Rheumatologie und Klinische Immunologie

Research Focus

• Human B cell development and dysregulation
• Modulaton of B cell function, development and activation
• In vitro models of human B cell development

Current Projects

FAS and B cells in humans

Extrinsic apoptosis pathway executed via FAS receptor (APO-1, APT-1, CD95,) signaling is central to lymphocyte homeostasis and clearance of activated and potentially autoreactive immune cells. FAS-mediated apoptosis has been shown to play a major role in pathogenesis of autoimmune lymphoproliferative syndrome (ALPS), a condition defined by presence of lymphoproliferation, autoimmune cytopenias, raised levels of CD3+TCRa/b+CD4-CD8- “double negative” T cells (DNT) and propensity to lymphoid malignancy. The disease manifestation is heterogeneous and patients may present with only partial phenotype (e.g. only lymphoproliferation or only autoimmunity). Most of the patients carry germline or somatic heterozygous mutations in FAS gene. In a case of FAS mutations with lower penetrance, accumulation of genetic defects (second mutation in FAS gene or loss of heterozygosity) has been shown to be indispensable for the disease manifestation. The observation that somatic mutations can cause the ALPS phenotype has been an important advance, indicating that presence of the mutation in a limited number of hematopoietic cells is sufficient to cause disease manifestations.  Interestingly, in mouse it has been demonstrated that FAS deficiency restricted to B cells is sufficient for the development of autoantibodies and lymphoproliferation. Conversely, in human the role of FAS in B cell selection, and its contribution to autoimmunity is still poorly understood.

Modulatory signal in B cell activation

In this project we analyze several candidates receptors, signaling pathways that may be involved in the modulation of B cell function, B cell homeostasis and B cell receptor signaling in a T-cell dependent and T-cell independent manner. To test this we assess the impact of triggering these signaling pathways on B cell activation and function in vitro.  

B cell development and function in models of autoimmune diseases

In collaboration with Dr.  Jens Thiel and Dr. Nils Venhoff we study the B cell function in vasculitidis patients. Vasculitides are potentially life-threatening multi-organ diseases. They often require prompt immunosuppressive therapy resulting in a considerable treatment-related mortality. Recently, we found that a substantial number of AAV patients develop secondary immunodeficiency. We plan to study the B cell function and activation in AAV patients, and their contribution to the pathogenesis of the disease and to the immune dysregulation that we clinically observe.  

Analysis of early BM development in primary antibody deficiency patients

Patients suffering from primary antibody deficiency (PAD) form a heterogeneous group characterized by a wide spectrum of disease severity and presentation. Genetic defects have been identified in about 10-15 % of these patients. In the remaining majority, the molecular mechanisms resulting in the disorders are not known. About 50% of the PAD patients lack both memory and marginal zone B cells, and about 10-15% of patients have less than 5% of circulating B cells. Analysis of B cell precursors in the bone marrow revealed that in about 20% of PAD patients B cell development is arrested at the transition from the pre-BI to the pre-BII cell stage. Therefore in PAD patients intrinsic or microenvironmental defect may be at the base of the disease. The understanding of the underlying defect would improve patient classification, and provide the base for the study of new therapeutic options.

Collaborations

Germany:

• Dr. Jens Thiel and Dr. Nils Venhoff, Department for Rheumatology and Clinical Immunology
• Prof. Hermann Eibel, Center for Chronic Immunodeficiency (CCI)
• Prof. Klaus Warnatz,Center for Chronic Immunodeficiency (CCI)
• Dr. Miriam Erlacher, Center for Pediatrics
• Dr. Miriam Kunze, Department of Obstetrics and Gynecology
• Prof. Jürgen Finke, Hematology, Oncology, and Stem-Cell Transplantation
• Prof. Stephan Ehl, Center for Chronic Immunodeficiency (CCI)
• Dr. Ulrich Salzer, Department for Rheumatology and Clinical Immunology and CCI.
• Prof. Klaus Schwarz, Institut für Klinische Transfusionsmedizin und Immungenetik Ulm (IKT)
• Joachim Roesler (Department of Pediatrics, University Clinic Carl Gustav Carus, Dresden, Germany)

International collaborations

• Prof. Mirjam van Der Burg, Erasmus MC, Rotterdam
• Dr. Elisabetta Traggiai, Novartis Institute for Biomedical Research
• Prof. Sandro Plebani, Divisione di Pediatria, Brescia
• European Society of Immunodeficiency (ESID)
• Blood and Marrow Transplantation Inborn Error working party (EBMT IE WP)

Funding

• Eliteprogramm 2015 - Baden Württemberg Stiftung
• Bristol-Myers Squipp (2015) to J. Thiel (PI) and M. Rizzi (PI)
• SFB 1160 (TP4) Immune-mediated pathology as a consequence of impaired immune reactions (IMPATH)
• Margarete von Wrangell Habilitation Fellowship, Ministerium für Wissenschaft, Forschung und Kunst Baden Württemberg (2014-2018)
• Walter Hitzig fellowship from the Center for Chronic Immunodeficiency: (2014-2016)
• Novartis Stiftung für therapeutische Forschung (2014-2016) to M. Rizzi (PI), J. Thiel, R. Voll, and N. Venhoff
• Pfizer ASPIRE Program (2013-2014) to J. Thiel (PI), M. Rizzi, R. Voll, and N. Venhoff

Publications

Please have  a look at the PubMed Search to find an up-to-date list of publications from Dr. Marta Rizzi.

Team