ANNA FOGDELL-HAHN GROUP

Clinical Neuroimmunology

About

Part of our research focus is to understand the disease mechanism behind the autoimmune reaction in MS and a possible viral etiology. Our hypothesis is that specific autoimmunity is triggered by immune response against host proteins incorporated into viral particles. We are therefore interested in common viruses that can establish latency and reactivate within the central nervous system and the myelin producing oligodendrocytes. Our current candidate virus is human herpesvirus 6 (HHV-6). We have shown that HHV-6B induce epigenetic modifications of the host cells during infection and that most of these are within the telomeric region of the chromosome and correlates with integration of the virus into the chromosome. These findings opens up for alternative pathways for treatment by targeting epigenetic pathways that might be essential for viral propagation. We have also found that MS patients have a higher production of antibodies against HHV-6A, but not the HHV-6B, immediate early protein sequences, especially at younger age.
 

Another research focus is the development and consequences of anti-drug antibodies (ADA). Immune reaction against human proteins can be triggered by repetitive injections and when human proteins are used as drugs this can cause a problem. We investigate response to treatment in chronic inflammatory diseases with a special focus on antibody formation against immunomodulatory drugs and we run routine analysis to determine these anti-drug antibody responses. Serum samples can be sent to our laboratory for analysis of anti-drug antibodies in MS patients treated with interferon beta and natalizumab (Tysabri). We have from 2017 assay for antibodies against rituximab (Mabthera) and a method called PandA to break up immune complexes between infliximab and anti-infliximab ADA. If you are interested in these tests, please contact us for further discussion.

 

Please visit this webpage for more information: http://ki.se/en/cns/the-laboratory-for-analysis-of-neutralizing-antibodies

 

Anti-drug antibodies

Many chronic inflammatory diseases can today be treated with biopharmaceuticals, which has extensively improved the quality of life for these patients. However, the repetitive administration of drugs can trigger the immune system to develop antibodies against the drug, so called anti-drug antibodies (ADA), which at high titers will block the effect of the drug. It is essential to monitor presence of ADA in order to know if the patient receives efficient therapy. Together with partners in Europe through the IMI consortium ABIRISK we are since 2012 investigating the impact that ADA has on the treatment and their biological significance.


We are measuring the titer levels of these ADA in our routine laboratory against interferon beta, natalizumab (Tysabri), rituximab and for infliximab we have the PandA method by which we can measure ADA despite the presence of infliximab in the serum. Our mission is to be able to provide ADA test for all biopharmaceuticals used in Europe in collaborations with other laboratories, pharmaceutical industry and large collaborations like ABIRISK.

 

Please contact us at Anna.Fogdell-Hahn@ki.se if you are interested in these test for clinical use or research.


For further information and to download referral forms please visit: http://ki.se/en/cns/the-laboratory-for-analysis-of-neutralizing-antibodies

 

Publications

Dunn N, Juto A, Ryner M, Manouchehrinia A, Fink K, Piehl A, Fogdell-Hahn A. Rituximab in multiple sclerosis; Frequency and clinical relevance of anti-drug antibodies. Mult Scler. 2017 Jul 1.

Link J, Ramanujam R, Auer M, Ryner M, Hässler S, Bachelet D, Mbogning C, Warnke C, Buck D, Hyldgaard Jensen PE, Sievers C, Ingenhoven K, Fissolo N, Lindberg R, Grummel V, Donnellan N, Comabella M, Montalban X, Kieseier B, Soelberg Sørensen P, Hartung HP, Derfuss T, Lawton A, Sikkema D, Pallardy M, Hemmer B, Deisenhammer F, Broët P, Dönnes P, Davidson J, Fogdell-Hahn A; ABIRISK Consortium. Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results. PLoS One. 2017 Feb 7.

Hermanrud C, Ryner M, Luft T, Jensen PE, Ingenhoven K, Rat D, Deisenhammer F, Sørensen Soelberg P, Pallardy M, Sikkema D, Bertotti E, Kramer D, Creeke P, Fogdell-Hahn A, on behalf of the ABIRISK consortium. Development and validation of cell-based luciferase reporter gene assays for measuring neutralizing anti-drug antibodies against interferon beta. J Immunol Methods. 2016 Mar;430:1-9.

         

Paolino M, Thien CB, Gruber T, Hinterleitner R, Baier G, Langdon WY, Penninger JM. Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions. J Immunol. 2011, 186 (4), 2138-2147.

Viral etiology in MS

The etiology of MS is unknown and the only treatments available today are working by suppressing the immune system. To be able to cure the disease we need to understand the triggering mechanisms and identify targets for prevention. We are investigating if the triggering of the disease could be due to viruses fooling the immune system to start an attack on the body’s own tissue (autoimmunity). When viral particles are formed from a host cell, many viruses incorporate part of that cells membrane and proteins into the viral particle. To understand how this might cause MS, it is important to investigate how viral particles are formed in cells of the brain and how these viral particles are handled by the immune system. Our candidate virus is human herpesvirus 6A (HHV-6A).

 

Publications

Hammarstedt M, Ahlqvist J, Jacobson S, Garoff H and Fogdell-Hahn. Purification of infectious Human herpesvirus 6A virions and association of host cell proteins. Virology Journal 4:101 (2007). 

Ahlqvist J, Donati D, Martinelli E, Akhyani N, Hou J, Major EO, Fogdell-Hahn A, Jacobson S (shared senior authorship). Complete replication cycle and acquisition of tegument in nucleus of Human herpesvirus 6A (HHV-6A) in astrocytes and in T-cells. J Med Virol. 2006 Dec;78(12):1542-53.

Viral etiology in epilepsy

In search for viruses in the brain we investigated epilepsy brain tissue removed as treatment for the disease. To our surprise some of the epilepsy patients had HHV-6B in their brain tissue and we are interested in understanding if this could be an essential part of the disease mechanism in epilepsy. The virus is inducing epigenetic modifications near the telomeric ends of the chromosomes, especially chromosome 17, and is associated with viral integration.

 

Publications

Engdahl E, Dunn N, Niehusmann P, Wideman S, Wipfler P, Becker AJ, Ekström TJ, Almgren M, Fogdell-Hahn A. Human herpesvirus 6B induces hypomethylation on chromosome 17p13.3 correlating with increased gene expression and virus integration. J Virol. 2017 Mar 15. 

Fotheringham J, Donati D, Akhyani N, Fogdell Hahn A, Vortmeyer A, John D. Heiss JD, Williams E, Weinstein S, Bruce DA, Gaillard WD, Sato S, Theodore WH, and Steven Jacobson. Association of human herpesvirus 6B with mesial temporal lobe epilepsy. PLoS Med. 2007 May;4(5):e180. 

Selected Publications

Engdahl E, Gustafsson R, Huang J, Biström M, Lima Bomfim I, Stridh P, Khademi M, Brenner N, Butt J, Michel A, Jons D, Hortlund M, Alonso-Magdalena L, Hedström AK, Flamand L, Ihira M, Yoshikawa T, Andersen O, Hillert J, Alfredsson L, Waterboer T, Sundström P, Olsson T, KockumI, Fogdell-Hahn Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis Frontiers in Immunology online November 2019, DOI: 10.3389/fimmu.2019.02715

Dunn N, Juto A, Ryner M, Manouchehrinia A, Fink K, Piehl A, Fogdell-Hahn A. Rituximab in multiple sclerosis; Frequency and clinical relevance of anti-drug antibodies. Mult Scler. 2018 Aug;24(9):1224-1233.

Engdahl E, Dunn N, Niehusmann P, Wideman S, Wipfler P, Becker AJ, Ekström TJ, Almgren M, Fogdell-Hahn A. Human herpesvirus 6B induces hypomethylation on chromosome 17p13.3 correlating with increased gene expression and virus integration. J Virol. 2017 May 12;91(11).

Link J, Ramanujam R, Auer M, Ryner M, Hässler S, Bachelet D, Mbogning C, Warnke C, Buck D, Hyldgaard Jensen PE, Sievers C, Ingenhoven K, Fissolo N, Lindberg R, Grummel V, Donnellan N, Comabella M, Montalban X, Kieseier B, Soelberg Sørensen P, Hartung HP, Derfuss T, Lawton A, Sikkema D, Pallardy M, Hemmer B, Deisenhammer F, Broët P, Dönnes P, Davidson J, Fogdell-Hahn A; ABIRISK Consortium. Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results. PLoS One. 2017 Feb 7;12(2):e0170395. 

Hermanrud C, Ryner M, Luft T, Jensen PE, Ingenhoven K, Rat D, Deisenhammer F, Sørensen Soelberg P, Pallardy M, Sikkema D, Bertotti E, Kramer D, Creeke P, Fogdell-Hahn A, on behalf of the ABIRISK consortium. Development and validation of cell-based luciferase reporter gene assays for measuring neutralizing anti-drug antibodies against interferon beta. J Immunol Methods. 2016 Mar;430:1-9.  

Link J, Lundkvist Ryner M, Fink K, Hermanrud C, Lima Bomfim I, Brynedal B, Kockum I, Hillert J, Fogdell-Hahn A. Human leukocyte antigen genes and interferon beta preparation influence on risk of developing neutralizing anti-drug antibodies in multiple sclerosis. PLoS One. 2014 Mar 7;9(3):e90479.

Warnke C, Ramanujam R, Plavina T, Bergström T, Goelz S, Subramanyam M, Kockum I, Rahbar A, Kieseier BC, Holmén C, Olsson T, Hillert J, Fogdell-Hahn A. Changes to anti-JCV antibody levels in a Swedish national MS cohort. J Neurol Neurosurg Psychiatry 2013;0:1–7.

 

Lundkvist M, Engdahl E, Holmén C, Movérare R, Olsson T, Hillert J, Fogdell-Hahn A. Characterization of anti-natalizumab antibodies in multiple sclerosis patients. Mult Scler. 2013 May;19(6):757-64. 

Jungedal R, Lundkvist M, Engdahl E, Ramanujam R, Westerlind H, Sominanda A, Hillert J, Fogdell-Hahn A. Prevalence of anti-drug antibodies against interferon beta has decreased since routine analysis of neutralizing antibodies became clinical practice. Mult Scler. 2012 Dec;18(12):1775-81. 

Sominanda A, Hillert J, Fogdell-Hahn A. In vivo bioactivity of interferon beta in multiple sclerosis patients with neutralizing antibodies is titer dependent. J Neurol Neurosurg Psychiatry. 2008 Jan;79(1):57-62. 

Hammarstedt M, Ahlqvist J, Jacobson S, Garoff H, Fogdell-Hahn. Purification of infectious Human herpesvirus 6A virions and association of host cell proteins. Virology Journal. 2007 Oct 19;4:101. 

Fotheringham J, Donati D, Akhyani N, Fogdell Hahn A, Vortmeyer A, John D. Heiss JD, Williams E, Weinstein S, Bruce DA, Gaillard WD, Sato S, Theodore WH, Jacobson S. Association of human herpesvirus 6B with mesial temporal lobe epilepsy. PLoS Med. 2007 May;4(5):e180.

Ahlqvist J, Donati D, Martinelli E, Akhyani N, Hou J, Major EO, Fogdell-Hahn A*, Jacobson S* (*shared senior authorship). Complete replication cycle and acquisition of tegument in nucleus of Human herpesvirus 6A (HHV-6A) in astrocytes and in T-cells. J Med Virol. 2006 Dec;78(12):1542-53.