Cells Involved In Immunity: The Haemopoietic System.
The great majority of cells involved in mammalian
immunity are derived from
precursors in the bone marrow (left half of figure) and circulate in the
blood, entering and sometimes leaving the tissues when required.
A very rare stem cell persists in the adult bone marrow (at a frequency of
about 1 in 100 000 cells), and retains the ability to differentiate into all
types of blood cell. Haemopeoisis has been studied either by injecting small
numbers of genetically marked marrow cells into recipient mice and observing
the progeny they give rise to (in vivo cloning) or by culturing the bone
marrow precursors in the presence of appropriate
growth factors (in vitro cloning). Proliferation and differentiation of
all these cells is under the control of soluble or membranebound growth
factors produced by the bone marrow stroma and by each other (see Fig. 24).
Within the cell these signals switch on specific transcription factors,
DNA-binding molecules which act as master switches that determine the
subsequent genetic programme, in turn giving rise to development of the
different cell types (known as line-ages). Remarkably, recent studies have
shown that it is possible to turn one
differentiated cell type into another by experimentally introducing the right
transcription factors into the cell. This finding has important therapeutic
implications, e.g. in curing genetic immunodeficiencies (see Fig. 33). Most
haemopoietic cells stop dividing once they are fully differentiated. However,
lymphocytes divide rapidly and expand following exposure to antigen. The increased
number of lymphocytes specific for an antigen forms the basis for immunological
memory.
A note on terminology
Haematologists recognize many
stages between stem cells and their fully differentiated progeny (e.g. for red
cells: proerythroblast, erythroblast, normoblast, erythrocyte). The suffix ‘blast’
usually implies an early, dividing, relatively undifferentiated cell, but is
also used to describe lymphocytes that have been stimulated, e.g. by antigen,
and are about to divide.
Bone marrow Unlike most other tissues or organs, the haemopoetic system is constantly renewing itself. In the
adult, the development of haemopoetic cells occurs predominantly in the bone
marrow. In the fetus, before bones develop, haemopoeisis occurs first in the
yolk sac and then in the liver.
Stroma Epithelial and endothelial cells that provide
support and secrete growth factors for haemopoiesis.
S Stem cell; the totipotent and self-renewing
marrow cell. Stem cells are found in low numbers in blood as well as bone
marrow and the numbers can be boosted by treatment with appropriate growth
factors (e.g. G-CSF), which
greatly facilitates the process of bone marrow transplantation (see Fig. 39).
LS Lymphoid stem cell, presumed to be capable of
differentiating into T or B lymphocytes. Very recent data suggest that the
distinction between lymphoid and myeloid stem cells may in fact be more
complex.
HS Haemopoietic stem cell: the precursor of spleen
nodules and probably able to differentiate into all but the lymphoid pathways,
i.e. granulocyte, erythroid, monocyte, megakaryocyte; often referred to as
CFU-GEMM.
ES Erythroid stem cell, giving rise to
erythrocytes. Erythropoietin, a glycoprotein hormone formed in the kidney in
response to hypoxia, accelerates the differentiation of red cell precursors and
thus adjusts the production of red cells to the demand for their
oxygen-carrying capacity, a typical example of ‘negative feedback’.
GM Granulocyte–monocyte common precursor; the
relative proportion of these two cell types is regulated by ‘growth-’ or
‘colony- stimulating’ factors (see Fig. 24).
Cloning The potential of individual stem cells to give
rise to one or more types of haemopoetic cells has been explored by isolating
single cells and allowing them to divide many times, and then observing what
cell types can be found among the progeny. This process is known as cloning (a
clone being a set of daughter cells all arising from a single parent cell).
Evidence suggests that in certain conditions a single stem cell can give rise
to all the fully differentiated cells of an adult haemopoetic system.
Neutrophil (polymorph) The most common leucocyte in human
blood, a short-lived phagocytic cell whose granules contain numerous
bactericidal substances. Neutrophils are the first cells to leave the blood and
enter sites of infection or inflammation.
Eosinophil A leucocyte with large refractile granules that
contain a number of highly basic or ‘cationic’ proteins, possibly important in
killing larger parasites including worms.
Basophil A leucocyte with large basophilic granules that
contain heparin and vasoactive amines, important in the inflammatory response.
The above three cell types are often
collectively referred to as ‘granulocytes’.
MK Megakaryocyte: the parent cell of the blood platelets.
Platelets Small cells responsible for sealing damaged
blood vessels (‘haemostasis’) but also the source of many inflammatory
mediators (see Fig. 7).
Monocyte A precursor cell in blood developing into a macrophage when it migrates into the tissues. Additional
monocytes are attracted to sites of inflammation, providing a reservoir of
macrophages and perhaps also dendritic cells.
Macrophage The principal resident phagocyte of the tissues
and serous cavities such as the pleura and peritoneum (see Fig. 8).
DC (dendritic cell) Dendritic cells are found in all tissues of
the body (e.g. the Langerhans’
cells of the skin) where they take up antigen and then migrate to the T-cell
areas of the lymph node or spleen via the lymphatics or the blood. Their major
function is to activate T-cell immunity (see Fig. 18), but they may also be
involved in tolerance induction (see Fig. 22). A second subset of plasmacytoid
DC (a name that derives from their morphological resemblance to plasma cells)
are the principal producers of type I interferons, an important group of
antiviral proteins. Although experimentally, dendritic cells are often derived
from myeloid cells, the developmental lineage of dendritic cells in bone marrow
is still the subject of debate.
NK (natural killer) cell A lymphocyte-like cell capable of killing some
virus-infected cells and some tumour cells, but with complex sets of receptors
that are quite distinct from those on true lymphocytes (for more details see
Fig. 10). NK cells and T cells may share a common precursor.
T and B lymphocytes T (thymus-derived) and B (bone marrow- derived
or, in birds, bursa-derived) lymphocytes are the major cellular components of
adaptive immunity and are described in more detail in Fig. 15. B lymphocytes
are the precursor of antibody-forming cells. In fetal life, the liver may play
the part of ‘bursa’.
Plasma cell A B cell in its high-rate antibody-secreting
state. Despite their name, plasma cells are seldom seen in the blood, but are
found in spleen, lymph nodes, etc., whenever antibody is being made. Plasma
cells do not divide and cannot be maintained for prolonged periods in vitro.
However, B lymphocytes producing specific antibody can be fused with a tumour
cell to produce an immortal hybrid clone or ‘hybridoma’, which continues to secrete
antibody of a predetermined specificity. Such monoclonal antibodies have
proved of enormous value as specific tools in many branches of biology, and
several are now being used routinely for the treatment of autoimmune disease
(see Fig. 38) and cancer (see Fig. 42).
Mast cell A large tissue cell derived from the
circulating basophil. Mast cells are rapidly triggered by tissue damage to
initiate the inflammatory response which causes many forms of allergy (see Fig.
35).
Growth factors The molecules that control the proliferation
and differentiation of haemopoietic cells are often also involved in regulating
immune responses – the interleukins or cytokines (see Figs 23 and 24). Some of
them were first discovered by haematologists and are called ‘colony-stimulating
factors’ (CSF), but the different names have no real significance, and indeed
one, IL-3, is often known as ‘multi- CSF’. Growth factors are used in clinical
practice to boost particular subsets of blood cell, and erythropoietin was one
of the first of the new generation of proteins produced by ‘recombinant’
technology to be used in the clinic, and also by athletes wishing to increase
their red cell numbers.
