Danish Medical Bulletin    |    Contact Front page  

 
The Possible Role of Human Endogenous Retroviruses and Herpesviruses in the Pathogenesis of Multiple Sclerosis

Tomasz Brudek  


  Download file   (3368 KB)

Accepted by: Faculty of Medical Science Aarhus University
Defended on: June 29, 2007
Official opponents: Klemens Ruprecht, MD, Julius-Maximilians University, Germany , Bent Faber Vestergaard, Professor, MD, DMSc, Statens Serum Institut, Denmark , Jacob Giehm Mikkelsen, Associate Professor, PhD, Aarhus University, Denmark
Tutors: Anné Møller-Larsen, Associate Professor, MD, DMSc , Per Höllsberg, Professor, MD, DMSc , Finn Skou Pedersen, Professor, PhD

Published in the PhD Database: June 13, 2007


English abstract
Multiple sclerosis (MS) is a complex, inflammatory, demyelinating disease of the central nervous system (CNS), occurring mainly in young adults. The leading hypothesis assumes that MS occurs as a result of exposition of genetically susceptible individuals to an unknown environmental agent(s). Several herpes viruses (HSV-1, HHV-6, VZV and EBV) together with human endogenous retroviruses (HERV-H and HERV-W) have been associated with MS for years, but none of the associations are conclusive. Herpes viruses are capable of HERV activation, and both virus groups are known to interact with each other in several ways.

This Ph.D. thesis presents further evidence of an association of HERVs and herpesviruses with MS. Inactivated (non-infectious) herpesviruses are capable of inducing reverse transcriptase (RT) activity, a hallmark for retrovirus activation. The observed RT activity is significantly higher in MS patients vs. healthy controls, and the reactivation is initiated earlier in the patients. Further, the consequential concomitant presence of HERV and herpesvirus antigens induces synergistic lymphocyte proliferation, resulting in a significantly higher INF-γ production in peripheral lymphocytes from MS patients. Additionally, this production correlates with the synergistic cell proliferations, whereas such correlation cannot be found in controls. The findings suggest that an induced imbalance in Th1/Th2 responses, favoring inflammatory reactions in MS patients, may lead to progression of the disease.

Increased presence of activated HERVs in MS patients has been demonstrated by flow cytometric evaluation of cell membrane expression of HERV-H and HERV-W Env on lymphocytes from patient with active and stable MS in comparison with healthy individuals. Results show significantly increased quantities of HERV-H Env and HERV-W Env together with an increased number of B cells in patients with active MS. B cells and monocytes are the only cell types expressing these envelope proteins. Moreover, active MS patients display high antibody activity towards the two envelope proteins.

These experiments entail additional evidence for the occurrence of activated HERVs in MS patients, especially in those with active MS, and the results further substantiate the theory that herpes viruses and HERVs may play a role in the pathogenesis of MS.



Danish abstract
Multipel sclerose (MS) udvikles sandsynligvis ved sammenfald af flere faktorer. Både arv og miljø spiller en rolle og det anses for sandsynligt at infektiøse agens, specielt virus kan være medvirkende faktorer ved udvikling af sygdommen. I en årrække har flere virus fra herpesgruppen (HSV-1, HHV-6, VZV og EBV) samt de humane endogene retrovirus (HERV-H og HERV-W) været forbundet med MS.

Ph.D. ¿afhandlingen viser, at visse herpesvirus i inaktiveret form (HSV-1, HHV-6A og VZV) kan inducere HERV ekspression i perifere blodlymfocytter (PBMC) både fra patienter og kontroller, men med en signifikant højere ekspression i MS patienter. Den heraf følgende samtidige tilstedeværelse af HERV og herpesvirus antigener kan udløse et kraftigt lymfocytrespons og dette respons inducerer signifikant højere IFN-γ niveau hos MS patienter samt forstyrrelse af T-hjælper cellernes Th1/Th2 ratio på en måde, som kan medføre progression af sygdommen.

Flow cytometriske undersøgelser af PBMCer fra MS patienter med aktiv og ikke aktiv MS samt fra raske kontroller har påvist øget ekspression af både HERV-H og HERV-W envelope proteiner på overfladen af B-celler og monocyter fra MS patienter ved aktiv sygdom. Disse MS patienter har også et øget antistofrespons mod HERV-H og HERV-W envelope proteiner.

De beskrevne undersøgelser underbygger, at HERV og herpesvirus kan spille en rolle ved udviklingen af MS.