In this article we will discuss about the primary and secondary lymphoid organs of immune system.
Primary or Central Lymphoid Organs:
Immature lymphocytes generated in hematopoiesis, the process of formation and development of blood cells, mature and become committed to a particular antigenic specificity within the primary lymphoid organs, namely, thymus, bursa of Fabricius (in birds) and bone marrow (in mammals). A lymphocyte becomes immuno-competent, i.e., capable of mounting an immune response only after it matures within a primary lymphoid organ.
Thymus is a greyish, flat, bilobed lymphoid organ situated above the heart and extending into the neck on the front and sites of trachea. It develops from the epithelium of third and fourth pharyngeal pouches and, on maturity, acts as the site of development and maturation of lymphocytes named thymus-derived lymphocytes or T-lymphocytes or T-cells.
The thymus reaches peak activity in childhood and attains its largest size at puberty. Thereafter, the thymus begins to atrophy without any apparent effect on T-lymphocyte function and is extremely small in old age.
For convenience, the average weight of the thymus is 70 g in infants and its age- dependent involution leaves the thymus with an average weight of 3 g in the old age. This is probably due to the fact that T-lymphocytes are very long-lived and can circulate in the resting state for long periods of time.
Each lobe of thymus is surrounded by a capsule and is divided into a series of lobules, which are separated from each other by strands of connective tissue called trabeculae. Each lobule is organized into two compartments-outer and inner. The outer component is called cortex, whereas the inner component is called medulla (Fig. 42.2).
The cortex is densely packed with thymocytes, whereas the medulla is sparsely populated with thymocytes. Thymocytes develop from prothymocytes. The latter are produced in bone marrow, migrate through blood stream, enter the cortex of the thymus, and act as thymocytes. Thymocytes divide rapidly in the cortex and give rise to T-lymphocytes.
Of the T-lymphocytes produced in thymus only 5% leave the thymus as viable cells. Though the reason for this apparent wasteful process is not known, some believe that it is the elimination of T-lymphocyte clones that react against self.
Both the cortex and the medulla of the thymus are criss-crossed by a three dimensional network consisting of epithelial cells, dendritic cells, and macrophages, which make up the framework of the organ and contribute to the growth and maturation, of thymocytes.
Some epithelial cells of the outer cortex possess long membrane extensions that surround as many as 50 thymocytes. These cells are called nurse cells. Other epithelial cells of the cortex have long interconnecting cytoplasmic extensions that form a network and have been found to interact with many of the thymocytes when they traverse the cortex.
The function of the thymus is to generate T-lymphocytes and to confer immunological competence on to them during their stay in the organ. T-lymphocytes so educated in the thymus become capable of mounting cell-mediated immune response against appropriate antigen.
This is effected under the influence of the thymic microenvironment and several hormones such as thymosin and thymopietin produced by the epithelial cells of the thymus. The competent T-lymphocytes immediately move from thymus to the secondary or peripheral lymphoid organs.
2. Bursa of Fabricius:
Bursa of Fabricius is a primary lymphoid organ in birds where stem cells from yolk sac, foetal lever, and bone marrow mature, proliferate, and differentiate into bursa-derived lymphocytes called B-lymphocytes or B-cells.
Bursa of Fabricius arises as a pouch from the dorsal part of cloaca (fluid gut) in birds, Bursa of Fabricius is sensitive to hormones: administration of testosterone at the early embryostage completely prevents its formation (hormonal bursectomy).
Surgical removal of bursa (bursectomy) from newly hatched chickens destroys their subsequent ability to produce antibodies. The B-cells mature, proliferate, and differentiate into bursa and then migrate from it and reach outer or superficial cortex of the germinal follicles and medullary cords of peripheral lymph nodes and lymphoid follicles of spleen where, following appropriate antigenic stimulation, transform into plasma cells and secrete antibodies. Like thymus, the bursal of Fabricius starts to shrink or atrophy at puberty.
3. Bone Marrow:
Bone marrow is the site of origin and development of B-lymphocytes or B-cells (bone marrow derived lymphocytes) in mammals particularly in humans and mice after birth. Before birth, the yolk sac, foetal lever, and total bone marrow are the major sites of B-lymphocyte maturation. Bone marrow, therefore, is the mammalian equivalent of the bursa of Fabricius in birds.
Development of B-lymphocytes (B-cells) begins with the differentiation of lymphoid stem cells into the earliest distinctive progenitor B cells (pro-B cell), which proliferate within the bone marrow filling the extravascular spaces between large sinusoids in the shaft of a bone.
Proliferation and differentiation of pro-B cells into precursor B cells (pre-B cells) requires the microenvironment provided by the bone marrow stromal cells.
The stromal cells within the bone marrow:
(1) Interact directly with the pro-B and pre-B cells and
(2) Secrete various cytokines that are required for development.
Bone marrow is not the site of origin and development of B-lymphocytes (B-cells) in all mammals. In cattle and sheep, the fietal spleen is the primary lymphoid tissue wherein the maturation, proliferation, and diversification of B-cells take place during early gestation.
During later gestation this function is performed by ideal Peyer’s patch, a patch of tissue embedded in the wall of the intestine. In rabbit, gut-associated tissues (e.g.. appendix) act as primary lymphoid tissue for maturation, proliferation, and diversification of B-cells.
Secondary or Peripheral Lymphoid Organs:
As stated earlier, the lymphocytes mature, proliferate, and differentiate in the primary or central lymphoid organs. These lymphocytes migrate therefrom via circulation to the secondary or peripheral lymphoid organs. Here they bind appropriate antigens and undergo further antigen-dependent differentiation.
Once in the secondary lymphoid organs, the lymphocytes do not remain there but move from one lymphoid organ to another through the blood and lymphatic’s. The passage of lymphocytes facilitates the induction of an immune response. Lymph nodes and the spleen are the most highly organized secondary or peripheral lymphoid organs, whereas mucosa-associated lymphoid tissue (MALT) is the less organized lymphoid tissue.
1. Lymph Nodes:
Lymph nodes are small, encapsulated, bean-shaped structures clustered at junctions of the lymphatic vessels which are distributed throughout the body. Lymph nodes contain a reticular network packed with lymphocytes, macrophages and dendritic cells, and filter out pathogenic microorganisms and antigens from the lymph.
As the lymph percolates through a lymph node, any pathogen or antigen that is brought in with the lymph is trapped by the phagocytic cells and dendritic cells.
A lymph node consists of three regions: the cortex, the paracortex, and the medulla (Fig. 42.3). Cortex is the outermost region and contains several rounded aggregates of lymphocytes (mostly B-lymphocytes), macrophages, and follicular dendritic cells arranged in primary follicles. Each follicle has a pale-staining germinal centre surrounded by small dark-staining lymphocytes.
The deeper region lying beneath the cortex is the paracortex. It is the zone between the cortex and the medulla. Paracortex possesses large number of T-lymphocytes and also contains inter-digitating dendritic cells thought to have migrated from tissues to the lymph node.
Because of the presence of large number of T-lymphocytes in it. the Para-cortex is also referred to as a thymus-dependent area in contrast to the cortex which is a thymus-independent area. Medulla, the inner most region of lymph node, is more sparsely populated with lymphoid-lineage cells. Of the lymphoid-lineage cells present, many are plasma cells actively secreting antibody molecules.
Each lymph node has a number of lymph vessels called afferent lymphatic vessels, which pierce the capsule of a lymph node at numerous sites and empty lymph into the sub-capsular sinus. The lymph now percolates slowly inward through the cortex, paracortex, and medulla, allowing phagocytic cells and dendritic cells to trap pathogens and antigens carried by the lymph.
The lymph then is drained into a single large lymph vessels called efferent lymphatic vessel that carries the lymph to the thoracic duct, which empties into a large vein in the neck.
The spleen, which is about 5 inches long and 200 g in weight in adults, is an ovoid encapsulated, and the largest secondary or peripheral lymphoid organ. Spleen is specialized for trapping blood-borne antigens and is present high in the left abdominal cavity and being encapsulated, its capsule extends a number of projections, called trabeculae, into the interior resulting in the formation of compartments.
These compartments are filled by two types of tissues, the red pulp and white pulp, which are separated by a diffuse marginal zone (Fig. 42.4). The red pulp consists of a network of sinusoids populated by large number of erythrocytes (red blood cells) and macrophages and few lymphocytes.
In fact, red pulp is the region where old and defective erythrocytes are destroyed and eliminated. The white pulp consist of the branches of the splenic artery that make a periarteriolar lymphoid sheath (PALS) populated heavily by T-lymphocytes.
Periarteriolar lymphoid sheath (PALS) is attached with primary lymphoid follicles that are rich in B-lymphocytes. The marginal zone separating the red pulp from white pulp is populated by lymphocytes and macrophages.
When the blood-borne antigens enter the spleen the B- and T-lymphocytes present in periarteriolar lymphoid sheath (PALS) are initially activated. Here interdigitating dendritic cells capture antigen and present it combined with class II MHC molecules (major histocompatibility molecules) to TH cells (T helper cells). Once activated, these TH cells can then activate B- lymphocytes (B-cells).
The activated B-lymphocytes, together with some TH cells then migrate to primary follicles in the marginal zone. When the primary follicles are challenged by antigen, they differentiate into characteristic secondary follicles.
The latter contain germinal centres (similar to those occurring in lymph nodes) where rapidly dividing B-lymphocytes and plasma cells are surrounded by dense clusters of concentrically arranged lymphocytes.
3. Mucosal-Associated Lymphoid Tissue (MALT):
The mucous membranes lining the alimentary, respiratory, and genitourinary systems have a very large combined surface area (about 400 m2; nearly the size of a basketball court), which is constantly exposed to numerous antigens and is the major site of entry for most pathogens.
These vulnerable membrane surfaces possess a group of organized lymphoid tissues which defend it from pathogens and antigens. The group of organized lymphoid tissues is known collectively as mucosal-associated lymphoid tissue (MALT).
There are several types of MALT; the most studied one is the gut-associated lymphoid tissue (GALT) which includes tonsils, Peyer’s patch, appendix, and loosely organised clusters of lymphoid cells in the lamina propria of intestinal villi.
Mucosal-associated lymphoid, tissue (MALT) is functionally very significant in immune system of the body because of the presence of large number of antibody-producing plasma cells in it. The number of plasma cells in MALT for exceeds that of the total of the number of plasma cells present in spleen, lymph nodes, and bone marrow.
There are three groups of tonsil present at three different locations: palatine, lingual, and pharyngeal (adenoids). Palatine group of tonsil occur at the sides of the back of the mouth; lingual in the basal region of the tongue; and pharyngeal (adenoids) in the roof of the nasopharynx (Fig. 42.5).
All the aforesaid tonsil groups are nodule-like and consist of a meshwork of reticular cells and fibres interspersed with lymphocytes, macrophages, granulocytes, and mast cells.
The B-lymphocytes are organised into follicles and germinal centres. The germinal centres are surrounded by regions showing T-lymphocyte activity. However, the tonsils protect against antigens that enter through the nausal and oral epithelial routes.
(ii) Peyer’s Patch:
Peyer’s patches occur in the sub-mucosal layer present beneath the lamina propria lying under the epithelial layer of intestinal villi. Each Peyer’s patch is a nodule of 30-40 lymphoid follicles. Like lymphoid follicles in other sites, those that compose Peyer’s patches can develop into secondary follicles with germinal centres (Fig. 42.6).
(iii) Lamina Propria:
Lamina propria occurs under the epithelial layer of intestinal villi (Fig. 42.6). It is populated with large number of plasma cells, macrophages, activated T helper cells (activated TH cells) in loose clusters. More than 15,000 lymphoid follicles have beer, reported within the lamina propria of a healthy child.