Description of Research Expertise:
Dr. Luning Prak studies the antibody repertoire in health and disease.
Key words: antibody, antibody repertoire, V(D)J recombination, receptor editing, immunoglobulin, autoimmunity, clone tracking, minimal residual disease
Description of Research
Antibodies are proteins produced by B lymphocytes that are important for immune defense, but also serve as ubiquitous biomarkers for immunity and disease. The proliferation of B cells derived from a single precursor cell (i.e., a clone) can reflect a robust immune response, an autoimmune disease process or herald B cell malignancy. Each B cell usually makes only one kind of antibody and each person has about 100 billion different B cells (this collection is called the antibody "repertoire"). My lab studies the B cell repertoire by sequencing the DNA rearrangements that create antibodies. These DNA rearrangements are diverse; hence, when sufficiently similar rearrangements are observed, they are likely to derive from B cells that are clonally related. By studying the clonal landscape of the human B cell repertoire using next-generation sequencing (NGS), we hope to better understand how B cells mature and evolve in different organs in health and disease. We are also harnessing this knowledge to create clinical lab tests that identify and track B cell clones.
1. An anatomic atlas of large B cell clones in the human body. By sequencing antibody heavy chain variable regions in different tissues of organ donors, we can trace how large B cell clones are distributed in the body. So far, we have found two major networks of clones, one in the blood/bone marrow/spleen/lung and another in the gastrointestinal tract. We also observed that the B cells in the GI tract, and especially the jejunum, have more somatic hypermutations. One of the most interesting aspects of this work was the finding that some individuals, but not others, had very large standing B cell clones. We are focusing on defining the antigens drive the formation of these clones by capturing their antibodies and characterizing their antigenic specificity.
2. Ontogeny of human B cell subsets. How human B cell subsets, particularly memory B cells (MBCs), develop and evolve remains poorly understood. We have been studying human B cell subset maturation in the blood and have published several papers describing how B cell subsets shift with time, with age, and during autoreconstitution following chemotherapy or immunosuppression. In this ongoing project, we have been tracking individual clones through different B cell subsets sorted from blood, bone marrow and other human tissues. These studies reveal a surprising degree of clonal sharing between subsets, suggesting that differentiation is not unidirectional or that certain subsets have cells with self-renewal and/or maintenance capacities, or that our definitions of the subsets are flawed.
3. Clone tracking and B cell subset analysis in autiommunity. Our longstanding hypothesis, based upon our work and the work of others, is that patients with certain forms of autoimmunity harbor pathogenic expanded B cell clones. We hope to define pathogenic B cell clones that expand during disease flares and potentially gain insights into their subset of origin and manner of tolerance breakdown, building upon our ongoing work in autoimmunity. In this ongoing project, we are tracking clonal lineages in blood and in some cases tissues from individuals with different autoimmune diseases including systemic lupus erythematosus and type 1 diabetes.
4. Clone tracking in malignancy. We are interested in developing and validating robust next generation sequencing (NGS) based methods to identify and track malignant and non-malignant B cell clones and lymphocyte subsets in patients with hematologic malignancies including multiple myeloma, chronic lymphocytic leukemia, acute lymphoblastic leukemia and other malignant and pre-malignant conditions. In addition to developing minimal residual disease NGS assays, we are studying the non-malignant B and T cell repertoires in cancer patients. Features of the non-malignant immune repertoire, such as its diversity and degree of somatic hypermutation, may inform immune therapies and provide prognostic information.
Lab and core lab personnel:
Wenzhao Meng, PhD
Patricia Tsao, MD, PhD
Ling Zhao, MD, PhD
Yang Zhu Du, MD, PhD
Ping Wei, MD
Zheng Cui, PhD
Zhenyu Huang, MD, PhD
Meng, W., Zhang, B., Schwartz, GW, Rosenfeld, AM, Ren, D., Thome, J JC, Carpenter, DJ, Matsuoka, N., Lerner, H., Friedman, A.L., Granot, T., Farber, D.L., Shlomchik, M.J., Hershberg: An atlas of B cell clonal distribution in the human body Nature Biotechnology 35 (9): 879-884,2017.
Rosenfeld, A., Meng, W., Luning Prak: ImmuneDB: A system for the analysis and exploration of high-throughput adaptive immune receptor sequencing data Bioinformatics 33 (2): 292-293,2017.
Hanley, P., Sutter, J.A., Goodman, N.G., Du, Y., Sekiguchi, D.R., Meng, W., Rickels, M.R., Naji: Circulating B cells in type 1 diabetics exhibit fewer maturation-associated phenotypes Clinical Immunology 183 : 336-343,2017.
Javaheri, A., Wang, A.R., Luning Prak, E.T., Lal, P., Goldberg: Fatal Accelerated Rejection with a Prominent Natural Killer Cell Infiltrate in a Heart Transplant Patient with Peripartum Cardiomyopathy Transplant Immunology : 2017.
Derfalvi, B., Maurer, K., McDonald, D.M., Zackai, E., Meng, W., Luning Prak: B cell development in chromosome 22q11.2 deletion syndrome Clinical Immunology 163 : 1-9,2016.
Zhang, B., Meng, W., Luning Prak: Discrimination of germline V genes at different sequencing lengths and mutational burdens: a new tool for identifying and evaluating the reliability of V gene assignment J. Immunol. Methods 427 : 105-116,2015.
Li, Y.R., Zhao, S., Mohebnasab, M., Li, J., Bradfield, J., Steel, L., Abrams, D., Kobie, J., Mentch, F., Glessner, J., Guo, Y., Wei, Z., Cardinale, C., Bakay, M., Connoly, J., Li, D., Maggadottir, M., Thomas, K.A., Qiu, H., Chiavacci, R., Kim, C., Wang, F., Snyder, J., Flato, B., Forre, O., Denson, L., Thompson, S.D., Becker, M., Guthery, S.L., Latiano, A., Perez, E., Resnick, E., Strisciuglio, C., Staiano, A., Miele, E., Silverberg, M., Lie, B.A., Punaro, M., Russell, R., Wilson, D., Dubinsky, M.C., Monos: Genetic Sharing and Heritability of Pediatric Age of Onset Autoimmune Diseases Nature Communications 6 : 8442,2015.
Kolhatkar, N.S., Brahmandam, A., Thouvenel, C., Becker-Herman, S., Jacobs, H.M., Schwartz, M.A., Khim, S., Panigrahi, A.K., Luning Prak, E.T., Thrasher, A.J., Notarangelo, L.D., Candotti, F., Torgerson, T.R., Sanz: Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich Syndrome Journal of Experimental Medicine 212 (10): 1663-1677,2015.
Li, Y.R., Li, J., Zhao, S.D., Bradfield, J.P., Mentch, F.D., Maggadottir, S.M., Hou, C., Abrams, D.J., Chang, D., Gao, F., Guo, Y., Wei, Z., Connolly, J.J., Cardinale, C.J., Bakay, M., Glessner, J.T., Li, D., Kao, C., Thomas, K.A., Qiu, H., Chiavacci, R.M., Kim, C.E., Wang, F., Snyder, J., Richie, M.D., Flato, B., Forre, O., Denson, L.A., Thompson, S.D., Beckerk, M.L., Guthery, S.L., Latiano, A., Perez, E., Resnick, E., Russell, R.K., Wilson, D.C., Silverberg, M.S., Annese, V., Lie, B.A., Punaro, M.: Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases Nature Medicine 21 (9): 1018-1027,2015.
Walter, J.E., Lo, M., Kis-Toth, K., Tirosh, I., Frugoni, F., Lee, Y.N., Abraham, R.S., Chen, K., Pillai, S., Dunham, J., Tsokos, G., Luning Prak*: Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus Journal of Allergy and Clinical Immunology 135 (1): 272-273,2015.
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