Anna Fogdell-Hahn's research group

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Clinical Neuroimmunology

The function of our immune system is to protect us from infections and we would not survive for long if we did not have our immune system. However, this potential is double edged and sometimes immunological reactions against the body’s own tissue can occur which leads to development of autoimmune diseases. Another unwanted effect is when the immune system reacts against injected biopharmaceuticals and anti-drug antibodies develop. Both these phenomenon are focuses of our research group. Our location is at the Center for Molecular Medicine  and here you will find information for donating support for our research.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system where the white substance in the brain is attacked by the immune system. The aim of our research is to understand the triggering mechanisms of autoimmunity and the main hypothesis we are testing is if viruses could be this trigger. When viruses are formed inside a host cell they will incorporate proteins and lipid membranes from the host cell as integrated parts of the viral particle. To understand the triggering mechanism of MS it is important to study viral particles that can form in the brain and investigate how the immune system will handle these. Our candidate virus is human herpesvirus 6 (HHV-6), which is a large enveloped virus that infects the majority of us and that can establish latency in the brain. We have identified several host cell proteins incorporated into HHV-6, but it is unclear if this leads to autoimmunity.

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-6 in their brain tissue and we are interested in understanding if this could be an essential part of the disease mechanism in epilepsy, especially through epigenetic modifications.

MS patients are today treated with interferon beta (IFNβ) and natalizumab (Tysabri).

When these are administered as repetitive injections or infusions over a longer period, some patients will develop anti-drug antibodies (ADA). These antibodies will block the effect of the drug which leads to loss of treatment response. Neutralizing antibodies (NAbs or nADA) against IFNβ can also block the body’s own IFNβ and it is unclear what biological effect this might have. We investigate immunological reactions against biopharmaceutical treatments in patients with chronic inflammatory diseases and have since 2003 a routine laboratory where samples can be sent for ADA analysis. For MS patients on IFNβ treatment we use a bioassay (iLite, producer Biomonitor, distributer Thermo Fisher) to analyze NAb/nADA, and for patients on natalizumab we use an ELISA (BiogenIdec) for ADA analysis.

For more information and recommendations see the Swedish MS Society and NAb lab.

For rheumatoid arthritis (RA) patients the iLite method can be used to analyze nADA against adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade). Assay for ADA analysis against rituximab (Mabthera or Rituxan) is under development. Please contact us if you are interested in this.

Since 2012 we are part of the ABIRISK project where we, together with other academic and EFPIA partners, study the effects of ADA.

If you are interested in immunology I recommend that you join the Swedish Society for Immunology (SWIMM). Then you will also be a member of the Scandinavian Society for Immunology (SSI), European Federation of Immunological Societies (EFIS) and International Union of Immunological Societies (IUIS). Here you will find knowledge and information about courses, meetings, conferences and be able to apply for stipends for travels and research in immunology.

Anti-drug antibodies

Many chronic inflammatory diseases can today be treated with biopharmaceuticals, which has extensively improved the prognosis and 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.

Interferon beta (IFN beta) is used as a first line therapeutic for treatment of MS patients. However, around 20-30% of the treated patients eventually develop neutralizing antibodies against the drug, which reduces the efficacy of the treatment. We are measuring the titer levels of these ADA in our routine laboratory, and have analyzed over 1000 samples per year since 2003. We also analyze antibodies against natalizumab (Tysabri) and we will monitor other treatments that become available for the MS patients regarding development of ADA.

For patients treated with adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), we are planning to set up the similar analyses. We are using a bioassay (iLite™, Biomoitor), that is CE marked. As with the tests for ADA in MS, the analysis is considered to still be under research development and the samples will be stored in a biobank and used for further development and research. Please contact us at Anna.Fogdell-Hahn@ki.se if you are interested in these test for clinical use or research.

Publications

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

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

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

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. It is therefore 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 6 (HHV-6).

Incoroporation of hos cell proteins and lipids

Publications:

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

Complete replication cycle and acquisition of tegument in nucleus of human herpesvirus 6A in astrocytes and in T-cells.
Ahlqvist J, Donati D, Martinelli E, Akhyani N, Hou J, Major E, et al
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-6 in their brain tissue and we are interested in understanding if this could be an essential part of the disease mechanism in epilepsy.

Publications:

Association of human herpesvirus-6B with mesial temporal lobe epilepsy.
Fotheringham J, Donati D, Akhyani N, Fogdell-Hahn A, Vortmeyer A, Heiss J, et al
PLoS Med. 2007 May;4(5):e180

Selected Publications

Human leukocyte antigen genes and interferon beta preparations influence risk of developing neutralizing anti-drug antibodies in multiple sclerosis.
Link J, Lundkvist Ryner M, Fink K, Hermanrud C, Lima I, Brynedal B, et al
PLoS ONE 2014 ;9(3):e90479

HLA-A(∗)02, gender and tobacco smoking, but not multiple sclerosis, affects the IgG antibody response against human herpesvirus 6.
Engdahl E, Gustafsson R, Ramanujam R, Sundqvist E, Olsson T, Hillert J, et al
Hum. Immunol. 2014 Jun;75(6):524-30

Changes to anti-JCV antibody levels in a Swedish national MS cohort.
Warnke C, Ramanujam R, Plavina T, Bergström T, Goelz S, Subramanyam M, et al
J. Neurol. Neurosurg. Psychiatry 2013 Nov;84(11):1199-205

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

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Group members

Nicky DunnProjektassistent
Pierre DönnesAnknuten
Elin EngdahlAnknuten
Anna Fogdell HahnForskare, Forskargruppsledare
Christina HermanrudDoktorand, Forskarstuderande
Anna MattssonLaboratorieassistent
Malin RynerPostdoc

Links

Neuroimmunology