Clinical & Translational Immunology最新文献

The coronavirus disease 2019 (COVID-19) pandemic is the latest in a series of global high-consequence respiratory virus outbreaks. In prior years, we faced the emergence of severe acute respiratory syndrome (SARS) during 2002–2003,¹ swine-like H1N1 influenza A virus in 2009² and Middle East respiratory syndrome coronavirus (MERS-CoV) during 2012.³ We continue to confront the seasonal recurrence of coronaviruses and influenza viruses, and our extensive agricultural practises and ongoing deforestation are considered major drivers of infectious zoonotic disease outbreaks. This, paired with the ever-increasing globalisation of our world, means additional respiratory pandemics are a real possibility in our future.

For COVID-19, early pandemic public health responses focussed on nonpharmaceutical interventions, and control measures were implemented globally to limit viral spread and slow down any potential overwhelming of healthcare systems. These interventions included border closures and travel restrictions, closing of day-care centres, schools, restaurants and shops, the cancellation of mass events, mandatory wearing of face masks and numerous physical isolation measures. The near-simultaneous global implementation of these nonpharmaceutical interventions helped to slow down the community transmission of SARS-CoV-2, mitigated the burden of disease on healthcare resources and allowed time to develop vaccines and treatments. An unexpected but positive phenomenon resulting from the mass implementation of these pandemic measures was the significant drop in non-COVID-19 respiratory viral infections and gastrointestinal viral infections globally.^4-7

An astounding decrease in influenza virus infections in both northern and southern hemispheres was by far one of the most noteworthy changes in non-COVID-19 disease incidence during the pandemic period.^8-10 Comprehensive analysis of the GISRS FluNet database in a 2022 study¹⁰ showed that influenza cases sharply fell during the initial months of the pandemic to <100 cases per week. Compared with prepandemic numbers of ~50 000 cases per week during the 2018–2020 winter seasons, this constituted an unprecedented 99.8% reduction in incidence of influenza disease. Similarly, in the Southern Hemisphere, activity during the 2017–2019 winter seasons peaked between 1500 and 3500 positive cases per week, with a sharp decline following the start of the pandemic; influenza cases dropped to < 12 per week during May 2020 in this hemisphere, with cases remaining < 100 per week until November 2021.¹¹ The reduction in community respiratory virus activity led to additional downstream effects, including associated decreases in secondary bacterial infections such as invasive pneumococcal diseases.^12-14

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Therapy for relapsing–remitting multiple sclerosis (MS) has advanced dramatically despite incomplete understanding of the cause of the condition. Current treatment involves inducing broad effects on immune cell populations with consequent off-target side effects, and no treatment can completely prevent disability progression. Further therapeutic advancement will require a better understanding of the pathobiology of MS. Interest in the role of Epstein–Barr virus (EBV) in multiple sclerosis has intensified based on strong epidemiological evidence of an association between EBV seroprevalence and MS. Hypotheses proposed to explain the biological relationship between EBV and MS include molecular mimicry, EBV immortalised autoreactive B cells and infection of glial cells by EBV. Examining the interaction between EBV and immunotherapies that have demonstrated efficacy in MS offers clues to the validity of these hypotheses. The efficacy of B cell depleting therapies could be consistent with a hypothesis that EBV-infected B cells drive MS; however, loss of T cell control of B cells does not exacerbate MS. A number of MS therapies invoke change in EBV-specific T cell populations, but pathogenic EBV-specific T cells with cross-reactivity to CNS antigen have not been identified. Immune reconstitution therapies induce EBV viraemia and expansion of EBV-specific T cell clones, but this does not correlate with relapse. Much remains unknown regarding the role of EBV in MS pathogenesis. We discuss future translational research that could fill important knowledge gaps.

Here, we offer a roadmap for what might be studied next in understanding how EBV triggers MS. We focus on two areas: The first area concerns the molecular mechanisms underlying how clonal antibody in the CSF emanates in widespread molecular mimicry to key antigens in the nervous system including GlialCAM, a protein associated with chloride channels. A second and equally high priority in the roadmap concerns various therapeutic approaches that are related to blocking the mechanisms whereby EBV triggers MS. Therapies deserving of attention include clinical trials with antivirals and the development of ‘inverse’ vaccines based on nucleic acid technologies to control or to eradicate the consequences of EBV infection. High enthusiasm is given to continuation of ongoing clinical trials of cellular adoptive therapy to attack EBV-infected cells. Clinical trials of vaccines to EBV are another area deserving attention. These suggested topics involving research on mechanism, and the design, implementation and performance of well-designed trials are not intended to be an exhaustive list. We have splendid tools available to our community of medical scientists to tackle how EBV triggers MS and then to perhaps change the world with new therapies to potentially eradicate MS, as we have done with nearly complete success for poliomyelitis.