Frontiers in immunology
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Frontiers in immunology · Jan 2021
Cell-Mediated Immunity to NAGLU Transgene Following Intracerebral Gene Therapy in Children With Mucopolysaccharidosis Type IIIB Syndrome.
Mucopolysaccharidosis type IIIB syndrome (Sanfilippo disease) is a rare autosomic recessif disorder caused by mutations in the α-N-acetylglucosaminidase (NAGLU) gene coding for a lysosomal enzyme, leading to neurodegeneration and progressive deterioration of cognitive abilities in affected children. To supply the missing enzyme, several recent human gene therapy trials relied on the deposit of adeno-associated virus (AAV) vectors directly into the brain. We reported safety and efficacy of an intracerebral therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03300453), with a recombinant AAV serotype 2/5 (rAAV2/5) coding human NAGLU in four children with MPS IIIB syndrome receiving immunosuppression. ⋯ We also report that gene therapy did not trigger neuroinflammation, evaluated through the expression of cytokines and chemokines in patients' CSF. Milder disease progression in the youngest patient was found associated with low level and less differentiated circulating NAGLU-specific T cells, together with the lack of proinflammatory cytokines in the CSF. Findings in this study support a systematic and comprehensive immunomonitoring approach for understanding the impact immune reactions might have on treatment safety and efficacy of gene therapies.
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Frontiers in immunology · Jan 2021
Longitudinal Profiling of Antibody Response in Patients With COVID-19 in a Tertiary Care Hospital in Beijing, China.
The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of the coronavirus disease 2019 (COVID-19), which elicits a wide variety of symptoms, ranging from mild to severe, with the potential to lead to death. Although used as the standard method to screen patients for SARS-CoV-2 infection, real-time PCR has challenges in dealing with asymptomatic patients and those with an undetectable viral load. Serological tests are therefore considered potent diagnostic tools to complement real-time PCR-based diagnosis and are used for surveillance of seroprevalence in populations. ⋯ Furthermore, the majority of cases could achieve IgM and IgG seroconversion at 2 weeks since the disease onset. Analysis of neutralizing antibodies indicated that these responses were able to last for more than 112 days but decline significantly after the peak. In summary, our findings demonstrate the longitudinally dynamic changes in antibody responses against SARS-CoV-2, which can contribute to the knowledge of humoral immune response after SARS-CoV-2 infection and are informative for future development of vaccine and antibody-based therapies.
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Frontiers in immunology · Jan 2021
Comprehensive Comparison of RNA-Seq Data of SARS-CoV-2, SARS-CoV and MERS-CoV Infections: Alternative Entry Routes and Innate Immune Responses.
The pathogenesis of COVID-19 emerges as complex, with multiple factors leading to injury of different organs. Some of the studies on aspects of SARS-CoV-2 cell entry and innate immunity have produced seemingly contradictory claims. In this situation, a comprehensive comparative analysis of a large number of related datasets from several studies could bring more clarity, which is imperative for therapy development. ⋯ First, our analyses support the existence of cell entry mechanisms for SARS and SARS-CoV-2 other than the ACE2 route with evidence of inefficient infection of cells without expression of ACE2; expression of TMPRSS2/TPMRSS4 is unnecessary for efficient SARS-CoV-2 infection with evidence of efficient infection of A549 cells transduced with a vector expressing human ACE2. Second, we find that innate immune responses in terms of interferons and interferon simulated genes are strong in relevant cells, for example Calu3 cells, but vary markedly with cell type, virus dose, and virus type.
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Frontiers in immunology · Jan 2021
Pathogenic Mechanisms of Vaccine-Induced Immune Thrombotic Thrombocytopenia in People Receiving Anti-COVID-19 Adenoviral-Based Vaccines: A Proposal.
VITT is a rare, life-threatening syndrome characterized by thrombotic symptoms in combination with thrombocytopenia, which may occur in individuals receiving the first administration of adenoviral non replicating vectors (AVV) anti Covid19 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by high levels of serum IgG that bind PF4/polyanion complexes, thus triggering platelet activation. Therefore, identification of the fine pathophysiological mechanism by which vaccine components trigger platelet activation is mandatory. ⋯ Moreover, AVV infection of mast cells may trigger aberrant inflammatory and immune responses in people affected by the mast cell activation syndrome (MCAS). The pre-existence of natural antibodies binding PF4/heparin complexes may amplify platelet activation and thrombotic events. Finally, neosynthesized Covid 19 Spike protein interacting with its ACE2 receptor on endothelia, platelets and leucocyte may trigger further thrombotic events unleashing the WITT syndrome.
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Frontiers in immunology · Jan 2021
ReviewThe Role of CD4+ Resident Memory T Cells in Local Immunity in the Mucosal Tissue - Protection Versus Pathology.
Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (TEM) cells, central memory T (TCM) cells, and tissue-resident memory T (TRM) cells have been identified. The most recently identified subset, TRM cells, is characterized by the expression of the C-type lectin CD69 and/or the integrin CD103. ⋯ In this review, we discuss the ambivalent feature of CD4+ TRM cells in the protective and pathological immune responses. We also review the transcriptional and epigenetic characteristics of CD4+ TRM cells in the lung that have been elucidated by recent technical approaches. A better understanding of the function of CD4+ TRM cells is crucial for the development of both effective vaccination against pathogens and new therapeutic strategies for intractable inflammatory diseases, such as inflammatory bowel diseases and chronic allergic diseases.