Page 41 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 2 Organization of the Immune System 27

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Upon activation and cross-linking of surface Ig by specific into CD3 NK cells. Such CD3 cells with variable CD16 expression
antigen, B cells undergo proliferation and differentiation to exist in the human thymus and can be induced to proliferate,
produce plasma cells, which lose expression of mIg and MHC express NK-associated antigens, and exhibit NK cell function in
class II molecules. Plasma cells (10–15 µm) are not normally vitro. These cells also express substantial levels of CD3δ and
found in blood. They display an eccentric nucleus and a basophilic CD3ε in the cytoplasm. 38
cytoplasm with a well-developed Golgi apparatus and parallel Mature NK cells in blood do not express conventional antigen
arrays of expanded Ig-containing RER. Plasma cells are nondivid- receptors, such as TCR or Ig, and the genes for these receptors
ing, specialized cells terminally differentiated from B cells and remain unrearranged. Some express FcγRIII (CD16) and others
whose primary function is to secrete Ig. express CD56, an adhesion molecule. More than 90% of these
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In vitro studies of cytokines involved in the development of cells are CD11b but CD27 . In tissues, subsets of human NK
early B-cell progenitors show that combinations of SCF (but cells express variable levels of both CD11b and CD27, and this
not IL-3) with IL-6, IL-11, or G-CSF can maintain B-lymphoid defines their function (tolerant, cytotoxic, or regulatory). NK
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potential. Stromal cell–dependent differentiation of fetal pro-B cells, like T cells, also express the CD2 molecule. NK cells express
cells occurs in conjunction with FLK-2/FLT-3 ligand and IL-7 the β chain of the IL-2 receptor, CD122, which allows resting
and on several transcription factors, including PU.1, IKAROS, NK cells to respond directly to IL-2.
E2A, EBF, PAX5, and IRF8. Unlike in mice, IL-7 is not an absolute The function of some NK cells is to provide nonspecific
requirement for B-cell development in humans. 35 cytotoxic activity toward virally infected cells and tumor cells
IL-4 has a variety of important effects on B-cell growth and (Chapter 17). When provided with an antibody, NK cells can
differentiation. Low doses of IL-4 induce pre-B cells to differentiate kill specifically. This death delivery mechanism, known as ADCC,
into B cells expressing surface membrane IgM, whereas higher occurs via binding of the antibody to the Fcγ receptor CD16.
doses of IL-4 inhibit differentiation of B cells. In mature B cells, After activation, NK cells produce cytokines, such as IFN-γ, and
IL-4 increases expression of MHC class II, CD23, and CD40; this affects proliferation and differentiation of other cell types,
promotes activation and progression to the G1 stage of the cell especially DCs. Some of the recognition molecules on human
cycle; enhances proliferation after stimulation through the Ig NK cells activate, some inhibit, and some act as receptors for
receptor; and induces immunoglobulin class switch in human MHC class I molecules.
to IgG4 and IgE (IgG1 and IgE in mouse). IL-13, which is closely NK cells express a number of membrane antigens in common
related to IL-4, has many similar effects on B cells. with T cells, and they share functional properties with some
IL-2, -5, -6, and -11 and nerve growth factor act on mature T-cell subsets, suggesting a common origin. NK cells are found
B cells to either enhance their proliferation or promote their in fetuses before the development of T cells or the thymus, and
differentiation into immunoglobulin-secreting cells. IL-10 they develop normally in nude, athymic mice. NK cells probably
enhances the viability of B cells in vitro, increases MHC class II develop extrathymically, and data suggest that they can develop
expression, and augments the proliferation and differentiation from stem cells in lymph nodes. NK cells arise from “triple-
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of B cells after stimulation through the Ig receptor or CD40. negative” (CD3 CD4 CD8 ) precursors that are CD56 , but
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TGF-β1 is a major switch factor for IgA. This cytokine induces CD34 and CD5 . T cells, in contrast, develop from triple-negative
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human B cells triggered by mitogen to switch to both IgA1 and precursors that are CD34 CD5 CD56 . It is likely that T cells
IgA2. Stromal cell-derived factor 1 (SDF-1) attracts early-stage and NK cells arise from a common triple-negative precursor
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B-cell precursors and is a likely mechanism whereby B cells form with the phenotype CD7 CD34 CD5 CD56 .
islands in bone marrow. The α chain of the IL-2 receptor, CD25, is the prime deter-
There are at least two major populations of B cells: B-1 cells, minant of T cell versus NK lineage specificity. Once CD25 is
which are found in the follicular mantle and peritoneal cavity, upregulated, the cell is destined to become a T cell. IL-15 and
and conventional B-2 cells, which are found in lymphoid follicles. IL-7 play major roles in the early development of NK cells. FLT
The B-1 lineage predominates early in gestation and produces ligand and c-KIT also facilitate NK cell expansion. In mature
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natural antibodies of the IgM isotype. There is good evidence NK cells, IL-2 induces proliferation and activation. This probably
for local expression of IgA plasma cell precursors in the ileum occurs via the IL-2 receptor β chain (CD122), as NK cells do
important for bacterial containment. 37 not express CD25. IL-2 also induces the growth of NK cells from
precursors in bone marrow cultures. Both IL-7 and IL-12 activate
Innate Lymphoid Cells NK cells. Although IL-4 inhibits the effects of IL-2 or IL-7 on
Natural Killer Cells NK cells, it acts synergistically with IL-12 to induce proliferation
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A new nomenclature has arisen to classify lymphocytes that have of CD56 cells. IL-6, despite having no effect by itself, enhances
cytolytic or noncytolytic functions typical of T cells, but do not NK cell activity in thymocytes cultured with IL-2. Finally, IL-15
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express a T cell receptor. The first described were cytolytic NK is involved in signaling NK cells for survival. Subsets of human
cells, which comprise about 10–15% of circulating lymphocytes NK cells develop on the basis of responsiveness to TGF-β and
(see Table 2.4). These cells are usually larger than typical lym- IL-10 (tolerant); IL-12 and IGF-1 (cytotoxic); and TGF-β, IL-7,
phocytes (10–12 µm), but have less nuclear material and more and IL-15. 40
cytoplasm. They possess electron-dense, peroxidase-negative
granules and a developed Golgi apparatus. Functional NK cells Noncytotoxic Innate Immune Cells
can be found in the fetal liver as early as 6 weeks’ gestation. These cells, which are similar in function to T-helper subsets,
These fetal NK cells express cytoplasmic CD3 proteins but no are divided into three main groups, ILC1, ILC2, and ILC3, defined
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TCR rearrangements. Evidence suggests that an Fcγ receptor– by the cytokines they produce. ILC1 cells are noncytotoxic
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positive cell that does not express lineage-specific markers (Lin ) Lin cells that produce INF-γ and TNF. ILC2 cells produce Th2
exists in the fetal mouse thymus, where it normally gives rise to cytokines, such as IL-4, -5, -9, and -13; and some produce
T cells. However, if removed from the thymus, the cells develop amphiregulin. ILC3 cells produce IL-17A, -17F, and -22; GM-CSF;