6 POPULÄRVETENSKAPLIG SAMMANFATTNING
förhindra inflammation, har ett metyleringsmönster som inte tillåter ett stabilt uttryck av FOXP3 genen. Denna upptäckt förklarar varför regulatoriska T celler är så unika i sin förmåga att uttrycka FOXP3-genen stabilt. Det unika metyleringsmönstret som vi upptäckte hos regulatoriska T celler kan även användas för att identifiera regulatoriska T celler i blodprover från patienter.
Vi fortsatte med att undersöka metyleringsmönster i T celler som återfinns inuti tjocktarmscancer. Vid cancer har det tidigare visat sig att det är fördelaktigt att ha T celler av Th1-typ. Th1 cellerna utsöndrar bland annat signaleringsproteinet IFNG som i sin tur kan medverka till att döda tumörceller.
När vi undersökte metyleringsmönstret hos IFNG genen i T celler från tjocktarmscancer så fann vi intressant nog att denna gen var nedtystad. Denna upptäckt skulle kunna förklara varför celler som återfinns i tumörer är så dåliga producenter av IFNG.
Eftersom metyleringsmönster hos arvsmassan kan förutspå genuttrycket i T cellerna utarbetade vi en metod för att kunna kartlägga T cellernas identitet utifrån deras epigenetiska förutsättningar för genuttryck. Genom att ta reda på vilka celler som finns närvarande i inflammerad vävnad hos patienter, kan man få ökad förståelse för de mekanismer som ligger till grund för sjukdomen, och på så vis kunna utarbeta bättre behandlingar. Med detta i åtanke använde vi vår metod för att kartlägga T celler från patienter med autoimmuna sjukdomar (reumatoid artrit och multipel skleros). Vi undersökte både T celler från blodprover, och även T celler från inflammerade leder. Vi fann att T cellerna inuti inflammerade leder från patienter med reumatism är av Th1 och T regulatorisk typ. I djurexperimentella modeller av reumatism och multipel skleros har man visat att T celler av Th17 typ är orsaken till inflammationen, men dessa celler återfanns inte i de prover som vi undersökte med vår metod.
Detta skulle kunna bero på att djurmodellerna inte korrekt återspeglar det inflammatoriska förloppet hos sjuka patienter.
I denna avhandlings sista projekt undersöktes hur små molekyler som uttrycks från arvsmassan i sin tur kan påverka uttrycket av andra gener. Vi upptäckte att mikro-RNA molekylen miR-155 kan styra uttrycket av proteinet CTLA-4. CTLA-4 är ett mycket viktigt protein som styr T cellernas delningshastighet. Det har bland annat visat sig att man kan behandla autoimmuna sjukdomar med mediciner som härmar CTLA-4 proteinets egenskaper. Eftersom miR-155 molekylen styr uttrycket av CTLA-4 kan man tänka sig att även denna molekyl kan utgöra en målmolekyl i syfte att behandla sjukdomar.
Sammanfattningsvis kan man säga att de projekt som är inkluderade i denna avhandling har bidragit till ökad förståelse för de mekanismer som ligger till grund för genuttryck hos T celler. Vi har hittat bidragande orsaker till varför immunförsvaret ibland inte kan bekämpa uppkomsten av tumörer. Vi har utarbetat en metod som kan kartlägga T cellernas identitet i patientprover, samt funnit ett mikro-RNA som styr delningshastigheten hos T cellerna.
7 ACKNOWLEDGEMENTS
Many people have contributed to the content of this book, not only the people directly involved in laboratory work and/or writing of manuscripts. I would like to send special thanks to the following people:
My supervisor Ola Winqvist, a visionary, a never ending source of inspiration and a wonderful person with contagious enthusiasm. Thank you for accepting me as a PhD student in your group and for being the best supervisor one can imagine. It never seize to amaze me how you always have a few extra minutes for a conversation, even though I know you are one of the busiest men on the planet.
Rolf Ohlsson, my co-supervisor, for introducing me into the epigenetic field of research, and for valuable education in your lab.
Per Marits, for being my teacher when working on my masters-thesis. I have learned so much from our discussions, and I am truly impressed by your immense knowledge in immunology.
Thank you Emma Lundgren, for being a great friend during these past years. I am so happy that we signed up for the ITG group at the same time.
Former and present colleagues of the ITG group; Signe Hässler and Mona Karlsson, for helping me out in the beginning. A special thanks to Mona for many laughs and op material arriving at my front door by taxi at 2 am. Johan Brännström, for nice company and for being my side-kick when harassing
“Milton”. My co-author Malin Winerdahl, for being more careful and deliberate than me during our mutual experiments, something I am very grateful for. Thanks to Petra Jones, for being such a gentle and kind person and for being a great company at morning coffee. Martina Jones, for nice company and for your spirited personality. Ludvig Linton, for great collaboration, those clown-school lessons really payed off!!! Emma Ahlén, for keeping track of things such as primer sheets etc that tend to disappear from me, and thank you for great collaboration. Michael Eberhardson, for an eccentric and entertaining personality, and for amusing stories about the suburban lifestyle on Lidingö.
The rest of the ITG group, including Evelina Lindmark, and Ali Zerakzadeh for creating a great atmosphere at work.
I would also like to thank my collaborators and coauthors Vivianne Malmström and Fredrik Piehl, for fruitful discussions and for your expertise in autoimmune diseases. Andor Pivarsci, for rewarding scientific collaboration and interesting discussions.
A special thanks to my mentor Hans Grönlund, for encouraging small talks and guidance in my scientific career.
All the rest of the staff at L2:04 for making every day at work enjoyable.
Ett alldeles speciellt tack till mina vänner och mina båda familjer:
Mina underbara systrar Barbro och Anna-Karin, för att ni alltid finns där. Min mamma Monica och min pappa Lennart för allt stöd och för att ni är så snälla och generösa. Jag vill även tacka Gunilla för all vänlighet och generositet.
Mina älsklingar Nadja och lilla Julia, som betyder allt för mig och som jag är så stolt över.
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