Polne razlike u patogenezi eksperimentalnog autoimunskog encefalomijelitisa kod pacova

Abstract

Multipla skleroza (MS) se, kao i većina drugih autoimunskih bolesti, češće javlja kod žena nego kod muškaraca. Polni dimorfizam je zapažen i u kliničkom ispoljavanju MS-e. Kod muškaraca se bolest javlja kasnije, motorni ispadi su teži i primarno progresivni tok češći nego kod žena. Eksperimentalni autoimunski encefalomijelitis (EAE) je animalni model MS-e, koji se kod osetljivih oglednih životinja izaziva različitim indukcionim protokolima. Podaci vezani za polni dimorfizam u kliničkoj prezentaciji EAE-a su relativno oskudni, a postojeći inkonzistentni, pre svega zbog genetskih razlika između korišćenih životinjskih vrsta i sojeva, ali i varijacija u indukcionim protokolima. Hronobiološko starenje organizma uključuje i promene u imunskom sistemu koje karakteriše značajan porast autoimunskih fenomena. Uprkos tome, incidenca mnogih autoimunskih bolesti, uključujući i MS-u, se smanjuje kod starih. Podaci o osetljivosti starih oglednih životinja na indukciju EAE-a su heterogeni, u zavisnosti od vrste i soja oglednih životinja, kao i od modela EAE-a. Mehanizmi koji stoje u osnovi manje incidence autoimunskih bolesti kod starih jedinki nisu u potpunosti razjašnjeni. Još su manje poznati mehanizmi polnog dimorfizma u razvoju ovih bolesti kod starih životinja, a posebno u čemu se oni razlikuju u odnosu na mehanizme odgovorne za ovaj fenomen kod mladih životinja. Ciljevi ove doktorske disertacije su bili da se: 1) ispitaju polne razlike u kliničkim parametrima indukovane autoimunske neuroinflamacije, kao važne patogenetske 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 i težini EAE-a i kod mladih i kod starih pacova. Incidenca EAE-a je kod pacova oba uzrasta bila manja kod mužjaka nego kod ženki, s tim što su mladi mužjaci, za razliku od starih, imali teži neurološki deficit u odnosu na ženke odgovarajućeg uzrasta...

Multiple sclerosis (MS) is one of the most common organ-specific autoimmune diseases of the central nervous system. As in other autoimmune diseases, the prevalence of MS is higher in women than in men. The clinical manifestations of MS are also sexually dimorphic. Men exhibit later onset of the disease, more severe motor symptoms and primary progressive course more often than women. Experimental autoimmune encephalomyelitis (EAE) is an animal model induced in susceptible strains of animals. Data on sexual dimorphism in the clinical presentation of EAE are limited and inconsistent, reflecting, most likely, the differences in the genetic background of the experimental animals and the induction protocols. Chronobiological ageing of the organism is accompanied by ageing of the immune system. Immunosenescence is characterized by an increase in autoimmune phenomena. However, despite this phenomenon, the incidence of many autoimmune diseases, including MS, declines with ageing. Data on the influence of aging on the incidence and severity EAE are inconsistent. Additionally, data on sex differences in the clinical presentation of EAE in aged animals are extremely limited. The aim of the study was to 1) investigate sex differences in the incidence and severity of autoimmune neuroinflammation, an important pathogenetic component 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 molecular mechanisms behind the observed sex differences. Irrespective of age, the incidence of EAE was lower in male than in age-matched female rats. However, contrary to aged 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 was associated with: (i) greater number of overall and reactivated CD4+ T cells isolated from 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 mononuclear cells and, consequently, greater percentage of Th17 cells among the T-lymphocytes and (iii) greater activation of myeloid cells (according to the mean fluorescence intensity of CD45 and CD11b molecules on the surface of these cells), accompanied by upregulated expression mRNA for TNF-α and iNOS in SC mononuclear cells...