AG Seifert

Human B cell immunology in health and disease

B-lymphocytes are a main component of the adaptive immune system. The antibodies they encode are indispensable in research, diagnostics, vaccination, and therapy. B-lymphocytes also harbor risks, as they can cause autoimmunity and transform; almost 90% of human lymphomas are of B cell origin. The underlying molecular mechanisms of B cell immunity and lymphomagenesis are poorly understood, especially in humans. My research aims at decoding the B cell system and the antibody repertoire in healthy people and to determine the critical alterations that occur during aging, or throughout the course of a disease. This research aims at unraveling B cell immune dynamics throughout life and clarifying which B cell subsets or antibody specificities are beneficial in health and limiting or even defective in patients. B cell immunology, deep sequencing, single-cell-based analyses, and BCR repertoire screens are essential components of my scientific expertise. The combination of these approaches is a powerful tool to research the dynamics of the normal immune system, as well as lymphomagenesis, immune aging, and B cell responses to infections. A particular focus at the Department of Hematology, Oncology and clinical Immunology of the Heinrich Heine University is the characterization of tumor-infiltrating lymphocytes and their interactions with cancer cells and the tumor microenvironment.

Human B cells during aging

The molecular mechanisms of the developmental and functional dynamics of B-1 and also MZ-B cells in humans are controversial. A central part of my research interest is the molecular characterization of human B-1, B-2 and marginal zone B cells based on an integrated analysis of antigen receptor repertoire, (single-cell) RNA-Seq, TWGBS and ATAC-Seq. Our research is based on a comprehensive collection of human tissue samples from a wide range of ages (early childhood to senior). We analyze and archive splenic tissue, tonsils, lymph nodes and intestinal resections, and umbilical cord blood. The molecular patterns in this comprehensive database are validated and extended by functional analyses (humanized mouse models and in vitro) for a systemic (body-wide) and systematic (planned) image of the human B cell system.

B cell receptor repertoire analyses, Ig-mutation phylogenetics and recombinant antibodies

Ig mutations occur in sequential order and thus, may serve as a molecular clock. The shape and structure of an Ig-mutation phylogenetic tree allows the analysis of diversification and selection of memory B cell clones. Antigen receptor repertoire analyses of human B cell populations in newborns, infants, adults, and the elderly helped to quantify the reactivity of B cells or analyze the specificity of BCRs by cloning and affinity measurements. Our analysis of human marginal zone B cells of the spleen has shown that the spleen is a veritable archive for memory B cells, in which external B cells are recruited and maintained. This archiving ability decreases with 40 years and is lost in seniors. We can determine the specificities that are missing as a result, and identify large, expanded B cell clones as premalignant stages in lymphomagenesis. In certain B cell tumors, Ig-mutation phylogenetics allow the sensitive and reliable identification of subclones and display their competitive outgrowth. Therefore, the B cell receptor repertoire is of particular interest in the analysis of cancer-dynamics GC-derived B cell lymphomas.

The cellular origin(s) of lymphomas

The systematic exploration of the human B cell pool allows us to identify the cellular origins and normal counterparts of lymphoma entities. The application of multi-omics comparisons of normal lymphocytes and their corresponding tumor counterparts allow the systematic and comprehensive picture of transforming events and tumor maturation stages. In this context, single-cell-based analyses represent a powerful tool to understand the composition of tumors, identify tumor subclones; and comparative analysis of sequential samples (e.g., pre-, or post-treatment) can reveal the outgrowth of aggressive subclones.

Hairy cell leukemia

HCL is a disease caused by transformed B lymphocytes that repress normal Blood formation. There are several strategies to treat HCL, including chemotherapy or the use of inhibitors, but none of these treatments is curative. Thus, we need to improve our knowledge how HCL cells survive and persist, even under successful treatment. Our aim in HCL leukemia research is to search for specific HCL features that can be targeted to disrupt the HCL life cycle. These features may be enclosed in the tumor cells themselves, but potentially also hidden in their interaction with the surrounding tissue. To detect such features, we compare HCL cells to their normal B cell counterpart, identify the specific perturbations and survival strategies that caused malignant outgrowth, and then estimate whether this may serve as specific vulnerabilities and exploit the possibility to use them as entry points in treating HCL.

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