Mechanisms of protective versus autoreactive B cells in systemic lupus erythematosus

• Applicant: Professor Dr. Thomas Dörner
• Subject Area: Rheumatology
• Term: from 2008 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 74975068

• Final Report Year: 2025

Final Report Abstract

This grant was able to successfully delineate certain characteristics of a defined antiviral protective immune response (mainly anti-RBD of SARS-Cov2 versus tetanus/TT) given that the SARS-Cov2 pandemia dominated largely the project start in 2020. After initial establishment of reliable assays to detect B lineage as well as T cell responses, we identified important variables for successful protective anti-RBD responses (disease: rheumatoid arthritis, dialysis, kidney transplantation; treatment: immunosuppressive agents, B cell depletion/rituximab) beyond conventional factors. In the normal human bone marrow, we originally identified hitherto unknown 10 plasma cell (PC) clans with a distinct cytokine signature including IL-21 dependent fraction of CD19- long-lived PC with enrichment of longerlive tetanus-specific BMPC. Additional BMPC studies evaluated the co-expression of CD56 on CD19low and CD19- BMPC. Here, CD19-CD56+ BMPC did not contain RBD specific clones while enriched for TT-specific BMPC. On the transcriptional level, NCAM-1+(encodes CD56)/CD19- BMPC carried a transcriptional profile of longevity and intense cell-cell interaction mandating ongoing studies in autoimmunity. Another critical observation was the requirement of 10 B cells/ul for proper IgG induction as well as activation of CD4 T cells as well as the description of CD19low/CXCR5- pre-plasmablasts. Such cells share functionally characteristics of BCR hyporesponsive memory B cells (anergic post-activated/exhausted) but able to respond to TLR 7/8 as well as via CD40 to T cell signals. The convergence of innate and adaptive immune signalling in particular by antigen-experienced memory B cells requires consideration as treatment targets. Related to the initial grant hypothesis if systemic autoimmune responses follow principles of a conventional primary or secondary immune response, the aggregate of available data suggest that the abnormalities of autoimmune B cell responses do not simply follow primary or secondary responses (i.e. against TT) but more closely following principles of an antiviral response. These results have implications for the deeper understanding of different responses by B and plasma cells, which appear to be clearly determined by the properties of the inciting antigens as well as the underlying T cell activation.

Publications

• Elevated STAT1 expression but not phosphorylation in lupus B cells correlates with disease activity and increased plasmablast susceptibility. Rheumatology, 59(11), 3435-3442.
  Aue, Arman; Szelinski, Franziska; Weißenberg, Sarah Y.; Wiedemann, Annika; Rose, Thomas; Lino, Andreia C. & Dörner, Thomas
  
• Human CD27+ memory B cells colonize a superficial follicular zone in the palatine tonsils with similarities to the spleen. A multicolor immunofluorescence study of lymphoid tissue. PLOS ONE, 15(3), e0229778.
  Lettau, Marie; Wiedemann, Annika; Schrezenmeier, Eva Vanessa; Giesecke-Thiel, Claudia & Dörner, Thomas
  
• Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus. RMD Open, 6(2), e001258.
  Dörner, Thomas; Szelinski, Franziska; Lino, Andreia C. & Lipsky, Peter E.
  
• Toll-like receptor signalling in B cells during systemic lupus erythematosus. Nature Reviews Rheumatology, 17(2), 98-108.
  Fillatreau, Simon; Manfroi, Benoît & Dörner, Thomas
  
• Altered increase in STAT1 expression and phosphorylation in severe COVID‐19. European Journal of Immunology, 52(1), 138-148.
  Rincon‐Arevalo, Hector; Aue, Arman; Ritter, Jacob; Szelinski, Franziska; Khadzhynov, Dmytro; Zickler, Daniel; Stefanski, Luisa; Lino, Andreia C.; Körper, Sixten; Eckardt, Kai‐Uwe; Schrezenmeier, Hubert; Dörner, Thomas & Schrezenmeier, Eva V.
  
• B and T Cell Responses after a Third Dose of SARS-CoV-2 Vaccine in Kidney Transplant Recipients. Journal of the American Society of Nephrology, 32(12), 3027-3033.
  Schrezenmeier, Eva; Rincon-Arevalo, Hector; Stefanski, Ana-Luisa; Potekhin, Alexander; Staub-Hohenbleicher, Henriette; Choi, Mira; Bachmann, Friederike; Proβ, Vanessa; Hammett, Charlotte; Schrezenmeier, Hubert; Ludwig, Carolin; Jahrsdörfer, Bernd; Lino, Andreia C.; Eckardt, Kai-Uwe; Kotsch, Katja; Dörner, Thomas; Budde, Klemens; Sattler, Arne & Halleck, Fabian
  
• B cells in systemic lupus erythematosus. Current Opinion in Rheumatology, 34(2), 125-132.
  Szelinski, Franziska; Lino, Andreia C. & Dörner, Thomas
  
• BTLA Expression and Function Are Impaired on SLE B Cells. Frontiers in Immunology, 12.
  Wiedemann, Annika; Lettau, Marie; Weißenberg, Sarah Y.; Stefanski, Ana-Luisa; Schrezenmeier, Eva-Vanessa; Rincon-Arevalo, Hector; Reiter, Karin; Alexander, Tobias; Hiepe, Falk; Lino, Andreia C. & Dörner, Thomas
  
• Deep Phenotyping of CD11c+ B Cells in Systemic Autoimmunity and Controls. Frontiers in Immunology, 12.
  Rincon-Arevalo, Hector; Wiedemann, Annika; Stefanski, Ana-Luisa; Lettau, Marie; Szelinski, Franziska; Fuchs, Sebastian; Frei, Andreas Philipp; Steinberg, Malte; Kam-Thong, Tony; Hatje, Klas; Keller, Baerbel; Warnatz, Klaus; Radbruch, Andreas; Lino, Andreia C.; Schrezenmeier, Eva & Dörner, Thomas
  
• Immune checkpoints and the multiple faces of B cells in systemic lupus erythematosus. Current Opinion in Rheumatology, 33(6), 592-597.
  Stefanski, Ana-Luisa & Dörner, Thomas
  
• Immunogenicity of COVID-19 Tozinameran Vaccination in Patients on Chronic Dialysis. Frontiers in Immunology, 12.
  Schrezenmeier, Eva; Bergfeld, Leon; Hillus, David; Lippert, Joerg-Detlev; Weber, Ulrike; Tober-Lau, Pinkus; Landgraf, Irmgard; Schwarz, Tatjana; Kappert, Kai; Stefanski, Ana-Luisa; Sattler, Arne; Kotsch, Katja; Dörner, Thomas; Sander, Leif Erik; Budde, Klemens; Halleck, Fabian; Kurth, Florian; Corman, Victor Max & Choi, Mira
  
• Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients. Science Immunology, 6(60), eabj1031.
  Rincon-Arevalo, Hector; Choi, Mira; Stefanski, Ana-Luisa; Halleck, Fabian; Weber, Ulrike; Szelinski, Franziska; Jahrsdörfer, Bernd; Schrezenmeier, Hubert; Ludwig, Carolin; Sattler, Arne; Kotsch, Katja; Potekhin, Alexander; Chen, Yidan; Burmester, Gerd R.; Eckardt, Kai-Uwe; Guerra, Gabriela Maria; Durek, Pawel; Heinrich, Frederik; Ferreira-Gomes, Marta ... & Dörner, Thomas
  
• SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nature Communications, 12(1).
  Ferreira-Gomes, Marta; Kruglov, Andrey; Durek, Pawel; Heinrich, Frederik; Tizian, Caroline; Heinz, Gitta Anne; Pascual-Reguant, Anna; Du, Weijie; Mothes, Ronja; Fan, Chaofan; Frischbutter, Stefan; Habenicht, Katharina; Budzinski, Lisa; Ninnemann, Justus; Jani, Peter K.; Guerra, Gabriela Maria; Lehmann, Katrin; Matz, Mareen; Ostendorf, Lennard ... & Mashreghi, Mir-Farzin
  
• B Cell Characteristics at Baseline Predict Vaccination Response in RTX Treated Patients. Frontiers in Immunology, 13.
  Stefanski, Ana-Luisa; Rincon-Arevalo, Hector; Schrezenmeier, Eva; Karberg, Kirsten; Szelinski, Franziska; Ritter, Jacob; Chen, Yidan; Jahrsdörfer, Bernd; Ludwig, Carolin; Schrezenmeier, Hubert; Lino, Andreia C. & Dörner, Thomas
  
• B Cell Numbers Predict Humoral and Cellular Response Upon SARS–CoV‐2 Vaccination Among Patients Treated With Rituximab. Arthritis & Rheumatology, 74(6), 934-947.
  Stefanski, Ana‐Luisa; Rincon‐Arevalo, Hector; Schrezenmeier, Eva; Karberg, Kirsten; Szelinski, Franziska; Ritter, Jacob; Jahrsdörfer, Bernd; Schrezenmeier, Hubert; Ludwig, Carolin; Sattler, Arne; Kotsch, Katja; Chen, Yidan; Claußnitzer, Anne; Haibel, Hildrun; Proft, Fabian; Guerra, Gabriela; Durek, Pawel; Heinrich, Frederik; Ferreira‐Gomes, Marta ... & Dörner, Thomas
  
• B- and Plasma Cell Subsets in Autoimmune Diseases: Translational Perspectives. Journal of Investigative Dermatology, 142(3), 811-822.
  Dang, Van Duc; Stefanski, Ana-Luisa; Lino, Andreia C. & Dörner, Thomas
  
• CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus. Frontiers in Immunology, 13.
  Dang, Van Duc; Mohr, Elodie; Szelinski, Franziska; Le Tuan, Anh; Ritter, Jacob; Hinnenthal, Timo; Stefanski, Ana-Luisa; Schrezenmeier, Eva; Ocvirk, Soeren; Hipfl, Christian; Hardt, Sebastian; Cheng, Qingyu; Hiepe, Falk; Löhning, Max; Dörner, Thomas & Lino, Andreia C.
  
• Cytokine levels associated with favorable clinical outcome in the CAPSID randomized trial of convalescent plasma in patients with severe COVID-19. Frontiers in Immunology, 13.
  Körper, Sixten; Schrezenmeier, Eva Vanessa; Rincon-Arevalo, Hector; Grüner, Beate; Zickler, Daniel; Weiss, Manfred; Wiesmann, Thomas; Zacharowski, Kai; Kalbhenn, Johannes; Bentz, Martin; Dollinger, Matthias M.; Paul, Gregor; Lepper, Philipp M.; Ernst, Lucas; Wulf, Hinnerk; Zinn, Sebastian; Appl, Thomas; Jahrsdörfer, Bernd; Rojewski, Markus ... & Schrezenmeier, Hubert
  
• Efficient CRISPR-Cas9-mediated mutagenesis in primary human B cells for identifying plasma cell regulators. Molecular Therapy - Nucleic Acids, 30, 621-632.
  Le, Tuan Anh; Chu, Van Trung; Lino, Andreia C.; Schrezenmeier, Eva; Kressler, Christopher; Hamo, Dania; Rajewsky, Klaus; Dörner, Thomas & Dang, Van Duc
  
• Induction of cross-reactive, mucosal anti-SARS-CoV-2 antibody responses in rheumatoid arthritis patients after 3rd dose of COVID-19 vaccination. Journal of Autoimmunity, 133, 102918.
  Bondareva, M.; Letz, P.; Karberg, K.; Schrezenmeier, E.; Semin, I.; Rincon-Arevalo, H.; Dörner, T.; Mashreghi, M.F.; Stefanski, A.-L. & Kruglov, A.A.
  
• Persistent but atypical germinal center reaction among 3rd SARS-CoV-2 vaccination after rituximab exposure. Frontiers in Immunology, 13.
  Stefanski, Ana-Luisa; Rincon-Arevalo, Hector; Schrezenmeier, Eva; Karberg, Kirsten; Szelinski, Franziska; Ritter, Jacob; Chen, Yidan; Meisel, Christian; Jahrsdörfer, Bernd; Ludwig, Carolin; Schrezenmeier, Hubert; Lino, Andreia C. & Dörner, Thomas
  
• Plasmablast‐like Phenotype Among Antigen‐Experienced CXCR5–CD19low B Cells in Systemic Lupus Erythematosus. Arthritis & Rheumatology, 74(9), 1556-1568.
  Szelinski, Franziska; Stefanski, Ana Luisa; Schrezenmeier, Eva; Rincon‐Arevalo, Hector; Wiedemann, Annika; Reiter, Karin; Ritter, Jacob; Lettau, Marie; Dang, Van Duc; Fuchs, Sebastian; Frei, Andreas P.; Alexander, Tobias; Lino, Andreia C. & Dörner, Thomas
  
• Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination–specific humoral and cellular immunity in kidney transplant recipients. JCI Insight, 7(9).
  Schrezenmeier, Eva; Rincon-Arevalo, Hector; Jens, Annika; Stefanski, Ana-Luisa; Hammett, Charlotte; Osmanodja, Bilgin; Koch, Nadine; Zukunft, Bianca; Beck, Julia; Oellerich, Michael; Proß, Vanessa; Stahl, Carolin; Choi, Mira; Bachmann, Friederike; Liefeldt, Lutz; Glander, Petra; Schütz, Ekkehard; Bornemann-Kolatzki, Kirsten; López, del Moral Covadonga ... & Budde, Klemens
  
• Cross-regulation of antibody responses against the SARS-CoV-2 Spike protein and commensal microbiota via molecular mimicry. Cell Host & Microbe, 31(11), 1866-1881.e10.
  Bondareva, Marina; Budzinski, Lisa; Durek, Pawel; Witkowski, Mario; Angermair, Stefan; Ninnemann, Justus; Kreye, Jakob; Letz, Philine; Ferreira-Gomes, Marta; Semin, Iaroslav; Guerra, Gabriela Maria; Momsen, Reincke S.; Sánchez-Sendin, Elisa; Yilmaz, Selin; Sempert, Toni; Heinz, Gitta Anne; Tizian, Caroline; Raftery, Martin; Schönrich, Günther ... & Kruglov, Andrey A.
  
• Transcriptional profiling upon T cell stimulation reveals down-regulation of inflammatory pathways in T and B cells in SLE versus Sjögren’s syndrome. npj Systems Biology and Applications, 9(1).
  Kwon, Gino; Wiedemann, Annika; Steinheuer, Lisa M.; Stefanski, Ana-Luisa; Szelinski, Franziska; Racek, Tomas; Frei, Andreas Philipp; Hatje, Klas; Kam-Thong, Tony; Schubert, David; Schindler, Thomas; Dörner, Thomas & Thurley, Kevin
  
• Translational implications of newly characterized pathogenic pathways in systemic lupus erythematosus. Best Practice & Research Clinical Rheumatology, 37(4), 101864.
  Gatto, Mariele; Depascale, Roberto; Stefanski, Ana Luisa; Schrezenmeier, Eva & Dörner, Thomas
  
• Dysregulation of immune checkpoint molecules as a characteristic of autoimmune congenital heart block. Annals of the Rheumatic Diseases, 83(11), 1598-1600.
  Stefanski, Ana-Luisa; Rincon-Arevalo, Hector; Dressler-Steinbach, Iris; Nomovi, Nadja; Mackert, Alma; Aue, Arman; Ritter, Jacob; Wiedemann, Annika; Szelinski, Franziska; Schrezenmeier, Eva; Kühl, Anja A.; Lino, Andreia C.; Henrich, Wolfgang & Dörner, Thomas
  
• Elevated unphosphorylated STAT1 and IRF9 in T and B cells of primary sjögren's syndrome: Novel biomarkers for disease activity and subsets. Journal of Autoimmunity, 147, 103243.
  Ritter, Jacob; Szelinski, Franziska; Aue, Arman; Stefanski, Ana-Luisa; Rincon-Arevalo, Hector; Chen, Yidan; Nitschke, Eduard; Dang, Van Duc; Wiedemann, Annika; Schrezenmeier, Eva; Lino, Andreia C. & Dörner, Thomas
  
• Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow. Nature Communications, 15(1).
  Ferreira-Gomes, Marta; Chen, Yidan; Durek, Pawel; Rincon-Arevalo, Hector; Heinrich, Frederik; Bauer, Laura; Szelinski, Franziska; Guerra, Gabriela Maria; Stefanski, Ana-Luisa; Niedobitek, Antonia; Wiedemann, Annika; Bondareva, Marina; Ritter, Jacob; Lehmann, Katrin; Hardt, Sebastian; Hipfl, Christian; Hein, Sascha; Hildt, Eberhard; Matz, Mareen ... & Mashreghi, Mir-Farzin
  
• The essential roles of memory B cells in the pathogenesis of systemic lupus erythematosus. Nature Reviews Rheumatology, 20(12), 770-782.
  Dörner, Thomas & Lipsky, Peter E.
  
• UNC93B1 variants underlie TLR7-dependent autoimmunity. Science Immunology, 9(92).
  Wolf, Christine; Lim, Ee Lyn; Mokhtari, Mohammad; Kind, Barbara; Odainic, Alexandru; Lara-Villacanas, Eusebia; Koss, Sarah; Mages, Simon; Menzel, Katharina; Engel, Kerstin; Dückers, Gregor; Bernbeck, Benedikt; Schneider, Dominik T.; Siepermann, Kathrin; Niehues, Tim; Goetzke, Carl Christoph; Durek, Pawel; Minden, Kirsten; Dörner, Thomas ... & Lee-Kirsch, Min Ae