Influence of aging on immune response and neuroinflamation: research in experimental autoimmune encephalomyelitis

Abstract

Starenje utiče na incidenciju većine inflamatornih autoimunskih bolesti, što se povezuje sa starenjem imunskog sistema, tzv. imunološkim starenjem (engl. immunosenescence). Budući da je pokazano da postoje značajne individualne razlike u procesu starenja ispitivan je značaj genetskih faktora (sojnih razlika) za starenjem uslovljene promene u incidenciji inflamatornih autoimunskih bolesti kod pacova. Korišćen je model eksperimentalnog autoimunskog encefalomijelitisa (EAE) indukovanog inokulacijom homogenata singene kičmene moždine u kompletnom Frojndovom adjuvansu uz ko-administraciju inaktivisane Bordetella pertussis, koji mimikrira ranu inflamatornu fazu multiple skleroze, najčešće inflamatorne autoimunske bolesti centralnog nervnog sistema, čija incidencija pokazuje jasnu uzrasnu zavisnost (smanjuje se starenjem). U istraživanja su uključene adultne i stare ženke pacova Dark Agouti (DA) soja, koji pokazuju izrazitu osetljivost na indukciju EAE-a u adultnom uzrastu i pacova Albino Oxford (AO) soja, koji su u adultnom uzrastu relativno rezistentni na indukciju EAE-a. Cilj je bio i da se definišu ćelijski i molekularni mehanizmi, koji bi mogli da budu odgovorni za moguće sojno zavisne starenjem uzrokovane razlike u osetljivosti na indukciju ove bolesti. Rezultati dobijeni u okviru ove doktorske disertacije pokazali su da starenje smanjuje incidenciju EAE-a i težinu bolesti kod DA pacova, a da kod AO pacova dovodi do razvoja bolesti blagog protrahovanog toka, koja pokazuje značajnu incidenciju (62,5%). Razlike u kliničkom ispoljavanju bolesti kod ova dva soja pacova su se mogle povezati sa sojnim razlikama u mehanizmima koji su uključeni u kontrolu intenziteta primarnog (auto)imunskog odgovora u drenirajućim limfnim čvorovima, ali i migracije aktivisanih neuroantigen-specifičnih T pomoćničkih 17 (engl. T helper 17, Th17) ćelija, posebno zadržavanja u slezini (ekspresija CD44s molekula na površini Th ćelija i zastupljenost CD4+CD25+Foxp3+ regulatornih T-limfocita), kao ključnih za razvoj bolesti u ovom modelu, u ciljni organ (kičmenu moždinu) i autoimunskog odgovora i inflamacije u kičmenoj moždini...Aging affects the incidence of most inflammatory autoimmune diseases, which is associated with the aging of the immune system, the so-called immunosenescence. Since it has been shown that there are significant individual differences in the aging process, the significance of genetic factors (strain differences) for age-related changes in the incidence of inflammatory autoimmune diseases in rats was investigated. The model of experimental autoimmune encephalomyelitis (EAE) induced by inoculation of the syngenic spinal cord homogenate in a complete Freund's adjuvant with co-administration of inactivated Bordetella pertussis was used. This model mimics the early inflammatory phase of multiple sclerosis, the most common inflammatory autoimmune disease of the central nervous system, whose incidence shows a clear age dependency (decreases with aging). Young adult and aged female rats of Dark Agouti (DA) strain, which show high susceptibility to EAE induction at an young adult age and rats of Albino Oxford (AO) strain, which are relatively resistant to EAE induction at an young adult age were used in this research. The aim of this doctoral dissertation was to define cellular and molecular mechanisms that could be responsible for presumed strain specificities in age-related changes in the disease induction and development. The results obtained in this doctoral dissertation showed that aging decreases the incidence of EAE and the disease severity in DA rats, while in AO rats it leads to development of mild clinical disease of prolonged duration, exhibiting a significant incidence (62.5%). Differences in the clinical manifestations of the disease in these two rat strains could be associated with strain differences in the mechanisms involved in controlling the intensity of the primary (auto) immune response in the draining lymph nodes, but also the migration of activated neuroantigen-specific T helper 17 (Th17) cells, in particular their retention in the spleen (Th cell surface expression of CD44s molecule and the frequency of CD4+CD25+Foxp3+ regulatory T lymphocytes), the key cells for the development of the disease in this model, to the target organ (spinal cord) and autoimmune response and inflammation in the spinal cord.