scholarly journals In situ visualisation of immunoglobulin genes in normal and malignant lymphoid cells

1995 ◽  
Vol 48 (3) ◽  
pp. M158-M164 ◽  
Author(s):  
C Carvalho ◽  
M Telhada ◽  
M do Carmo-Fonseca ◽  
L Parreira
Keyword(s):  
Lymphoid Cells ◽  
Immunoglobulin Genes

scholarly journals THE EFFECT OF EPITHELIAL REMNANT AND WHOLE ORGAN GRAFTS OF THYMUS ON THE RECOVERY OF THYMECTOMIZED IRRADIATED MICE

1969 ◽  
Vol 129 (6) ◽  
pp. 1235-1246 ◽  
Author(s):  
Esther F. Hays
Keyword(s):  
Direct Action ◽  
Lymphoid Cells ◽  
Lymphoid Tissues ◽  
Functional Development ◽  
Reticular Cells ◽  
Microscopic Morphology ◽  
Two Parameters ◽  
A Minor ◽  
Cellular Components

Work has been presented which suggests that thymus epithelial reticular cells are not effective in restoring the microscopic morphology of lymphoid tissues and their immunologic capacities. They function in recruiting precursors of thymus lymphocytes from the host animals to produce an organ which, after it becomes architecturally normal, can reconstitute the defective host. Intact thymus grafts in situ from 10–14 days, but not for shorter periods of time, have been shown to result in a return toward normal of these two parameters. Evidence is offered to show that few dividing cellular components in the lymphoid tissue originate from the thymus remnant grafts, and that a minor cellular component is contributed by the intact grafts. These data support the concept that the structural and functional development of the lymphatic tissue in thymectomized animals is dependent on thymus lymphoid cells and/or their products, and that the epithelial-reticular cells do not have a direct action in peripheral lymphoid reconstitution.

scholarly journals Current treatment of double hit and double expressor lymphoma

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 295-297 ◽  
Author(s):  
Patrick M. Reagan ◽  
Andrew Davies
Keyword(s):  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Total Abdominal Hysterectomy ◽  
Abdominal Hysterectomy ◽  
Current Treatment ◽  
Current Data ◽  
Lymphoid Cells ◽  
High Grade ◽  
Computed Tomography Scans

Abstract A 60-year-old female presented with abdominal pain and distension. Following computed tomography scans of the abdomen and pelvis, she was taken urgently to the operating room, with the belief that she had appendicitis with perforation. At laparotomy, the findings were consistent with an ovarian carcinoma; there was extensive infiltration of the ovary, bowel, and omental deposits. Cytoreductive surgery was performed including total abdominal hysterectomy and bilateral salpingo-oophorectomy. The final pathology, however, revealed infiltration with medium-sized atypical lymphoid cells positive for CD20, CD10, MYC, BLC2, and BCL6 by immunohistochemistry. MYC and BCL2 translocations were identified by fluorescence in situ hybridization consistent with a diagnosis of high-grade B-cell lymphoma with rearrangements of MYC and BCL2. With the current data available, what is the optimal treatment of this patient?

The Pro-Inflammatory IL23/IL23R/IL17 Axis Is Active in IL23R-Expressing Circulating CLL Cells in Patients with Poor Prognosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3889-3889
Author(s):  
Fortunato Morabito ◽  
Giovanna Cutrona ◽  
Anna Grazia Recchia ◽  
Sonia Fabris ◽  
Serena Matis ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Lymphoid Cells ◽  
Fish Analysis ◽  
Number Of Patients ◽  
Significant Difference

Abstract Abstract 3889 Inflammatory cytokines play a biological role in the pathogenesis of Chronic lymphocytic leukemia (CLL). IL23 is a pro-inflammatory cytokine involved in T-cell responses and in tissue remodeling. It has been shown that the IL23 receptor (IL23R) is up-regulated in primary acute lymphoblastic leukemia (ALL) cells, and that IL23 inhibits ALL cell growth. Nevertheless, the anti-tumor function of IL23 still remains controversial. The role of the IL23R/IL23 axis in CLL has not been investigated so far. Herein we evaluated the expression pattern of IL23R/IL23 axis and its correlation with progression free survival (PFS) in CLL patients. A total of 233 newly diagnosed Binet stage A CLL cases from Italian institutions (clinicaltrials.gov NCT00917540) were studied for IL23R expression by flow-cytometry (FC) (median percentage IL23R expression=22.7, range 1.2–91.1). The median follow-up was 23 months (range 1–47). PFS information was obtained in 203 patients. Using the median value of 23% of IL23R as threshold, 8/102 IL23Rneg and 23/101 IL23Rpos CLL cases progressed with therapy requirement. The 2-year PFS probability of IL23Rneg patients was 89.7% as compared to 80.7% of IL23Rpos cases [χ2 7.7, P=.006; HR=3.0, 95%CI (1.3–6.6)]. Cases were then stratified according to IL23R positivity [IL23Rneg (102 cases) versus IL23Rpos (101 cases)]. No significant difference in terms of CD38 and ZAP-70 positive cases was observed, however, the IGVH mutational status could distinguish the two groups: IGHV-mutated in 92 (78.6%) of IL23Rneg vs 70 (61.9%) IL23Rpos and IGHV-unmutated in 25 (21.4%) vs 43 (38.1%), p=.006]. FISH analysis showed that IL23Rneg and IL23Rpos cases carrying 13q14.3 were respectively 53 (51.4%) and 44 (42.7%), while the number of patients with trisomy 12 were 8 and 10 respectively in cases with low and high IL23R expression. Deletion of 11q was detected in 3.9% (4/103) of IL23Rneg and in 8.7% (9/103) of IL23Rpos cases. Only 3 cases with 17p deletion were seen in this cohort of early CLL patients and all belonged to the IL23Rpos group. Overall, no significant differences in the incidence of the major genetic lesions were observed between the two groups. Il23R expression still remained independently associated with PFS also in multivariate analysis. In situ expression analysis of IL23R and of its ligand IL23 was then performed by immunohistochemistry (IHC) in 16 CLL samples [10 lymph node (LN) and 6 bone marrow (BM) biopsies] collected on diagnosis and in 8 control biopsies (4 lymph nodes with reactive follicular hyperplasia and 4 normal BM biopsies). IL23R was variably expressed in CLL and significantly expressed in the neoplastic clones of 9 (6 lymph nodes and 3 BM biopsies) of the 16 cases tested; IL23R was diffusely present along the membrane and cytoplasm of neoplastic cells effacing the lymph node or BM architecture (Fig. 1, upper-left). In CLL cases with low IL23R expression, IL23R was detected in few scattered lymphoid cells intermingling with neoplastic lymphocytes (Fig. 1, upper-right). IL23 was also detected, with a variable staining intensity (Fig. 1, middle-left), paralleling in part that of IL23R. Double-marker analysis confirmed the concomitant expression of IL23 and IL23R in CLL neoplastic infiltrates highlighting the co-localization of the two markers (Fig.1 middle-right) and suggesting the possibility of an autocrine IL23/IL23R loop in CLL clones. We speculated that the microenvironment of CLL cases rich in IL23R and IL23 could be enriched in IL17-producing cells. The IHC expression of IL17 in CLL cases with low or high IL23R and IL23 expression showed that CLL cases rich in IL23Rpos cells, also characterized by high IL23 expression, displayed significantly higher numbers of IL17pos infiltrating cells (Fig. 1 bottom-left), as compared with CLL cases with no or low expression of IL23R or IL23 (Fig. 1 bottom-right). In conclusion, our study shows that high IL23R expression predicts a worse PFS. Furthermore, we linked this picture with, the in situ engendering of a clone-related microenvironment characterized by the preponderancy of pro-inflammatory signals such as those of the IL23/IL23R/IL17 axis, and its correlates in the peripheral blood (i.e. IL23R expression on circulating CLL cells), may endorse its strong prognostic significance. This analysis prompts further investigation into the specific function of the IL23/IL23R/IL17 axis and its targets in the context of CLL. Figure 1. Figure 1. Disclosures: No relevant conflicts of interest to declare.

Identification of a Developmentally-Restricted Hematopoietic Stem Cell That Gives Rise to Innate-like Lymphocytes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4302-4302
Author(s):  
Anna E Beaudin ◽  
Scott W. Boyer ◽  
Gloria Hernandez ◽  
Camilla E Forsberg
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Lineage Tracing ◽  
Lymphoid Cells ◽  
Gfp Expression ◽  
Hematopoietic Stem

Abstract The generation of innate-like immune cells distinguishes fetal hematopoiesis from adult hematopoiesis, but the cellular mechanisms underlying differential cell production during development remain to be established. Specifically, whether differential lymphoid output arises as a consequence of discrete hematopoietic stem cell (HSC) populations present during development or whether the fetal/neonatal microenvironment is required for their production remains to be established. We recently established a Flk2/Flt3 lineage tracing mouse model wherein Flk2-driven expression of Cre recombinase results in the irreversible switching of a ubiquitous dual-color reporter from Tomato to GFP expression. Because the switch from Tom to GFP expression in this model involves an irreversible genetic excision of the Tomato gene, a GFP+ cell can never give rise to Tom+ progeny. Using this model, we have definitively demonstrated that all functional, adult HSC remain Tomato+ and therefore that all developmental precursors of adult HSC lack a history of Flk2 expression. In contrast, adoptive transfer experiments of Tom+ and GFP+ fetal liver Lin-cKit+Sca1+ (KLS) fractions demonstrated that both Tom+ and GFP+ fetal HSC support serial, long-term multilineage reconstitution (LTR) in irradiated adult recipients. We have therefore identified a novel, developmentally restricted HSC that supports long-term multilineage reconstitution upon transplantation into an adult recipient but does not normally persist into adulthood. Developmentally-restricted GFP+ HSC display greater lymphoid potential, and regenerated both innate-like B-1 lymphocytes and Vg3-expressing T lymphocytes to a greater extent than coexisting Tom+ FL and adult HSC. Interestingly, whereas developmental regulation of fetal-specific B-cell subsets appears to be regulated cell-instrinsically, as fetal HSC generated more innate-like B-cells than adult HSC even within an adult environment, T-cell development may be regulated both cell intrinsically and extrinsically, as both the cell-of-origin and the fetal microenvironment regulated the generation of innate-like T-cells. Our results provide direct evidence for a developmentally restricted HSC that gives rise to a layered immune system and describes a novel mechanism underlying the source of developmental hematopoietic waves. As early lymphoid cells play essential roles in establishing self-recognition and tolerance, these findings are critical for understanding the development of autoimmune diseases, allergies, and tolerance induction upon organ transplantation. Furthermore, by uncoupling self-renewal capacity in situ with that observed upon transplantation, our data suggests that transplantation- and/or irradiation-induced cues may allow for the engraftment of developmental HSC populations that do not normally persist in situ. As LTR upon transplantation has served as the prevailing definition of adult HSC origin during development, our data challenge the current conceptual framework of adult HSC origin. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Ets protein Spi-B is expressed exclusively in B cells and T cells during development.

1996 ◽  
Vol 184 (1) ◽  
pp. 203-214 ◽  
Author(s):  
G H Su ◽  
H S Ip ◽  
B S Cobb ◽  
M M Lu ◽  
H M Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Expression Patterns ◽  
Lymphoid Cells ◽  
Cell Maturation ◽  
White Pulp ◽  
Ets Family ◽  
T Cell Lines

Spi-B and PU.1 are hematopoietic-specific transcription factors that constitute a subfamily of the Ets family of DNA-binding proteins. Here we show that contrary to previous reports, PU.1 and Spi-B have very different expression patterns. PU.1 is expressed at high levels in B cells, mast cells, megakaryocytes, macrophages, neutrophils, and immature erythroid cells and at lower levels in mature erythrocytes. PU.1 is completely absent from peripheral T cells and most T cell lines based on sensitive RT-PCR assays. In contrast, Spi-B is expressed exclusively in lymphoid cells and can be detected in early fetal thymus and spleen. In situ hybridizations of adult murine tissues demonstrate Spi-B mRNA in the medulla of the thymus, the white pulp of the spleen, and the germinal centers of lymph nodes. Spi-B expression is very abundant in B cells and both Spi-B mRNA and protein are detected in some T cells. In situ hybridization and Northern blot analysis suggest that Spi-B gene expression increases during B cell maturation and decreases during T cell maturation. Gel-retardation experiments show that Spi-B can bind to all putative PU.1 binding sites, but do not reveal any preferred Spi-B binding site. Finally, both PU.1 and Spi-B function as transcriptional activators of the immunoglobulin light-chain enhancer E lambda 2.4 when coexpressed with Pip (PU.1-interaction partner) in NIH-3T3 cells. Taken together, these data suggest that differences in patterns of expression between Spi-B and PU.1 distinguish the function of each protein during development of the immune system.

scholarly journals IL7R⍺ is required for hematopoietic stem cell reconstitution of tissue-resident lymphoid cells

2021 ◽  
Author(s):  
Atesh K Worthington ◽  
Taylor S Cool ◽  
Donna M Poscablo ◽  
Adeel Hussaini ◽  
Anna E Beaudin ◽  
...  
Keyword(s):  
Cell Types ◽  
Lineage Tracing ◽  
Lymphoid Cells ◽  
Lymphoid Tissues ◽  
Hematopoietic Stem ◽  
Functional Roles ◽  
Reciprocal Transplants ◽  
B1a Cells

Traditional, adult-derived lymphocytes that circulate provide adaptive immunity to infection and pathogens. However, subsets of lymphoid cells are also found in non-lymphoid tissues and are called tissue-resident lymphoid cells (TLCs). TLCs encompass a wide array of cell types that span the spectrum of innate-to-adaptive immune function. Unlike traditional lymphocytes that are continuously generated from hematopoietic stem cells (HSCs), many TLCs are of fetal origin and poorly generated from adult HSCs. Here, we sought to understand the development of murine TLCs across multiple tissues and therefore probed the roles of Flk2 and IL7R⍺, two cytokine receptors with known roles in traditional lymphopoiesis. Using Flk2- and Il7r-Cre lineage tracing models, we found that peritoneal B1a cells, splenic marginal zone B (MZB) cells, lung ILC2s and regulatory T cells (Tregs) were highly labeled in both models. Despite this high labeling, highly quantitative, in vivo functional approaches showed that the loss of Flk2 minimally affected the generation of these cells in situ. In contrast, the loss of IL7R⍺, or combined deletion of Flk2 and IL7R⍺, dramatically reduced the cell numbers of B1a cells, MZBs, ILC2s, and Tregs both in situ and upon transplantation, indicating an intrinsic and more essential role for IL7Rα. Surprisingly, reciprocal transplants of WT HSCs showed that an IL7Rα-/- environment selectively impaired reconstitution of TLCs when compared to TLC numbers in situ. Taken together, our data revealed functional roles of Flk2 and IL7Rα in the establishment of tissue-resident lymphoid cells.

scholarly journals A Novel Humanized Bone Marrow Niche Xenotransplantation Model Allows Superior Engraftment of Human Normal and Malignant Hematopoietic Cells and Reveals Myelofibrosis-Initiating Cells in the HSC Compartment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 349-349 ◽  
Author(s):  
Andreas Reinisch ◽  
Dita Gratzinger ◽  
Wan-Jen Hong ◽  
Ravi Majeti
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Jak2 V617f ◽  
Lymphoid Cells ◽  
Human Bone ◽  
Bone Marrow Niche ◽  
Post Transplantation ◽  
Bm Niche ◽  
Xenotransplantation Model

Abstract Xenotransplantation into immunocompromised mice is a powerful tool for studying human normal and malignant hematopoiesis. However, xenotransplant models do not necessarily recapitulate human physiology since environmental factors provided by bone marrow (BM) niche cells may differ between mice and humans. Although existing mouse models allow for propagation of hematopoietic stem and progenitor cells (HSPCs) and aggressive acute leukemias, engraftment of more committed normal progenitor cells and many other hematopoietic malignancies is still lacking. Here, we report the development of a novel mouse model bearing a subcutaneously accessible human bone ossicle formed by in situ differentiation of BM-derived mesenchymal stromal cells (MSCs). These human ossicles contain a functional humanized BM niche that facilitates robust engraftment of normal human HSPC and exhibits superior engraftment and expansion of primary AML. Interestingly, this model allows robust engraftment of PML-RARA positive APL and JAK2 V617F+ PMF, both of which fail to engraft in conventional xenotransplantation models. Subcutaneous injection of human BM-derived MSCs resulted in the formation of human ossicles through endochondral ossification resulting in a bone marrow cavity harboring normal mouse hematopoietic elements. After conditioning irradiation, direct intraossicle injection of cord blood CD34+ HSPC (n=5) resulted in robust multi-lineage human engraftment including B cells, T cells, NK cells, mature neutrophils, eosinophils, monocytes, as well as red blood cell precursors and platelets, as assessed by flow cytometric analysis of aspirates taken directly from the ossicles. The self-renewal potential of engrafted HSPCs was demonstrated by re-establishing multi-lineage hematopoiesis in secondary recipients. Unlike conventional NSG mice, this xenograft model allowed engraftment of phenotypically defined L-MPP (n=7) and GMP (n=7). Engraftment analysis 2 weeks post transplantation showed human engraftment with a majority of CD33+ myeloid cells (LMPP: 77.3±14.4%; GMP: 97.3±1.8%) and intermediate (LMPP: 20.8±14.4%) to low (GMP: 1.8±1.8%) numbers of B lymphoid cells. In the investigation of AML, direct intraossicle transplantation of blasts (n=5) resulted in faster (as early as 6 weeks) and significantly higher leukemic engraftment in humanized niches compared to mouse BM. Furthermore, engraftment was also significantly higher in humanized niches after intravenous transplantation and demonstrated a paratrabecular engraftment pattern, suggesting preferential homing and expansion of AML cells in a human BM microenvironment. Limiting dilution analysis revealed a 10-250 fold higher leukemia-initiating cell frequency using direct intraossicle transplantation compared to intrafemoral injection into mouse BM. Intraossicle transplantation also allowed for engraftment and propagation of PML-RARA-positive APL blasts (n=3) resulting in almost 100% leukemic chimerism and granulocytic sarcoma formation 10-15 weeks post-transplantation. Finally, transplantation of PMF patient-derived CD34+ cells (n=5) into the humanized niche led to robust engraftment with up to 50% human chimerism, and further subpopulation studies demonstrated that PMF-engraftment was exclusively initiated from the HSC (CD34+/CD38-/CD90+) population. Engrafted cells showed marked myeloid skewing with JAK2 V617F-positive cells, and detection of only minimal JAK2 wild type lymphoid cells. In summary, we report the development of a novel xenotransplantation model using human bone ossicles formed by in situ differentiation of BM-derived MSCs that substantially improves the engraftment of normal and malignant hematopoietic populations, leading to the formal demonstration that PMF-initiating cells reside in the immunophenotypic HSC compartment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Receptor Usage and Fetal Expression of Ovine Endogenous Betaretroviruses: Implications for Coevolution of Endogenous and Exogenous Retroviruses

2003 ◽  
Vol 77 (1) ◽  
pp. 749-753 ◽  
Author(s):  
Thomas E. Spencer ◽  
Manuela Mura ◽  
C. Allison Gray ◽  
Philip J. Griebel ◽  
Massimo Palmarini
Keyword(s):  
Lymphoid Cells ◽  
Cellular Receptor ◽  
Endogenous Viruses ◽  
Fetal Lamb ◽  
Enzootic Nasal Tumor Virus ◽  
Tumor Virus ◽  
Nasal Tumor ◽  
Etiological Agents ◽  
Hyaluronidase 2

ABSTRACT Betaretroviruses of sheep include two exogenous viruses, Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), and a group of endogenous viruses known as enJSRVs. The exogenous JSRV and ENTV are the etiological agents of ovine pulmonary adenocarcinoma (OPA) and enzootic nasal tumor (ENT), respectively. Sheep affected by OPA or ENT do not show an appreciable antibody response to JSRV or ENTV. Consequently, it is conceivable that enJSRV expression in the fetal lamb tolerizes sheep to the related exogenous viruses. In this study, possible mechanisms of interference between the sheep exogenous and endogenous betaretroviruses were investigated. In situ hybridization detected enJSRV RNAs in lymphoid cells associated with the lamina propria of the small intestine and in the thymus of sheep fetuses. Low-level expression of enJSRVs was also detected in the lungs. In addition, expression of enJSRVs was found to block entry of the exogenous JSRV, presumably via mechanisms of receptor interference. Indeed, enJSRVs, like JSRV and ENTV, were found to utilize hyaluronidase-2 as a cellular receptor.

Phagosomal acidification: measurement, manipulation and functional consequences

2007 ◽  
Vol 35 (5) ◽  
pp. 1083-1087 ◽  
Author(s):  
B.E. Steinberg ◽  
K.K. Huynh ◽  
S. Grinstein
Keyword(s):  
Electrical Potential ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Central Position ◽  
Protonmotive Force ◽  
Phagosome Maturation ◽  
Critical Determinant ◽  
Functional Consequences ◽  
Phagosomal Membrane

Phagocytosis holds a central position in the development of a successful innate immune response and in the initiation of the corresponding adaptive response. The destruction of invading pathogens and the presentation of their antigens to lymphoid cells require acidification of the phagosomal lumen. The present review discusses the mechanism of phagosome acidification, with particular reference to the two components of the protonmotive force: the chemical (pH) gradient and the electrical potential across the phagosomal membrane. A method for the in situ measurement of the electrical potential across the phagosomal membrane is described. In addition, we discuss the finding that acidification is not only a consequence, but also a critical determinant of phagosome maturation. Luminal acidification appears to function as a timing device controlling the transition between early and late phagosomes.

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