Andre Ortlieb Team

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, where immune attack to the myelin sheet that envelops axons, and possibly to neurons themselves, leads to impairment of proper neuronal signaling and subsequent cell death. Evidence from genetics, pathology and animal studies points to CD4+ T cells as the key effector cells in the disease, while data from therapies suggests that B cells promote the maintenance of the CD4+ T cell response. Additionally, other immune cells that infiltrate the tissue during inflammation as well as tissue-resident glia may contribute to disease initiation and/or chronification. Both genetics and environment play a role in disease predisposition and can interact and potentiate each other. Such interactions have been shown by our lab, such as being carrier of a specific HLA and smoking, and more recently, being carrier of the same HLA and having high titers of antibodies against Epstein-Barr virus. In my research in autoimmune neuroinflammation I address the effects of genetic polymorphisms and environmental factors in immune function as well as what kind of antigens are targeted by T and B cells.

1. The effect of genetic polymorphisms and environment in immune cell function during MS

We have taken findings from genomewide association studies (GWAS) as well as rat crosses (Nat Gen 2013) to find and dissect the effect of genetic variations in different loci on disease incidence and severity (JI 2019; Sci Imm 2020; JCI 2019) with a major focus on T cells (Il22ra2), microglia (Atg7) and macrophages (C-type lectin receptors), respectively. We have also delved into the effect of vitamin D on T cell function (PNAS 2017).

Currently my research focuses on a locus that controls the degradation of the aminoacid valine (Hibadh) and its effect on T cells during neuroinflammation.  Additionally, in collaboration with the group of Maja Jagodic (CMM), we continue to look at the effects of autophagy genes (Atg7, Ulk1) specifically in microglia as well as autophagy-promoting substances (trehalose), and how different autophagy pathways affect inflammation resolution.

2. T cell antigen specificity in disease

In collaboration with the lab of Hans Grönlund (CMM) and others, we have found novel B cell and T cell antigen targets in MS patients (PNAS 2016; Sci Adv 2022) and showed that they can contain regions of antigenic mimicry with proteins from Epstein-Barr virus (Sci Adv 2023), suggesting that viral infections could work as triggers for autoimmune neuroinflammation. The current focus of my team is on the development of animal models for the mechanistic characterization of these responses.

3. Oligodendrocyte phenotypes in disease development and progression

In collaboration with the lab of Gonçalo Castelo-Branco, we characterized an oligodendrocyte precursor cell population that arises during inflammation and upregulates antigen presentation machinery typical of antigen-presenting cells (Nat Med 2018). While these cells are able to stimulate effector CD4+ T cell in vitro, the question remains on what kind of effect this interaction has in vivo.

Andre Ortlieb Guerreiro-Cacais, PhD, andre.ortlieb@ki.se

A biologist at heart and an immunologist by training, I divided my PhD time between the Karolinska Institute and Johns Hopkins University, both at its former branch in Singapore as well as in Baltimore, USA. My research focused on Epstein-Barr virus (EBV) replication and how that affected the composition of the viral envelope as well as the recognition of infected cells by the immune system. Given the longstanding observation that individuals that develop late EBV infection in the form of infectious mononucleosis are at increased risk of developing a number of autoimmune conditions, I set out to focus on autoimmunity during my post-doc back in Sweden, under the guidance of Prof. Tomas Olsson. The initial focus on genetic polymorphisms and their impact on immune function in T cells was followed by a broader, collaborative effort to study genetic variation during inflammation in other cell types such as peripheral myeloid cells, microglia and oligodendrocytes. Recently I have again turned by focus towards EBV and autoimmunity, given that novel data suggests that molecular mimicry between viral antigens and self antigens could work as the long-sought trigger for this autoimmune condition.

Rianne van der Burgt, Master student

Alex Hill Rique, Undergraduate student

Klaudia Wojciechowska, BSc

Jin Hong Min, BSc

Manuel Araujo, BSc

Mathias Linnerbauer, BSc

Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis. Thomas OG, Bronge M, Tengvall K, Akpinar B, Nilsson OB, Holmgren E, Hessa T, Gafvelin G, Khademi M, Alfredsson L, Martin R, Guerreiro-Cacais AO, Grönlund H, Olsson T, Kockum I. Science Advances. 2023 May 19;9(20):eadg3032. https://www.science.org/doi/10.1126/sciadv.adg3032

Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis. Bronge M, Högelin KA, Thomas OG, Ruhrmann S, Carvalho-Queiroz C, Nilsson OB, Kaiser A, Zeitelhofer M, Holmgren E, Linnerbauer M, Adzemovic MZ, Hellström C, Jelcic I, Liu H, Nilsson P, Hillert J, Brundin L, Fink K, Kockum I, Tengvall K, Martin R, Tegel H, Gräslund T, Al Nimer F, Guerreiro-Cacais AO, Khademi M, Gafvelin G, Olsson T, Grönlund H. Science Advances. 2022 Apr 29;8(17):eabn1823. https://www.science.org/doi/10.1126/sciadv.abn1823

Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation. Berglund R, Guerreiro-Cacais AO, Adzemovic MZ, Zeitelhofer M, Lund H, Ewing E, Ruhrmann S, Nutma E, Parsa R, Thessen-Hedreul M, Amor S, Harris RA, Olsson T, Jagodic M. Science Immunology. 2020 Oct 16;5(52):eabb5077. https://www.science.org/doi/10.1126/sciimmunol.abb5077

C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation. N’diaye M, Brauner S, Flytzani S, Kular L, Warnecke A, Adzemovic MZ, Piket E, Min JH, Edwards W, Mela F, Choi HY, Magg V, James T, Linden M, Reichardt HM, Daws MR, van Horssen J, Kockum I, Harris RA, Olsson T, Guerreiro-Cacais AO*, Jagodic M*.  Journal of Clinical Investigation. 2019 Nov 14. https://www.jci.org/articles/view/125857 *authors contributed equaly to this work

IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis. Lindahl H, Guerreiro-Cacais AO, Bedri SK, Linnerbauer M, Lindén M, Abdelmagid N, Tandre K, Hollins C, Irving L, Glover C, Jones C, Alfredsson L, Rönnblom L, Kockum I, Khademi M, Jagodic M, Olsson T. Journal of Immunology. 2019 Aug 15;203(4):888-898.  https://doi.org/10.4049/jimmunol.1900400

Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Falcão AM,  Bruggen D, Marques S, Meijer M, Jäkel S, Agirre E, Samudyata, Floriddia EM, Vanichkina EP, ffrench-Constant C, Williams A, Guerreiro-Cacais AO, Castelo-Branco G. Nature Medicine. 2018, Dec;24(12):1837-1844. https://doi.org/10.1038/s41591-018-0236-y

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis. Zeitelhofer M, Adzemovic MZ, Gomez-Cabrero D, Bergman P, Hochmeister S, N’diaye M, Paulson A, Ruhrmann S, Almgren M, Tegnér JN, Ekström TJ, Guerreiro-Cacais AO, Jagodic M. PNAS. 2017 Feb 28;114(9):E1678-E1687. https://doi.org/10.1073/pnas.1615783114

Rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3L exhibit distinct phenotypical and functional characteristics. N’diaye M, Warnecke A, Flytzani S, Abdelmagid N, Ruhrmann S, Olsson T, Jagodic M*, Harris RA*, Guerreiro-Cacais AO*. The Journal of Leukocyte Biology. 2016 Mar;99(3):437-46.  https://doi.org/10.1189/jlb.1AB0914-433RR *authors contributed equaly to this work

Anoctamin 2 identified as an autoimmune target in multiple sclerosis. Ayoglu B, Mitsios N, Kockum I, Khademi M, Zandian A, Sjöberg R, Forsström B, Bredenberg J, Bomfim IL, Holmgren E, Grönlund H, Guerreiro-Cacais AO, Abdelmagid N, Uhlén M, Waterboer T, Alfredsson L, Mulder J, Schwenk JM, Olsson T, Nilsson P. PNAS. 2016 Feb 23;113(8):2188-93. https://doi.org/10.1073/pnas.1518553113

Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Rat Genome Sequencing and Mapping Consortium, Baud A, Hermsen R, Guryev V, Stridh P, Graham D, McBride MW, Foroud T, Calderari S, Diez M, Ockinger J, Beyeen AD, Gillett A, Abdelmagid N, Guerreiro-Cacais AO, Jagodic M, Tuncel J, Norin U, Beattie E, Huynh N, Miller WH, Koller DL, Alam I, Falak S, Osborne-Pellegrin M, Martinez-Membrives E, Canete T, Blazquez G, Vicens-Costa E, Mont-Cardona C, Diaz-Moran S, Tobena A, Hummel O, Zelenika D, Saar K, Patone G, Bauerfeind A, Bihoreau MT, Heinig M, Lee YA, Rintisch C, Schulz H, Wheeler DA, Worley KC, Muzny DM, Gibbs RA, Lathrop M, Lansu N, Toonen P, Ruzius FP, de Bruijn E, Hauser H, Adams DJ, Keane T, Atanur SS, Aitman TJ, Flicek P, Malinauskas T, Jones EY, Ekman D, Lopez-Aumatell R, Dominiczak AF, Johannesson M, Holmdahl R, Olsson T, Gauguier D, Hubner N, Fernandez-Teruel A, Cuppen E, Mott R, Flint J. Nature Genetics. 2013 May 26. doi: 10.1038/ng.2644. https://doi.org/10.1038/ng.2644