Chapter 13 – Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus

Question 1

What are the components of the hematopoietic system?

Answer 1

The components of the hematopoietic system have been traditionally divided into the:

• myeloid tissues, which include the bone marrow and the cells derived from it (e.g., red cells, platelets,granulocytes, and monocytes), and the
• lymphoid tissues, consisting of the thymus, lymph nodes, and spleen.

It is important to recognize, however, that this subdivision is artificial with
respect to both the normal physiology of hematopoietic cells and the diseases affecting them.

For example, although bone marrow contains relatively few lymphocytes, it is the source of all
lymphoid progenitors. Similarly, neoplastic disorders of myeloid progenitor cells (myeloid
leukemias) originate in the bone marrow but secondarily involve the spleen and (to a lesser
degree) the lymph nodes. Some red cell disorders (such as immunohemolytic anemia,
discussed in Chapter 14 ) result from the formation of autoantibodies, signifying a primary
disorder of lymphocytes. Thus, it is not possible to draw neat lines between diseases involving
the myeloid and lymphoid tissues.

Question 2

When do blood cell progenitors first appear?

Answer 2

Blood cell progenitors first appear during the third week of embryonic development in the yolk
sac, but definitive hematopoietic stem cells (HSCs) are believed to arise several weeks later in
the mesoderm of the intraembryonic aorta/gonad/mesonephros region

Question 3

When does definitive hematopoietic stem cells (HSCs) arise?

Answer 3

during the third week of embryonic development in the yolk sac, but definitive hematopoietic stem cells (HSCs) are believed to arise several weeks later in
the mesoderm of the intraembryonic aorta/gonad/mesonephros region

Question 4

On the third week of embyrogenensis, what becomes the chief site of blood cell
formation until shortly before birth.

Answer 4

During the third
month of embryogenesis, HSCs migrate to the liver, which becomes the chief site of blood cell
formation until shortly before birth.

Question 5

By fourth month of development, where is the HSCs?

Answer 5

By the fourth month of development, HSCs begin to shift in location yet again, this time to the bone marrow.

Question 6

At birth where is hematopoietically active?

Answer 6

By birth, marrow throughout the skeleton is
hematopoietically active and hepatic hematopoiesisdwindles( dec in size) to a trickle, persisting only in
widely scattered foci that become inactive soon after birth.

Until puberty, hematopoietically
active marrow is found throughout the skeleton, but soon thereafter it becomes restricted to the
axial skeleton. Thus, in normal adults, only about half of the marrow space is hematopoietically
active.

Question 7

Until what age is the hematopoietically
active marrow is found throughout the skeleton?

Answer 7

puberty

Until puberty, hematopoietically
active marrow is found throughout the skeleton, but soon thereafter it becomes restricted to the
axial skeleton.

Thus, in normal adults, only about half of the marrow space is hematopoietically
active.

Question 8

After puberty hematopoeisis is restricted to which skeleton?

Answer 8

axial skeleton.

Thus, in normal adults, only about half of the marrow space is hematopoietically
active.

Question 9

What are the formed elements of blood?

Answer 9

The formed elements of blood—

• red cells,
• granulocytes,
• monocytes,
• platelets, and
• lymphocytes

—have a common origin from HSCs, pluripotent cells that sit at the apex of a hierarchy of bone
marrow progenitors ( Fig. 13-1 ).

Question 10

What are the two
kinds of multipotent cells HSCs give rise to?

Answer 10

HSCs give rise to two
kinds of multipotent cells,

• the common lymphoid and
• common myeloid progenitors

Question 11

What is the lymphoid progenitor?

Answer 11

The common
lymphoid progenitor is the source of T-cell, B-cell, and natural killer (NK) cell precursors

Question 12

What arise in the myeloid progenitors?

Answer 12

From
the common myeloid progenitors arise various kinds of committed progenitors restricted to
differentiation along particular lineages.

These cells are referred to as colony-forming units
(CFUs)(see Fig. 13-1 ), because theygive rise to colonies composed of specific kinds of
mature cells when grown in culture.

From the various committed progenitors are derived the morphologically recognizable precursors, such as myeloblasts, proerythroblasts, and
megakaryoblasts, which in turn give rise to mature granulocytes, red cells, and platelets.

Question 13

WHat are CFUs?

Answer 13

colony-forming units
(CFUs) (see Fig. 13-1 ), because they give rise to colonies composed of specific kinds of
mature cells when grown in culture.

Question 14

Answer 14

FIGURE 13-1 Differentiation of blood cells. CFU, colony forming unit; SCF, stem cell factor;
Flt3L, Flt3 ligand; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocytemacrophage
colony-stimulating factor;LIN–, negative for lineage-specific markers;M-CSF,
macrophage colony-stimulating factor.

Question 15

What are the two essential properties of HSCs that are required for the maintenance of hematopoiesis:

Answer 15

• pluripotency
• capacity for self-renewal.

Question 16

What is Pluripotency?

Answer 16

Pluripotency refers to the ability of a single HSC
to generate all mature hematopoietic cells.

When an HSC divides at least one daughter cell
must self-renew to avoid stem cell depletion.

Question 17

What must HSC do to avoid stem cell depletion?

Answer 17

When an HSC divides at least one daughter cell
must self-renew to avoid stem cell depletion.

Question 18

Where does self-renewing divisions believed to occur?

Answer 18

Self-renewing divisions are believed to occur within
a specialized marrow niche, in which stromal cells and secreted factors nurture and somehow
maintain the HSCs.

Question 19

T or F

HSCs sessile ( fix in place)

Answer 19

FALSE

As you may have already surmised from their ability to migrate during embryonic development, HSCs are not sessile.

Particularly under conditions of marked stress,
such as severe anemia,

HSCs are mobilized from the bone marrow and appear in the peripheral blood.

In such circumstances, additional HSC niches are sometimes induced or “unveiled” in
other tissues, such as the spleen and liver, which can then become sites of extramedullary
hematopoiesis.

Question 20

What regulates the marrow response to short-term physiologic needs?

Answer 20

The marrow response to short-term physiologic needs is regulated by hematopoietic growth
factors through effects on the committed progenitors.

Question 21

Why do mature blood elements must be constantly replenished?

Answer 21

Since mature blood elements are
terminally differentiated cells with finite life spans, their numbers must be constantly
replenished.

Question 22

How does HSCs develop?

Answer 22

Some divisions of HSCs, a single daughter cell begins to differentiate.

Once past this threshold, these newly committed cells lose the capacity for self-renewal and
commence an inexorable journey down a road that leads to terminal differentiation and death.

However, as these progenitors differentiate they also begin to express receptors for lineagespecific
growth factors, which stimulate their short-term growth and survival.

Some growth
factors, such as stem cell factor (also called c-KIT ligand ) and FLT3-ligand, act on very early
committed progenitors.

Others, such as erythropoietin, granulocyte-macrophage colonystimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and
thrombopoietin, act on committed progenitors with more restricted potentials.

Feedback loops
that are mediated through growth factors tune the marrow output, allowing the numbers of
formed blood elements (red cells, white cells, and platelets) to be maintained within appropriate
ranges (given in Table 13-1 ).

Question 23

What is the ultimate source of all cells?

Answer 23

Many diseases alter the production of blood cells .

The marrow is the ultimate source of all cells
of the innate and adaptive immune system and responds to infectious or inflammatory
challenges by increasing its output of granulocytes under the direction of specific growth factors
and cytokines.

Conversely, other disorders are associated with defects in hematopoiesis that
lead to deficiencies of one or more type of blood cell.

Primary tumors of hematopoietic cells are
among the most important diseases that interfere with marrow function, but specific genetic
diseases, infections, toxins, and nutritional deficiencies, as well as chronic inflammation of any
cause, can also decrease the production of blood cells by the marrow.

Question 24

Tumors of hematopoietic origin are often associated with ____________________

Answer 24

• *mutations** that block progenitor cell
• *maturation or abrogate their growth factor dependence**

The net effect of such derangements
is an unregulated clonal expansion of hematopoietic elements, which replace normal marrow
progenitors and often spread to other hematopoietic tissues. In some instances, these tumors
originate from transformed HSCs that retain the ability to differentiate along multiple lineages,
whereas in other instances the origin is a more differentiated progenitor that has acquired an
abnormal capacity for self-renewal. Whether this latter situation merely reflects a block in
differentiation, or derives instead from the reactivation of a program of gene expression that
supports the self-renewal of normal stem cells, is an area of current investigation.

Question 25

What is the morphology of the bone marrow?

Answer 25

Morphology.

The bone marrow is a unique microenvironment that supports the orderly proliferation, differentiation, and release of blood cells.

It is filled with a network of thin-walled
sinusoids lined by a single layer of endothelial cells, which are underlaid by a discontinuous
basement membraneandadventitial cells.

Within the interstitium lie clusters of hematopoietic
cells and fat cells.

Differentiated blood cells enter the circulation by transcellular migration through the endothelial cells.

Question 26

How do the blood cells enter the circulation?

Answer 26

Differentiated blood cells enter the circulation by transcellular migration through the endothelial cells.

Question 27

Where does normal megakaryocytes lie in the marrow?

Answer 27

The normal marrow is organized in subtle, but important, ways.

For example, normal
megakaryocytes lie next to sinusoids and extend cytoplasmic processes that bud off into the
bloodstream to produce platelets,whilered cell precursors often surround macrophages
(so-called nurse cells) that provide some of the iron needed for the synthesis of hemoglobin.

Diseases that distort the marrow architecture, such as deposits of metastatic cancer or granulomatous disease, can cause the abnormal release of immature precursors
into the peripheral blood, a finding that is referred to as leukoerythroblastosis.

Question 28

What are nurse cells?

Answer 28

red cell precursors often surround macrophages
(so-called nurse cells) that provide some of the iron needed for the synthesis of hemoglobin.

Question 29

What provide the best assessment of the morphology of hematopoietic cells?

Answer 29

Marrow aspirate

Question 30

The most mature marrow precursors can be identified based on their morphology
alone.

T or F

Answer 30

True

The most mature marrow precursors can be identified based on their morphology
alone.

Question 31

How will you identify Immature precursors of different types?

Answer 31

Immature precursors (“blast” forms) of different types are **morphologically similar** and
**must be identified definitively using lineage-specific antibodies and histochemical markers**
(described later under white cell neoplasms).

Question 32

What is the good means for estimating marrow cavity?

Answer 32

Biopsies are a good means for estimating
marrow activity.

Question 33

What is the ratio of fat cells to hematopoetic elements in normal adults?

Answer 33

In normal adults, the ratio of fat cells to hematopoietic elements is about 1 : 1.

Question 34

Give example when the ratio of fat cells to hematopoetic cells are greatly increased.

Answer 34

In hypoplastic states (e.g., aplastic anemia) the proportion of fat cells is greatly increased

Question 35

Give example when fat cells often disappear in the marrow?

Answer 35

conversely, fat cells often disappear when the marrow is involved by hematopoietic tumors
and in diseases characterized by compensatory hyperplasias (e.g., hemolytic anemias), and
neoplastic proliferations such as leukemias

Question 36

What disorders induce local marrow fibrosis?

Answer 36

Other disorders (such as metastatic cancers
and granulomatous diseases) induce local marrow fibrosis.

Such lesions are usually
inaspirable and best seen in biopsies