Secondary Lymphoid Organs
sites where lymphocytes interact with antigen and with other cells of the immune system
In mammals:
lymph nodes
spleen
MALT (Mucosal-associated lymphoid tissue)
BONE MARROW
All cells of the blood orginate from pluripotent stem cells in the bone marrow.
Animals including humans will die when given high dose radiation because stem cells will be destroyed. Theoretically 1 stem cell can reconstitute the animal.
In addition:
Bone Marrow serves as site of maturation of B lymphocytes in most mammals studied to date.
Because there is not a discrete site, the process is very difficult to study. **There is known to be a selection process. Stromal cells in the bone marrow very important in this process. Soluble factors are not as well characterized in the bone marrow but IL-7 is known to be an important signal. Many pre-B cells die in the bone marrow. If they do not form functional Ig molecules or if they possess Ig molecules which recognize and bind to self antigens. B cells that survive this selection process leave the bone marrow through efferent blood vessels.
THYMUS
Flat, bilobed organ situated above the heart and below the thyroid gland. Each lobe is surrounded by a capsule and is divided into lobules, which are separated from each other by strands of connective tissue called trabeculae. Each lobule is organized into two compartments: the cortex (outer compartment) the medulla (inner compartment).
Cortex and Medulla are both crisscrossed by a 3D network of stromal cells composed of:
loosely packed epithelial cells
interdigitating dendritic cells
macrophages
These cells physically interact with the developing T cells as well as secreting soluble factors which influence T cell maturation. In cortex, network is densely packed with thymocytes and less dense in medulla. In medulla, the epithelial cells are more visible and you also find HASSAL's Corpuscles. Function Unknown.
The thymus is at its largest relative size at birth and its largest actual size is at puberty. Following puberty the thymus begins to shrink. In elderly individuals hardly any of it left. Relationship between aging and a decline in immune responsiveness. Stress can also result in shrinkage of the thymus.
Please see figure in text.
Progenitor T cells enter thymus from the blood (no afferent lymphatic vessels] and mature into functional T lymphocytes. Progenitor T cells first enter the cortex which is densely packed with cells due to tremendous degree of proliferation. However, the vast majority of these cells are destined to die due to (APOPTOSIS) - programmed cell death. The T cells (thymocytes) go through a selection process in the thymus based upon the TcR that they possess. Only T cells which can recognize self MHC + foreign peptides are allowed to mature. An estimated 95-99% of the T cells die.
Actually the process of thymic education is a two-step process in which Thymic cortical epithelial cells function as the effector cells in a process known as POSITIVE SELECTION.
In positive selection, T cells which bear a TcR which can bind SELF-MHC are selected to survive and proliferate. Cells which are not positively selected are triggered to undergo APOPTOSIS.
Positively selected thymocytes must go through a second phase of selection known as NEGATIVE SELECTION.
During negative selection any T cell that is presented antigen + MHC within the thymus is triggered to undergo APOPTOSIS.
The self peptides encountered in the thymus are derived from proteins expressed in thymus + other proteins brought to the thymus via the blood stream. Of course not all potentially auto-reactive T cells can be deleted and peripheral deletion of autoreactive T cells is also important. Negative selection can apparently be mediated by a variety of different cell types. Most importantly:: thymic macrophages and dendritic cells
The surviving T cells migrate to the medulla where they continue maturation and finally leave the thymus through the postcapillary venules or efferent lymphatics.
Stromal cells secrete soluble factors which are important in T cell maturation.
alpha- 1- thymosin
beta - 4- thymosin
thymopoietin
thymulin
Individual roles not well known but all are relatively small 1-15kDa.
In addition, IL-7 also known to play a role in T cell maturation within the thymus.
Peyer's Patches
Peyer's patches are areas of lymphoid tissue located in the wall of the intestine, and in some mammalian species such as sheep and rabbits, Peyer's patches have a function similar to the bursa of birds. B cell differentiation and maturation.
Actually: Two types of Peyer's patches seem to occur: one with primary lymphoid function and one type with secondary lymphoid function.
LYMPH NODES
Encapsulated bean-shaped structures (normally <1 cm in diameter) containing a reticular network packed with lymphocytes, macrophages, and dendritic cells. They are present at the junctions of lymphatic vessels. Serve as the first organized structures to encounter most antigens. The major function of the lymph nodes is to filter antigen from the lymph.
3 regions to the lymph node
Cortex (outermost layer- contains mostly B lymphocytes, follicular dendritic cells and macrophages arranged in clusters called primary follicles). Following antigenic stimulation they primary follicles become secondary follicles consisting of concentric rings of densely packed lymphocytes and central lymphocytes, macrophages, and dendritic cells. The GCs (germinal centers) contain large proliferating B lymphocytes and plasma cells interspersed with macrophages and dendritic cells. The GC is a site of intense B-Cell activation and differentiation into plasma cells and memory cells.
Paracortex - layer just beneath the cortex
It is an area populated with T lymphocytes and also interdigitating dendritic cells. It is an important site for T cell activation by these APCs.
Medulla- inner most layer, more sparsely populated
Many of the cells are plasma cells so there is a fairly high concentration of immunoglobulin at this site.
Please see figure in text.
-Afferent lymphatic vessels pierce the capsule of a lymph node at various sites and empty into the subcapsular sinus. There is a single efferent lymphatic vessel leading from the lymph node.
- High antibody concentration in the lymph leaving via the efferent lymphatic vessel and 50X more lymphocyes than in the afferent lymphatic vessels. This is due to proliferation of lymphocytes within the lymph node and due to an influx of lymphocytes from the circulatory system.
-There is an affferent artery which enters the lymph node. Lymphocytes can enter the node by passing between specialized capillary endothelial cells in the postcapillary venules. This process is called extravasation.
Antigenic stimulation can enhance this process 10X.
Therefore, the concentration of lymphocytes in the lymph nodes can increase greatly following antigenic stimulation accounting for "swelling of lymph nodes".
-LYMPH- fluid from the tissues flows from the intercellular tissue spaces into lymphatic capillaries and then into a series of larger collecting vessels called lymphatic vessels. Lymphatic vessels converge into the thoracic duct, which returns the fluid to the circulatory system by dumping into the left subclavian vein.
-The lymphatics carry the lymph through regional lymph nodes, where it filters through a cellular network containing reticular dendritic cells and phagocytic cells which trap antigen carried by the lymph.
SPLEEN
The spleen is a large, oval secondary lymphoid organ positioned high in the left abdominal cavity. Spleen is adapted to filter the blood, it responds therefore to systemic infections. It is surrounded by a capsule, which sends trabeculae into the interior to form a compartmentalized structure. Two types of compartments with a Marginal Zone in between:
Red Pulp- Network of sinusoids populated with macrophages and numerous erythrocytes. Site where old RBCs are destroyed and removed.
White Pulp- Surrounds the splenic arteries, forming a periarteriolar lymphoid sheath (PALS) populated mainly by T lymphocytes. Clusters of B lymphocytes in the PALS form primary follicles occupying a more peripheral position. Upon antigenic challenge, these primary follicles develop into characteristic secondary follicles containing germinal centers.
THe spleen is NOT supplied by afferent lymphatics. Blood-borne cells and antigens are carried into the spleen through the splenic artery, which empties into the marginal zone. Antigen enters the marginal zone, it is trapped by interdigitating dendritic cells, which carry the antigen to the PALS. More re-circulating lymphocytes pass daily through the spleen than all of the lymph nodes combined.
Please see figure in text
Mucosal-Associated Lymphoid Tissue (MALT)
A variety of lymphoid tissues are found at various locations along mucous membrane surfaces [digestive system, respiratory system and urogenital system]. Major role appears to be as secondary lymphoid tissue. Probably most antigens enter the body through this route so incredibly important and previously under-emphasized.
GALT gut associated lymphoid tissue - dispersed
BALT bronchus associated lymphoid tissue - dispersed
There are also organized clusters: tonsils, appendix, Peyer's patches
3 tonsil groups: lingual at base of tongue, palatine at side of back of mouth, nasopharyngeal in the roof of the nasopharynx [adenoids]
Antigens are delivered across the epithelial cell boundary of the mucosa by M cells. The M cells have broad membrane processes on the lumen side and a deep pocket in basolateral plasma membrane for clusters of B cells, T cells, and macrophages.
Please see figures in text.
Antigens are endocytosed into vesicles that are transported to the cells in the pocket. MHC is expressed but it is not known if presentation to Th cells occurs. Presentation to B cells does occur. The B cells leave the follicles and go to diffuse MALT where they differentiate into PLASMA CELLS and secrete IgA
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