Plasma proteins defending infected, intact nasal mucosa.

Huang et al1Huang D. Taha M.S. Nocera A.L. Workman A.D. Amiji M.M. Bleier B.S. Cold exposure impairs extracellular vesicle swarm-mediated nasal antiviral immunity.J Allergy Clin Immunol. 2023; 151: 509-525Abstract Full Text Full Text PDF Scopus (1) Google Scholar admirably use current state-of-the-art in vitro approaches highlighting the innate antiviral potential of extracellular vesicle swarms on human nasal mucosa. They introduce their concept as an “active host mucosal defense” on the airway surface, implicitly distinguishing the mechanism of extracellular vesicle swarms from the more passive roles of mucus.1Huang D. Taha M.S. Nocera A.L. Workman A.D. Amiji M.M. Bleier B.S. Cold exposure impairs extracellular vesicle swarm-mediated nasal antiviral immunity.J Allergy Clin Immunol. 2023; 151: 509-525Abstract Full Text Full Text PDF Scopus (1) Google Scholar However, a 30-year-old reference regarding mucus that is cited by Huang et al (Kaliner MA. Human nasal host defense and sinusitis. J Allergy Clin Immunol 1992;90:424-30) additionally mentioned that “outpouring of plasma proteins might represent the first line of defense at mucosal surfaces.”1Huang D. Taha M.S. Nocera A.L. Workman A.D. Amiji M.M. Bleier B.S. Cold exposure impairs extracellular vesicle swarm-mediated nasal antiviral immunity.J Allergy Clin Immunol. 2023; 151: 509-525Abstract Full Text Full Text PDF Scopus (1) Google Scholar Much has been learned regarding the occurrence and physiologic control of the humoral, early antimicrobial defense opportunity involving cooperation between the systemic mucosal microcirculation of human conducting airways and its overlying pseudostratified epithelial lining. However, innate humoral airways defense is not mentioned by Huang et al1Huang D. Taha M.S. Nocera A.L. Workman A.D. Amiji M.M. Bleier B.S. Cold exposure impairs extracellular vesicle swarm-mediated nasal antiviral immunity.J Allergy Clin Immunol. 2023; 151: 509-525Abstract Full Text Full Text PDF Scopus (1) Google Scholar; typically, the profuse superficial mucosal microcirculation is absent from their article's text and graph. Winther et al demonstrated that large and adhesive fibrinogen is coexuded with albumin into human nasal surface liquids in the rhinovirus 16–induced common cold known to proceed without epithelial injury.2Winther B. Gwaltney Jr., J.M. Humphries J.E. Hendley J.O. Cross-linked fibrin in the nasal fluid of patients with common cold.Clin Infect Dis. 2002; 34: 708-710Crossref PubMed Scopus (10) Google Scholar Importantly, the size-independent protein exudation lasted until infection resolution. These data confirmed observations regarding coronavirus 229E–induced human nasal infection, in which case fibrinogen exudation is associated with maintained mucosal barrier function.3Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health.Am J Physiol Lung Cell Mol Physiol. 2022; 322: L503-L506Crossref PubMed Scopus (3) Google Scholar Observations regarding the common cold demonstrate that the humoral response to viral infection is in agreement with the basic features of airways' physiologic plasma exudation: (1) nonsieved microvascular-epithelial exudation of plasma macromolecules at least up to the size of α2-macroglobulin indicates that plasma-derived molecules with known antiviral potential (coagulation, kinin-kallikrein, complement, natural antibody, pentraxin, lectin, cathelicidin, and other systems) would extravasate, move all around epithelial cells, appear, and liaise on the airway surface at sites of infection3Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health.Am J Physiol Lung Cell Mol Physiol. 2022; 322: L503-L506Crossref PubMed Scopus (3) Google Scholar; (2) the nonsieved exudation across a normally tight nasal mucosa reflects dramatic, direction-dependent epithelial barrier asymmetry, pivotally defining the plasma exudation response as first-line mucosal defense, its precision being further defined by well-controlled magnitude, distribution, and duration3Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health.Am J Physiol Lung Cell Mol Physiol. 2022; 322: L503-L506Crossref PubMed Scopus (3) Google Scholar; and (3) inhibition of rhinovirus infection–induced plasma exudation is associated with increased viral titers, but without reducing rhinorrhea.4Gustafson L.M. Proud D. Hendley J.O. Hayden F.G. Gwaltney Jr., J.M. Oral prednisolone therapy in experimental rhinovirus infections.J Allergy Clin Immunol. 1996; 97: 1009-1014Abstract Full Text PDF PubMed Scopus (97) Google Scholar These human in vivo data agree with patchy infection sites and localized plasma exudation responses, together comprising small volumes.3Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health.Am J Physiol Lung Cell Mol Physiol. 2022; 322: L503-L506Crossref PubMed Scopus (3) Google Scholar Mucosal exudative challenges produce venular interendothelial gaps just beneath and facing the epithelium. Through the gaps, nonsieved plasma proteins are extravasating. The endothelial response is an active, reversible, repeatable process that is likely sensitive to changes in temperature5Rippe B. Grega G.J. Effects of isoprenaline and cooling on histamine-induced changes of capillary permeability in the rat hindquarter vascular bed.Acta Physiol Scand. 1978; 103: 252-262Crossref PubMed Scopus (69) Google Scholar and less so to reduced blood flow.3Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health.Am J Physiol Lung Cell Mol Physiol. 2022; 322: L503-L506Crossref PubMed Scopus (3) Google Scholar Physiologic data suggest that extravasated plasma itself, by slightly increasing basolateral epithelial hydrostatic pressure, makes way for swift and safe epithelial transmission of its proteins even without sieving and without impeding the normal mucosal barrier functions.3Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health.Am J Physiol Lung Cell Mol Physiol. 2022; 322: L503-L506Crossref PubMed Scopus (3) Google Scholar The details of the outward passage of bulk macromolecules through the tight junctional belt with all of its interconnected strands and grooves remain an enigma. It would be of interest to compare the humoral response to extracellular vesicle swarms from the standpoints of antiviral efficacy and temperature dependence. Huang et al1Huang D. Taha M.S. Nocera A.L. Workman A.D. Amiji M.M. Bleier B.S. Cold exposure impairs extracellular vesicle swarm-mediated nasal antiviral immunity.J Allergy Clin Immunol. 2023; 151: 509-525Abstract Full Text Full Text PDF Scopus (1) Google Scholar claim that their investigation is of “unique clinical relevance in that all in vitro findings were directly validated in live human tissue.” It seems important to underscore that "live" cannot be equated with in vivo, in which case a profuse mucosal microcirculation cooperates with its juxtaposed pseudostratified epithelium. Cold exposure impairs extracellular vesicle swarm–mediated nasal antiviral immunityJournal of Allergy and Clinical ImmunologyVol. 151Issue 2PreviewThe human upper respiratory tract is the first site of contact for inhaled respiratory viruses and elaborates an array of innate immune responses. Seasonal variation in respiratory viral infections and the importance of ambient temperature in modulating immune responses to infections have been well recognized; however, the underlying biological mechanisms remain understudied. Full-Text PDF