Secondary Lymphoid Organs And Lymphocyte Traffic
The ability to recirculate from blood to
tissues and back through the lymphoid
system is unique to lymphocytes and, coupled with their long lifespan and
specificity for individual antigens, equips them for their central role in
adaptive immune responses.
The thorough mixing of lymphocytes,
particularly in the spleen and lymph nodes, ensures the maximum
contact of antigen-presenting cells that have newly encountered antigen, with T
and B lymphocytes potentially able to respond, which would otherwise be a very
rare event. The body-wide dissemination of expanded T and B populations in
readiness for a second encounter with the same antigen ensures that ‘memory’ is
available at all sites.
Different types of lymphocyte
‘home’ to different regions in the lymphoid organs (T and B areas
in the figure; B areas are shaded). This ‘lymphocyte traffic’ is regulated by a
combination of chemotactic factors released from particular sites (mostly
members of the chemokine family; see Fig. 7) and direct contact via adhesion
receptors (sometimes known
as ‘addressins’ because
they direct lymphocytes to particular sites in the body)
between lymphocytes and the
extracellular matrix or other cells such as the inner surface of the vascular
endothelium or the dendritic antigen-presenting cells (not shown here, but see
Fig. 8). The introduction of a new form of fluorescent microscopy, known as
two-photon microscopy, has allowed the visualization of lymphocyte movement
within living lymphoid tissue.
In general, lymph nodes respond to
antigens introduced into the tissues they drain, and the spleen responds to
antigens in the blood. The gut, lungs, breast and external mucous surfaces also
have their own less specialized lymphoid areas that to some extent behave as a
separate circuit for recirculation purposes and are often known as the mucosa-associated
lymphoid tissues (MALT). These can be further subdivided into
gut-associated (GALT), bronchial-associated (BALT) and skin-associated (SALT)
lymphoid tissue. In each case, the objective seems to be to provide a local
lymphoid system specialized for the
antigens most likely to be encountered there.
Lymph nodes (or ‘glands’)
constitute the main bulk of the organized lymphoid tissue. They are
strategically placed so that lymph from most parts of the body drains through a
series of nodes before reaching the thoracic duct (TD), which empties
into the left subclavian vein to allow the lymphocytes to recirculate again via
the blood.
AL, EL Afferent and efferent lymphatics, through which lymph passes from the
tissues to first peripheral and then central lymph nodes. The cells found in
afferent and efferent lymph are quite different. Naïve T cells enter lymph
nodes from blood, but then leave via the efferent lymphatics, before eventually
rejoining the blood. Memory or effector T cells enter tissues at sites of
infection, and then travel back to lymph nodes via the afferent lymphatics.
Afferent lymph also carries antigen and dendritic cells (known as veiled cells
while in lymph) as they migrate from tissues such as the skin to the T-cell
areas of the lymph node.
S Lymphatic sinus, through which lymph flows from
the afferent lymphatic into the cortical and medullary sinuses. The lymph
carries antigens and antigen-presenting cells from tissues to lymphoid tissue,
and a series of fine collagen tubes runs from the cortical sinus into the
T-cell areas, facilitating the movement of antigens directly to the
antigen-presenting dendritic cells.
M Medullary sinus, collecting lymph for exit via
the efferent lymphatic. It is in the medulla that antibody formation takes
place and plasma cells are prominent.
G Germinal centre; an area of rapidly dividing
cells that develops within the follicle after antigenic stimulation. It is the
site of B memory-cell generation, and contains special follicular dendritic
cells that retain antigens on their surface for weeks and perhaps even years
(for further details see Fig. 19).
T T-cell area, or ‘paracortex’, largely occupied
by T cells but through which B cells travel to reach the medulla. The dendritic
cells here are specialized for presentation of antigen to T cells, and are
probably the site where T and B lymphocytes of the right specificity meet and
cooperate, which would otherwise be a very rare event.
PCV Post-capillary venule; a specialized small
venule with high cuboidal endothelium (known as a high endothelial venule
[HEV]) through which lymphocytes leave the blood to enter the paracortex and
thence the efferent lymphatic, ultimately returning to blood via the thoracic
duct.
The spleen differs from a lymph
node in having no lymphatic drainage, and also in containing large numbers of
red cells. In some species it can act as an erythropoietic organ or a reservoir
for blood.
T T-cell area; the lymphoid sheath surrounding
the arteries is mostly composed of T lymphocytes.
B B-cell area, or lymphoid follicle, typically
lying to one side of the lymphoid sheath. Germinal centres are commonly
found in the follicle, alongside the follicular artery.
MZ Marginal zone; the region between the lymphoid
areas and the red pulp, where lymphocytes chiefly leave the blood to enter the lymphoid
areas, and red cells and plasma cells enter the red pulp.
RP Red pulp; a reticular meshwork through which
blood passes to enter the venous sinusoids, and in which surveillance and
removal of damaged red cells is
thought to occur. For contrast, the lymphoid areas are some-times called ‘white
pulp’. Macrophages in the red pulp and in the marginal zone can retain
antigens, as the dendritic cells in the lymph nodes do. As in the medulla of
the lymph node, plasma cells are frequent.
S Sinusoids; the large sacs that collect blood
for return via the splenic vein.
Mucosa-associated lymphoid
tissues
At least 50% of all tissue
lymphocytes are associated with mucosal surfaces, emphasizing that these are
the main sites of entry of foreign material. It is estimated that the total
area of mucosal surfaces is 400 times that of the body, and that the number of
bacteria colonizing these surfaces is many times more than the total number of
cells in the body.
Gut The GALT is composed of two types of tissue: organized
and diffuse. Typical organized tissues are the lymphoid aggregates,
e.g. the Peyer’s patches analogous to the lymphoid follicles in lymph nodes.
The transfer of antigens from the gut lumen to the subepithelial area occurs
via specialized M (membrane) cells, which pass them to dendritic cells where
they are presented to T and B cells in the normal way. However, dendritic cells
within the epithelium may also extend processes between the epithelial cells
and take up antigens directly from the gut lumen. Although the ability to take
up antigens is important in starting an adaptive immune response, some
pathogens (e.g. HIV, Sal- monella) may use this ‘Trojan horse’ route to
invade their hosts.
Most of the B cells are specialized
for IgA production, and B-cell memory develops in germinal centres. Cells that
leave the follicles circulate in the blood to the diffuse lymphoid areas in the
lamina propria, where large numbers of IgA plasma cells are found, as
well as CD8+ γδ T cells, NK cells and mast cells. This preferential homing of
MALT cells to MALT sites is mediated by specialized surface molecules on the
lymphocytes and on the endothelium of blood vessel walls.
IgA Lamina propria B cells are responsible for the
majority of IgA antibody, although a small amount is made in other sites such
as bone marrow. IgA occurs mainly as dimers of two molecules held together by a
J (joining) chain (see Fig. 14). IgA is protected against proteolytic digestion
by a polypeptide secretory piece derived from the poly-Ig receptor and
added to the IgA dimers in the epithelial cells.
Pharynx Lymphoid aggregates are prominent at this
vulnerable site (tonsil and adenoids). The salivary glands also contain
lymphocytes of MALT origin.
Lung The lung alveoli are largely protected from
inhaled antigens by the upward movement of mucus propelled by beating cilia and
ultimately coughed up or swallowed (the ‘mucociliary escalator’). Organized and
diffuse lymphoid tissues are present in the walls of the bronchi (the upper
respiratory tract) but are absent from the lung alveoli (the lower respiratory
tract). However, alveoli contain large numbers of alveolar macrophages that
take up any debris or microorganisms that reach them. Alveolar macrophages can
rapidly recruit T lymphocytes if an infection develops.
Skin Antigens entering via the skin can reach the
local lymph node by being taken up in Langerhans’ cells (LC) or dermal
dendritic cells, which then can pass from the skin to the node, where they
settle in the T-cell areas. Alternatively, soluble antigens can travel directly
via the lymphatics to the draining lymph nodes. The skin also contains
specialized populations of T cells that have a rather limited range of specificities and may act as an initial barrier
to infection.
