Description of Research Expertise:
Dr. Luning Prak works on the genetics of the antibody repertoire in autoimmunity.
Key words: antibody, V(D)J recombination, receptor editing, immunoglobulin, autoimmunity, antibody repertoire, lupus, diabetes
Description of Research
B cells produce antibodies and are important for innate and adaptive immunity. B cells that are improperly regulated can also cause or contribute to autoimmunity. Our major research interest is in defining B cell tolerance checkpoint defects in mouse models and patients with autoimmune diseases. B cells with a functional antibody can undergo further rearrangement, a process termed receptor editing. Receptor editing is a significant mechanism for central (early) B cell tolerance. Recent work from our lab demonstrates lower levels of editing in approximately 30% of patients with lupus and 30% of patients with type 1 diabetes, as well as in mouse models of these diseases. These findings suggest that a significant proportion of patients with different autoimmune diseases have defects in early B cell tolerance, and may provide insights into which patients will respond best to B cell targeted therapy.
In collaboration with our colleagues in Rheumatology, Transplant Surgery and Endocrinology, we are analyzing B cell subsets in humans with lupus, Sjogren's Syndrome and in non-human primates (NHPs) with drug-induced diabetes. We observe a direct correlation between the length of B cell depletion and improvement in disease (lower disease activity score for SLE, longer period of tolerance to allogeneic pancreatic islet transplants in the non-human primates). Of great interest in these studies are the shifts that occur in the B cell repertoire over time. A repertoire in which immature B cells dominate may be more susceptible to tolerance induction. We are currently testing this idea in patients with type 1 diabetes who are receiving pancreatic islet transplants as part of a multi-center Clinical Islet Transplantation consortium.
We also pursue a number of basic research projects involving mice. These include studying the frequency, timing and pathways of receptor editing rearrangements in immunoglobulin knock-in mice, mapping genetic causes for tolerance checkpoints and analyzing the antibody repertoire following manipulations of the B cell compartment. Rotation and thesis projects are available in basic as well as human translational immunology pertaining to B cell autoimmunity.
Please come visit the lab to discuss rotation projects in any of the areas discussed above. Projects will be tailored to the background and interests of the student.
Sara Smith, graduate student
Debora Sekiguchi, MD, PhD, research fellow
Wenzhao Meng, PhD, postdoctoral fellow
Yang Zhu Du, Ph.D., research specialist
Noah Goodman, research specialist
Emily Xue, Penn undergraduate
Yang Liu, Carnegie Mellon undergraduate
Derfalvi, B., Maurer, K., McDonald, D.M., Zackai, E., Meng, W., Luning Prak, E.T. and K.E. Sullivan.: B cell development in chromosome 22q11.2 deletion syndrome Clinical Immunology 163 : 1-9,2016.
Zhang, B., Meng, W., Luning Prak, E.T. and U. Hershberg: 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, I.A. and D. J. Rawlings: 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., Dubins: 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*, E.T. and L.D. Notarengelo
*co-corresponding author: 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.
Hui, JZ, Zaki, AA, Cheng, Z, Popik, V., Zhang, H., Luning Prak, ET and A Tsourkas: A facile method for the site-specific, covalent attachment of full-length IgG onto nanoparticles Small in press : 2014.
V. Gigi, S. Lewis, O. Shestova, M. Mijuskovic, L. Deriano, W. Meng, E. T. Luning Prak and D. B. Roth: RAG2 mutants alter DSB repair pathway choice in vivo and illuminate the nature of "alternative NHEJ" Nucleic Acids Research : 2014.
Hershberg, U., Meng, W., Zhang, B., Haff, N., St. Clair, EW, Cohen, PL, McNair, PD, Li, L, Levesque, MC and ET Luning Prak: Persistence and selection of an expanded B cell clone in the setting of rituximab therapy for Sjögren’s syndrome Arthritis Research and Therapy 16 (1): R51 (Epub ahead of print),2014.
Radic, M., Weigert, M., Khan, S.N., Han, J., Kalinina, O. and E.T. Luning Prak: Antibodies that bind complex glycosaminoglycans accumulate in the golgi Proc Natl Acad Sci USA 110 (29): 11958-63,2013.
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