A growing number of diseases can be treated with a bone marrow transplant or haematopoietic stem cell transfer; this is often achieved by harvesting suitable donor stem cells from the posterior iliac crests of the hip bone, where the concentration of red bone marrow is highest.
The thymus gland is a bi-lobed, pinkish-grey organ located just above the heart in the mediastinum, where it rests below the sternum breastbone. Structurally, the thymus resembles a small bow tie, which gradually atrophies shrinks with age. In pre-pubescents, the thymus is a relatively large and very active organ that, typically, weighs around 40g, but in a middle-aged adult it may have shrunk sufficiently to be difficult to locate.
Each of the two lobes of the thymus is surrounded by a capsule, within which are numerous small lobules — typically measuring mm in width — which are held together by loose connective tissue.
Lobules have two distinct areas:. In addition to being a major lymphoid organ, the thymus is also recognised as part of the endocrine system because it secretes a family of hormones collectively referred to as thymosin; this is a group of several structurally related hormones secreted by the thymic epithelial cells. These hormones are essential for normal immune function and many members of the thymosin family are used therapeutically to treat cancers, infections and diseases such as multiple sclerosis Severa et al, T-cells originate as haematopoietic stem cells from the red bone marrow Fig 2.
A population of these haematopoietic stem cells infiltrate the thymus, dividing further within the cortical regions of the lobules then migrating into the medullary regions to mature into active T-cells; this process of T-cell maturation is controlled by the hormone thymosin. The importance of these cells is apparent in patients who have depleted T-cell populations, such as those infected with HIV.
This process allows mature T-cells to distinguish foreign, and therefore potentially pathogenic, material from antigens that belong to the body. It has been demonstrated that removal of the thymus may lead to an increase in autoimmune diseases, as this ability to recognise self is diminished Sherer et al, Diseases of the thymus include thymic cancer and myasthenia gravis MG. MG occurs when the thymus produces antibodies that block or destroy the muscle-receptor sites, causing the muscles to become weak and easily tired.
It most commonly affects muscles that control the eyes and eyelids, resulting in droopy eyelids and difficulty making facial expressions; chewing, swallowing and speaking also become difficult. In most cases of either MG or thymic cancer, thymectomy is recommended.
Patients who have had a thymectomy may develop an immunodeficiency known as Good syndrome, which increases their susceptibility to bacterial, fungal and viral opportunistic pathogens; this condition is, however, relatively rare. When foreign antigens reach these organs, they initiate lymphocyte activation and subsequent clonal expansion and maturation of these important white blood cells.
Mature lymphocytes can then leave the secondary organs to enter the circulation, or travel to other areas, and target foreign antigens. The spleen is the largest lymphoid organ. Due to its extensive vascularisation, the spleen is a dark-purplish oval-shaped organ; in adults it is approximately 12cm long, 7cm wide and weighs around g.
However, the size of the spleen can vary with circumstance: it diminishes in starvation, after heavy exercise and following severe haemorrhage Gujar et al, , and recent investigations indicate an increase in size in well-fed individuals and during the ingestion of food Garnitschnig et al, Blood enters the spleen from the splenic artery and leaves via the splenic vein, both of which are at the hilum; the splenic vein eventually becomes a tributary of the hepatic portal vein.
White pulp is a mass of germinal centres of dividing B-lymphocytes B-cells , surrounded by T-cells and accessory cells, including macrophages and dendritic cells; these cells are arranged as lymphatic nodules around branches of the splenic artery.
As blood flows into the spleen via the splenic artery, it enters smaller, central arteries of the white pulp, eventually reaching the red pulp. Splenic cords are made up of red and white blood cells and plasma cells antibody-producing B-cells ; therefore, the red pulp primarily functions as a filtration system for the blood, whereas the white pulp is where adaptive T- and B-cell responses are mounted.
The lymphatic nodules are arranged as sleeves around the blood vessels, bringing blood into the spleen. Within the white pulp are splenic nodules called Malpighian corpuscles, which are rich in B-cells, so this portion of lymphoid tissue is quick to respond to foreign antigenic stimulation by producing antibodies.
The walls of the meshwork of sinuses in the red pulp also contain phagocytes that engulf foreign particles and cell debris, effectively filtering and removing them from circulation. The haemoglobin is then split apart into haem and globin. The globin is broken down into its constituent amino acids, which can be utilised in the synthesis of a new protein.
Haem consists of an iron atom surrounded four non-iron pyrrole rings. The iron is removed and transported to be stored as ferritin, then reused to make new haemoglobin in the red bone marrow; macrophages convert the pyrrole rings into the green pigment biliverdin and then into the yellow pigment bilirubin.
Both are transported to the liver bound to plasma albumin. Bilirubin, the more toxic pigment, is conjugated in the liver to form a less toxic compound, which is excreted in bile. In some animals — particularly athletic mammals such as horses, greyhounds and foxes — the spleen is also an important reservoir of blood, which is released into circulation during times of stress to improve aerobic performance. In humans, however, the spleen contributes only a small percentage of blood cells into active circulation under physiological stress; the total stored blood volume is believed to be only ml Bakovic et al, The capsule of the spleen may contract following haemorrhage, releasing this reserve into circulation in the body.
As the spleen is the largest collection of lymphoid tissue in the body, infections that cause white blood cell proliferation and antigenic stimulation may cause germinal centres in the organ to expand, resulting in its enlargement splenomegaly. This happens in many diseases — for example, malaria, cirrhosis and leukaemia.
The spleen is not usually palpable, but an enlarged spleen is palpable during deep inspiration. Enlargement may also be caused by any obstruction in blood flow, for example in the hepatic portal vein. The anatomical position of the spleen coincides with the left tenth rib. Age-dependent cell trafficking defects in draining lymph nodes impair adaptive immunity and control of West Nile virus infection. PLoS Pathog e Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance.
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Immune responses then continue in a similar manner to the spleen with germinal centres being formed at the T-B border. Stromal cells such as blood endothelial cells which form high endothelial venules and lymphatic endothelial cells help coordinate the movement of cells into, and out of, the blood and lymphatic fluid, respectively Rouse et al.
Structural organisation of lymph nodes and changes with age. On the afferent side of the lymph nodes B cell follicles form distinct follicles in the cortex. Adjacent to the follicle are the T cells in the paracortical area.
In the medullary region medullary cord and medullary sinus macrophages are found. In aged lymph nodes B cell follicles no longer form distinct follicles and there is an increase in macrophage populations, especially in the medullary region.
There are three main types of macrophages in the lymph node Fig. Medullary sinus and medullary cord macrophages are situated in the medullary region and are important in the clearance of pathogens and antigens from the lymph. Subcapsular sinus macrophages, in contrast, are present in a thin layer surrounding the node under the capsule and are adjacent to B cell follicles. Lymphatic fluid enters from the afferent side of the lymph node into the subcapsular sinus region.
Thus, these macrophages are the first cells in the lymph node that are exposed to the lymphatic fluid Gray and Cyster Subcapsular sinus macrophages are a distinct, poorly endocytic and degradative macrophage subset Phan et al.
These unique cells capture antigen-containing immune complexes arriving in the lymph node via cell processes that they extend into the lumen of the subcapsular sinus Junt et al. In contrast to other macrophage subsets, subcapsular sinus macrophages retain immune complexes on their surfaces to facilitate their rapid translocation through the floor of the subcapsular sinus to underlying, non-cognate non-specific follicular B cells Phan et al.
These B cells then acquire the immune complexes via their complement receptors and deliver them to FDC. The higher immune complex-binding affinities of FDC most likely strips the B cells of their cargo.
Thus, the immune complex relay from subcapsular sinus macrophages to B cells represents an efficient route through which antigens are delivered to FDC Junt et al. Studies on tissues from rats, cattle and dogs have together reported no consistent effect of ageing on lymph node weight Ahmadi et al. Our own histological analysis of murine lymph nodes has demonstrated altered follicular structure in those from aged mice and disturbances to the delineation of the T cell and B cell zones Fig.
B cells from aged lymph nodes, in contrast, do not appear to be impaired in their ability to migrate, acquire immune complexes or produce immunoglobulins Richner et al. The numbers of subcapsular sinus, medullary cord and medullary sinus macrophages is also increased in aged lymph nodes Fig. Stromal cells are important in maintaining the structural integrity of the lymph node and in immune responses.
These cells are important components of high endothelial venules, but the functional implications of this age-related increase is uncertain. Currently, there are some lymph node stromal cell populations which remain poorly defined and require further characterisation Malhotra et al.
These undefined cells express many chemokines and cytokines important in immune responses, but whether these cells are also significantly affected by ageing remains to be determined.
Mesenteric lymphatic vessels from aged rats also display hyper-permeability due to reductions in the composition of their glycocalyx and GAP junctions Zolla et al. FDC are significantly decreased in both their size and number in aged lymph nodes Szakal et al.
The ability of FDC to retain immune complexes is also dramatically impaired in the draining lymph nodes of aged mice when compared to those from young mice Fig. The decreased size and abundance of FDC in the aged lymph node appears to have a negative impact on germinal centre responses Aydar et al.
Enhanced vulnerability of aged mice to West Nile virus infection has also been proposed to be linked to impaired IgM and IgG responses and delayed germinal centre responses in the draining lymph nodes Richner et al. Decreased FDC size impairs immune complex uptake.
Young and aged mice were given polyclonal anti-phycoerythrin intraperitoneally 16 h before phycoerytherin was given subcutaneously into each side of the flank, as adapted from a previously published protocol Phan et al. Mice were culled 2, 8 and 24 h after phycoerytherin injection and inguinal LN collected for immunostaining.
FDC networks are shown in white. Results were analysed via Mann—Whitney U test and are pooled from two separate experiments, totalling seven mice per group. Impairments in the movement, localisation and response of T cells in the aged lymph node have also been reported Becklund et al. We have compared the distribution of immune complexes within young and aged murine lymph nodes, from their arrival in the subcapsular sinus to their uptake by FDC. By injecting mice with PE-labelled immune complexes PE-IC we were able to observe their initial uptake by subcapsular sinus macrophages, subsequent association with follicular B cells and deposition onto FDC Fig.
At 2 h post-injection, the immune complexes were co-localised with the subcapsular sinus macrophages in draining lymph nodes from each mouse group, but more were present within the inter-follicular regions of aged mice Fig. Thus, our data suggested that aged mice displayed no initial impairment in the ability of subcapsular sinus macrophages to take up immune complexes.
Furthermore, flow cytometric analysis revealed that there was no significant difference in the ability of young or aged B cells to acquire immune complexes, indicating that the ability of B cells to acquire immune complexes also was not affected by ageing Fig.
Whereas large accumulations of immune complexes were detected in association with young FDC by 24 h post-injection, limited amounts were detected in association with aged FDC at this time Fig. Whilst no significant changes were observed at 2 h post-injection in the abundance and distribution of the immune complexes retained by FDC of each age group, by 8 h post-injection more were present outside the aged FDC than those from young mice. At 24 h aged FDC had significantly less immune complexes inside, outside, or on their surfaces Fig.
This suggests that the impaired ability of FDC to acquire and retain immune complexes in the lymph nodes of aged mice is a consequence of the decreased size of their FDC. Together our data suggest that the subcapsular sinus macrophage-B cell immune complex relay is unaffected in the draining lymph nodes of aged mice, but the decreased size of aged FDC adversely affects their ability to retain immune complexes Turner and Mabbott b.
Human and murine lymph nodes are more similar in structure than their spleens. Human lymph nodes have similar localisation of B cell follicles in the cortex with T cells situated in the adjacent paracortical region Willard-Mack Detailed phenotyping of human lymph node macrophages is not as developed as in the mouse, although similar populations are considered to be present Martens et al. Furthermore, research has indicated two distinct lymphatic endothelial cell populations in the human lymph node Park et al.
The number of lymph nodes reduces with age in humans although no change in the actual size of the lymph node has been reported Ahmadi et al. Significant structural changes have been described within ageing human lymph nodes. The area and volume of paracortical, cortex and medullary regions gradually reduces with age Luscieti et al. However, the involution of these predominant T cell regions was not observed in all lymph nodes suggestion evidence of some regional variability Luscieti et al.
Indeed, whereas the size of the B cell follicles and B cell abundance was shown to be similar in young and old individuals Lazuardi et al. Whether the effects on germinal centres are due to the dysregulated T-B cell interactions within ageing human lymph nodes remains to be determined Lazuardi et al. There is also a documented reduction in the abundance of high endothelial venules Hadamitzky et al. On face value, many of these ageing-related changes appear similar to those observed in murine lymph nodes.
This suggests that aged murine lymph nodes may represent a physiologically-relevant model in which to further investigate the impact of ageing-related changes to lymph node microarchitecture to the function of the immune cells within. The UK elderly population continues to expand due to a combination of factors such as increasing life expectancy and reduced birth rates.
A House of Commons report in estimated that the number of people over 65 years old was predicted to rise to If significant advances to improved well-being in the human ageing population are not achieved, this significant demographic change has the potential to bring with it important health care system challenges. As reviewed here, large structural changes occur to both spleen and lymph nodes with age which may have significant impact on the functional ability of the immune cells within them. Perhaps if the structural organisation of these organs could be repaired the functioning of the immune system could be boosted.
Further cellular and molecular analysis into the effects of ageing on the microarchitecture of secondary lymphoid tissues may therefore help identify therapeutic candidates which could be used to repair or restore the ageing-related disturbances to those tissues, and in doing so, enhance immunity and vaccine responsiveness in the elderly. Despite some important progress in our understanding of how ageing influences the microarchitecture of the spleen and lymph nodes, significant knowledge gaps remain.
Much progress has been made from the comparative analysis of ageing rodents, especially mice. But as described above, background strain differences may potentially play a role.
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