Abstract Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8 + and CD4 + T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.
The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR).
Amino acid ester substituted polyphosphazenes are attractive candidates for various biomedical applications because of their biocompatibility, controllable hydrolytic degradation rates, and nontoxic degradation products. In this study, the biocompatibility of three L-alanine ethyl ester functionalized polyphosphazenes was evaluated in a subcutaneous rat model. The polymers used in the study were poly[bis(ethylalanato)phosphazene] (PNEA), poly[(50% ethylalanato) (50% methylphenoxy) phosphazene] (PNEA(50)mPh(50)), and poly[(50% ethylalanato)(50% phenyl phenoxy) phosphazene] (PNEA(50)PhPh(50)). Polymer disks of diameter 7.5 mm were prepared by a solvent evaporation technique and were implanted subcutaneously in rats. After 2, 4, and 12 weeks, the polymer along with the surrounding tissues were excised, prepared, and viewed by light microscopy to evaluate the tissue responses of the implanted polymers. The tissue responses were classified as minimal, mild, or moderate, based on a biocompatibility scheme developed in our laboratory. Minimal inflammation was characterized by the presence of few neutrophils, erythrocytes, and lymphocytes; mild response was characterized by the predominant presence of macrophages, fibroblasts, or giant cells; and moderate inflammation was characterized by the abundance of macrophages, giant cells, and by the presence of tissue exudates. The in vivo degradation profiles of the polymers at various time points were evaluated by gel permeation chromatography (GPC). PNEA and PNEA(50)mPh(50) matrices elicited varying levels of tissue responses during the 12-week implantation period. At 2 weeks both polymers evoked a moderate response, and by 12 weeks the response was found to be mild. However, PNEA(50)PhPh(50) elicited a mild response at the end of 2 weeks and demonstrated a further decreased inflammatory response after 12 weeks. The in vivo degradation of the polymers was followed by determining the molecular weights of the explanted polymer disks. PNEA and PNEA(50)mPh(50) disks showed significant decrease in molecular weight after 2 weeks of implantation. The molecular weights of PNEA and PNEA(50)mPh(50) residues could not be determined by GPC after 12 weeks of implantation because of almost complete degradation. On the other hand the in vivo degradation of PNEA(50)PhPh(50) was found to be slow, with a 63% loss in molecular weight in 12 weeks. Furthermore, this polymer maintained its shape and structure during the entire study. Thus, these polymers demonstrated excellent tissue compatibility and in vivo biodegradability and can be potential candidates for various biomedical applications.
