Immune response gets started in the secondary lymphoid organs

In this article, I briefly explain the beginning of the immune response in the secondary lymphoid organs.

Table of Contents

Development of lymphocytes

Development of lymphocytes takes place in the primary lymphoid system. However, the response is initiated in the secondary lymphoid organs as soon as the lymphocytes encounter antigens in the microenvironment.

The bone marrow and the thymus are the primary lymphoid organs. The B cells, along with monocytes, dendritic cells, and granulocytes, mature in the bone marrow. The maturation of T-lymphocytes takes place in the thymus. The major secondary lymphoid organs are the lymph nodes and the spleen, which filter out pathogens. They also help in maintaining the population of mature lymphocytes.

Knowing the lymphatic system

Immune cells are mobile and gain entry to tissues through blood and lymphatic systems. The lymphatic system in vertebrates is a part of the immune system, which is akin to the circulatory system. It includes a vast network of lymph nodes, lymphatic vessels, lymphoid organs, and lymphoid tissues.

The lymphatic system is an open system, unlike a closed circulatory system. The blood vessels connect almost every organ and tissue, which are lined with endothelial cells, giving a response to inflammatory signals.

The endothelial cells with the help of innate immune cells, give access to white blood cells to reach near infected cells. In a few minutes, the blood cells flow away from the heart through the arteries and travel back to the heart via veins.

Lymphatic vessels carry a clear fluid called lymph. Lymph is akin to blood plasma, and it contains waste products along with bacteria and proteins. Activated immune cells and antigens travel from sites of infection to secondary lymphoid organs through lymphatic vessels. They can encounter and activate lymphocytes at the secondary lymphoid organs.

Our circulatory system processes nearly 20 liters of blood every day through a process called capillary filtration, in which the plasma is separated from the blood. The blood vessels directly reabsorb nearly 17 liters of blood, leaving 3 liters of blood in the interstitial fluid.

The lymphatic system plays a major role by returning the remaining blood into the circulatory system through lymphatic vessels. If the interstitial fluid were not reverted into the circulation, then the tissues would swell causing edema, which could be life-threatening. This interstitial fluid bathes the tissues, accumulating cell debris and bacteria. After this, it ultimately drains into lymphatic capillaries and lymphatic vessels as lymph.

Lymph

The lymph is carried all over the body through lymphatic vessels. The primary lymphatic vessels possess thinner and porous walls than blood vessels and consist of a single layer of endothelial cells. These cells allow the easy and quick entry of fluid and cells into the lymphatic vessels.

The lymph is passed through the lymph nodes, which helps to filter out cellular debris, including bacteria and proteins. Afterward, the lymph is passed through the lymph ducts (larger lymph vessels). The largest lymphatic vessels include the thoracic duct, which drains the left side of the body and empties into the left subclavian vein.

The lymph from the right arm and right side of the head is collected into the right lymphatic duct, which drains into the right subclavian vein. By its precise way of working, the lymphatic system maintains steady levels of fluid within the circulatory system.

The lymphatic system also aids in activating the adaptive immune system by transporting immune cells and foreign antigens from the sites of infection to secondary lymphoid tissues and organs.

Secondary lymphoid organs: The inception of immunity

Secondary lymphoid organs initiate an adaptive response when lymphocytes get activated by the antigens. Activated lymphocytes undergo clonal expansion and maturation. The matured lymphocytes recirculate between the blood and secondary lymphoid organs to encounter specific antigens.

The secondary lymphoid organs include lymph nodes and spleen. However, the lymph nodes are the specialized dedicated organs for regulating immune response. A lymph node is an encapsulated, bean-shaped structure that consists of an organized collection of lymphoid tissue through which lymph passes back to blood.

The lymph nodes are filled with lymphocytes, macrophages, and dendritic cells and are the first organized lymphoid structures to encounter antigens. They establish a connection with both the blood vessels and the lymphatic vessels and also provide a suitable micro-environment for antigen-lymphocyte interaction.

A brief description of the lymph node

The lymph node (Figure 1) has three-layered partitions, i.e., outer cortex, middle paracortex, and inner medulla. The outer cortex consists of mostly B-lymphocytes, immature T-lymphocytes, follicular dendritic cells, and macrophages. The layer just beneath the cortex (middle layer) is the paracortex, which consists of mostly T-lymphocytes (both mature and immature) and dendritic cells (migrated from tissues).

The paracortex has specialized high endothelial venules through which lymphocytes enter the lymph nodes. The medulla is the innermost layer, which is surrounded by the cortex on all sides except at the hilum, which is present as a depression on the surface of the lymph node, giving it a bean-shaped appearance.

The hilum is the point from which the efferent lymph vessel directly emerges from the lymph node. The arteries and veins that supply blood to the lymph node gain an entrance and exit through the hilum. The medulla consists of a small number of plasma cells (antibody-secreting cells).

The path of the antigen from infected tissues to the cortex of the lymph node goes through the afferent lymphatic vessels. This perforates the lymph node capsule at multiple sites and unloads lymph into the subcapsular sinus.

In the subcapsular sinus, resident antigen-presenting cells can capture particulate antigen and pass it on to other antigen-presenting cells. Otherwise, resident dendritic cells in the paracortex can process the particulate antigen and present it with peptide-MHC complex on the surface.

The activity of B cells in the lymph node

The B cells get activated in the lymph node and differentiate into plasma cells, which secrete antibodies. Both the B cells and T cells circulate in the blood and lymph and enter the lymph node regularly through high endothelial venules.

The lymphocytes get near the lymph node follicles by responding to some specific signals along with chemokines. A B cell encounters an antigen inside a B-cell follicle (lymph node follicle). The small, soluble antigens can easily get entry into a B-cell follicle. The larger antigens stay in the follicular dendritic cells, encountered by macrophages and non-antigen-specific B cells.

The B cell gets activated after the interaction of the B cell receptor with an antigen. Then, it processes the antigen and presents it as a peptide-MHC complex to a T-helper cell.

When the B cell is about to present a processed antigen, it changes its path and enters into the paracortex. The paracortex is the zone of abundance of T cells. The interaction of a T-cell with a MHC-antigen complex presented by a B-cell activates the B cell. The T cell emits activating signals, which help the B cell to proliferate and differentiate.

The activated B cells act differently

All activated B cells don’t follow a similar pathway rather, they act differently. Some activated B cells, instead of differentiating directly into plasma cells, choose a re-entry into the follicle. In doing so, they set up a germinal center and ultimately convert this follicle into a secondary follicle.

The follicle without a germinal center is termed a primary follicle. The proliferation and clonal selection of the B cells in germinal centers produce a colony of B cells. These B cells have the greatest affinity for a specific antigen. Within a week of the start of the infection, germinal centers are established and stay active for 3 weeks or more.

The activity of T cells in the lymph node

The T-lymphocytes like B-cells, enter the lymph node cortex through high endothelial venules of the bloodstream. These veins are lined with very long endothelial cells, which compress the T-cells into the functional tissue of the lymph node.

The naïve T cells, after entering the lymph node, start searching for MHC-peptide antigen complexes. They search it on the surfaces of antigen-presenting cells in the paracortex.

The T-cells find their respective MHC-peptide complex with the help of a fibroblastic reticular cells conduit system (an interconnected network). This interconnected network is formed by the fibroblast reticular cells. This network gives support to the lymphocytes and antigen-presenting cells via associated adhesion molecules and chemokines.

The conduit system contains tubules that only allow the movement of fluid with small molecules and antigens to flow along it. If the naïve T-cells are not able to find their compatible MHC-peptide complex, they leave through the efferent lymphatics in the medulla of the lymph node.

A T cell stops migrating when it engages its TCR (T cell receptor) with an MHC-peptide complex. Then, it stays in the lymph node for many days for proliferation. After proliferation, it gradually differentiates into effector cells with advanced functions. The T-cells develop into killer CD8⁺ T-lymphocytes and CD4⁺helper T-lymphocytes in secondary lymphoid organs.

The lymph node generates memory T cells and B cells

The memory T cells and B cells emerge by the interaction between the T cells and antigen-presenting cells or the interaction between the T-helper cells and B cells. The memory cells can remain in the lymph node or exit through the lymph node to circulate in other tissues.

The central memory cells are the memory T cells that stay inside lymphoid tissues. The effector memory T cells circulate among other tissues. A third variety of memory cells is the tissue-resident memory cells, which reside in peripheral tissues for a long and give an agile response to reinfection.

The spleen gives immune response to antigens in the bloodstream

The spleen is an organ found in the majority of vertebrates. In humans, the spleen is about 5 inches long, purple, and placed on the left side of the abdominal cavity. It is the largest secondary lymphoid organ.

It primarily filters the blood by trapping blood-borne antigens. The blood-borne antigens and lymphocytes get entry into the spleen through the splenic artery and exit through the splenic vein. The spleen recycles old blood cells and stores platelets and white blood cells.

Structure of the spleen

The structure of the spleen (Figure 2) shows that it is surrounded by an outer capsule. The capsule extends into the interior, due to which the spleen is divided into functionally similar lobes. In each splenic lobe, red pulp and white pulp are the two micro-environments being separated by the marginal zone.

The red pulp is the site where old red blood cells are destroyed and recycled. A network of sinuses populated by red blood cells, macrophages, and a few lymphocytes constitute the red pulp. The branches of the splenic artery are surrounded by the white pulp composed of nodules known as the Malpighian corpuscles.

The Malpighian corpuscles are composed of the lymphoid follicles and the periarteriolar lymphoid sheath(PALS). The lymphoid follicles are rich in B-lymphocytes, and the PALS is populated with T-lymphocytes.

The white pulp gives an active immune response through both humoral and cell-mediated pathways. As in lymph nodes, the lymphoid follicles (B-cell follicles) develop germinal centers during an immune response.

The marginal zone consists of specialized dendritic cells, macrophages, and marginal zone B cells. These B cells are the first line of defense against blood-borne pathogens. The B cells trap antigens entering through the splenic artery.

After binding with the target antigen, the marginal B cells differentiate rapidly and secret high levels of antibodies. These B cells possess unique B cell receptors along with the toll-like receptors. The B cell receptors recognize conserved molecular patterns in antigens, whereas toll-like receptors are the innate immune receptors.

Starting the adaptive immune response in the spleen

The process of adaptive response initiation varies in the spleen and lymph nodes. In the spleen, the naïve B cells and T cells encounter antigens differently. The B cells interact with the antigens in the follicles. However, the CD8⁺ and CD4⁺ T cells meet antigens presented as MHC-peptide complexes on the surface of dendritic cells in the PALS.

The activated T-helper cells help to activate the B cells and CD8⁺ T cells. Some activated B cells, along with some T helper cells, create germinal centers in the spleen. The B cells in the germinal center may become memory cells or plasma cells circulating in different tissues.

The skin and mucosal tissues possess secondary lymphoid tissue

Apart from the spleen and lymph node, the skin and mucosal tissues ( barrier tissues) also have T-cell zones and lymphoid follicles. The skin and mucosal membranes of the digestive, respiratory, and urinogenital tracts are lined with epithelial cells.

These delicate membrane surfaces are given protection by a group of organized lymphoid tissues known as the mucosal-associated lymphoid tissues (MALT). There are different mucosal areas associated with different lymphoid tissues. These tissues can be categorized as gut-associated lymphoid tissue (GALT), skin-associated lymphoid tissue (SALT), nasal-associated lymphoid tissue (NALT), and bronchus-associated lymphoid tissue (BALT).

These tissues play a vital role by providing us with innate immunity. The epithelial cells secret cytokines, chemokines, and antimicrobial substances to give an active pathogen response. The innate and adaptive immune cells in the skin and mucosal tissues provide our first response to pathogens. They also help us maintain tolerance to commensal microbes.

Conclusion

The lymphocyte development takes place in the primary lymphoid system. However, the immune response gets started in the secondary lymphoid organs.

The lymphatic system in vertebrates includes a vast network of lymph nodes, lymphatic vessels, lymphoid organs, and lymphoid tissues. The activated immune cells and antigens travel from sites of infection to secondary lymphoid organs through lymphatic vessels.

The lymph nodes are filled with lymphocytes, macrophages, and dendritic cells and are the first organized lymphoid structures to encounter antigens. The lymph node produces memory T cells and B cells.

The spleen filters the blood by trapping blood-borne antigens. Some activated B cells, along with some T-helper cells, create germinal centers in the spleen while traveling back to follicles.

Different mucosal areas associated with different lymphoid tissues play a vital role in providing us with innate immunity. These can be categorized as gut-associated lymphoid tissue (GALT), skin-associated lymphoid tissue (SALT), nasal-associated lymphoid tissue (NALT), and bronchus-associated lymphoid tissue (BALT).