Rheumatologie und Klinische Immunologie

Translational immunology focusing on:

• changes in early and late B cell development and B cell function in vasculitides and rheumatoid arthritis
• modulation of B cell function and B cell selection processes by immunomodulatory agents
• immunosuppressive therapy-related secondary immunodeficiency
• pathogenesis of primary vasculitides (ANCA-associated vasculitides, giant cell arteritis)
• role of mitochondria in autoimmune diseases (no current project)

B cell development and function in models of autoimmune diseases

ANCA-associated vasculitides (AAV) are potentially life-threatening multi-organ diseases, requiring prompt immunosuppressive therapy. Long-term mortality is increasingly affected by treatment-related complications. We recently made the observation that a large proportion of patients (around 70%) have long-lasting complete B cell depletion (median 24 months, range up to 7 years) after one cycle of B-cell depleting therapy with rituximab. We currently aim at finding out the molecular basis for this long-term B cell depletion by in vitro analysis of patients’ B cells by flow cytometry, in vitro B cell development assays and in vitro analysis of early bone marrow development, to answer the question whether microenvironmental defects or B cell intrinsic changes are responsible for the long-term B cell depletion. To answer this question is of immediate clinical relevance as it will affect the  design of rituximab re-treatment schedules and will allow a deeper understanding of the increased risk of hypogammaglobulinemia in AAV-patients. This project is realized in close collaboration with the group of Marta Rizzi.  

Impact of tofacitinib treatment on human B-cells in vitro and in vivo

B-cells are pivotal to the pathogenesis of rheumatoid arthritis and tofacitinib, a JAK inhibitor, is effective and safe in its treatment. Tofacitinib interferes with signal transduction via cytokine receptors using the common γ-chain. Despite extensive data on T-lymphocytes, the impact of tofacitinib on B-lymphocytes is poorly understood. In this study we assessed the effect of tofacitinib on B-lymphocyte differentiation and function. Tofacitinib treatment strongly impaired in vitro plasmablast development, immunoglobulin secretion and induction of B-cell fate determining transcription factors, Blimp-1, Xbp-1, and IRF-4, in naïve B-cells. Interestingly, class switch and activation-induced cytidine deaminase (AICDA) induction was only slightly reduced in activated naïve B-cells. The effect of tofacitinib on plasmablast formation, immunoglobulin secretion and proliferation was less profound, when peripheral blood B-cells, including not only naïve but also memory B-cells, were stimulated. In line with these in vitro results, the relative distribution of B-cell populations remained stable in tofacitinib treated patients. Nevertheless, a temporary increase in absolute B-cell numbers was observed 6-8 weeks after start of treatment. In addition, B-cells isolated from tofacitinib treated patients responded rapidly to in vitro activation. We demonstrate that tofacitinib has a direct impact on human naïve B-lymphocytes, independently from its effect on T-lymphocytes, by impairing their development into plasmablasts and immunoglobulin secretion. The major effect of tofacitinib on naïve B-lymphocyte development points to the potential inability of tofacitinib-treated patients to respond to novel antigens, and suggests planning vaccination strategies prior to tofacitinib treatment. In close collaboration with Dr. Marta Rizzi und Prof. Dr. Diego Kyburz, we currently assess the effect of JAK-Inhibition on early B cell development.  

Effect of blockade of co-stimulation by CTLA-4-Ig on the B cell compartment and the frequency of autoreactive memory B cells and plasma cells

1. In this study we assess the direct, T-cell independent effect of CTLA-4-Ig on B cell subpopulations (in vivo) as well as B cell differentiation (in vivo). We furthermore examine potential changes in signal transduction in B cells mediated by CTLA-4-Ig and assess the effect on B-T-cell cooperation.
2. ATARA study (IIT): effect of the treatment with CTLA-4 Ig in combination with methotrexate in early rheumatoid arthritis on ACPA-isotype titers, ACPA-Ig subclasses and the B cell repertoire (this is an project in cooperation with Marta Rizzi, Freiburg und Miriam van Der Burg, Rotterdam).

B cell compartment in eosinophilic granulomatosis with polyangiitis (EGPA)

EGPA is a very rare disease. We follow a cohort of >80 EGPA patients in our outpatient clinic. We recently reported, that B-cell directed therapy is effective in EGPA patients. To date, the role of the B cells has not been defined in EGPA. We characterized B cell subpopulations in EGPA and currently check if there is increased intrinsic switch capacity of naive B cells to IgE-expressing B cells in EGPA.  

The role of cannabinoid-receptors in B cell differentiation and migration

In this project we focus on cannabinoid receptor type 2 (CB2). We were able to show that CB2 expression characterizes different memory B cell subsets and are planning to evaluate the properties of CB2-negative and CB2-positive B cells. Furthermore, we assess the effect of monogenetic defects in molecules important for B cell proliferation and differentiation on the expression of CB2.  

The role of DOCK8 in humoral immune functions

DOCK8 deficiency results in a phenotype of severe combined immunodeficiency. In a cooperation with PD Dr. Michael Albert and Dr. Marta Rizzi we currently do an in-depth analysis of B cell subpopulations and B cell functions in patients with DOCK4-deficiency.

• Risk of reactivation of mycobacterium tuberculosis in patients treated with IL-17- directed therapies
• Differences in clinical and treatment characteristics of patients with PsA treated by rheumatologists or dermatologists
• Clinical studies in ANCA-associated vasculitides (Advocate-study, Mirrai-study)
• Treatment response to abatacept in early rheumatoid arthritis (ASCEND-study, investigator initiated study)

Germany:

• Prof. Dr. Marta Rizzi, Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, University of Vienna
• Dr. Ulrich Salzer, Department for Rheumatology and Clinical Immunology and Center for Chronic Immunodeficiency, Medical Center - University of Freiburg
• Prof. Dr. Schempp, Department of Dermatology, Medical Center - University of Freiburg 
• PD Dr. Michael Albert, Dr. von Hauner Children's Hospital, University Hospital of Munich (LMU) 
• Prof. Dr. Stephan Meckel, Department of Neuroradiology, Medical Center - University of Freiburg
• Prof. Dr. S. Herget, Department of Orthopedics and Trauma Surgery, Medical Center - University of Freiburg

International collaborations:

• Prof. Dr. Diego Kyburz, Rheumatology, University Hospital Basel, Switzerland
• Prof. Dr. Mirjam van Der Burg, Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
• Prof. Dr. Carola Vinuesa, John Curtin School of Medical Research, Canberra City, Australia
• Prof. Dr. Kaan Boztug, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

• Deutsche Forschungsgemeinschaft (DFG)
• Hans-Hench Stiftung zur Förderung der Rheumatologie  Krebs-Stiftung
• Walter Hitzig fellowship (BMBF)
• Novartis Stiftung für therapeutische Forschung
• Pfizer ASPIRE Progra
• Bristol-Myers Squibb Research Grant

Please find an up-to-date list of publications

• for Prof. Jens Thiel at pubmed: whttps://www.ncbi.nlm.nih.gov/pubmed/?term=thiel+jens
• for Prof. Nils Venhoff: whttps://www.ncbi.nlm.nih.gov/pubmed/?term=venhoff+nils