TBL 14: Bone Marrow Flashcards
From what are endothelial cells and blood cells derivatives of?
Hemangioblasts
Describe the initial actions of hemangioblast-derived hematopoietic stem cells.
Hemangioblast-derived hematopoietic stem cells intially form blood islands in mesoderm surround the yolk sack then they colonize in the liver.
What is the major hematopoietic organ from the 2nd to 7th month of gestation? What happens in the 7th month?
The liver.
In the 7th month, stem cells from the liver colonize the bone marrow that becomes the definitive blood-forming tissue after birth..
What are the two microscopic methods for studying bone marrow?
What are the two common sites for aspirations and needle biopsies of bone marrow?
Smears and trephine needle biopsy are the two microscopic methods for studying bone marrow.
What is lymphedema?
LYMPHEDEMA – localized edema due to failure of lymph drainage
cite the normal duration of granulocytopoiesis
The maturation sequence whereby the three types of granulocytes are produced—granulocytopoiesis—takes 14-18 days
Define common sites for aspirations and needle biopsies of the marrow and compare their clinical applications
The optimal site for both aspiration and trephine biopsies is the posterior iliac crest, the sternum and tibia.
Smears:
Smears are the best preparations for evaluating cell details, studying maturation of hematopoietic cells, making differential counts, and assessing the ratio of myeloid (leukocyte) to erythroid (erythrocyte) cells. An advantage is preservation of individual cells so that subtle morphologic changes and infiltration by malignant cells in disease can be detected. Smears can also detect anemias, leukemias, and myeloma.
Biopsies:
provide a panoramic view of bone marrow and its normal architecture. They are also useful for estimating bone marrow cellularity, which is an index of the proportion of hematopoietic cells to adipocytes.
define ERC hormonal functions
Epithelial reticular cells secrete the hormones thymosin and thymopoietin, which induce T cell maturation and maintain cell-mediated immunity.
Define erythropoiesis’s normal duration
Erythropoiesis is regulated by the glycoprotein hormone erythropoietin, which is secreted by interstitial peritubular cells of the kidneys, mostly in response to hypoxia. Erythropoiesis, from the proerythroblast to the mature erythrocyte, takes 7-8 days.
What are some characteristics of pluripotential stem cells ?
pluripotential stem cells are direct hematopoietic descendants of hemangioblasts and have the capacity for self-renewal, replication, and differentiation
What are pluripotential stem cell’s direct descendants?
How do colony-forming units form?
pluripotential stem cell’s direct descendants are progenitor cells that when injected experimentally into the spleen, proliferate into colony-forming units (CFUs)
thus progenitor cells and CFUs are interchangeable terms
Name the CFU units
Different CFUs form depending on cell of origin; four types of progenitors exist:
1) erythroid lineage production contain progenitor cells known as colony-forming unit-erythrocytes (CFU-E).
2) Granulocyte and monocyte cell lines develop from one progenitor cell known as the colony-forming unit-granulocyte-monocyte (CFU-GM). As cells mature, progeny become committed to either granulocytes or monocytes.
3) Cells of the lymphocyte lineage are generated from colony-forming unit-lymphocytes (CFU-L).
4) Progenitor cells for megakaryocytes produce colonies that contain colony-forming unit-megakaryocytes (CFU-Meg)
What do erythroid cells and myeloid cells form?
What do Megakaryocytes form?
erythroid cells form RBCs via erythropoiesis
myeloid cells form PMNs, eosinophils and basophils via granulopoeisis, they also form monocytes via monocytopoiesis and lymphocytes via lymphocytopoiesis.
Megakaryocytes form the **platelets. **
What are the first precursor cells during erythropoiesis?
during erythropoiesis, the first precursor cells are proerythroblasts
What do progressive cytoplasmic color changes distinguish?
progressive cytoplasmic color changes distinguish basophilic, polychromatophilic, and orthochromatophilic erythroblasts during the differentiation of erythrocytes.
When does nuclear extrusion occur?
What are reticulocytes?
Nuclear extrusion occurs in the later stages of erythropoiesis.
Reticulocytes are released from bone marrow and are anucleate but lack central pallor.
What does erythropoitein do?
erythropoietin, which is a glycoprotein hormone produced in the kidneys, stimulates and sustains erythropoiesis
What regulates erythropoeisis and what is its normal duration?
Erythropoiesis is regulated by the glycoprotein hormone erythropoietin, which is secreted by interstitial peritubular cells of the kidneys, mostly in response to hypoxia. Erythropoiesis, from the proerythroblast to the mature erythrocyte, takes 7-8 days.
Why is hypoxia the principal stimulus for erythropoietin secretion?
Hypoxia = principal stimulus for erythropoietin secretion b/c increased RBCs help carry more oxygen
EPO is produced mainly by peritubular capillary lining cells of the renal cortex, which are highly specialized, epithelial-like cells. It is synthesized by renal peritubular cells in adults, with a small amount being produced in the liver. Regulation is believed to rely on a feedback mechanism measuring blood oxygenation. Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen.
Why does cytoplasmic color change from blue to reddish pink during erythropoiesis?
RBC cytoplasm color changes during erythropoiesis due to buildup of hemoglobin + builddown of rRNA
How do autologous and allogeneic bone marrow transplants differ?
_Autologous _
- *1. Remove marrow from person A
2. High dose chemo + radiation
3. Reintroduce marrow to person A **
Allogenic
- transplant from person A to person B (must have matching MHC complexes, on chromosome 6)
During granulopoiesis, the first precursor cells are?
Myeloblasts
(based on their similar microscopic appearance to the proerythroblasts, you are not expected to distinguish them in bone marrow smears.)
What do promyelocytes have?
What happens during their transformation into myelocytes and metamyelocytes?
promyelocytes have large, round nuclei and reddish blue cytoplasmic granules (lysosomes).
During their transformation into myelocytes, the nuclei become eccentrically positioned and flattened on one side. Indentation of the flattened side occurs during transformation of myelocytes into metamyelocytes.
When do the neutrophilic, eosinophilic, or basophilic granules in the cytoplasm become more distinct?
What does progressive deepening of the nuclear indentations of these cells do?
during the differentiation of metamyelocytes.
progressive deepening of the nuclear indentations transforms metamyelocytes into band cells with horseshoe-shaped nuclei.
What completes the maturation process of metamyelocytes?
lobulation of the horseshoe-shaped nuclei completes the maturation process
cite the normal duration of granulopoiesis
The maturation sequence whereby the three types of granulocytes are produced—granulocytopoiesis—takes 14-18 days
Where is the thymus?
When is it fully developed?
the thymus resides in the superior mediastinum
it is fully developed before birth
What happens to production of immunocompetent T cells before puberty?
What happens in adulthood?
When are progenies of T cells established and what significance does this have?
before puberty, production of immunocompetent T cells remains significant but during adulthood, T cell production decreases
progenies of T cells are established by the mid-twenties; thus immune responses can be sustained in adulthood without significant generation of new T cells in the thymus.
What are the two lobes of the thymus surrounded by?
What projects from it?
a connective tissue capsule
short trabeculae project from it into outer portions of the lobes.
What do the trabeculae do?
trabeculae subdivide the lobes into multiple lobules
What does each lobe have?
trabeculae subdivide the lobes into multiple lobules. Each lobule has an outer dark stained cortex and a central pale stained medulla.
What extends between the trabeculae?
What accounts for the dark staining of the cortex?
a meshwork of epithelial reticular cells (ERC) extends between the trabeculae thus supporting billions of maturing T cells in the cortex.
this vast cell population accounts for dark staining of the cortex
define ERC hormonal functions, bitch.
Epithelial reticular cells secrete the hormones thymosin and thymopoietin, which induce T cell maturation and maintain cell-mediated immunity.
What does lymphocytopoiesis generate in bone marrow? Where are they delivered to?
in the bone marrow, lymphocytopoiesis generates mature B cells and immature T cells; thus T cells are delivered by the bloodstream **to capillaries in the thymic medulla. **
Where is maturation of immature T cells completed?
immature T cells traverse the capillary endothelium and migrate into the cortex of the thymus where their maturation is completed i.e., the cells become immunocompetent.
What are cortical capillaries invested by?
processes of epithelial reticular cells
What else contributes to formation of the blood-thymus barrier?
- *1) tight junctions between capillary endothelial cells
2) thick basement membranes
3) macrophages**
What does the blood-thymus barrier block?
the barrier blocks **premature exposure of nonself and self antigens to the maturing T cells. **
*premature antigen exposure by circumvention of the barrier drives T cells that react to the antigens into apoptosis; thus immune reactions in the thymus are prevented. *
What is the consequence of medullary capillaries lacking a blood-thymus barrier?
What accounts for the medulla’s weak staining intensity?
After reaching maturation, mature T cells have to return to the medulla to enter the bloodstream.
the transitory presence of immature and mature T cells in the medulla accounts for its weak staining intensity.
What corpuscles uniquely characterize the thymus?
the medullary thymic (aka Hassall’s) corpuscles uniquely characterize the thymus
What are the medullary thymic (aka Hassall’s)?
they contain clusters of ERC, many of which are undergoing degeneration.
What do viable ERC in the corpuscles produce?
viable ERC in the corpuscles produce cytokines that induce the development of regulatory T cells, a subclass that contributes to initiating and terminating cell-mediated and humoral immune responses; they may also play a role in removing apoptotic thymocytes
What happens to the thymus after puberty?
after puberty, the thymus progressively involutes and is largely replaced by white fat.
Why do recurrent opportunist infections characterize DiGeorge syndrome?
*DIGEORGE SYNDROME (AKA thymic aplasia) – involves failure of thymus to develop properly *
- **Selective T cell deficiency –> opportunist infection **
- Lymph nodes will have atrophied paracortex (site of T cells)
How is apoptosis of maturing T cells in the thymus related to prevention of autoimmune diseases?
Apoptosis of suppressor t cells prevents down regulation of autoimmune antibody production.
Suppressor T cells are necessary to prevent autoimmune diseases (like systemic lupus erythematosus)
Why do immature T cells migrate from the medulla into the cortex and mature T cells return to the medulla?
the blood thymus barrier blocks premature exposure of nonself and self antigens to the maturing T cells. Premature antigen exposure by circumvention of the barrier drives T cells that react to the antigens into apoptosis; thus immune reactions in the thymus are prevented.
Medullary capillaries lack a blood-thymus barrier; thus T cells achieving maturation return to the medulla to enter the bloodstream
Where do lymphatic capillaries exist?
What would happen if excess capillary filtrate could not be removed as lymph by lymphatic capillaries?
lymphatic capillaries exist almost everywhere blood capillaries are found.
About 3 liters of excess capillary filtrate enter the interstitial fluid daily; thus without removal as lymph by the relatively porous lymphatic capillaries, expansion of interstitial fluid volume would create massive edema.
Where are lymphatic capillaries particularly abundant?
What are invading pathogens removed by?
in organ systems open to the external environment e.g. integument and the respiratory, urogenital, and digestive systems.
invading pathogens (e.g., bacteria and viruses) are removed by **lymph entering the lymphatic capillaries of these systems and adjoining lymphatic vessels transport the lymph to local lymph nodes. **
What do the thin-walled lymphatic vessels course with?
the thin-walled lymphatic vessels course with the arterioles and venules
What do bicuspid values insure?
bicuspid values insure unidirectional lymph flow toward the local lymph nodes.
What do lymphocyte aggregations (aka lymphoid nodules) join lymphatic capillaries and vessels to form?
mucosa-associated lymphoid tissue (MALT) in organ systems open to the external environment
What are lymphoid nodules? Where are they found? What do they consist of?
They are densely packed spherical clusters of lymphocytes, usually located in mucosa associated lympoid tissue.
lymphoid nodules consist mainly of B cells.
What happens to B cells in lymphoid nodules that selectively bind to the invading antigens?
they differentiate into plasma cells that synthesize and release immunoglobulins (aka antibodies), which selectively bind to the antigens thus initiating their destruction
What else are consituents of MALT?
T cells loosely dispersed among the lymphoid nodules are also constituents of MALT.
distinguish primary and secondary lymphoid nodules
In response to antigen exposure, primary nodules become secondary nodules, which contain pale-stained germinal centers. They are sites of extensive B lymphocyte proliferation and differentiation into plasma cells for antibody production.
What kind of lymphoid nodule is in the image below and explain why you know this.
What is a humoral immune response?
It is a secondary lymphoid nodule because it contains a pale stained germinal center.
the combined actions of nodular B cells, plasma cells and immunoglobulins are designated humoral immune responses
What do cell-mediated immune responses include?
How do T cells destroy tumor cells?
cell-mediated immune responses include **T cell destruction of virus-infected cells that require T cells to selectively bind both viral (nonself) antigens and fragments of cell membrane proteins (self antigens) expressed by the infected cells. **
T cells destroy tumor cells via **cell-mediated responses that employ a similar recognition mechanism for tumor antigens and self proteins expressed by the tumor cells. **
What are lymphangitis and lymphadenitis and why are these conditions potentially dangerous?
LYMPHANGITIS – secondary inflammation of lymphatic vessels
• Dangerous because risk of septicemia
LYMPHADENITIS - secondary inflammation of lymph nodes by infection
• Dangerous because risk of septicemia, bacteria gets into circulatory system which can be fatal
What is lymphedema?
LYMPHEDEMA – localized edema due to failure of lymph drainage
What conditions can cause lymphadenopathy?
CAUSES OF LYMPHADENOPATHY (abnormal enlargement of lymph nodes
less severe than lymphadenitis since bacteria has NOT overcome that lymph node yet).
**• increased number of lymphocytes + macrophages in the node during antigenic stimulation in a bacterial or viral infx
• Metastasis **
Why can graft-versus-host disease (GVHD) occur after allogeneic bone marrow transplantation?
Occurs after allogenic bone marrow transplantation due to a mismatch of major histocompatibility antigens of donor + recipient
DONOR ATTACKS THE HOST WITH BONE MARROW TRANSPLANT! (with organ transplant usually the host attacks the donor)
What do lymph nodes contain?
What happens to lymphocytes that fail to bind self antigens but selectively react with nonself antigens?
lymph nodes contain billions of immunocompetent lymphocytes that can distinguish self and nonself antigens in the lymph.
lymphocytes that fail to bind self antigens but selectively react with nonself antigens (e.g., pathogens) are replicated in the lymph nodes.
What are lymph nodes surrounded by?
What accounts for dark staining of cortex?
they are surrounded by dense connective tissue capsules and organized into a darkly stained outer cortex and paler stained central medulla.
lymphoid nodules in the cortex account for its dark staining.
What do trabeculae extend from?
the capsule of lymph nodes
What structure is the trabeculae spanned by?
What is this structure’s purpose and what is formed from?
a three-dimensional reticular fiber meshwork to provide a suspension system for the resident lymphocytes.
type III collagen forms the reticular fibers, which are thinner than the cable-like type I collagen fibers.
What does the dotted line in the image below separate?
the dotted-line separates the cortex and medulla
Where do venules lined with simple cuboidal endothelium reside?
Why do HEV endothelia selectively bind B cells and T cells ?
venules lined with simple cuboidal endothelium (aka high endothelial venules or HEV) reside along the boundary of the cortex and medulla.
HEV endothelia selectively bind B cells and T cells enabling their passage from the bloodstream into the reticular fiber meshwork.
What are the subcapsular and trabecular sinuses lined by and what is the purpose of these sinuses?
the subcapsular and trabecular sinuses, which are lined by discontinuous endothelium, represent portions of the sinus system that filters the lymph as it goes through the lymph node.
What do macrophages closely associate with?
What are lymph borne antigens filtered by?
macrophages closely associate with the sinuses; thus lymph-borne antigens are readily filtered by macrophages, B cells, and T cells in the cortex
What are trabecular sinuses continuous with?
trabecular sinuses are continuous with the medullary sinuses that permeate between the medullary cords, which contain aggregates of antigen-activated lymphocytes and plasma cells.
What accounts for pale staining of the medulla?
What readily traverses the porous medullary sinuses into the percolating lymph?
extensive branching of the medullary sinuses accounts for pale staining of the medulla.
plasma cell-derived antibodies and activated lymphocytes readily traverse the porous medullary sinuses into the percolating lymph.
How does lymph get delivered into the subcapsular sinus?
What does coalescence of the medullary sinuses form?
multiple afferent lymphatic vessels pierce the capsule delivering lymph into the subcapsular sinus.
coalescence of the medullary sinuses forms a single efferent lymphatic vessel that transports lymph out of the node at the hilum.
Why do arteries enter the hilum?
arteries enter the hilum to supply the medullary and cortical capillaries that drain into HEV, which empty into veins for exit at the hilum.
How after selective activation by antigens in afferent lymph, do activated lymphocytes exit a local lymph node and locate MALT that had initiated the humeral immune response?
Lymphocytes can leave nodes by entering the efferent lymphatics to travel in lymph –> reenter systemic circulation
• **Circulating lymphocytes can reenter node by preferential migration across walls of HEV **
o Endothelial cells in HEV have cell adhesion molecules that facilitate highly specific transmigration of T+B cells
o T+B cells squeeze between adjacent HEV endothelial cells and penetrate the basement membrane
o T cells stay in paracortex ; B cells migrate to lymphoid nodules
