Biography
Professor Robert A. Harris
Professor Robert A. Harris (Bob) was born in Harpenden in Southern UK in 1966. He conducted a Bsc.Hons undergraduate degree at Portsmouth Polytechnic, majoring in Parasitology in 1987. PhD studies at University College London studying innate immune agglutinins in Schistosoma host snail species with Terry Preston and Vaughan Southgate as supervisors culminated with a thesis defence in early 1991. A 2.5 year postdoc at the London School of Hygiene & Tropical Medicine in Paul Kaye’s research group ensued, with focus on understanding the intracellular fate of Leishmania spp. protozoans in macrophages. Bob was awarded a Wellcome Trust postdoctoral fellowship that permitted his relocation to the Karolinska Institutet (Stockholm, Sweden) in the spring of 1994. A postdoc period was spent split between the labs of Anders Örn and Tomas Olsson, in which he studied Trypanosoma cruzi and Trypanosoma bruceii protozoan proteins. Bob became an Associate Professor at the Karolinska Institutet in 1999, heralding his establishment as a PI. Bob started to work with autoimmune diseases in 1996 and began study of therapy using live parasite infections or parasite molecules. His research group has developed autoantigen-specific vaccines, defined the effects of post-translational biochemical molecules on autoantigenicity and developed a macrophage adoptive transfer therapy that prevents pathogenesis in several experimental disease models. He became Professor of Immunotherapy in Neurological Diseases in 2013. In recent years research focus has centred on understanding the immunopathogenesis of incurable neurodegenerative diseases, with particular emphasis on development of immunotherapies directed at microglial cells as potential therapeutic paradigms.
Bob Harris CV July 2020
ERIK HERLENIUS GROUP
Development of autonomic control
About
Immature or deficient autonomic control is a common problem in infants born at a premature age and is of central importance in apneas, secondary hypoxic brain damage and sudden infant death syndrome.
PER ERIKSSON GROUP
Research
For better understanding of disturbances in respiratory control we study early development of cardiorespiratory control, brainstem neural networks and its associations with normal and pathological breathing. The conceptual change introduced by our recent data that endogenous prostaglandins are central pathogenic factors in respiratory disorders and the hypoxic response, open new diagnostic and therapeutic avenues that should significantly better the diagnostics and treatment of newborns and adult patients.
Inflammation is a major culprit in breathing disorders and we hypothesize that by using a newly developed urinary prostaglandin biomarker we can screen, detect and protect against inflammation related breathing disorders.
Our collaborative efforts enable us to move from a clinical problem to molecular understanding of the disease and studies are performed in patients, animal & in vitro models.
Our research is focused on the development of autonomic control with normal and paediatric patients as the target. Autonomic dysfunction in breathing and circulatory control often has its origin in neurodevelopment disorders. Furthermore, our basic research in developmental neuroscience how neural activity and stem cells form activity dependent networks is vital for the development of therapeutic interventions.
Read more
Contact: communication@cmm.se
CENTER FOR MOLECULAR MEDICINE
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 A 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.