Mark Jay Shlomchik, M.D., Ph.D.
Campus: Biomedical Science Tower, 203 Lothrop St
Pittsburgh, PA 15261
- M.D., University of Pennsylvania Medical School, 1989
- Ph.D., University of Pennsylvania, 1989
- UPMC Endowed and Distinguished Professor, Department of Immunology
- Chair, Department of Immunology
Overview: Our lab is interested in systemic autoimmune diseases, long-lived B cell immunity, and in immunopathogenesis more broadly.
Autoimmunity research: We are using genetically modified mouse models to address the roles of specific cell types (e.g. B cells, T cells and DCs) in systemic autoimmunity. Currently we are particularly interested in the identity and function of autoreactive T cells that help autoreactive B cells and that infiltrate target tissues using novel TCR cloning methods. A second major area is investigating the regulatory role of TLR9 and stimulatory role of TLR7 in lupus, and to define how TLRs function in tissue-specific fashion. To this end we have made conditional alleles of both TLR7 and TLR9 on a lupus-prone mouse genetic background and we are dissecting the tissue-specific roles of these receptors. We have also introduced key point mutants and chimeric molecules into the germline of this mouse strain to test hypothesis about function in vivo and in signaling assays in vitro. Finally, we continue to work on the role of B cells in lupus and how best to therapeutically target them.
B cell immunity: we are investigating the mechanisms of cellular selection and differentiation in the germinal center (GC), a site of rapid proliferation, mutation, and differentiation into memory B cells (MBC). We recently showed that the GC shifts its output from MBC to plasma cells as it matures with time. We are actively working on “non-canonical” extrafollicular B cell responses, which induce isotype switch and mutation outside of GC as well as generate MBC; a key question is what controls the choice between these two types of response. We have also identified novel subsets of MBC in mice and are studying their origins and function using epigenetic, single cell, and subpopulation gene expression analysis. Our work on MBC has now been extended to humans, where, by studying multiple lymphoid and mucosal tissues, we have identified novel populations of MBC.
Training and mentoring: Dr. Shlomchik is the PI of a T32 on Autoimmunity and Immunopathology. He has trained over 41 students and fellows, most of whom remain in science and several of whom have independent faculty positions. His position as a physician-scientist conducting disease-related basic research has enabled him to provide a combination of scientific and career advice and mentoring that have in turn made his lab an attractive destination for trainees with similar interests and background.
- Zuccarino-Catania GV, Sadanand S, Weisel FJ, Tomayko MT, Meng H, Kleinstein S, Good-Jacobson KL, Shlomchik MJ. Definition of functionally distinct memory B cell subsets based on expression of CD80 and PD-L2 but independent of antibody isotype. Nat Immunol. 2014; 15:631-637. PMCID: PMC4105703.
- Di Niro R, Elsner RA, Vander Heiden JA, Trivedi N, Lee S-J, Bannock JM, Gupta N, Kleinstein SH, Vigneault F, Gilbert TJ, Meffre E, McSorley SJ, Shlomchik MJ. The B cell response to Salmonella: promiscuous B cell recruitment for early antibody production followed by extrafollicular affinity maturation. Immunity. 2015;43:120-131. PMCID: PMC4523395.
- Weisel FW, Chikina M, Shlomchik MJ. A temporal switch in the germinal center determines differential output of memory B and plasma cells. Immunity. 2016;44: 116-130. PMCID: PMC4724390.
- Giles JR, Turqueti-Neves A, Marshak-Rothstein A, Shlomchik MJ. Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation. JCI Insight. 2017;2(4):e90870. doi:10.1172/jci.insight.90870. PMCID: PMC5313065.
- Gordon RA, Herter JM, Rosetti F, Campbell AM, Nishi H, Kashgarian M, Bastacky SI, Marinov A, Nickerson KM, Mayadas TN, Shlomchik MJ. Lupus and Proliferative Nephritis are PAD4 Independent in Murine Models. JCI Insight. 2017;2(10):e92926. doi:10.1172/jci.insight. 92926. PMCID: PMC5436537.
- Luo W, Weisel F, Shlomchik MJ. B Cell receptor and CD40 signaling Are rewired for synergistic induction of the c-Myc transcription factor in germinal center B cells. Immunity. 2018;48:313-326. PMCID: PMC5821563.
- Tilstra JS, Avery L, Menk AV, Gordon RA, Smita S, Kane LP, Chikina M, Delgoffe GM, Shlomchik MJ. Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted. J Clin Inv. 2018;128: 4884-4897.
- Luo W, Hawse WF, Conter LJ, Trivedi N, Weisel F, Wikenheiser DJ, Cattley RT, Shlomchik MJ. The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells. Nature Immunol, 2019;20: 736-46.
- Elsner RA and Shlomchik MJ. IL-12 blocks Tfh cell differentiation during Salmonella infection, thereby contributing to germinal center suppression. Cell Reports, 2019; 29: 2796-2809 e2795.
- Trivedi N, Weisel F, Smita S, Joachim S, Kader M, Radhakrishnan A, Clouser C, Rosenfeld AM, Chikina M, Vigneault F, Hershberg U, Ismail N and Shlomchik MJ. Liver is a generative site for the B cell response to Ehrlichia muris. Immunity, 2019.
- Shlomchik MJ, Luo W, Weisel F. Linking Signaling and Selection in the Germinal Center. Immunological Reviews. DOI: 10.1111/imr.12744, 2019; 288:49-63.