Hematopoesis, Anatomy and Physiology of Immune System

Question 1

List the types of myeloid cells found in the bone marrow.

Answer 1

In this series of lectures the term myeloid will refer to non-lymphoid, marrow-derived blood cells (i.e. granulocytes, red cells, platelets, and monocytes).

Question 2

Define stem cell, progenitor cell, and precursor cell.

Answer 2

Stem cells give rise to progenitor cells, which in turn give rise to precursor cells.Stem cells are self renewable and capable of differentiating along all myeloid lineages. Progenitor cells are also referred to as committed stem cells. However, since their ability to self-renew is severely limited, and since they are irreversibly committed to differentiate along one or at most two lineages, the term progenitor cell is increasingly preferred.Precursor cells. Precursor cells mature into the mature cells found in the peripheral blood, lymphoid organs, and reticuloendothelial system.These cells are the recognizable, maturing cells that are enumerated when a marrow differential is performed. Precursors are capable, up to a point, of cell division, but cannot self-renew . Precursor cells give rise to the mature, functional cells in the peripheral blood, lymphoid organs, and reticuloendothelial system.

Question 3

Describe how the phenomenon of self-renewal prevents the bone marrow from rapidly becoming depleted.

Answer 3

Self-renewal involves production of daughter cells that are completely unchanged – genetically, morphologically, in any way – from the original dividing cell. Of course, the self-renewed daughter cell ceases to proliferate, but can at a later time either self-renew or commit to differentiation. In essence, self-renewal ensures that there is always a reserve of undifferentiated, uncommitted stem cells. Clearly without this reserve and the ability to self-renew the stem cell population would soon be exhausted.

Question 4

Discuss maturation and differentiation as they relate to hematopoiesis.

Answer 4

Differentiation: As a hematopoietic cell progresses from a stem cell to a functional cell in the peripheral blood, lymphoid organs, or reticuloendothelial system, it undergoes genetic changes that facilitate the expression of some genes, and restrict the expression of other genes. The pattern of gene expression that results leads to commitment of cells to a particular lineage (e.g. erythroid, granulocytic, lymphoid).Maturation: The difference between maturation and differentiation is not terribly clear when reading the literature. Your humble lecturer prefers to think of maturation as the accumulation of protein products and refinement of cellular structure dictated by the pattern of gene expression in a cell committed to a particular lineage.

Question 5

Discuss the role of hematopoietic growth factors in hematopoiesis. Include the names of the major hematopoietic growth factors, where hematopoietic growth factors are produced, and how they work.

Answer 5

Hematopoietic growth factors are produced by many of the cells of the HIM (hematopoietic inductive microenvironment) including fibroblasts, endothelium, and activated macrophages and T and B lymphocytes.These five factors are erythropoietin (Epo); interleukin-3 (IL-3, also called Multi-CSF); granulocyte colony-stimulating factor (G-CSF); granulocyte-macrophage colony - stimulating factor (GM-CSF); macrophage colony-stimulating factor (M-CSF). As might be inferred from the names of the hematopoietic growth factors, each factor has a propensity to stimulate particular hematopoietic cells in in vitro clonal assays.HGF have multiple biologic activities. They regulate the proliferation, and differentiation/maturation of stem, progenitor, and precursor cells. They also enhance the survival and functional activities of mature blood cells and act synergistically.

Question 6

List and be able to recognize the granulocytic and erythoid precursors. Be able to recognize a megakaryocyte.

Answer 6

Granulocytic precurors in ascending order of maturity are: myeloblast → promyelocyte → myelocyte → metamyelocyte → neutrophil (band form) → neutrophil (segmented form). As we mature, goes from blue/purple to reddish.Erythroid precursors in ascending order of maturity are: pronormoblast → basophilic normoblast → polychromatophilic normoblast → orthochromatic normoblast → reticulocyte → erythrocyte.The megakaryocyte maturation scheme is as follows: Megakaryoblast → promegakaryocyte → megakaryocyte → platelet.The mature megakaryocyte has a lobulated, endoreduplicated (it doubles DNA but doesn’t divide) nucleus, and copious cytoplasm that appears finely granular and purplish.

Question 7

Define cellularity as it relates to the bone marrow.

Answer 7

The cellularity” of the bone marrow simply means the portion of the marrow that is hematopoietically active; non-hematopoietically active marrow is occupied by fat. For example if half of the marrow is occupied by hematopoietic cells the cellularity is 50%.”

Question 8

Describe how bone marrow cellularity changes with age.

Answer 8

The cellularity of the bone marrow decreases with age. After the age of 50 years the cellularity should be equal to (more or less) 100 – age.

Question 9

Define the M:E ratio and what this ratio should be in a normal person.

Answer 9

Myeloid to Erythroid (M:E) ratio that is estimated when a bone marrow biopsy from a patient is examined. This estimation is an assessment of the ratio of granulocytic precursors to erythroid precursors.The ratio of granulocytic to erythroid precursors should be around 3:1.Thus the M:E ratio is better termed by some people as the G:E (Granulocyte to Erythroid) ratio.

Question 10

What are leukocytes?

Answer 10

Nucleated cells of the blood; white blood cells. When you centrifuge anticoagulated blood, they sediment on top of the packed red cells, forming the “buffy coat.”

Question 11

What are mononuclear cells?

Answer 11

Leukocytes whose nucleus has a smooth outline; monocytes (immature, becoming mature macrophages in the tissues), and lymphocytes.In tissues it’s sometimes hard to tell the difference between macrophages and lymphocytes.

Question 12

What is a polymorphonuclear cell?

Answer 12

Cells whose nucleus is lobulated, also called granulocytes because they usually have rather prominent cytoplasmic granules.They include eosinophils, basophils (closely related to tissue mast cells), and neutrophils.

Question 13

What is a granulocyte?

Answer 13

Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. Same as polymorphonuclear cells.

Question 14

What is a mast cell?

Answer 14

Mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin.Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens.

Question 15

What is plasma?

Answer 15

Blood plasma is the yellow liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume.

Question 16

What is serum?

Answer 16

In blood, the serum is the component that is neither a blood cell (serum does not contain white or red blood cells) nor a clotting factor; it is the blood plasma with the fibrinogens removed. Serum includes all proteins not used in blood clotting (coagulation) and all the electrolytes, antibodies, antigens, hormones, and any exogenous substances (e.g., drugs and microorganisms).

Question 17

List the normal adult white blood cell count and differential percentages. From these, calculate absolute counts for the different cell types (as cells of that type /μL).

Answer 17

Total white blood cells (WBC): 4,500-10,500 per μL of blood (4.5-10.5 x 109/L). Use multiplication to solve for the counts of the different types.

Question 18

Name the major central and peripheral lymphoid organs.

Answer 18

The lymphoid system can be divided into central and peripheral lymphoid organs.Central organs are ones in which lymphocytes develop: the bone marrow and the thymus.In the peripheral organs, mature cells are organized to trap and respond to foreign invaders: these organs include lymph nodes, spleen, Peyer’s patches and mesenteric lymph nodes of the gut, tonsils and adenoids. At any moment a large number of lymphocytes are found in the blood and lymph, too, but most are in the peripheral lymphoid organs.

Question 19

Describe the recirculation of lymphocytes from blood to lymph and back; include in your discussion the specialized features of lymph node blood vessel endothelium that permit recirculation.

Answer 19

The pattern of recirculation is this: a lymphocyte in the blood encounters the cells lining certain ►postcapillary venules in the peripheral lymphoid tissues, especially lymph nodes. These endothelial cells are unusual⎯not flat as is the usual case, but ►high and cuboidal. Recirculating lymphocytes may bind to and pass between the endothelial cells into the lymph node, where they may stay, or pass eventually into the lymph which drains from that lymph node to the next in the chain. Lymph works its way into the largest lymph channels such as the thoracic duct near the heart; from there it is emptied into the venous blood and the circulatory loop can start over again.Thus there are two circulations, blood and lymphatic, in which lymphocytes cross from blood to lymph at the nodes, and from lymph back to blood at the heart.

Question 20

Define antigen, and compare it to immunogen. Define antigenic determinant and epitope.

Answer 20

Antigen refers to a substance which can be recognized by the immune system. An antigen frequently is also an immunogen, which is an antigen in a form which can give rise to an immune response, that is, which can immunize. The part of an antigen that fits into the receptor is the antigenic determinant or epitope. For example, an isolated antigenic determinant is not usually an immunogen; it can be recognized by antibody, but is too small to trigger an immune response.A tolerogen is antigen delivered in a form, or by a route, which does not give rise to an immune response, and which furthermore prevents an immune response to subsequently administered immunogen which has the same epitopes.

Question 21

Discuss lymphocyte activation by antigen with respect to: receptor binding, proliferation, differentiation. Draw a graph showing relative time on one axis and relative lymphocyte numbers on the other, in response to antigen administration.

Answer 21

To activate the T or B cell several conditions must be met: the fit between receptor and the antigen it sees must be good enough, several nearby receptors must be simultaneously bound by antigen, and for T cells, other cell surface molecules must be involved too. The activated cell begins to proliferate and differentiate. ►Lymphocytes can divide as fast as every 6 hours, so that 1 could give rise to 64,000 at the end of 4 days!

Question 22

Distinguish between “humoral” (antibody-mediated) and cell-mediated immunity in terms of: the types of lymphocytes involved, the nature of the molecules they release when activated, the types of inflammatory cells they preferentially involve. State which of these immunities can be transferred by serum.

Answer 22

Humoral: this is the antibody mediated response, and this occurs extracellularly where all the bacteria etc. live. B lymphocytes are the main cells involved. B cells transform into plasma cells which secrete antibodies. Cytokines are also released. Can be transferred by serum.Cell mediated immunity: T lymphocytes become activated. These in turn activate macrophages, NK cells, and cytotoxic T lymphocytes. Cytokines are released when the T cells become activated. Not transferred by serum.