ; COVID-19 Vaccines ; Membrane Glycoproteins ; Spike Glycoprotein, Coronavirus ; Viral Envelope Proteins ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-07-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abq3511
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Article ; Online: Risk factors for impaired respiratory function post COVID-19: A prospective cohort study of nonhospitalized and hospitalized patients.

Björsell, Tove / Sundh, Josefin / Lange, Anna / Ahlm, Clas / Forsell, Mattias N E / Tevell, Staffan / Blomberg, Anders / Edin, Alicia / Normark, Johan / Cajander, Sara

Journal of internal medicine

2023 Volume 293, Issue 5, Page(s) 600–614

Abstract: Background: Severe COVID-19 increases the risk for long-term respiratory impairment, but data after mild COVID-19 are scarce. Our aims were to determine risk factors for reduced respiratory function 3-6 months after COVID-19 infection and to investigate ...

Abstract	Background: Severe COVID-19 increases the risk for long-term respiratory impairment, but data after mild COVID-19 are scarce. Our aims were to determine risk factors for reduced respiratory function 3-6 months after COVID-19 infection and to investigate if reduced respiratory function would relate to impairment of exercise performance and breathlessness. Methods: Patients with COVID-19 were enrolled at the University Hospitals of Umeå and Örebro, and Karlstad Central Hospital, Sweden. Disease severity was defined as mild (nonhospitalized), moderate (hospitalized with or without oxygen treatment), and severe (intensive care). Spirometry, including diffusion capacity (DL Results: Between April 2020 and May 2021, 337 patients were enrolled in the study. Forced vital capacity and DL Conclusion: Reduced DL
MeSH term(s)	Humans ; COVID-19/complications ; Prospective Studies ; Dyspnea/etiology ; Spirometry ; Risk Factors ; Lung
Language	English
Publishing date	2023-02-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	96274-0
ISSN	1365-2796 ; 0954-6820
ISSN (online)	1365-2796
ISSN	0954-6820
DOI	10.1111/joim.13614
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Article ; Online: Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages.

Chernyshev, Mark / Sakharkar, Mrunal / Connor, Ruth I / Dugan, Haley L / Sheward, Daniel J / Rappazzo, C G / Stålmarck, Aron / Forsell, Mattias N E / Wright, Peter F / Corcoran, Martin / Murrell, Ben / Walker, Laura M / Karlsson Hedestam, Gunilla B

Nature communications

2023 Volume 14, Issue 1, Page(s) 2249

Abstract: Vaccination of SARS-CoV-2 convalescent individuals generates broad and potent antibody responses. Here, we isolate 459 spike-specific monoclonal antibodies (mAbs) from two individuals who were infected with the index variant of SARS-CoV-2 and later ... ...

Abstract	Vaccination of SARS-CoV-2 convalescent individuals generates broad and potent antibody responses. Here, we isolate 459 spike-specific monoclonal antibodies (mAbs) from two individuals who were infected with the index variant of SARS-CoV-2 and later boosted with mRNA-1273. We characterize mAb genetic features by sequence assignments to the donors' personal immunoglobulin genotypes and assess antibody neutralizing activities against index SARS-CoV-2, Beta, Delta, and Omicron variants. The mAbs used a broad range of immunoglobulin heavy chain (IGH) V genes in the response to all sub-determinants of the spike examined, with similar characteristics observed in both donors. IGH repertoire sequencing and B cell lineage tracing at longitudinal time points reveals extensive evolution of SARS-CoV-2 spike-binding antibodies from acute infection until vaccination five months later. These results demonstrate that highly polyclonal repertoires of affinity-matured memory B cells are efficiently recalled by vaccination, providing a basis for the potent antibody responses observed in convalescent persons following vaccination.
MeSH term(s)	Humans ; Cell Lineage ; SARS-CoV-2 ; COVID-19/prevention & control ; B-Lymphocytes ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus/genetics ; Vaccination
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37972-1
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Article ; Online: Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis.

Dernstedt, Andy / Leidig, Jana / Holm, Anna / Kerkman, Priscilla F / Mjösberg, Jenny / Ahlm, Clas / Henriksson, Johan / Hultdin, Magnus / Forsell, Mattias N E

Frontiers in immunology

2021 Volume 11, Page(s) 599647

Abstract: Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also ... ...

Abstract	Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAF
MeSH term(s)	B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; CD55 Antigens/immunology ; Gene Expression Regulation/immunology ; Germinal Center/cytology ; Germinal Center/immunology ; Humans ; Lymphocyte Activation ; Phagocytosis ; Positive Regulatory Domain I-Binding Factor 1/immunology
Chemical Substances	CD55 Antigens ; PRDM1 protein, human (138415-26-6) ; Positive Regulatory Domain I-Binding Factor 1 (EC 2.1.1.-)
Language	English
Publishing date	2021-01-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.599647
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Article ; Online: High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19.

Ahmad, Irma / Edin, Alicia / Granvik, Christoffer / Kumm Persson, Lowa / Tevell, Staffan / Månsson, Emeli / Magnuson, Anders / Marklund, Ingela / Persson, Ida-Lisa / Kauppi, Anna / Ahlm, Clas / Forsell, Mattias N E / Sundh, Josefin / Lange, Anna / Cajander, Sara / Normark, Johan

Frontiers in public health

2023 Volume 11, Page(s) 1104267

Abstract: Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in ... ...

Abstract	Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in relation to functional exercise capacity, 6 months after infection, and explored risk factors for COVID-19 sequalae. Methods: This was a prospective, multicenter, cohort study including 434 patients. At 6 months, physical exercise capacity was assessed by a 1-minute sit-to-stand test (1MSTST) and persistent symptoms were reported and HRQoL was evaluated through the EuroQol 5-level 5-dimension (EQ-5D-5L) questionnaire. Patients with both persistent symptoms and reduced HRQoL were classified into a new definition of post-acute COVID syndrome, PACS+. Risk factors for developing persistent symptoms, reduced HRQoL and PACS+ were identified by multivariable Poisson regression. Results: Persistent symptoms were experienced by 79% of hospitalized, and 59% of non-hospitalized patients at 6 months. Hospitalized patients had a higher prevalence of self-assessed reduced overall health (28 vs. 12%) and PACS+ (31 vs. 11%). PACS+ was associated with reduced exercise capacity but not with abnormal pulse/desaturation during 1MSTST. Hospitalization was the most important independent risk factor for developing persistent symptoms, reduced overall health and PACS+. Conclusion: Persistent symptoms and reduced HRQoL are common among COVID-19 survivors, but abnormal pulse and peripheral saturation during exercise could not distinguish patients with PACS+. Patients with severe infection requiring hospitalization were more likely to develop PACS+, hence these patients should be prioritized for clinical follow-up after COVID-19.
MeSH term(s)	Humans ; COVID-19 ; Cohort Studies ; Post-Acute COVID-19 Syndrome ; Prevalence ; Prospective Studies ; Quality of Life ; Self Report
Language	English
Publishing date	2023-02-02
Publishing country	Switzerland
Document type	Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2711781-9
ISSN	2296-2565 ; 2296-2565
ISSN (online)	2296-2565
ISSN	2296-2565
DOI	10.3389/fpubh.2023.1104267
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Article ; Online: Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer.

Lidström, Tommy / Cumming, Joshua / Gaur, Rahul / Frängsmyr, Lars / Pateras, Ioannis S / Mickert, Matthias J / Franklin, Oskar / Forsell, Mattias N E / Arnberg, Niklas / Dongre, Mitesh / Patthey, Cedric / Öhlund, Daniel

Cancer immunology research

2022 Volume 11, Issue 1, Page(s) 72–92

Abstract: ... system, we observed that extracellular gal 4 induced apoptosis in T cells by binding N-glycosylation ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell-produced protein that was deposited into the ECM of PDAC tumors and detected high-circulating levels of gal 4 in patients with PDAC. In orthotopic transplantation experiments, we observed increased infiltration of T cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. By performing single-cell RNA-sequencing, we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression associated with a higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T cells, and antigen-presenting dendritic cells in tumors with reduced gal 4 expression. Using a coculture system, we observed that extracellular gal 4 induced apoptosis in T cells by binding N-glycosylation residues on CD3ε/δ. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC.
MeSH term(s)	Animals ; Mice ; Galectin 4 ; Immune Evasion ; Pancreatic Neoplasms/pathology ; Carcinoma, Pancreatic Ductal/pathology ; Apoptosis ; Pancreatic Neoplasms
Chemical Substances	Galectin 4
Language	English
Publishing date	2022-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-21-1088
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