Ancient Evolutionary Origin and Properties of Universally Produced Natural Exosomes Contribute to Their Therapeutic Superiority Compared to Artificial Nanoparticles.

Extracellular vesicles (EVs), such as exosomes, are newly recognized fundamental, universally produced natural nanoparticles of life that are seemingly involved in all biologic processes and clinical diseases. Due to their universal involvements, understanding the nature and also the potential therapeutic uses of these nanovesicles requires innovative experimental approaches in virtually every field. Of the EV group, exosome nanovesicles and larger companion micro vesicles can mediate completely new biologic and clinical processes dependent on the intercellular transfer of proteins and most importantly selected RNAs, particularly miRNAs between donor and targeted cells to elicit epigenetic alterations inducing functional cellular changes. These recipient acceptor cells are nearby (paracrine transfers) or far away after distribution via the circulation (endocrine transfers). The major properties of such vesicles seem to have been conserved over eons, suggesting that they may have ancient evolutionary origins arising perhaps even before cells in the primordial soup from which life evolved. Their potential ancient evolutionary attributes may be responsible for the ability of some modern-day exosomes to withstand unusually harsh conditions, perhaps due to unique membrane lipid compositions. This is exemplified by ability of the maternal milk exosomes to survive passing the neonatal acid/enzyme rich stomach. It is postulated that this resistance also applies to their durable presence in phagolysosomes, thus suggesting a unique intracellular release of their contained miRNAs. A major discussed issue is the generally poorly realized superiority of these naturally evolved nanovesicles for therapies when compared to human-engineered artificial nanoparticles, e.g., for the treatment of diseases like cancers.

A subset of AID-dependent B-1a cells initiates hypersensitivity and pneumococcal pneumonia resistance.

We propose that there is a special B-1a B cell subset ("sB-1a" cells) that mediates linked processes very early after immunization to initiate cutaneous contact sensitivity (CS), delayed-type hypersensitivity (DTH), and immune resistance to pneumococcal pneumonia. Our published data indicate that in CS and DTH, these initiating processes are required for elicitation of the delayed onset and late-occurring classical T cell-mediated responses. sB-1a cells resemble memory B2 cells, as they are stimulated within 1 h of immunization and depend on T helper cytokines-uniquely IL-4 from hepatic iNKT cells--for activation and rapid migration from the peritoneal cavity to the spleen to secrete IgM antibody (Ab) and Ab-derived free light chains (FLCs) by only 1 day after immunization. Unlike conventional B-1a (cB-1a) cell-produced IgM natural Ab, IgM Ab produced by sB-1a cells has high Ag affinity owing to immunoglobulin V-region mutations induced by activation-induced cytidine deaminase (AID). The dominant cB-1a cells are increased in immunized AID-deficient mice but do not mediate initiation, CS, or pneumonia resistance because natural Ab has relatively low Ag affinity because of unmutated germ-line V regions. In CS and DTH, sB-1a IgM Ag affinity is sufficiently high to mediate complement activation for generation of C5a that, together with vasoactive mediators such as TNF-α released by FLC-sensitized mast cells, activate local endothelium for extravascular recruitment of effector T cells. We conclude by discussing the possibility of functional sB-1 cells in humans.