A5026026841- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Immunodeficiency and Autoimmune Disorders
- Chronic Lymphocytic Leukemia Research
- Cancer-related gene regulation
- Monoclonal and Polyclonal Antibodies Research
- Lymphoma Diagnosis and Treatment
- RNA modifications and cancer
- Glycosylation and Glycoproteins Research
- CAR-T cell therapy research
- T-cell and Retrovirus Studies
- Galectins and Cancer Biology
- Zebrafish Biomedical Research Applications
- Adolescent and Pediatric Healthcare
- Virus-based gene therapy research
- Diabetes and associated disorders
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- Immune Response and Inflammation
- Epigenetics and DNA Methylation
- Acute Lymphoblastic Leukemia research
- Hematopoietic Stem Cell Transplantation
- IL-33, ST2, and ILC Pathways
- Myeloproliferative Neoplasms: Diagnosis and Treatment
Fox Chase Cancer Center
2015-2025
Istituto Dermopatico dell'Immacolata
2002
Sidney Kimmel Cancer Center
1998-2002
Rockefeller University
1994
We have resolved B220+ IgM- B-lineage cells in mouse bone marrow into four fractions based on differential cell surface expression of determinants recognized by S7 (leukosialin, CD43), BP-1, and 30F1 (heat stable antigen). Functional differences among these can be correlated with Ig gene rearrangement status. The largest fraction, lacking S7, consists pre-B whereas the others, expressing include B lineage before pre-B. These S7+ fractions, provisionally termed Fr. A, B, C, differentiate a...
Lymphocyte development is critically influenced by self-antigens. T cells are subject to both positive and negative selection, depending on their degree of self-reactivity. Although B it has been difficult test whether self-antigen plays any role in cell development. A murine model system naturally generated autoreactive with a germ line gene–encoded specificity for the Thy-1 (CD90) glycoprotein was developed, which presence promotes accumulation serum autoantibody secretion. Thus, can be...
The TCL1 gene at 14q32.1 is involved in chromosomal translocations and inversions mature T cell leukemias. These leukemias are classified either as prolymphocytic leukemias, which occur very late life, or chronic lymphocytic often arise patients with ataxia telangiectasia (AT) a young age. In transgenic animals, the deregulated expression of leads to leukemia, demonstrating role initiation malignant transformation neoplasia. Expression high levels Tcl1 have also been found variety human...
Abstract Although immature/transitional peripheral B cells may remain susceptible to selection pressures before full maturation, the nature and timing of these events unclear. We show that correlated expression surface (s) IgM (sIgM), CD23, AA4 defines three nonproliferative subpopulations cells. designate populations transitional (T) 1 (AA4+CD23−sIgMhigh), T2 (AA4+CD23+sIgMhigh), T3 (AA4+CD23+sIgMlow). Cells within all subsets are functionally immature as judged by their failure proliferate...
We have examined the regulatory role of individual components immunoglobulin antigen receptor in B-cell development by transgenic complementation Rag-1 deficient (Rag-1-) mice. Complementation with a membrane mu heavy chain (mu HC) gene allows progression developmentally arrested Rag-1- pro-B-cells to small pre-B cell stage, whereas introduction independently integrated HC and kappa light (kappa LC) transgenes promotes appearance peripheral lymphocytes which, however, remain unresponsive...
The E2A gene products, E12 and E47, are required for proper B cell development. Mice lacking the products generate only a very small number of B220+ cells, which lack immunoglobulin DJH rearrangements. We have now generated mice expressing either or E47. development in but E47 is perturbed at pro-B stage, these IgM+B220+ cells both bone marrow spleen. can be detected, albeit significantly reduced levels, spleen E12. Ectopic expression null mutant background shows that act concert to promote...
By establishing hybridomas from two distinct surface IgM+ splenic B cell populations, Ly-1 cells and "conventional" (Ly-1-) cells, we found that the population includes a 30 to 70 times higher frequency (1 2%) of with specificity for bromelain treated autologous red blood (anti-BrMRBC) when compared conventional (0.03%). We cloned sequenced V genes encoding anti-BrMRBC antibody made sorted spleen SM/J mice. The VH sequence (for both) is identical previously reported associated this belongs...
We describe here three CD19− B cell precursor populations in mouse bone marrow identified using 12-color flow cytometry. Cell transfer experiments indicate lineage potentials consistent with multilineage progenitor (MLP), common lymphoid (CLP), and lineage–restricted pre-pro–B (Fr. A), respectively. However, single vitro assays reveal plasticity: lymphoid/myeloid potential for CLP B/T Fr. A. Despite myeloid potential, recombination activating gene 2 reporter activation is first detected at...
Mouse B cell precursors from fetal liver and adult bone marrow (BM) generate distinctive progeny when transplanted into immunodeficient recipients, supporting a two-pathway model for lymphopoiesis, “B-1” “B-2.” Recently, Lin28b was shown to be important the switch between pathways; however, neither mechanism of action nor importance antigen receptor (BCR) signaling in this process addressed. Here, we report key advances our understanding regulation B-1/B-2 development. First, modulation...
In developing B lymphocytes, a successful V(D)J heavy chain (HC) immunoglobulin (Ig) rearrangement establishes HC allelic exclusion and signals pro-B cells to advance in development the pre-B stage. A subsequent functional light (LC) then results surface expression of IgM at immature cell Here we show that interruption basal signaling cells, either by inducible deletion Ig via Cre-mediated excision or incubating with tyrosine kinase inhibitor herbimycin phosphatidylinositol 3-kinase...
A natural serum autoantibody specific for the Thy-1 glycoprotein (anti–Thy-1 [ATA]) is produced by B-1 cells that are positively selected self-antigen. Here, using ATAμκ transgenic mice we show with this B cell receptor negatively during bone marrow (BM) development. In a null environment, BM ATA progress to normal follicular stage in spleen. However, self-antigen–positive development arrested at an immature spleen, concomitant induction of CD5. Such tolerant and short-lived, different from...
Abstract T and B lymphocytes are developmentally functionally related cells of the immune system, representing two major branches adaptive immunity. Although originating from a common precursor, they play very different roles: contribute to drive cell-mediated immunity, whereas secrete Abs. Because their functional importance well-characterized differentiation pathways, ideal cell types with which understand how differences encoded at transcriptional level. there has been great deal interest...
The expression of different sets immunoglobulin specificities by fetal and adult B lymphocytes is a long-standing puzzle in immunology. Recently it has become clear that production μ heavy chain subsequent assembly with surrogate light to form the pre-B cell receptor complex critical for development cells. Here we show instead promoting pre–B progression as bone marrow, this inhibits growth liver. Curiously, identify fetal-associated VH11 allows continued proliferation Interestingly, does...
One of the predominant VH genes utilized to encode anti-BrMRBC specificity is a member small VH11 family rearranged JH1. Using polymerase chain reaction (PCR) we have determined that frequency B cells with rearrangement 10-20 times higher in Ly-1 than Ly-1- "conventional" regardless location (spleen or peritoneal cavity). Conventional rearrange this gene at comparable levels pre-B and mature utilizing all JH segments. In contrast, increased are restricted JH1 (and some JH2) therefore appear...
In mice, generation of autoreactive CD5+ B cells occurs as a consequence BCR signaling induced by (self)-ligand exposure from fetal/neonatal B-1 cell development. A fraction these self-renew and persist minor B1 subset throughout life. Here, we show that transfer early generated Eμ-TCL1 transgenic mice resulted in chronic lymphocytic leukemia (CLL) with biased repertoire, including stereotyped BCRs. Thus, bearing restricted BCRs can become CLL during aging. Increased anti-thymocyte/Thy-1...
CD79a and CD79b proteins associate with Ig receptors as integral signaling components of the B cell Ag receptor complex. To study development in zebrafish, we isolated orthologs these genes performed situ hybridization, finding that their expression colocalized IgH-μ kidney, which is site development. CD79 transgenic lines were made by linking promoter upstream regulatory segments to enhanced GFP identify cells, demonstrated PCR analysis sorted cells. We crossed CD79-GFP a recombination...
Introduction Newborn screening for immunodeficiency has led to the identification of numerous cases which causal etiology is unknown. Methods Here we report diagnosis T lymphopenia unknown in a male proband. Whole exome sequencing (WES) was employed nominate candidate variants, were then analyzed functionally zebrafish and mice bearing orthologous mutations. Results WES revealed missense mutations CHTF18 that inherited an autosomal recessive manner. CTF18, encoded by gene, component...