Immunomodulatory approaches targeting autoreactive B lineage cells while leaving protective B memory intact
B Cell Memory
Immune memory protects our body against foreign antigens but can also cause damage in autoimmune diseases (AID). B cells and plasma cells play a central role by producing antibodies and cytokines to activate and regulate other immune cells. A better understanding of B cell functions and selective targeting of B cells holds promise for future therapeutic applications. We characterize B and plasma cell functions during the formation of immunological memory in health and autoimmunity to understand the processes leading to the induction and maintenance of protective versus autoreactive B cells with the goal of selective targeting of autoimmune cells.
In autoimmune patients, we found reduced responsiveness of B cells to B cell receptor (BCR) and Toll-like receptor (TLR)9 stimulation. We defined this phenotype as ‘post-activation’ and found B cells from patients with systemic lupus erythematosus (SLE) to be characterized by a distinct pattern of checkpoint molecules. The latter are candidates of selective expression and hence distinct treatment targets.
Other differences between healthy and autoimmune individuals may be provided by the dynamics of (auto) antigen reactive cells. Here, vaccination studies in healthy donors showed that antigen-specific B cells are recruited from naïve, as well as from cross-reactive memory B cells, upon primary vaccination, whereas they are recruited from the memory pool upon secondary challenge. In lupus nephritis, PTX3 specific B cells that are candidate antigen-specific regulatory B cells, were found to be reduced in comparison to both SLE patients without nephritis and healthy donors, indicating substantial differences in differentiation.
A better understanding of the maintenance of plasma cell subsets in the bone marrow could help targeting auto-antibody producing cells in AID. We demonstrated that the composition and functionality of B cells are stable at the individual donor level.
As an overall goal, we aim to identify selective therapeutic strategies which include 1) modulating post-activated B cells, 2) using check-point molecules for immunomodulatory approaches and 3) using antigen-specific B lineage cells to improve regulatory and suppress autoreactive cells including selectively targeting harmful autoreactive plasma cells in autoimmune diseases while providing sufficient protective functions.
Systemic lupus erythematosus (SLE)
Rheumatoid arthritis (RA)
Primary Sjögren‘s syndrome (pSS)
Prof. Dr. med. Thomas Dörner
Andreia C. Lino, PhD
Dr. Eva V. Schrezenmeier
Dr. Ana-Luisa Stefanski
Dr. Marie Lettau
Dr. Thomas Rose
Annika Wiedemann, Dipl.-Ing.
Sarah Y. Weißenberg, M. Sc.
Franziska Szelinski, M. Sc.
Hector Rincon, M. Sc.
Dr. Mariele Gatto
Finn Moritz Wilkens
Prof. Dr. Jörn Walter, Saarland University, Department of Genetics and Epigenetics, Saarbrücken, Germany
Prof. Dr. Lars Rönnblom, Uppsala University, Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala, Sweden
Prof. Dr. Peter Lipsky, RILITE Research Institute, Charlottesville, VA, USA
Prof. Simon Fillatreau, PhD, Institute Necker – Inserm, Paris, France
Prof. Dr. Hans-Peter Brezinschek, Medical Faculty, University Graz, Austria
Prof. Klaus Rajewsky, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
Dr. Van Trung Chu, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
Prof. Changchun Xiao, Xiamen University, Xiamen, China
Lisney AR, Szelinski F, Reiter K, Burmester GR, Rose T, Dörner T. (2017). High maternal expression of SIGLEC1 on monocytes as a surrogate marker of a type I interferon signature is a risk factor for the development of autoimmune congenital heart block. Ann Rheum Dis 76(8): 1476-1480.
Schrezenmeier E, Jayne D, Dörner T. (2018) Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives. J Am Soc Nephrol. Mar;29(3):741-758. doi: 10.1681/ASN.2017040367.
Giesecke C, Meyer T, Durek P, Maul J, Preiß J, Jacobs JFM, Thiel A, Radbruch A, Ullrich R, Dörner T. (2018). “Simultaneous Presence of Non- and Highly Mutated Keyhole Limpet Hemocyanin (KLH)-Specific Plasmablasts Early after Primary KLH Immunization Suggests Cross-Reactive Memory B Cell Activation.” J Immunol 200(12): 3981-3992.
Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, Simon Q, Thalmensi J, Baures A, Flühler V, Sakwa I, Stervbo U, Ries S, Jouneau L, Boudinot P, Tsubata T, Adachi T, Hutloff A, Dörner T, Zimber-Strobl U, de Vos AF, Dahlke K, Loh G, Korniotis S, Goosmann C, Weil JC, Reynaud CA, Kaufmann SHE, Walter J, Fillatreau S (2018) LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Immunity. Jul 17;49(1):120-133.e9.
Schrezenmeier E, Weißenberg SY, Stefanski A-L, Szelinski F, Wiedemann A, Lino AC, Dörner T (2019) Postactivated B cells in systemic lupus erythematosus: update on translational aspects and therapeutic considerations. Curr Opin Rheumatol. Mar;31(2):175-184.
Gatto M, Wiedemann A, Nomovi N, Reiter K, Schrezenmeier E, Rose T, Lino AC, Valentino S, Ghirardello A, Dörner T, Doria A. (2019) Circulating Pentraxin3-specific B cells are Decreased in Lupus Nephritis. Front Immunol. Jan 25;10:29.
Stefanski A-L, Wiedemann A, Reiter K, Lino AC, Dörner T. (2019) Enhanced PD-1 and diminished PD-L1 expression mark post-activated lupus B cells. Arthritis Rheumatol.
Wiedemann A, Lino AC, Dörner T. (2019) B cell subset distribution in human bone marrow is stable and similar in left and right femur. PLoS One. Feb 22;14(2):e0212525.