Major Areas of Research
- Hematopoietic development and function in health and disease
- Pathogenesis of autoimmune and inflammatory diseases
- Mechanisms of lymphoma/leukemia development
Studies in the Virology and Cellular Immunology Section relate to three overlapping areas of interest: normal hematopoietic differentiation with a primary focus on B cells, autoimmunity, and neoplastic transformation. Most studies are mouse-based and use a wide range of experimental approaches to understand important biologic questions including cellular immunology, genetic analyses (FISH, SKY, microarray, and NextGen gene expression profiling), development and analysis of genetically engineered mice (conditional knockouts, knockins, reporters), and bioinformatics. Efforts are made to translate basic findings made in these studies to the understanding of normal human biology and diseases.
Analyses of hematopoietic development and function have defined roles for interferon regulatory factor 8 (IRF8) throughout hematopoietic differentiation with critical contributions to B-cell lineage specification, commitment and differentiation into mature B-cell subsets, the germinal center reaction, and terminal differentiation to plasma cells. Recent ongoing studies are exploring the contributions of IRF8 to T-cell development and function. Studies of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression were critical to defining previously unrecognized subsets of B-1a cells that play distinct roles in production of natural antibodies, antigen responsiveness, mucosal immunity, and immunosuppression. Ongoing studies suggest specific contributions from one of these subsets to the development of CD5+ B cell leukemias with similarities to human chronic lymphocytic leukemia. Detailed analyses of the chemokine receptor, CXCR7, and the IgM-specific Fc receptor, FCRM, identified central roles in the biology of marginal zone B cells and the development and function of other B-cell subsets.
The development of B-cell lineage neoplasms in humans and mice involves complex interplays between the activation of proto-oncogenes, such as Myc, by chromosomal translocations often involving the immunoglobulin heavy chain locus (IgH) and inactivation of tumor suppressor genes (TSG) including p53. Studies of mechanisms involved in the development of plasma cell neoplasms, termed plasmacytomas (PCT), identified distinct cellular origins for two histologically defined subsets of PCT. Additional studies were critical for defining the IgH elements that regulate expression of translocated Myc genes. Analyses of genetically engineered mice with B-cell-specific deficiencies in the TSG p53, TRAF3, PTEN, and SHIP uncovered their contributions to selective development of B-cell lymphomas less mature than plasmacytomas.
Analyses of systemic lupus erythematosus (SLE)-like diseases in mice have centered on the BXSB.Yaa model, which is critically dependent on a duplication of TLR7, an endosomal receptor for single-stranded RNA. Development of disease was found to require signaling to B cells by the cytokine, IL21, which is produced by CD4+ T follicular helper cells (TFH). Unexpectedly, IL21 is also responsible for stimulating the activity of CD8+ T suppressor cells that retard disease development, indicating that it functions as a double-edged sword in the development of BXSB.Yaa disease. Ongoing studies have identified that young mice express an “interferon signature” very similar to that found in humans with SLE, as well as a disease-promoting activity of IL6 and a disease-suppressive activity of IL10. Parallel studies of the autoimmune-prone strain, SJL, showed that a CD8+ T suppressor population retards the development of lethal B- cell lineage tumors that are responsible for the death of most mice of this strain.
Dr. Morse graduated from Harvard Medical School and then completed his internship and residency at Peter Bent Brigham Hospital, Boston. Following postdoctoral studies at NIAID, he joined the Laboratory of Viral Diseases in 1980 and became chief of the Laboratory of Immunopathology (LIP) in 1985. In 2011, LIP merged with the Laboratory of Immunogenetics, and Dr. Morse became chief of the Virology and Cellular Immunology Section.
Wang H, Shin DM, Abbasi S, Jain S, Kovalchuk AL, Beaty N, Chen S, Gonzalez-Garcia I, Morse HC 3rd. Expression of plasma cell alloantigen 1 defines layered development of B-1a B-cell subsets with distinct innate-like functions. Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):20077-82.
Kovalchuk AL, Ansarah-Sobrinho C, Hakim O, Resch W, Tolarová H, Dubois W, Yamane A, Takizawa M, Klein I, Hager GL, Morse HC 3rd, Potter M, Nussenzweig MC, Casellas R. Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation. Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):10972-7.
Wang H, Beaty N, Chen S, Qi CF, Masiuk M, Shin DM, Morse HC 3rd. The CXCR7 chemokine receptor promotes B-cell retention in the splenic marginal zone and serves as a sink for CXCL12. Blood. 2012 Jan 12;119(2):465-8.
McPhee CG, Sproule TJ, Shin DM, Bubier JA, Schott WH, Steinbuck MP, Avenesyan L, Morse HC 3rd, Roopenian DC. MHC class I family proteins retard systemic lupus erythematosus autoimmunity and B cell lymphomagenesis. J Immunol. 2011 Nov 1;187(9):4695-704.
Feng J, Wang H, Shin DM, Masiuk M, Qi CF, Morse HC 3rd. IFN regulatory factor 8 restricts the size of the marginal zone and follicular B cell pools. J Immunol. 2011 Feb 1;186(3):1458-66.
Shin DM, Lee CH, Morse HC 3rd. IRF8 governs expression of genes involved in innate and adaptive immunity in human and mouse germinal center B cells. PLoS One. 2011;6(11):e27384.