Full Time Faculty: A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Joint Faculty
Emeritus Faculty
Voluntary Faculty
Faculty Publications
Information for Faculty

Mark Shlomchik, MD, PhD

Professor of Laboratory Medicine and Immunobiology
Associate Director, Blood Bank
TAC S541
mark.shlomchik@yale.edu

BA, 1981 Harvard College
MD: 1989, University of Pennsylvania
Ph.D: 1989, University of Pennsylvania
Fellowship: Fox Chase Cancer Center and Hospital of University of Pennsylvania

Community of Science Biosketch

Research Interests
The long-term interests of our lab include the regulation of autoreactive B lymphocytes and the development of high affinity B cell immune responses and memory cells. More recently, we have also developed an interest in the mechanisms by which T cells are activated in Graft vs. Host Disease (GVHD) and the subsets of T cells that are pathogenic. We have emphasized in vivo models in all the work.

To study the regulation of autoreactive B cells in normal mice and the loss of regulation in autoimmune-prone animals, we have used transgenic (Tg) mouse models to ask how B cells which express a disease-related autoantibody, Rheumatoid Factor (RF), are prevented from causing harm in normal mice. We first demonstrated that these cells develop, mature and are immunocompetent in non-autoimmune mice (Hannum et al., 1996). Recent results demonstrate that these Tg RF B cells are spontaneously activated in autoimmune-prone mice, but only when the autoantigen is present (Wang and Shlomchik, 1999). We have recently used this system to develop a method to visualize the initiating events of B cell autoimmunity (William et al., 2005a; William et al., 2005b), an elusive goal. We expect this to be a powerful new model system for understanding of the origins of autoimmunity. For example, we have recently found that the early and perhaps chronic events in the MRL.Faslpr lupus model are not taking place in the germinal center (GC) as originally thought, but instead involve continuous proliferation at the outer edge of the T cell zone, where T and B cells normally interact only transiently (William et al., 2002). Quite surprisingly, we have shown that very active somatic hypermutation of Ig V regions is taking place at this site, thus dissociating mutation from the GC environment for the first time and also raising the possibility that mutation outside of GCs can lead to loss of self-tolerance (William et al., 2002). Interestingly, we found that autoreactive B cells on a normal BALB/c background still entered GCs and began to mutate there, but never made autoantibodies, thus suggesting a new self-tolerance checkpoint. We are actively investigating how autoreactive B cells become activated at extrafollicular sites, using a new method that we discovered to induce it (rather than wait for it to happen spontaneously) as well as a cell transfer system. These techniques greatly improve our ability to dissect the mechanisms. We are currently investigating the roles of TLRs, DCs, T cells, BAFF/APRIL family members and other costimulatory molecules using a combination of knockout mice and inhibitors. We also recently developed a BCR knockin version of the AM14 mouse, which undergoes isotype switch. This facilitates our identification of activated cells, the study of switch regulation, and also the development of memory.

An emerging interest in this area is the role of Toll-like receptors in activating autoreactive B cells (Leadbetter et al., 2002, Vigliante et al., 2003, Christensen, et al., submitted, 2005). These studies, partly in collaboration with Dr. Marshak-Rothstein at Boston University, have provided significant new insights into how self-Ags stimulate the immune system in autoimmunity by stimulating TLRs. In two recent studies, we have shown how this explains the generation of the two major types of lupus-related autoantibodies, anti-DNA and anti-RNA. Using knockout mice, we showed that the former is controlled by TLR9 and the latter by TLR7. Surprisingly though, we found that while deletion of TLR7 ameliorated disease, deletion of TLR9 exacerbated it; thus, only TLR7 appears to be a good therapeutic target (Christensen et al., 2005; Christensen et al., 2006). We are currently investigating the mechanism by which TLR9 normally regulates disease, as well as the cell types that need to express both TLRs to promote disease.

An important related focus has been on how activated autoreactive B cells contribute to pathogenesis in systemic autoimmunity. Traditionally B cells have been thought of mainly as sources of pathogenic autoantibody. We challenged this view with the notion that a main function of B cells is to activate autoreactive, pathogenic T cells, in an antigen-specific way. First, we deleted B cells from autoreactive mice and showed that T cell activation and disease was ablated (Chan and Shlomchik, 1998; Shlomchik et al., 1994). Second, we created a novel mouse model which had B cells expressing only the membrane form of IgM and that could not secrete Ab (Chan et al., 1999). In the autoimmune-prone mouse, such B cells promoted both T cell activation and disease. We have recently developed a Tg mouse that expresses human CD20 on all B cells and can be used to deplete B cells with anti-CD20 at any time. Using this model, we recently found that depletion of B cells in adult autoimmune-prone mice can indeed ameliorate disease, but at the same time we discovered that depleting B cells in the midst of autoimmunity is markedly more difficult than in normal strains, thus revealing an unexpected therapeutic barrier (Ahuja, et al, submitted). We are now working on why this is the case.

The second major interest in B cell biology is the development of high affinity B cell immune responses and memory. We are using a Tg mouse model which has B cells that cannot secrete antibody to explore whether antigen retained as immune complexes on follicular dendritic cells (FDCs) is necessary for the development and maintenance of memory B cells. B cells in these mice make normal primary and secondary immune responses including germinal centers and somatic mutation (Hannum et al., 2000). We have also recently found that normal memory B cells form in these animals survive without further cell division for months after their initial development (Anderson et al., 2006b). Thus, immune complexes on FDCs are not necessary for these processes. We are now investigating the identity and functional capacity of the memory cells formed and have used microarray expression profiling to identify a host of genes differentially expressed between naïve and memory B cells. Many of these have been confirmed at the protein level, providing new insights into the functions of memory B cells. We are currently using knockout mice to test the roles of some of these molecules in memory development and function in vivo We also have a program to study the dynamics of germinal center B cells using both experimental and computer modeling approaches, as well as in vivo multiphoton microscopy, a program led by Associate Research Scientist Dr. Ann Haberman (Hauser, et al., submitted).

Over the past several years we have developed an interest in the immunopathology surrounding stem cell transplantation We have focused on chronic GVHD (cGVHD), applying modern genetics and molecular techniques to a murine model. We have already shown (surprisingly) that host-derived antigen-presenting cells are not required to induce cGVHD. Further, we have found that host-derived CD4+/CD25+ T cells play an important role in regulating cGVHD (Anderson et al., 2005; Anderson et al., 2004). Most recently, in collaboration with Dr. Warren Shlomchik, we found that donor memory T cells do not cause GVHD, although they engraft and function (Anderson et al., 2003). This could represent a major therapeutic approach to minimize GVHD while preserving GVL and immunocompetence in recipients. We are currently investigating the reasons why memory T cells do not cause GVHD.

  
click to view larger images

Publications and Citations
(Chan and Shlomchik 2000; Debelak, Shlomchik et al. 2000; Hannum, Haberman et al. 2000; Kima, Constant et al. 2000; Levine, Haberman et al. 2000; Macy, Weir et al. 2000; Rifkin, Leadbetter et al. 2000; Chan, Paliwal et al. 2001; Liu, Anderson et al. 2001; Matthews, Weiss et al. 2001; Matthews, Weiss et al. 2001; Shlomchik, Craft et al. 2001; Shlomchik, Radebold et al. 2001; Whitmire, Asano et al. 2001; Dal Porto, Haberman et al. 2002; Leadbetter, Rifkin et al. 2002; Ramakrishna, Stohlman et al. 2002; Shlomchik, Cormier et al. 2002; William, Euler et al. 2002; William, Euler et al. 2002; Anderson, McNiff et al. 2003; Haberman and Shlomchik 2003; Kleinstein, Louzoun et al. 2003; Rossbacher and Shlomchik 2003; Shlomchik, Euler et al. 2003; Shlomchik and Madaio 2003; Viglianti, Lau et al. 2003; Anderson, McNiff et al. 2004; Kaplan, Anderson et al. 2004)

Rossbacher, J., Haberman, A. M., Neschen, S., Khalil, A., and Shlomchik, M. J. (2006). Antibody-independent B cell intrinsic and extrinsic roles for CD21/35. Eur J Immunol 36:  2384-2393

William, J., Euler, C., Primarolo, N., and Shlomchik, M. J. (2006). B cell tolerance checkpoints that restrict pathways of antigen-driven differentiation. J Immunol 176, 2142-2151.

 Anderson, S. E., Tomayko, M. M., and Shlomchik, M. J. (2006a). Intrinsic Properties of Human and Murine Memory B Cells. Immunological Rev 211, 280-294.

Anderson, S. M., Hannum, L. G., and Shlomchik, M. J. (2006b). Memory B cell survival and function in the absence of secreted antibody and immune complexes on follicular dendritic cells. J Immunol 176, 4515-4519.

Christensen, S. R., Shupe, J., Nickerson, K., Kashgarian, M., Flavell, R. A., and Shlomchik, M. J. (2006). Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417-428.

Anderson, B. E., McNiff, J. M., Jain, D., Blazar, B. R., Shlomchik, W. D., and Shlomchik, M. J. (2005). Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ. Blood 105, 2227-2234.

Kaplan, D. H., Jenison, M. C., Saeland, S., Shlomchik, W. D., and Shlomchik, M. J. (2005). Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity 23, 611-620.

Anderson, B. E., J. M. McNiff, et al. (2004). "Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease." Blood 104(5): 1565-73.

Kaplan, D., B. E. Anderson, et al. (2004). "Target antigens determine GVHD phenotype." J. Immunol. in press.

Anderson, B. E., J. McNiff, et al. (2003). "Memory CD4+ T cells do not induce graft-versus-host disease." J Clin Invest 112(1): 101-8.

Viglianti, G. A., C. M. Lau, et al. (2003). "Activation of autoreactive B cells by CpG dsDNA." Immunity 19(6): 837-47.

Haberman, A. M. and M. J. Shlomchik (2003). "Reassessing the function of immune-complex retention by follicular dendritic cells." Nat Rev Immunol 3(9): 757-64.

Kleinstein, S. H., Y. Louzoun, et al. (2003). "Estimating hypermutation rates from clonal tree data." J Immunol 171(9): 4639-49.

Rossbacher, J. and M. J. Shlomchik (2003). "The B cell receptor itself can activate complement to provide the complement receptor 1/2 ligand required to enhance B cell immune responses in vivo." J Exp Med 198(4): 591-602.

Shlomchik, M. J., C. W. Euler, et al. (2003). "Activation of rheumatoid factor (RF) B cells and somatic hypermutation outside of germinal centers in autoimmune-prone MRL/lpr mice." Ann N Y Acad Sci 987: 38-50.

Shlomchik, M. J. and M. P. Madaio (2003). "The role of antibodies and B cells in the pathogenesis of lupus nephritis." Springer Semin Immunopathol 24(4): 363-75.

Dal Porto, J. M., A. M. Haberman, et al. (2002). "Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced." J Exp Med 195(9): 1215-21.

Leadbetter, E. A., I. R. Rifkin, et al. (2002). "Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors." Nature 416(6881): 603-7.

Ramakrishna, C., S. A. Stohlman, et al. (2002). "Mechanisms of central nervous system viral persistence: the critical role of antibody and B cells." J Immunol 168(3): 1204-11.

Shlomchik, W. D., J. Cormier, et al. (2002). "Costimulation, Activation and Maturation of Host APCs during GVHD." Blood 100(11): 820.

William, J., C. Euler, et al. (2002). "Visualizing the early events and evolution of B cell autoimmunity." Manuscript in preparation.

William, J., C. Euler, et al. (2002). "Evolution of autoantibody responses via somatic hypermutation outside of germinal centers." Science 297: 2066-70.

Chan, O. T., V. Paliwal, et al. (2001). "Deficiency in beta(2)-microglobulin, but not CD1, accelerates spontaneous lupus skin disease while inhibiting nephritis in MRL-Fas(lpr) nice: an example of disease regulation at the organ level." J Immunol 167(5): 2985-90.

Matthews, A. E., S. R. Weiss, et al. (2001). "The role of B cells in mouse hepatitis virus infection and pathology." Adv Exp Med Biol 494: 363-8.

Matthews, A. E., S. R. Weiss, et al. (2001). "Antibody is required for clearance of infectious murine hepatitis virus A59 from the central nervous system, but not the liver." J Immunol 167(9): 5254-63.

Shlomchik, M. J., J. Craft, et al. (2001). "From T to B and back again: positive feedback in systemic autoimmune disease." Nature Reviews Immunology 1(1): 147-153.

Shlomchik, M. J., K. Radebold, et al. (2001). "Neuroinvasion by a Creutzfeldt-Jakob disease agent in the absence of B cells and follicular dendritic cells." Proc Natl Acad Sci U S A 98(16): 9289-94.

Whitmire, J. K., M. S. Asano, et al. (2001). "Requirement of B cells for CD4 T cell memory." Manuscript in preparation.

Liu, J., B. E. Anderson, et al. (2001). "Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease." Blood 98(12): 3367-75.

Chan, O. T. M. and M. J. Shlomchik (2000). "Cutting Edge: B Cells promote CD8 T cell activation in MRL-Fas lpr mice independently of MHC Class I antigen presentation." J. Immunol. 164: 1658-62.

Hannum, L. G., A. M. Haberman, et al. (2000). "Germinal center initiation, variable gene region hypermutation, and mutant B cell selection without detectable immune complexes on follicular dendritic cells." J Exp Med 192(7): 931-42.

Debelak, J., M. J. Shlomchik, et al. (2000). "Isolation and flow cytometric analysis of T-cell-depleted CD34+ PBPCs." Transfusion 40(12): 1475-81.

Kima, P. E., S. L. Constant, et al. (2000). "Internalization of Leishmania mexicana complex amastigotes via the Fc receptor is required to sustain infection in murine cutaneous leishmaniasis." J Exp Med 191(6): 1063-8.

Levine, M. H., A. M. Haberman, et al. (2000). "A B-cell receptor-specific selection step governs immature to mature B cell differentiation." Proc Natl Acad Sci U S A 97(6): 2743-8.

Macy, J. D., Jr., E. C. Weir, et al. (2000). "Dual infection with Pneumocystis carinii and Pasteurella pneumotropica in B cell-deficient mice: diagnosis and therapy." Comp Med 50(1): 49-55.

Rifkin, I. R., E. A. Leadbetter, et al. (2000). "Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells [In Process Citation]." J Immunol 165(3): 1626-33.

Shlomchik, W. D., M. S. Couzens, et al. (1999). "Prevention of graft versus host disease by inactivation of host antigen- presenting cells." Science 285(5426): 412-5.

Chan, O. T., L. G. Hannum, et al. (1999). "A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus." J Exp Med 189(10): 1639-1648.

Wang, H. and M. J. Shlomchik (1999). "Autoantigen-specific B cell activation in Fas-deficient rheumatoid factor immunoglobulin transgenic mice." J Exp Med 190(5): 639-49.

Chan, O. and M. J. Shlomchik (1998). "A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice." J. Immunol. 160: 51-59.

Hannum, L. G., D. Ni, et al. (1996). "A disease-related RF autoantibody is not tolerized in a normal mouse: implications for the origins of autoantibodies in autoimmune disease." J. Exp. Med. 184: 1269-78.

Shlomchik, M. J., M. P. Madaio, et al. (1994). "The role of B cells in lpr/lpr-induced autoimmunity." J. Exp. Med. 180: 1295-1306.