Bio

Bio


Mrinmoy Sanyal obtained his undergraduate and master's degree in Human Physiology at the University of Calcutta. He did his Ph.D. in Biochemistry at All India Institute of Medical Sciences, New Delhi, working on reproductive immunology, with the focus on trophoblast invasion and differentiation and their role in human blastocyst implantation. Then, he moved to Stanford University for a postdoctoral fellowship on the role of transcription factor Pbx1, a leukemia proto-oncogene, on B cell development. Currently, he is Research Scientist at Department of Biochemistry, Stanford University. His work covers various topics, including B cell responses to viral infection and vaccination, human primary immunodeficiency, and biology of lymphocyte development and function and to elucidate etiology of immunological disorders.

Education & Certifications


  • Postdoctoral Fellowship, Stanford University, Immunology
  • PhD, All India Institute of Medical Sciences, Biochemistry

Professional

Professional Interests


Immune response to natural infection and viral vaccine

Reverse Vaccinology

Human immunodeficiency

Publications

All Publications


  • Diminished B-cell response after repeat influenza vaccination. The Journal of infectious diseases Sanyal, M., Holmes, T. H., Maecker, H., Albrecht, R. A., Dekker, C. L., He, X., Greenberg, H. B. 2018

    Abstract

    Annual vaccination with influenza vaccines is recommended for protection against influenza in the United States. Past clinical studies and meta-analysis, however, have reported conflicting results on the benefits of annual vaccination. B-cell responses elicited following repeat influenza vaccinations over multiple seasons have not been examined in detail. We analyzed the B-cell and antibody responses in volunteers vaccinated yearly with seasonal trivalent inactivated influenza vaccines (TIV) from 2010 or 2011 to 2014. Statistical analyses were designed to help correct for possible bias due to reduced sample size in the later years of the study. We show that after the second annual vaccination the frequency of vaccine-specific plasmablasts and the binding reactivity of plasmablast-derived polyclonal antibodies (PPAb) are reduced and do not increase in subsequent years. Similar trends are observed with the serum hemagglutination inhibition antibody response after each annual vaccination, as well as the binding reactivity of PPAb for the hemagglutinin of influenza A vaccine components, even with changes in the seasonal vaccine components during the study. Our findings indicate a diminished B-cell response to annually repeated TIV vaccination. These results emphasize the need of developing improved strategies to enhance the immunogenicity and efficacy of annual influenza vaccination.

    View details for PubMedID 30496437

  • A Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension. Circulation research Tamosiuniene, R., Manouvakhova, O., Mesange, P., Saito, T., Qian, J., Sanyal, M., Lin, Y. C., Nguyen, L. P., Luria, A., Tu, A. B., Sante, J. M., Rabinovitch, M., Fitzgerald, D. J., Graham, B. B., Habtezion, A., Voelkel, N. F., Aurelian, L., Nicolls, M. R. 2018

    Abstract

    Rationale: Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. Objective: To evaluate whether and how Treg-deficiency differentially affects male and female rats in experimental PH. Methods and Results: Male and female athymicrnu/rnurats, lacking Tregs, were treated with the vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution (IR) before SU5416 administration. Plasma prostacyclin (PGI2) levels were measured. Lung and right ventricles (RVs) were assessed for the expression of the vasoprotective proteins cyclooxygenase-2 (COX-2), prostacyclin synthase (PTGIS), programmed death ligand-1 (PDL-1), and heme oxygenase-1 (HO-1). Inhibitors of these pathways were administered to athymic rats undergoing Treg IR. Finally, human cardiac microvascular endothelial cells co-cultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and estrogen receptor (ER) expression, and culture supernatants were assayed for PGI2 and IL-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented RV fibrosis, lower plasma PGI2 levels, decreased lung COX-2, PTGIS, HO-1 and PDL-1 expression and reduced RV PDL-1 levels. In both sexes, Treg IR protected against PH development and raised levels of plasma PGI2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and programmed death-1 (PD1)/PDL1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL1, HO-1, ERs and increased supernatant levels of PGI2 and IL-10. Conclusions: In two animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.

    View details for PubMedID 29545367

  • VP4-and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans SCIENCE TRANSLATIONAL MEDICINE Nair, N., Feng, N., Blum, L. K., Sanyal, M., Ding, S., Jiang, B., Sen, A., Morton, J. M., He, X., Robinson, W. H., Greenberg, H. B. 2017; 9 (395)

    Abstract

    Human rotaviruses (RVs) are the leading cause of severe diarrhea in young children worldwide. The molecular mechanisms underlying the rapid induction of heterotypic protective immunity to RV, which provides the basis for the efficacy of licensed monovalent RV vaccines, have remained unknown for more than 30 years. We used RV-specific single cell-sorted intestinal B cells from human adults, barcode-based deep sequencing of antibody repertoires, monoclonal antibody expression, and serologic and functional characterization to demonstrate that infection-induced heterotypic immunoglobulins (Igs) primarily directed to VP5*, the stalk region of the RV attachment protein, VP4, are able to mediate heterotypic protective immunity. Heterotypic protective Igs against VP7, the capsid glycoprotein, and VP8*, the cell-binding region of VP4, are also generated after infection; however, our data suggest that homotypic anti-VP7 and non-neutralizing VP8* responses occur more commonly in people. These results indicate that humans can circumvent the extensive serotypic diversity of circulating RV strains by generating frequent heterotypic neutralizing antibody responses to VP7, VP8*, and most often, to VP5* after natural infection. These findings further suggest that recombinant VP5* may represent a useful target for the development of an improved, third-generation, broadly effective RV vaccine and warrants more direct examination.

    View details for PubMedID 28637924

  • Selective expansion of human regulatory T cells in nasal polyps, and not adjacent tissue microenvironments, in individual patients exposed to steroids. Clinical immunology Edward, J. A., Sanyal, M., Le, W., Soudry, E., Ramakrishnan, V. R., Bravo, D. T., Nguyen, A. L., Zarabanda, D., Kingdom, T. T., Hwang, P. H., Garrison Fathman, C., Nayak, J. V. 2017; 179: 66-76

    Abstract

    Severe forms of chronic rhinosinusitis (CRS), a common upper airway inflammatory disorder, are associated with nasal polyps (NPs). NP disease is ameliorated by glucocorticoid (GC) treatment, whose cellular effects are poorly understood. We therefore assessed the influence of GC therapy on NPs in CRS patients, focusing on regulatory T (Treg) cells. Treg cell populations were analyzed by flow cytometry in NPs and control tissues from GC-treated CRS patients and controls. After GC exposure, selective expansion of Treg cells was seen within NPs, and not blood or adjacent ethmoid tissues. To confirm direct GC effects, NPs from the same patients were biopsied prior to, and following, 1week of oral GC exposure. Direct expansion of Tregs into the same NP bed was detected in 4/4 CRS patients following GC exposure. Treg cell spikes into NPs were secondary to cellular recruitment given limited Ki67 expression within these regulatory cells. Chemokine gene expression profiling identified several chemokines, notably CCL4, induced within NPs upon GC treatment. Neutralization of chemokine receptor/ligand interactions using CCR4 small molecule antagonists reduced Treg migration towards GC-treated NPs in an ex vivo migration assay. Our findings suggest that the common use of GCs in the treatment of NP disease leads to recruitment of Treg cells from peripheral sites into NP tissues, which may be critical to the anti-inflammatory effect of GCs. Mechanistically Treg expansion appears to be conferred, in part, by chemokine receptor/ligand interactions induced following corticosteroid therapy.

    View details for DOI 10.1016/j.clim.2017.02.002

    View details for PubMedID 28279811

  • Lack of IL7Ra expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD). Clinical immunology Sanyal, M., Morimoto, M., Baradaran-Heravi, A., Choi, K., Kambham, N., Jensen, K., Dutt, S., Dionis-Petersen, K. Y., Liu, L. X., Felix, K., Mayfield, C., Dekel, B., Bokenkamp, A., Fryssira, H., Guillen-Navarro, E., Lama, G., Brugnara, M., Lücke, T., Olney, A. H., Hunley, T. E., Polat, A. I., Yis, U., Bogdanovic, R., Mitrovic, K., Berry, S., Najera, L., Najafian, B., Gentile, M., Nur Semerci, C., Tsimaratos, M., Lewis, D. B., Boerkoel, C. F. 2015; 161 (2): 355-365

    Abstract

    Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7R?) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7R? expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.

    View details for DOI 10.1016/j.clim.2015.10.005

    View details for PubMedID 26499378

  • Distinct patterns of B-cell activation and priming by natural influenza virus infection versus inactivated influenza vaccination. journal of infectious diseases He, X., Holmes, T. H., Sanyal, M., Albrecht, R. A., García-Sastre, A., Dekker, C. L., Davis, M. M., Greenberg, H. B. 2015; 211 (7): 1051-1059

    Abstract

    The human B-cell response to natural influenza virus infection has not been extensively investigated at the polyclonal level.The overall B-cell response of patients acutely infected with the 2009 pandemic influenza A(H1N1)pdm09 virus (A[H1N1]pdm09) was analyzed by determining the reactivity of plasmablast-derived polyclonal antibodies (PPAbs) to influenza proteins. Recipients of inactivated influenza vaccine containing the same A(H1N1)pdm09 strain were studied for comparison.During acute infection, robust plasmablast responses to the infecting virus were detected, characterized by a greater PPAb reactivity to the conserved influenza virus nuclear protein and to heterovariant and heterosubtypic hemagglutinins, in comparison to responses to the inactivated A(H1N1)pdm09 vaccine. In A(H1N1)pdm09 vaccinees, the presence of baseline serum neutralizing antibodies against A(H1N1)pdm09, suggesting previous exposure to natural A(H1N1)pdm09 infection, did not affect the plasmablast response to vaccination, whereas repeated immunization with inactivated A(H1N1)pdm09 vaccine resulted in significantly reduced vaccine-specific and cross-reactive PPAb responses.Natural A(H1N1)pdm09 infection and inactivated A(H1N1)pdm09 vaccination result in very distinct patterns of B-cell activation and priming. These differences are likely to be associated with differences in protective immunity, especially cross-protection against heterovariant and heterosubtypic influenza virus strains.

    View details for DOI 10.1093/infdis/jiu580

    View details for PubMedID 25336731

    View details for PubMedCentralID PMC4366605

  • Peripheral blood-derived mesenchymal stem cells: candidate cells responsible for healing critical-sized calvarial bone defects. Stem cells translational medicine Li, S., Huang, K., Wu, J., Hu, M. S., Sanyal, M., Hu, M., Longaker, M. T., Lorenz, H. P. 2015; 4 (4): 359-368

    Abstract

    Postnatal tissue-specific stem/progenitor cells hold great promise to enhance repair of damaged tissues. Many of these cells are retrieved from bone marrow or adipose tissue via invasive procedures. Peripheral blood is an ideal alternative source for the stem/progenitor cells because of its ease of retrieval. We present a coculture system that routinely produces a group of cells from adult peripheral blood. Treatment with these cells enhanced healing of critical-size bone defects in the mouse calvarium, a proof of principle that peripheral blood-derived cells can be used to heal bone defects. From these cells, we isolated a subset of CD45(-) cells with a fibroblastic morphology. The CD45(-) cells were responsible for most of the differentiation-induced calcification activity and were most likely responsible for the enhanced healing process. These CD45(-) fibroblastic cells are plastic-adherent and exhibit a surface marker profile negative for CD34, CD19, CD11b, lineage, and c-kit and positive for stem cell antigen 1, CD73, CD44, CD90.1, CD29, CD105, CD106, and CD140?. Furthermore, these cells exhibited osteogenesis, chondrogenesis, and adipogenesis capabilities. The CD45(-) fibroblastic cells are the first peripheral blood-derived cells that fulfill the criteria of mesenchymal stem cells as defined by the International Society for Cellular Therapy. We have named these cells "blood-derived mesenchymal stem cells."

    View details for DOI 10.5966/sctm.2014-0150

    View details for PubMedID 25742693

    View details for PubMedCentralID PMC4367504

  • Systemic prednisone administration selectively alters granulocyte subsets in nasal polyps from aspirin-exacerbated respiratory disease and chronic rhinosinusitis patients. International forum of allergy & rhinology Edward, J. A., Sanyal, M., Ramakrishnan, V. R., Le, W., Nguyen, A. L., Kingdom, T. T., Hwang, P. H., Nayak, J. V. 2013; 3 (11): 866-876

    Abstract

    Nasal polyps (NPs) are hallmark inflammatory lesions of sinusitis. Despite the spectrum of NP conditions, cellular differences between NPs from patients with chronic rhinosinusitis with NPs (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) are poorly understood. NPs are associated with abundant eosinophils; the contributions of neutrophil and basophil granulocytes are less defined. We therefore sought to assess granulocyte subpopulations, and differential effects following prednisone pretreatment, within NPs of CRSwNP and AERD patients.NPs, adjacent ethmoid sinus tissue, and peripheral blood mononuclear cells (PBMCs) were obtained from patients undergoing endoscopic sinus surgery. Samples from 5 cohorts: CRSwNP ± prednisone (n = 6 each), AERD ± prednisone (n = 6 each), and controls (n = 9), were analyzed by high-dimensional flow cytometry to gate granulocyte populations. Specimens were also assessed using immunohistochemistry (IHC) staining.Systemic prednisone administration was associated with a lower frequency of eosinophils (p < 0.0001, n = 6) in NPs in both CRSwNP and AERD patients, whereas a decrease in neutrophils (p = 0.0070, n = 6) in NPs was only observed in CRSwNP patients after prednisone treatment. In contrast, steroids do not alter basophil proportions (p = 0.48, n = 6) within NPs from either group. No significant shift in granulocyte subsets after steroid treatment was identified in the adjacent ethmoid mucosa or PBMCs from the same patients. Immunohistochemistry (IHC) staining supported these findings.Granulocyte subpopulations are focally affected within NPs by systemic steroid exposure, without notable granulocyte alterations in the surrounding regional tissues. These data provide direct insights into the cellular effects of routine prednisone exposure in CRS patients, and highlight a unique microenvironment present within NP lesions.

    View details for DOI 10.1002/alr.21221

    View details for PubMedID 24106221

  • Characterization of human upper airway epithelial progenitors. International forum of allergy & rhinology Bravo, D. T., Soudry, E., Edward, J. A., Le, W., Nguyen, A. L., Hwang, P. H., Sanyal, M., Nayak, J. V. 2013; 3 (10): 841-847

    Abstract

    New epithelial cells are generated through the proliferation and differentiation of resident progenitor cells in the nasal cavity. In several upper airway diseases, such as cystic fibrosis and chronic rhinosinusitis, self-renewing progenitor cells may be functionally defective, or compromised in their ability, to regenerate cells that maintain normal mucociliary clearance. Herein, we describe our early work to define and characterize a rare population of human nasal epithelial putative progenitors.Single-cell suspensions of human ethmoid sinus tissues were prepared following endoscopic sinus surgery. Cell surface antibodies were analyzed as candidate markers for detecting progenitor cells. A panel of antibodies, including epithelial cell adhesion molecule (EpCAM, epithelial cells), CD45 (hematopoietic cells), nerve growth factor receptor (NGFR/CD271), intercellular adhesion molecule-1 (ICAM1/CD54), and integrin-?6 (ITGA6/CD49f) were used to resolve epithelial progenitor candidates by high-dimensional flow cytometry and the gating technique of fluorescence minus one (FMO) controls.A rare population of approximately 0.06% of total ethmoid cells was discriminated as EpCAM(-) CD45(-) NGFR(+) ICAM1(+) by surface markers. Use of ITGA6 was excluded based on FMO control analysis. This lineage-negative population was purified to 99% homogeneity by cell sorting and analyzed by immunofluorescence microscopy. Sorted cells were subsequently confirmed to uniformly express the transcription factor p63. Upon in vitro culture, lineage-negative clonal cells were confirmed to spontaneously differentiate into epithelial lineage-positive cells.Using the NGFR and ICAM1 cellular coordinates, we have identified a promising population of native human nasal epithelial progenitor cells that require more formal investigation for their role in upper airway regeneration.

    View details for DOI 10.1002/alr.21205

    View details for PubMedID 23901007

  • Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression HUMAN MOLECULAR GENETICS Baradaran-Heravi, A., Cho, K. S., Tolhuis, B., Sanyal, M., Morozova, O., Morimoto, M., Elizondo, L. I., Bridgewater, D., Lubieniecka, J., Beirnes, K., Myung, C., Leung, D., Fam, H. K., Choi, K., Huang, Y., Dionis, K. Y., Zonana, J., Keller, K., Stenzel, P., Mayfield, C., Luecke, T., Bokenkamp, A., Marra, M. A., van Lohuizen, M., Lewis, D. B., Shaw, C., Boerkoel, C. F. 2012; 21 (11): 2572-2586

    Abstract

    Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficiency of the SMARCAL1 orthologs alone is insufficient to cause disease in fruit flies and mice, although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD.

    View details for DOI 10.1093/hmg/dds083

    View details for Web of Science ID 000304053100017

    View details for PubMedID 22378147

    View details for PubMedCentralID PMC3349428

  • PBX1: A Novel Stage-Specific Regulator of Adipocyte Development STEM CELLS Monteiro, M. C., Sanyal, M., Cleary, M. L., Sengenes, C., Bouloume, A., Dani, C., Billon, N. 2011; 29 (11): 1837-1848

    Abstract

    Although adipocyte terminal differentiation has been extensively studied, the early steps of adipocyte development and the embryonic origin of this lineage remain largely unknown. Here we describe a novel role for the pre-B-cell leukemia transcription factor one (PBX1) in adipocyte development using both mouse embryonic stem cells (mESCs) and human multipotent adipose-derived stem (hMADS) cells. We show that Pbx1(-/-) mESCs are unable to generate adipocytes, despite normal expression of neuroectoderm and neural crest (NC) markers. Early adipocyte lineage markers are not induced in Pbx1(-/-) mESCs, suggesting that Pbx1 controls the generation and/or the maintenance of adipocyte progenitors (APs) from the NC. We further characterize the function of PBX1 in postnatal adipogenesis and show that silencing of PBX1 expression in hMADS cells reduces their proliferation by preventing their entry in the S phase of the cell cycle. Furthermore, it promotes differentiation of hMADS cells into adipocytes and partially substitutes for glucocorticoids and rosiglitazone, two key proadipogenic agents. These effects involve direct modulation of PPAR? activity, most likely through regulation of the biosynthesis of PPAR? natural endogenous ligand(s). Together, our data suggest that PBX1 regulates adipocyte development at multiple levels, promoting the generation of NC-derived APs during embryogenesis, while favoring APs proliferation and preventing their commitment to the adipocyte lineage in postnatal life.

    View details for DOI 10.1002/stem.737

    View details for Web of Science ID 000296565500020

    View details for PubMedID 21922607

  • CD8(+)CD44(hi) but not CD4(+)CD44(hi) memory T cells mediate potent graft antilymphoma activity without GVHD BLOOD Dutt, S., Baker, J., Kohrt, H. E., Kambham, N., Sanyal, M., Negrin, R. S., Strober, S. 2011; 117 (11): 3230-3239

    Abstract

    Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL(1)) without GVHD after recipients were given T cell-depleted bone marrow transplantations from major histocompatibility complex-mismatched donors. Lethal GVHD was observed when total T cells, naive CD4(+) T cells, or naive CD8(+) T cells were used. Memory CD4(+)CD44(hi) and CD8(+)CD44(hi) T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8(+) T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8(+) memory T cells after transplantation was able to eradicate the BCL(1) lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8(+) T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4(+) T cells, or memory total T cells.

    View details for DOI 10.1182/blood-2010-10-312751

    View details for PubMedID 21239702

  • CD81 protein is expressed at high levels in normal germinal center B cells and in subtypes of human lymphomas HUMAN PATHOLOGY Luo, R. F., Zhao, S., Tibshirani, R., Myklebust, J. H., Sanyal, M., Fernandez, R., Gratzinger, D., Marinelli, R. J., Lu, Z. S., Wong, A., Levy, R., Levy, S., Natkunam, Y. 2010; 41 (2): 271-280

    Abstract

    CD81 is a tetraspanin cell surface protein that regulates CD19 expression in B lymphocytes and enables hepatitis C virus infection of human cells. Immunohistologic analysis in normal hematopoietic tissue showed strong staining for CD81 in normal germinal center B cells, a cell type in which its increased expression has not been previously recognized. High-dimensional flow cytometry analysis of normal hematopoietic tissue confirmed that among B- and T-cell subsets, germinal center B cells showed the highest level of CD81 expression. In more than 800 neoplastic tissue samples, its expression was also found in most non-Hodgkin lymphomas. Staining for CD81 was rarely seen in multiple myeloma, Hodgkin lymphoma, or myeloid leukemia. In hierarchical cluster analysis of diffuse large B-cell lymphoma, staining for CD81 was most similar to other germinal center B cell-associated markers, particularly LMO2. By flow cytometry, CD81 was expressed in diffuse large B-cell lymphoma cells independent of the presence or absence of CD10, another germinal center B-cell marker. The detection of CD81 in routine biopsy samples and its differential expression in lymphoma subtypes, particularly diffuse large B-cell lymphoma, warrant further study to assess CD81 expression and its role in the risk stratification of patients with diffuse large B-cell lymphoma.

    View details for DOI 10.1016/j.humpath.2009.07.022

    View details for Web of Science ID 000276493600015

    View details for PubMedID 20004001

    View details for PubMedCentralID PMC2813949

  • Enhanced B cell activation in the absence of CD81 INTERNATIONAL IMMUNOLOGY Sanyal, M., Fernandez, R., Levy, S. 2009; 21 (11): 1225-1237

    Abstract

    CD81 is a component of the CD19/CD21 co-receptor complex in B cells. However, the role of CD81 in B cell activation has not been clearly elucidated. Here, we demonstrate that Cd81(-/-) B cells stimulated via their B cell receptor fluxed higher intracellular-free calcium ion along with increased phosphorylation of spleen tyrosine kinase and phospholipase gamma 2. Additionally, Cd81(-/-) B cells responded to toll like receptor 4 stimulation with increased nuclear factor-kappa B activation, cell proliferation and antibody secretion compared with wild-type B cells. Cd81(-/-) mice also mounted a significantly higher immune response to T-independent antigens than their wild-type counterparts. Finally, analysis of Cd81(-/-) B cells that were generated by bone marrow transplantation into Rag1(-/-) mice confirmed that the hyperactive phenotype is not dependent on the CD81-deficient environment. Taken together, these results indicate that CD81 plays a negative role in B cell activation in vitro and in vivo.

    View details for DOI 10.1093/intimm/dxp090

    View details for Web of Science ID 000271382200004

    View details for PubMedID 19737782

  • Wiskott-Aldrich syndrome protein is an effector of Kit signaling BLOOD Mani, M., Venkatasubrahmanyam, S., Sanyal, M., Levy, S., Butte, A., Weinberg, K., Jahn, T. 2009; 114 (14): 2900-2908

    Abstract

    The pleiotropic receptor tyrosine kinase Kit can provide cytoskeletal signals that define cell shape, positioning, and migration, but the underlying mechanisms are less well understood. In this study, we provide evidence that Kit signals through Wiskott-Aldrich syndrome protein (WASP), the central hematopoietic actin nucleation-promoting factor and regulator of the cytoskeleton. Kit ligand (KL) stimulation resulted in transient tyrosine phosphorylation of WASP, as well as interacting proteins WASP-interacting protein and Arp2/3. KL-induced filopodia in bone marrow-derived mast cells (BMMCs) were significantly decreased in number and size in the absence of WASP. KL-dependent regulation of intracellular Ca(2+) levels was aberrant in WASP-deficient BMMCs. When BMMCs were derived from WASP-heterozygous female mice using KL as a growth factor, the cultures eventually developed from a mixture of WASP-positive and -negative populations into a homogenous WASP-positive culture derived from the WASP-positive progenitors. Thus, WASP expression conferred a selective advantage to the development of Kit-dependent hematopoiesis consistent with the selective advantage of WASP-positive hematopoietic cells observed in WAS-heterozygous female humans. Finally, KL-mediated gene expression in wild-type and WASP-deficient BMMCs was compared and revealed that approximately 30% of all Kit-induced changes were WASP dependent. The results indicate that Kit signaling through WASP is necessary for normal Kit-mediated filopodia formation, cell survival, and gene expression, and provide new insight into the mechanism in which WASP exerts a strong selective pressure in hematopoiesis.

    View details for DOI 10.1182/blood-2009-01-200733

    View details for Web of Science ID 000270387100013

    View details for PubMedID 19643989

    View details for PubMedCentralID PMC2756200

  • Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease CIRCULATION RESEARCH Stankunas, K., Shang, C., Twu, K. Y., Kao, S., Jenkins, N. A., Copeland, N. G., Sanyal, M., Selleri, L., Cleary, M. L., Chang, C. 2008; 103 (7): 702-709

    Abstract

    Congenital heart diseases are traditionally considered to be multifactorial in pathogenesis resulting from environmental and genetic interactions that determine penetrance and expressivity within a genetically predisposed family. Recent evidence suggests that genetic contributions have been significantly underestimated. However, single gene defects occur only in a minority of cases, and multigenetic causes of congenital heart diseases have not been fully demonstrated. Here, we show that interactions between alleles of 3 Pbx genes, which encode homeodomain transcription factors, are sufficient to determine the phenotypic presentation of congenital heart diseases in mice. A major role is served by Pbx1, whose inactivation results in persistent truncus arteriosus. Reduction or absence of Pbx2 or Pbx3 leads to Pbx1 haploinsufficiency and specific malformations that resemble tetralogy of Fallot, overriding aorta with ventricular septal defect, and bicuspid aortic valves. Disruption of Meis1, which encodes a Pbx DNA-binding partner, results in cardiac anomalies that resemble those caused by Pbx mutations. Each of the observed cardiac defects represents developmental abnormalities affecting distinct stages of cardiac outflow tract development and corresponds to specific types of human congenital heart disease. Thus, varied deficiencies in the Pbx gene family produce a full spectrum of cardiac defects involving the outflow tract, providing a framework for determining multigenetic causes of congenital heart anomalies.

    View details for DOI 10.1161/CIRCRESAHA.108.175489

    View details for Web of Science ID 000259528800006

    View details for PubMedID 18723445

    View details for PubMedCentralID PMC2633052

  • B-cell development fails in the absence of the Pbx1 proto-oncogene BLOOD Sanyal, M., Tung, J. W., Karsunky, H., Zeng, H., Selleri, L., Weissman, I. L., Herzenberg, L. A., Cleary, M. L. 2007; 109 (10): 4191-4199

    Abstract

    Pbx1, a homeodomain transcription factor that was originally identified as the product of a proto-oncogene in acute pre-B-cell leukemia, is a global regulator of embryonic development. However, embryonic lethality in its absence has prevented an assessment of its role in B-cell development. Here, using Rag1-deficient blastocyst complementation assays, we demonstrate that Pbx1 null embryonic stem (ES) cells fail to generate common lymphoid progenitors (CLPs) resulting in a complete lack of B and NK cells, and a partial impairment of T-cell development in chimeric mice. A critical role for Pbx1 was confirmed by rescue of B-cell development from CLPs following restoration of its expression in Pbx1-deficient ES cells. In adoptive transfer experiments, B-cell development from Pbx1-deficient fetal liver cells was also severely compromised, but not erased, since transient B lymphopoiesis was detected in Rag-deficient recipients. Conditional inactivation of Pbx1 in pro-B (CD19(+)) cells and thereafter revealed that Pbx1 is not necessary for B-cell development to proceed from the pro-B-cell stage. Thus, Pbx1 critically functions at a stage between hematopoietic stem cell development and B-cell commitment and, therefore, is one of the earliest-acting transcription factors that regulate de novo B-lineage lymphopoiesis.

    View details for DOI 10.1182/blood-2006-10-054213

    View details for Web of Science ID 000246609100023

    View details for PubMedID 17244677

    View details for PubMedCentralID PMC1885499

  • Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression MOLECULAR AND CELLULAR BIOLOGY Yokoyama, A., Wang, Z., Wysocka, J., Sanyal, M., Aufiero, D. J., Kitabayashi, I., Herr, W., Cleary, M. L. 2004; 24 (13): 5639-5649

    Abstract

    MLL (for mixed-lineage leukemia) is a proto-oncogene that is mutated in a variety of human leukemias. Its product, a homolog of Drosophila melanogaster trithorax, displays intrinsic histone methyltransferase activity and functions genetically to maintain embryonic Hox gene expression. Here we report the biochemical purification of MLL and demonstrate that it associates with a cohort of proteins shared with the yeast and human SET1 histone methyltransferase complexes, including a homolog of Ash2, another Trx-G group protein. Two other members of the novel MLL complex identified here are host cell factor 1 (HCF-1), a transcriptional coregulator, and the related HCF-2, both of which specifically interact with a conserved binding motif in the MLL(N) (p300) subunit of MLL and provide a potential mechanism for regulating its antagonistic transcriptional properties. Menin, a product of the MEN1 tumor suppressor gene, is also a component of the 1-MDa MLL complex. Abrogation of menin expression phenocopies loss of MLL and reveals a critical role for menin in the maintenance of Hox gene expression. Oncogenic mutant forms of MLL retain an ability to interact with menin but not other identified complex components. These studies link the menin tumor suppressor protein with the MLL histone methyltransferase machinery, with implications for Hox gene expression in development and leukemia pathogenesis.

    View details for DOI 10.1128/MCB.24.13.5639-5649.2004

    View details for Web of Science ID 000222149200001

    View details for PubMedID 15199122

    View details for PubMedCentralID PMC480881

  • The TALE homeodomain protein pbx2 is not essential for development and long-term survival MOLECULAR AND CELLULAR BIOLOGY Selleri, L., DiMartino, J., van Deursen, J., Brendolan, A., Sanyal, M., Boon, E., Capellini, T., Smith, K. S., Rhee, J., Popperl, H., GROSVELD, G., Cleary, M. L. 2004; 24 (12): 5324-5331

    Abstract

    Pbx2 is one of four mammalian genes that encode closely related TALE homeodomain proteins, which serve as DNA binding partners for a subset of Hox transcription factors. The expression and contributions of Pbx2 to mammalian development remain undefined, in contrast to the essential roles recently established for family members Pbx1 and Pbx3. Here we report that Pbx2 is widely expressed during embryonic development, particularly in neural and epithelial tissues during late gestation. Despite wide Pbx2 expression, mice homozygous mutant for Pbx2 are born at the expected Mendelian frequencies and exhibit no detectable abnormalities in development and organogenesis or reduction of long-term survival. The lack of an apparent phenotype in Pbx2(-)/(-) mice likely reflects functional redundancy, since the Pbx2 protein is present at considerably lower levels than comparable isoforms of Pbx1 and/or Pbx3 in embryonic tissues. In postnatal bone marrow and thymus, however, Pbx2 is the predominant high-molecular-weight (MW)-isoform Pbx protein detectable by immunoblotting. Nevertheless, the absence of Pbx2 has no measurable effect on steady-state hematopoiesis or immune function in adult mice, suggesting possible compensation by low-MW-isoform Pbx proteins present in these tissues. We conclude that the roles of Pbx2 in murine embryonic development, organogenesis, hematopoiesis, immune responses, and long-term survival are not essential.

    View details for DOI 10.1128/MCB.24.12.5324-5331.2004

    View details for Web of Science ID 000221864200021

    View details for PubMedID 15169896

    View details for PubMedCentralID PMC419882

  • K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis: An in vivo study using the severe combined Immunodeficient mouse-human skin model JOURNAL OF INVESTIGATIVE DERMATOLOGY Raychaudhuri, S. R., Sanyal, M., Weltman, H., Kundu-Raychaudhuri, S. 2004; 122 (3): 812-819

    Abstract

    The peripheral nervous system, in addition to its sensory and motor functions, can induce a local inflammatory response known as neurogenic inflammation. This phenomenon plays a critical role in several inflammatory diseases, e.g., asthma, atopy, rheumatoid arthritis, psoriasis, and ulcerative colitis. Neurogenic inflammation and the role of nerve growth factor (NGF) have been extensively studied in psoriasis. There are increased levels of NGF in the keratinocytes and upregulation of NGF receptor (NGF-R) in the cutaneous nerves of psoriatic plaques. NGF can influence all the salient pathologic events noticed in psoriasis such as proliferation of keratinocytes, angiogenesis, T cell activation, expression of adhesion molecules, proliferation of cutaneous nerves, and upregulation of neuropeptides. In this double-blinded, placebo-controlled study, we addressed the role of NGF/NGF-R in psoriasis in an in vivo system using the severe combined immunodeficient (SCID) mouse-human skin model of psoriasis. The transplanted psoriatic plaques on the SCID mice (n=12) were treated with K252a, a high-affinity NGF receptor blocker. Psoriasis significantly improved following 2 wk of therapy. The length of the rete pegs changed from 308.57+/-98.72 to 164.64+/-46.78 microm (p<0.01, Student's t test). A similar improvement of psoriasis was observed by directly inhibiting NGF with NGF-neutralizing antibody. NGF-neutralizing antibody in normal saline at 10 ng (n=4) and 20 ng (n=4) per kilogram of body weight doses were used. Both doses of NGF-neutralizing antibody reduced rete peg lengths significantly, e.g., from 298.5+/-42.69 to 150.52+/-32.93 microm (p<0.05, Student's t test). This study provides evidence for the role of NGF and its high-affinity receptor in the pathogenesis of psoriasis and insights to develop novel therapeutic modalities.

    View details for Web of Science ID 000220660500039

    View details for PubMedID 15086569

  • Severe combined immunodeficiency mouse-human skin chimeras: a unique animal model for the study of psoriasis and cutaneous inflammation BRITISH JOURNAL OF DERMATOLOGY Raychaudhuri, S. P., Sanyal, M., Raychaudhuri, S. K., Dutt, S., Farber, E. M. 2001; 144 (5): 931-939

    Abstract

    Elucidation of the molecular and cellular mechanisms responsible for the pathogenesis of psoriasis had been significantly handicapped due to lack of an ideal animal model. To overcome this hurdle several investigators have developed a number of animal models for psoriasis. Recent establishment of the SCID-human skin chimeras with transplanted psoriasis plaques has opened new vistas to study the molecular complexities involved in psoriasis. This model also offers a unique opportunity to investigate various key biological events such as cell proliferation, angiogenesis, homing in of T cells in target tissues, neurogenic inflammation and cytokine/chemokine cascades involved in an inflammatory reaction. The SCID mouse model will be of immense help to target the cellular and molecular events associated with these pathogenic processes and develop novel drugs for psoriasis and other inflammatory diseases. In this article we have reviewed the prospects and the limitations of the SCID mouse model of psoriasis.

    View details for Web of Science ID 000169131600002

    View details for PubMedID 11359377

  • Localization of nitric oxide synthase in human trophoblast cells: Role of nitric oxide in trophoblast proliferation and differentiation AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY Sanyal, M., Nag, T. C., Das, C. 2000; 43 (2): 70-77

    Abstract

    There are conflicting reports about the isoform of nitric oxide synthase (NOS) present in trophoblast cells. In this study, we have examined the presence of different NOS isoforms in trophoblast cells. In addition, the role of nitric oxide (NO) in trophoblast function has also been studied by investigating the possible role of nitric oxide in trophoblast proliferation and differentiation.NOS isoforms in primary-term trophoblast and JEG-3 cells were identified by immunocytochemistry. The intracellular localization of this enzyme was determined by confocal laser scanning microscopy. Trophoblast proliferation was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasolium bromide (MTT) conversion assay and cellular differentiation was monitored by human chorionic gonodotropin (hCG) and progesterone secretion, measured by radioimmunoassay.The immunoreactive NOS was present in human trophoblast cells of normal term placenta and JEG-3 cells (a choriocarcinoma cell line) maintained in culture. Nicotinamide adenine dinucleotide phosphate (NADPH)-dependent diaphorase activity overlapped with the immunostaining of NOS. Specific antibodies against the different isoforms of NOS detected the presence of neuronal-type NOS (nNOS) only. The other two isoforms, i.e., eNOS (endothelial) and iNOS (macrophage specific) were completely absent. The nNOS was localized in cell cytoplasm. In culture, JEG-3 cells normally undergo proliferation and cytotrophoblast cells in primary culture differentiate to form hormone-secreting syncytial cells. Sodium nitroprusside (SNP), a nitric oxide donor, when added to the culture, significantly increased proliferation of JEG-3 cells and inhibited the differentiation of cytotrophoblast cells. The arrest by SNP in the formation of syncytial cells was further evidenced by the low secretion profile of hCG and progesterone.Our findings suggest for the first time the presence of nNOS in the human trophoblast cells and a previously unrecognized role of NO in trophoblast proliferation and differentiation.

    View details for Web of Science ID 000085399300002

    View details for PubMedID 10735597

  • Expression of Inducible and Neuronal Nitric Oxide Synthase in 20-Methyl Cholanthrene (20-MCA) Induced Fibrosarcoma. Indian Journal Pharmacology Sengupta, S., Sanyal, M., Kochupillai, V., Gupta, S. K. 1999; 31: 315-318.
  • Immunomodulators in Human Trophoblast-Uterus Cross Talk: Cytokines, Growth Factors and nitric oxide. Reproductive Immunology Sanyal, M. edited by Gupta, S. K. Narosa Publishing House. 1999; 1 st: 99?109

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