Polne razlike u patogenezi eksperimentalnog autoimunskog encefalomijelitisa kod pacova

Abstract

Multipla skleroza (MS) se, kao i većina drugih autoimunskih bolesti, češćejavlja kod žena nego kod muškaraca. Polni dimorfizam je zapažen i u kliničkomispoljavanju MS-e. Kod muškaraca se bolest javlja kasnije, motorni ispadi su teži iprimarno progresivni tok češći nego kod žena. Eksperimentalni autoimunskiencefalomijelitis (EAE) je animalni model MS-e, koji se kod osetljivih oglednihživotinja izaziva različitim indukcionim protokolima. Podaci vezani za polnidimorfizam u kliničkoj prezentaciji EAE-a su relativno oskudni, a postojećiinkonzistentni, pre svega zbog genetskih razlika između korišćenih životinjskihvrsta i sojeva, ali i varijacija u indukcionim protokolima. Hronobiološko starenjeorganizma uključuje i promene u imunskom sistemu koje karakteriše značajanporast autoimunskih fenomena. Uprkos tome, incidenca mnogih autoimunskihbolesti, uključujući i MS-u, se smanjuje kod starih. Podaci o osetljivosti starihoglednih životinja na indukciju EAE-a su heterogeni, u zavisnosti od vrste i sojaoglednih životinja, kao i od modela EAE-a. Mehanizmi koji stoje u osnovi manjeincidence autoimunskih bolesti kod starih jedinki nisu u potpunosti razjašnjeni. Jošsu manje poznati mehanizmi polnog dimorfizma u razvoju ovih bolesti kod starihživotinja, a posebno u čemu se oni razlikuju u odnosu na mehanizme odgovorne zaovaj fenomen kod mladih životinja.Ciljevi ove doktorske disertacije su bili da se: 1) ispitaju polne razlike ukliničkim parametrima indukovane autoimunske neuroinflamacije, kao važnepatogenetske komponente MS-e, na modelu aktivnog EAE-a, kod mladih adultnih(uzrast 3 meseca) i starih (uzrast 22-26 meseci) pacova Dark Agouti soja i 2)identifikuju ćelijski i molekularni mehanizmi odgovorni za uočene polne razlike.Dobijeni rezultati su pokazali postojanje polnog dimorfizma u incidenci itežini EAE-a i kod mladih i kod starih pacova. Incidenca EAE-a je kod pacova obauzrasta bila manja kod mužjaka nego kod ženki, s tim što su mladi mužjaci, zarazliku od starih, imali teži neurološki deficit u odnosu na ženke odgovarajućeguzrasta...

Multiple sclerosis (MS) is one of the most common organ-specificautoimmune diseases of the central nervous system. As in other autoimmunediseases, the prevalence of MS is higher in women than in men. The clinicalmanifestations of MS are also sexually dimorphic. Men exhibit later onset of thedisease, more severe motor symptoms and primary progressive course more oftenthan women. Experimental autoimmune encephalomyelitis (EAE) is an animalmodel induced in susceptible strains of animals. Data on sexual dimorphism in theclinical presentation of EAE are limited and inconsistent, reflecting, most likely, thedifferences in the genetic background of the experimental animals and theinduction protocols. Chronobiological ageing of the organism is accompanied byageing of the immune system. Immunosenescence is characterized by an increasein autoimmune phenomena. However, despite this phenomenon, the incidence ofmany autoimmune diseases, including MS, declines with ageing. Data on theinfluence of aging on the incidence and severity EAE are inconsistent. Additionally,data on sex differences in the clinical presentation of EAE in aged animals areextremely limited.The aim of the study was to 1) investigate sex differences in the incidenceand severity of autoimmune neuroinflammation, an important pathogeneticcomponent of MS, on an active EAE model in 3-month-old (young adult) and 22-26-month-old (aged) Dark Agouti rats and 2) identify the cellular and molecularmechanisms behind the observed sex differences. Irrespective of age, the incidenceof EAE was lower in male than in age-matched female rats. However, contrary toaged male rats, young male rats, which developed clinically manifested disease,exhibited more severe motor deficit than the age-matched female rats.Irrespective of age, at the peak of EAE, the greater mean maximal score wasassociated with: (i) greater number of overall and reactivated CD4+ T cells isolatedfrom spinal cord (SC); (ii) upregulated expression of mRNA for CD4+ T helper(Th)17 polarizing cytokines (IL-6, IL-1β, IL-23/subunit p19) in SC mononuclearcells and, consequently, greater percentage of Th17 cells among the T-lymphocytesand (iii) greater activation of myeloid cells (according to the mean fluorescenceintensity of CD45 and CD11b molecules on the surface of these cells), accompaniedby upregulated expression mRNA for TNF-α and iNOS in SC mononuclear cells...