RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a morbid fibrotic lung disease with limited treatment options. The pathophysiology of IPF remains poorly understood, and elucidation of the cellular and molecular mechanisms of IPF pathogenesis is key to the development of new therapeutics. B-1 cells are an innate B cell population which play an important role linking innate and adaptive immunity. B-1 cells spontaneously secrete natural IgM and prevent inflammation in several disease states. One class of these IgM recognize oxidation-specific epitopes (OSE), which have been shown to be generated in lung injury and to promote fibrosis. A main B-1 cell reservoir is the pleural space, adjacent to the typical distribution of fibrosis in IPF. In this study, we demonstrate that B-1 cells are recruited to the lung during injury where they secrete IgM to OSE (IgM OSE ). We also show that the pleural B-1 cell reservoir responds to lung injury through regulation of the chemokine receptor CXCR4. Mechanistically we show that the transcription factor Id3 is a novel negative regulator of CXCR4 expression. Using mice with B-cell specific Id3 deficiency, a model of increased B-1b cells, we demonstrate decreased bleomycin-induced fibrosis compared to littermate controls. Furthermore, we show that mice deficient in secretory IgM ( sIgM -/- ) have higher mortality in response to bleomycin-induced lung injury, which is partially mitigated through airway delivery of the IgM OSE E06. Additionally, we provide insight into potential mechanisms of IgM in attenuation of fibrosis through RNA sequencing and pathway analysis, highlighting complement activation and extracellular matrix deposition as key differentially regulated pathways.
RESUMEN
BACKGROUNDThe criteria used to allocate scarce COVID-19 vaccines are hotly contested. While some are pushing just to get vaccines into arms as quickly as possible, others advocate prioritization in terms of risk. OBJECTIVEOur aim is to use demographic models to show the enormous potential of vaccine risk-prioritization in saving lives. METHODSWe develop a simple mathematical model that accounts for the age distribution of the population and of COVID-19 mortality. This model considers only the direct live-savings for those who receive the vaccine, and does not account for possible indirect effects of vaccination. We apply this model to the United States, Japan, and Bangladesh. RESULTSIn the United States, we find age-prioritization would reduce deaths during a vaccine campaign by about 93 percent relative to no vaccine and 85 percent relative to age-neutral vaccine distribution. In countries with younger age structures, such as Bangladesh, the benefits of age-prioritization are even greater. CONTRIBUTIONFor policy makers, our findings give additional support to risk-prioritized allocation of COVID-19 vaccines. For demographers, our results show how the age-structures of the population and of disease mortality combine into an expression of risk concentration that shows the benefits of prioritized allocation. This measure can also be used to study the effects of prioritizing other dimensions of risk such as underlying health conditions.