Herbert C. Morse, M.D.

Senior Investigator

Virology and Cellular Immunology Section

NIAID/DIR

4 Memorial Drive, Room 228B
Bethesda, MD 20814

301-496-6379

hmorse@niaid.nih.gov

Research Topics

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.

Studies in mice and humans have linked CD5+ B-1a-like cells to development of autoimmunity and B-cell lineage tumors including chronic lymphocytic leukemia and mantle cell lymphoma. TLR7, IL21 and interferon (IFN) signaling, IL6, and IL10 are risk factors

Above: Studies in mice and humans have linked CD5+ B-1a-like cells to development of autoimmunity and B-cell lineage tumors including chronic lymphocytic leukemia and mantle cell lymphoma. TLR7, IL21 and interferon (IFN) signaling, IL6, and IL10 are risk factors for human SLE and mouse models of the disease. IL21 and IL6 and activation-induced cytidine deaminase (AID) have clearly defined roles in the development of normal post-germinal center B cells and their neoplastic counterparts.

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.

Biography

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.

Selected Publications

  1. Sakai T, Miyazaki T, Shin DM, Kim YS, Qi CF, Fariss R, Munasinghe J, Wang H, Kovalchuk AL, Kothari PH, Fermaintt CS, Atkinson JP, Perrino FW, Yan N, Morse HC 3rd. DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice. J Autoimmun. 2017;81:13-23.

  2. Hayakawa K, Formica AM, Brill-Dashoff J, Shinton SA, Ichikawa D, Zhou Y, Morse HC 3rd, Hardy RR. Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression. J Exp Med. 2016;213(13):3007-3024.

  3. Yoshida Y, Yoshimi R, Yoshii H, Kim D, Dey A, Xiong H, Munasinghe J, Yazawa I, O'Donovan MJ, Maximova OA, Sharma S, Zhu J, Wang H, Morse HC 3rd, Ozato K. The transcription factor IRF8 activates integrin-mediated TGF-β signaling and promotes neuroinflammation. Immunity. 2014;40(2):187-98.

  4. Wang H, Coligan JE, Morse HC 3rd. Emerging Functions of Natural IgM and Its Fc Receptor FCMR in Immune Homeostasis. Front Immunol. 2016;7:99.

  5. Wang H, Yan M, Sun J, Jain S, Yoshimi R, Abolfath SM, Ozato K, Coleman WG Jr, Ng AP, Metcalf D, DiRago L, Nutt SL, Morse HC 3rd. A reporter mouse reveals lineage-specific and heterogeneous expression of IRF8 during lymphoid and myeloid cell differentiation. J Immunol. 2014;193(4):1766-77.


This page was last updated on February 15th, 2017