Our laboratory has a long-standing interest in studying immunoglobulins (antibodies) and B lymphocytes in health and diseases, starting with Dr. Casali’s groundbreaking work on human monoclonal antibodies almost 30 years ago. B cells and high-affinity class-switched (mature) antibodies are central to host immunity and immune memory elicited by infectious pathogens, tumoral cells and vaccines. Dysregulation of B cell functions contributes to a range of pathological conditions, from immunodeficiency and immunoageing to autoimmune diseases, allergy mediated by atopic IgEs, and neoplasia.
With the recent addition of Dr. Xu and Dr. Zan, Dr. Casali’s formal mentorees and now close collaborators, as independent Principle Investigators, this integrated laboratory will study the same subject, B cell biology, from different perspectives. Dr. Casali is focusing on our fundamental understandings of how epigenetic marks, particularly combinatorial histone modification and non-coding RNAs, drive B cell differentiation processes, such as somatic hypermutation (SHM), class switch DNA recombination (CSR), and B cell differentiation into plasma cells and memory B cells. He is using a cutting-edge epigenetic modulating approach, e.g., by using histone deacetylase (HDAC) inhibitors (HDIs), to manipulate immunity in normal mice and autoimmunity in mouse models, such as MRL/Faslpr/lpr mice, which develop disease symptoms similar to those of human systemic lupus erythematosus (SLE).
Dr. Paolo Casali
Professor & Chairman
Dr. Xu is building a research program based on his recent findings that the Rab7 small GTPase plays a B cell-intrinsic and critical role in T-independent and T-dependent antibody responses and does so by mediating induction of AID (which is critical for CSR and SHM). This work has been done in Igh+/Cg1-creRab7fl/fl mice, in which Rab7 is abrogated in B cells activated undergoing germline Ig1-Sg1-Cg1 transcription. Dr. Xu has also recently generated Tg(Aicda-cre)Rab7fl/fl mice, in which Rab7 is abrogated in activated B cells, which can express initial modest levels of AID but cannot sustain AID expression for CSR and SHM due to the important role of Rab7 in AID induction. Using these novel genetic tools, Dr. Xu is studying how Rab7, which preferentially localizes in intracellular membrane compartments, promotes transduction of specific signals triggered by receptors, such as activation of the canonical NF-kB pathway. He is also studying how Rab7 modulates Dicer expression, thereby affecting expression of microRNAs that target AID-encoding mRNAs in normal mice or lupus-prone MRL/Faslpr/lpr mice.
Dr. Zhenming Xu
Dr. Zan has a wide-range interest in molecular mechanisms underlying CSR and SHM, including how AID mediates generation of DNA lesions and how these lesions are processed by error-prone DNA polymerases and DNA repair factors, leading to insertion of mutations in V(D)J region DNA for SHM or double strand DNA break (DSB) end joining for CSR. He has also found that the HoxC4 homeodomain transcription factor directly binds to AID gene promoter to induce AID and that estrogen upregulates HoxC4 expression. Prompted by his findings that HoxC4 and AID are important for the production of autoantibodies in lupus, Dr. Zan is studying the protective effect of estrogen receptor antagonists, such as fulvestrant, in preventing autoantibody production and lupus symptoms in MRL/Faslpr/lpr mice. He is also studying the relationship of gut immunity with microbiota and nutrition.
Dr. Hong Zan