Page 1176 - Williams Hematology ( PDFDrive )

1150 Part IX: Lymphocytes and Plasma Cells Chapter 74: Lymphopoiesis 1151

The third phase occurs from 16 weeks’ gestation until age 1 to 2 lineage may emerge prior to the development of the adaptive immune
years and is characterized by robust intrathymic T-cell maturation system. At present, there is no clear evidence that humans have similar
12
(Chaps. 6 and 76). subpopulations of B-1 and B-2 cells during development. 31
An exhaustive study of 136 human postnatal thymuses ranging
from neonatal life to more than 90 years old, found that essentially all NATURAL KILLER CELL DEVELOPMENT
postnatal thymic growth (based on weight and volume) occurs during
28
the first postnatal year, mostly in the first few months of life. From Functional NK cells can be detected in the human fetal liver as early as
26
the age of 12 months, the human thymus undergoes steady involution, 9 to 10 weeks of gestation, but NK cell differentiation can be induced
with a reduction of thymocytes and thymic epithelium, particularly in vitro from progenitors derived at all stages of hematopoietic develop-
the medulla, and a corresponding increase in fatty infiltration of the ment, even those from the yolk sac. 1,17,18 Thus, the onset of NK potential
perivascular space. 28 is not equivalent to the full lymphoid potential of definitive hemato-
Whereas mice lose approximately 90 percent of the wet weight of poiesis, as NK potential can be assigned to a range of progenitor types
the thymus during life, the increasing fatty infiltration in the perivascu- that exist at different stages, including primitive hematopoiesis. NK cell
lar space in the aging human thymus maintains the total size of the thy- production can be considered as providing an essential defense mech-
mus in healthy people into late life. Radiologic studies using computed anism for the developing mammalian embryo prior to development of
28
tomography (CT) scans have confirmed that total thymic size remains more complex pathways of adaptive immunity.
stable in humans throughout life although parenchymal tissue atrophies
dramatically (~95 percent; Chaps. 6 and 9). 29 DENDRITIC CELL DEVELOPMENT
B-CELL DEVELOPMENT Dendritic-like cells which express class II major histocompatibil-
ity (MHC) antigens are produced at all stages of embryonic and fetal
The hallmark characteristic of a mature B cell circulating in blood or hematopoiesis, being first detected in the human yolk sac and mes-
residing in secondary lymphoid tissue is the expression of cell-surface enchyme as early as 4 to 8 weeks, before development of the fetal mar-
immunoglobulin (Ig). The cell-surface Ig consists of μ, δ, γ, α, or ε heavy row or thymus. Dendritic cells (DCs) are detectable at each site of
31
chains disulfide-linked to κ or λ light chains (Chap. 75). The cell-surface hematopoiesis as soon as they become active, in the human fetal thy-
Ig and the associated signaling molecules Igα (CD79a) and Igβ (CD79b) mus at 11 to 14 weeks, marrow at 14 to 17 weeks, spleen at 16 weeks,
are referred to as the B-cell receptor (BCR). Progenitor (pro-) B cells are and tonsils at 23 weeks. 39,40 DC and macrophages are closely related and
defined by the absence of both cytoplasmic μ heavy chains and cell- phenotypically similar (Chap. 67), both expressing MHC class II. Thus,
surface BCR. Precursor (pre-) B cells are defined by the presence of cyto- clear discrimination of these two cell types can be difficult, particularly
plasmic μ heavy chains in the absence of cell-surface BCR. This minimal as many studies that provided information on human DC development
definition of pro-B, pre-B, and B cells forms the basis of the current were conducted before all the molecular and antibody tools for analysis
detailed model of human B-cell development. B-cell development can of DC were available.
30
be divided into two stages: an antigen-independent stage that occurs
primarily in fetal liver and fetal and adult marrow, and an antigen-
dependent stage that occurs primarily in secondary lymphoid tissue, DIFFERENTIATION PATHWAYS FOR
such as spleen and lymph node. LYMPHOCYTE PRODUCTION
The first B cells detectable in the human fetus are found in the fetal
liver at approximately 8 weeks’ gestation, with the appearance of cyto- The conceptual framework for how the lymphocyte lineages are gen-
25
plasmic IgM+ pre-B cells; by 10 to 12 weeks, surface IgM+ B cells are erated from HSC was developed largely from studies using genetically
seen in the fetal liver and fetal omentum. B-cell and IgM production engineered mice and murine transplant models. Although necessary
32
31
move to the fetal marrow and spleen by 17 weeks of gestation (Chaps. and useful as a starting point, caution should be exercised in translating
6, 7, and 75). 33,34 From the end of the second trimester throughout adult the results of the murine studies to human lymphopoiesis, or in assum-
life, marrow is the exclusive origin of B-cell development. The fre- ing for any species that only one pathway to lymphopoiesis exists at all
35
quency of early B-lineage cells as a percentage of the total nucleated stages of ontogeny. 41,42 Additionally, the conclusions about lineage rela-
lymphohematopoietic cell pool is higher in fetal than in adult marrow. tionships of isolated populations are influenced by limitations inherent
However, the ratio between pro-B, pre-B, and immature B cells and the in any of the in vitro or in vivo assays employed to examine differentia-
mitotic activity within these fractions is relatively constant. 36 tion potential. 43
In murine B-cell development, two functionally and immunophe- For several decades, our understanding of hematopoiesis has been
notypically distinct types of B cells, B-1 and B-2, have been described. built on a hierarchical schema in which all the pathways of differentia-
31
Most B cells in adult mice are B-2 cells, which form part of the adap- tion lead away from a multipotent HSC, and progress through discrete
tive immune system by their ability to interact with T cells and undergo progenitor stages that mark each branch-point of lineage commit-
immunoglobulin heavy chain class switching. The B-1 cells make up ment (Chap. 18). In the classical paradigm, the earliest differentiation
approximately 5 percent of adult murine lymphocytes, but demon- “decision” made by an HSC is to enter one of two pathways, marked
strate a far less diverse immunoglobulin repertoire than the B-2 cells, by either a common lymphoid progenitor (CLP) or a common myeloid
responding to carbohydrate antigens and other T-cell–independent progenitor (CMP), which has full myeloid and erythromegakaryocytic
immunogens and forming part of the innate immune system. Murine differentiation potential (Fig. 74–2). With each successive stage of
44
B-1 cells are marked by their expression of CD11b, and are found in differentiation, lineage-specific cell-surface markers and transcription
multiple sites, including the spleen, intestine, and the pleural and peri- factors are upregulated, and alternative lineage potentials are lost. Con-
toneal cavities. 37,38 The B-1 cells can be further divided into B-1a cells sequently, the CLP is defined as a single cell that can give rise to all lym-
(which secrete immunoglobulins spontaneously) and B-1b cells (in phoid lineages (B, T, and NK), but cannot generate myeloid, erythroid,
which immunoglobulin production is induced) based on the expression or megakaryocytic lineages. The concept of progenitor populations
of the marker CD5. The demonstration of a B-1a/marginal zone B-cell– marking two mutually exclusive differentiation pathways, one limited to
restricted progenitor in the E9 extraembryonic yolk sac suggests the B-1 myeloid and erythromegakaryocytic potential and the second defining

Kaushansky_chapter 74_p1149-p1158.indd 1151 9/18/15 2:26 PM