Dornmair Lab – Disease-relevant lymphocytes
We are investigating properties and target antigens of disease-relevant B- and T-cells of patients with multiple sclerosis, encephalitis, narcolepsy, psoriasis, and of other disease conditions. Over the years we have established several techniques that now allow us to distinguish disease-relevant cells from bystander cells and to identify the target antigens of antibodies and CD8+ T cells. To this end, we analyze the lymphocyte repertoire by mRNAseq and isolate disease-relevant cells by flow cytometry and 10X technology from body fluids or by laser microdissection from tissue. From single putatively disease-relevant B- and T-cells we then identify matching chains of antibodies or T cell receptors (TCR), clone their heavy and light or α- and β-chains, and functionally express the antibodies or TCRs in vitro.
We analyze the antigens of antibodies by conventional biochemical methods, and found that “oligoclonal band” antibodies, which are important diagnostic markers in multiple sclerosis and other inflammatory neurological diseases, often recognize debris released from dead cells. By contrast, antibodies from patients with encephalitis may recognize surface proteins on cells in the brain and may thus directly contribute to clinical symptoms.
Due to the very low affinities of TCRs to their target antigens (i.e. MHC/peptide complexes), biochemical methods are not suited for T cell antigen identification. Therefore, we have developed an unbiased technology to identify their as yet unknown antigens. This method is based on plasmid-encoded combinatorial peptide libraries which can be loaded onto class I MHC molecules and an extremely sensitive screening system, which uses fluorescent reporter molecules that are expressed upon T cell activation. This technology may be applied to all conditions where CD8+ T cells are relevant, i.e. to many autoimmune, tumor and infectious diseases.
We bring the bedside to the bench:
The left panel shows T cell infiltrates in the brain of an MS patient. Cells are stained for CD8 molecules and a T cell receptor marker indicating expanded T cell clones. A putatively disease-related clone is indicated by an arrow. The right panel shows "resurrected" T cells that light up green when they recognize their specific antigen.
Contact
PD. Dr. rer. nat. Klaus Dornmair
Klaus.Dornmair@med.uni-muenchen.de
Key Publications
Hohlfeld R, Beltran E, Gerdes LA, Dornmair K. Tissue-resident CD8+ memory T cells in multiple sclerosis. Brain. 2021 Feb 12;144(1):e7.
Beltrán E, Paunovic M, Gebert D, Cesur E, Jeitler M, Höftberger R, Malotka J, Mader S, Kawakami N, Meinl E, Bradl M, Dornmair K, Lassmann H. Archeological neuroimmunology: resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis. Acta Neuropathol. 2021 Jan;141(1):67-83. doi: 10.1007/s00401-020-02239-2. Epub 2020 Oct 29.
Beltrán E, Gerdes LA, Hansen J, Flierl-Hecht A, Krebs S, Blum H, Ertl-Wagner B, Barkhof F, Kümpfel T, Hohlfeld R, Dornmair K. Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis. J Clin Invest. 2019 Nov 1;129(11):4758-4768.
Konjevic Sabolek M, Held K, Beltrán E, Niedl AG, Meinl E, Hohlfeld R, Lassmann H, Dornmair K. Communication of CD8+ T cells with mononuclear phagocytes in multiple sclerosis. Ann Clin Transl Neurol. 2019 Jul;6(7):1151-1164.
Beltrán E, Nguyen XH, Quériault C, Barateau L, Dauvilliers Y, Dornmair K, Liblau RS. Shared T cell receptor chains in blood memory CD4+ T cells of narcolepsy type 1 patients. J Autoimmun. 2019 Jun;100:1-6.
Brändle SM, Obermeier B, Senel M, Bruder J, Mentele R, Khademi M, Olsson T, Tumani H, Kristoferitsch W, Lottspeich F, Wekerle H, Hohlfeld R, Dornmair K. Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins. Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7864-9.
Rühl G, Niedl AG, Patronov A, Siewert K, Pinkert S, Kalemanov M, Friese MA, Attfield KE, Antes I, Hohlfeld R, Dornmair K. Multiple sclerosis: Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor. Neurol Neuroimmunol Neuroinflamm. 2016 May 17;3(4):e241.
Arakawa A, Siewert K, Stöhr J, Besgen P, Kim SM, Rühl G, Nickel J, Vollmer S, Thomas P, Krebs S, Pinkert S, Spannagl M, Held K, Kammerbauer C, Besch R, Dornmair K, Prinz JC. Melanocyte antigen triggers autoimmunity in human psoriasis. J Exp Med. 2015 Dec 14;212(13):2203-12.
Beltrán E, Obermeier B, Moser M, Coret F, Simó-Castelló M, Boscá I, Pérez-Miralles F, Villar LM, Senel M, Tumani H, Hohlfeld R, Casanova B, Dornmair K. Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation. Brain. 2014 Oct;137(Pt 10):2703-14.
Siewert K, Malotka J, Kawakami N, Wekerle H, Hohlfeld R, Dornmair K. Unbiased identification of target antigens of CD8+ T cells with combinatorial libraries coding for short peptides. Nat Med. 2012 May;18(5):824-8.
Krishnamoorthy G, Saxena A, Mars LT, Domingues HS, Mentele R, Ben-Nun A, Lassmann H, Dornmair K, Kurschus FC, Liblau RS, Wekerle H. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med. 2009 Jun;15(6):626-32.
Obermeier B, Mentele R, Malotka J, Kellermann J, Kümpfel T, Wekerle H, Lottspeich F, Hohlfeld R, Dornmair K. Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis. Nat Med. 2008 Jun;14(6):688-93.
PD Dr. Klaus Dornmair,
Principal Investigator
Read more about the PI on the next tab.
Dr. Eduardo Beltrán,
Postdoctoral fellow
Dr. Alina Huth,
Postdoctoral fellow
Dr. Katharina Deschler,
Postdoctoral fellow
Julia Hansen,
PhD student
David Gebert,
PhD student
Vladyslav Kavaka,
MD student
Pauline Graf,
technician
Markus Utzt,
technician
PD. Dr. rer. nat. Klaus Dornmair
1984 Diploma in Biochemistry, University of Tübingen.
1987 PhD degree, Max-Planck-Institute of Biology, Tübingen.
1987 – 1988 Postdoctoral Fellow Max-Planck-Institute of Biology, Tübingen.
1988 – 1990 Postdoctoral Fellow, Department of Chemistry, Stanford University, Stanford, CA, USA, sponsored by EMBO.
1990 – 1999 Group Leader, Max-Planck-Institute of Neurobiology, Martinsried.
since 1999 Group Leader, Institute of Clinical Neuroimmunology, LMU Munich
We gratefully acknowledge support for our work by the following agencies:
Germam Research Foundation
Munich Cluster for Systems Neurology (SyNergy)
LMUexcellent
Collaborative Research Center 128 – German Research Foundation (DFG)
ERA-Net for Research Programmes on Rare Diseases
Bundesministerium für Bildung und Forschung
Wilhelm Sander-Stiftung
