Secondary lymphoid organs

LYMPH NODES, SPLEEN, TONSILS,MUCOSA ASSOCIATED TISSUES, APPENDIX, PAYERS PATCHES

1. LYMPHOID ORGANS [SECONDARY LYMPHOID ORGANS] Dr. R. RENUKA ASSOCIATE PROFESSOR OF BIOCHEMISTRY V.V.VANNIAPERUMAL COLLEGE FOR WOMEN MADURAI KAMARAJ UNIVERSITY, INDIA.

2. SECONDARY OR PERIPHERAL LYMPHOID ORGANS While primary lymphoid organs are concerned with production and maturation of lymphoid cells , the secondary or peripheral lymphoid organs are sites where the lymphocytes localise , recognise foreign antigen and mount immune response against it by producing either antibodies or sensitized cells. Thus, the matured lymphocytes received from the primary lymphoid organs are made active in secondary lymphoid organs.

3. SECONDARY OR PERIPHERAL LYMPHOID ORGANS Secondary lymphoid organs include lymph nodes , spleen , tonsils , adenoids , appendix , and clumps of lymphoid tissue in the small intestine known as Peyer's patches . They trap and concentrate foreign substances, and they are the main sites of production of antibodies. Some lymphoid organs are capsulated such as lymph node and spleen while others are non-capsulated, which include mostly mucosa-associated lymphoid tissue (MALT).

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5. 1. LYMPH NODES Lymph nodes are well-organized forms of lymphoid tissue situated at the junction of lymphatic vessels, and are present in all parts of the body. They are numerous in areas such as neck, retroperitoneum, media sternum, axilla, groin and abdominal cavity. It is the major site where APC’s present antigen to activate T cells and where T cells ‘help’ B cells undergo immunoglobulin class switching.

6. LYMPH NODES Lymph node appear in the human foetus in the third month along the course of lymphatic vessels. Most nodes survive for 60 years or more with only slight atrophy and retain the capacity to enlarge throughout life

7. STRUCTURE OF LYMPH NODE Human lymph nodes are encapsulated bean or ovoid shaped complex cellular structures ranging from few millimetre to a centimetre. One side is convex and the other side has an indentation, the hilus through which efferent lymphatic vessels leave the node and blood vessels enter and leave. Afferent lymphatic vessels pierce the convex surface of the capsule and empty into the tube.

8. STRUCTURE OF LYMPH NODE CONTD… The lymph node is covered by a capsule (made of dense collagenous tissue) which penetrates in to the lymph node to form septa called trabeculae. Each lymph node is made up of three regions namely an outer cortex, a middle paracortex and an inner medulla . The cortex contains B cells; the paracortex contains T cells and the medulla contains both B and T cells.

9. STRUCTURE OF LYMPH NODE CONTD… CORTEX: A group of lymphoid and non-lymphoid cells (macrophages, follicular dendritic cells) is organised in a spherical or ovoid structure termed as lymphoid follicle or nodules.

10. STRUCTURE OF LYMPH NODE CORTEX CONTD… Primary follicles consists of tightly packed small naïve (not yet encountered ag) lymphocytes and follicular dendritic cells. After antigenic exposure, primary follicle becomes a larger secondary follicles which contain a central, pale staining area called germinal centres . These centres are the sites of rapid multiplication of lymphocytes. Follicular dendritic cells which reside in the germinal centres display Ags on their surface and selectively activate B cells to differentiate into plasma cells and memory cells.

11. STRUCTURE OF LYMPH NODE CORTEX CONTD… The cortex consists of primary and secondary lymphoid follicles containing B lymphocytes, macrophages and follicular dendritic cells (FDCs). T cell activation occurs in the cortex. Activated T cells migrate to primary follicles and activate B cells, converting the primary follicle into secondary follicle with germinal centres (GCs). The GCs are surrounded by densely packed proliferating B cells with the central thinly populates area consisting of B cells, T cells, macrophages, FDCs, plasma cells and antibodies.

12. STRUCTURE OF LYMPH NODES LYMPBANNN KJJN M, KNKJL

13. STRUCTURE OF LYMPH NODE CONTD… PARACORTEX: Beneath the cortex is the paracortex , which is populated largely by Th cells and sparsely by Tcyt cells. It also contains many Ag presenting cells such as Langerhans cells, follicular dendritic cells (FDCs) and interdigitating dendritic cells (IDCs) which have large quantities of MHC class II antigens on their suface . These Ag presenting cells transport Ags from the external and internal surfaces of the body to the lymph nodes where they encounter naïve T cells particularly Th cells. Thus, paracortex region of the lymph node is the site where T-cell responses to lymph-borne antigen are initiated.

14. STRUCTURE OF LYMPH NODE CONTD… MEDULLA: The medulla is the innermost region of the lymph node and extends to the hilus . It contains both T and B cells in addition to macrophages, plasma cells and some granulocytes. The lymphocytes are arranged along strands of connective tissue fibres known as medullary cords. These medullary cords are separated by large sinuses known as medullary sinuses which contain plasma cells.

15. PHYSIOLOGY OF LYMPH NODE CONT... As lymph carrying Ags percolate through the lymph nodes, they encounter macrophages, interdigitating dendritic cells which readily phagocytose the Ags . These Ags are then processed and presented together with class II MHC molecules by these ag-presenting cells to Th cells in the paracortex. This sensitized Th cells activates B cells to differentiate into IgM and IgG-secreting B cells and memory B cells. Some of the plasma cells generated in the germinal centre move to the medulla and leave the node by efferent lymphatics.

16. PHYSIOLOGY OF LYMPH NODE CONT... The lymphocytes whether T or B, remain in their characteristic sites for several hours, and if they do not engage in ab production they migrate to the medulla and exit via efferent lymphatics. The lymphocytes then recirculate and may also enter a lymph node again through afferent lymphatics. If T and B cells become engaged in ab formation in a node, the lymph leaving a node is enriched with newly synthesized abs or increased conc. of lymphocytes.

17. FUNCTIONS OF LYMPH NODES The lymph nodes act as filters and they filter lymph by trapping damaged cells, microorganisms, foreign substances and tumour cells. Macrophages phagocytose some of the above mentioned and lymphocytes destroy some by immune defence. Lymph nodes are also responsible for the initiation and development of humoral and cell mediated immune responses. Recirculation of mature lymphocytes between blood and lymph nodes.

18. 2. SPLEEN Spleen is the flat, ovoid , well organized lymphoid organ situated at the left upper region of the abdominal cavity behind the stomach and close to the diaphragm. It is deep red in colour and has direct communication with main arterial circulation. Spleen filters blood as the lymph node filters lymph.

19. SPLEEN cont … The spleen drains the blood borne antigens of pathogens and does not allow systemic infection to occur. Actually spleen conducts dual function: 1. It removes the damaged or old RBCs. 2. It serves as a secondary lymphoid organ. In the embryo, before the bone marrow starts producing the RBCS (till 5 th month) the spleen is only concerned with the production of RBCs. In the adult, when there is a sudden demand for RBCs, for eg. during recovery from sudden anaemia, the spleen takes over the function of haematopoiesis temporarily, along with the bone marrow.

20. STRUCTURE OF SPLEEN cont … This is the only lymphoid organ which is not supplied with lymphatic vessels. The spleen is surrounded by a capsule. The capsule penetrates into the tissues as septa called trabeculae.

21. STRUCTURE OF SPLEEN The spleen is made up of red pulp and white pulp, separated by marginal zone: 76-79% of a normal spleen is red of pulp.

22. STRUCTURE OF SPLEEN cont … RED PULP Splenic red pulp consists of a reticular network of splenic cords and large number of blood filled sinusoids containing macrophages, granulocytes, platelets, lymphocytes, plasma cells and most importantly red blood cells which imports the red colour to red pulp. This is the site where old or damaged blood cells are destroyed. The red pulp is also reserve site for haematopoiesis.

23. STRUCTURE OF SPLEEN cont … WHITE PULP The splenic artery enters the spleen (through hilus ) and branches into the white pulp as arterioles. The arteriole is surrounded by a densely – packed periarteriolar lymphatic sheath (PALS) of T and B cells with a few DCs and macrophages. Enclosed in the sheath are T cells (mainly Th and partly Tc), IDCs, primary lymphoid follicles containing FDCs and naïve B cells. During immune response, these primary follicles develop into germinal centres and become secondary follicles. The whole splenic material enclosed within PALS constitutes the white pulp. Several white pulps are scattered in the spleen.

24. STRUCTURE OF SPLEEN cont … RED PULP AND WHITE PULP

25. DEVELOPMENT OF IMMUNE RESPONSE IN SPLEEN Cells and Ags carried through the blood enter the white pulp nodule through the splenic artery. The Ags is trapped in the PALS by IDCs present in PALS. They process and present the ags to T cells in PALS. The T cells proliferate and differentiate into CD4+ Th cells and CD8+ Tc cells. Activated Th cells enter the B cell zone and provide help for B cell activation. Some of the activated B cells along with the Th cells migrate to primary follicles in the marginal zone. They form germinal centres where activated B cells divide rapidly and differentiate.

26. DEVELOPMENT OF IMMUNE RESPONSE IN SPLEEN cont... Active proliferation of B cells, their differentiation in plasma cells, affinity maturation and isotype switch occurs in germinal centres. Plasma cells produce antibodies specific for the ags of the infectious microbe, recognized by the B cells. The activated Tc cells, plasma cells and antibodies leave the spleen through the splenic vein, and are eventually taken to the site of infection.

27. 3. MUCOSA ASSOCIATED LYMPHOID TISSUE The mucous membranes lining the digestive, respiratory and urogenital systems represent the main sites for the entry of microbes into the body through air, food and tissue injury. These three systems make up the largest area which needs protection from foreign invaders. It is for this reason that almost 50% of the lymphoid tissue in the human body is located within the lining of the major tracts, defending these venerable membrane surfaces against invading microbes. These uncapsulated tissues are collectively called as mucosa associated lymphoid tissues ( MALT ).

28. MUCOSA ASSOCIATED LYMPHOID TISSUE cont … Mucosa Associated Lymphoid Tissues (MALT) include nasal - associated lymphoid tissues (nasopharynx) ( NALT ), gut – associated lymphoid tissues ( GALT ), bronchus – associated lymphoid tissues ( BALT ) and lymphoid tissue associated with the genitourinary system. Lymphoid tissues such as Payer’s patches in the small intestine, adenoids, appendix and tonsils are well demarcated.

29. NASAL - ASSOCIATED LYMPHOID TISSUES ( NALT) Nasal – associated lymphoid tissues are found in three locations and involved in the defence against the Ags entering through the nasal and oral routes. A pair of pharyngeal tonsils (adenoids) at the back of the nasopharynx A pair of palatine tonsils placed at the back of the mouth on both sides. A third pair called lingual tonsils is located at the base of the tongue.

30. NASAL - ASSOCIATED LYMPHOID TISSUES ( NALT) cont … These three main kinds of tonsils constitute an anatomical structure called Waldeyer’s ring. All these lymphoid tissues protect the mouth and nasal passage from air borne pathogens.

31. In humans, the tonsils contain a meshwork of reticular fibres and cells co-mingled with lymphocytes, granulocytes, macrophages and mast cells. B cells organized into primary follicles and larger secondary follicles with germinal centres surrounded by the regions of T cell activity is the hall mark of the secondary lymphoid organs.

32. PAYER’S PATCHES or GALT Payer’s patches are diffuse lymphoid tissue, named after the 17 th century Swiss anatomist Johann Conrad Peyer. They are aggregations of lymphoid tissue that are usually found in the lowest portion of the small intestine, the ileum in humans.

33. PAYER’S PATCHES or GALT Peyer’s patches are fairly well- organised small nodules of lymphoid tissues. They extend from lamina propria to submucosa. Nodules of Payer’s patches consist of 30 – 40 lymphoid follicles. B cell follicles with germinal centres are predominantly seen in Payer’s patches. Germinal centres are surrounded by regions showing T cell activity. Cross sectional Diagram of intestine

34. PAYER’S PATCHES or GALT cont … Cross section of Payer’s patches

35. PAYER’S PATCHES or GALT cont … A cross sectional area of Peyer’s patches shows a dome- like structure with the mucosal layers lined with columnar epithelial cells. This outer mucosal epithelial layer contains Intra epithelial lymphocytes. Most of these lymphocytes are Tc cells and express CD8+ on their surface. These cells may be involved in immunosurveillance. Specialized cells called microfold cells or M cells are situated in between the mucosal cells. Below the epithelial layer is lamina propria which contains loose clusters of B cells and T cells along with DCs and macrophages. Most of the T cells in lamina propria are CD4+. Beneath the lamina propria is the submucosal layer which contains secondary follicles with Germinal Centres.

36. PAYER’S PATCHES or GALT cont … M cells in the mucosal epithelial layer have microfolds on their surface; hence the name. These cells are distinct from epithelial cells and have no microvilli and mucous on their surface. M cells contain deep invagination in the basolateral plasma membrane which forms pockets filled with B and T cells, macrophages and DCs. The antigens enter Peyer’s patches directly from the lumen of the gut through M cells by forming endocytic vesicles (endocytosis or transcytosis).

37. PAYER’S PATCHES or GALT cont … These vesicles fuse with pocket membrane, delivering Ags to the clusters of immune cells in the lamina propria or Payer’s patches. Antigens, processed and presented by DCs activate Th cells. The helper T cells help to activate B cells to mature into ab producing plasma cells. These immune cells leave the follicles, pass into mesenteric lymph nodes and enter the lymphatic and blood circulation.

38. PAYER’S PATCHES or GALT cont … Moreover, lymphocytes stimulated in the GALT can migrate to other MALT sites such as salivary glands, mammary glands, respiratory passages and other parts of the gastrointestinal tract and protect these surfaces from invasion by pathogens.

39. PAYER’S PATCHES or GALT cont … In the nodules of Payer’s patches, the activated Th cells (by the ags processed and presented by DCs) activates B cells to mature and differentiate into sedentary, local plasma cells. The abs produced in the GALT are mostly IgA type , which enter the intestinal lumen through the epithelial lining with the help of secretory piece by the process of transcytosis. In the lumen dimeric form of secretory IgA neutralizes viruses, bacteria and toxins and also blocks the entry of these Ags into circulation by acting as an antiseptic paint.

40. PAYER’S PATCHES or GALT cont …

41. PAYER’S PATCHES or GALT cont … Transport of IgA

42. PAYER’S PATCHES or GALT cont … Peyer’s patches thus establish their importance in the immune surveillance of the intestinal lumen and in facilitating the generation of the immune response within the mucosa.

43. PAYER’S PATCHES or GALT cont … In short:

44. BRONCHUS ASSOCIATED LYMPHOID TISSUE (BALT) Bronchial – associated lymphoid tissues are found in all the lobes of the lungs and are situated along the bronchi and forms an important defensive tissue protecting the lungs from the entry of pathogens. The tissue is not encapsulated and consists of diffuse accumulation of phagocytic cells, lymphocytes and plasma cells. B cells are organized into follicles situated under the epithelium. Antigens are captured by the M cells. Antigen-presenting cells are transported to underlying lymphoid tissues which give an appropriate immune response to the invading pathogens.

45. CUTANEOUS – ASSOCIATED LYMPHOID TISSUES (CALT) The skin serves as a protective barrier and sensing buffer between an organism and the environment. The outer layer of the skin, the epidermal layer consists of specialized cells called keratinocytes. They are rich in keratin as the name suggests. These cells secrete pro – inflammatory cytokines such as IL-1,IL-3, IL-6, tumour necrosis factor and IFN- . They can be induced to express class II MHC molecules on their surface by IFN- and therefore can act as APS. This suggests that keratinocytes may augment local inflammation and lymphocyte activation.  

46. LANGERHANS CELL Langerhans cells constitute only about 1% of the epidermal cells and they cover almost 25 – 30% of the surface because of their long membranous dendritic extensions. These extensions sense the ag or microbes, pick them up by phagocytosis or endocytosis. Then they migrate from the epidermis to the nearest lymph nodes where they differentiate into IDCs. These cells express high levels of class II MHC molecules and function as ag – presenting cells to activate Th cells. They activate the Th cells with appropriate TCR and initiate the process of immune response. CALT con…

47. CALT con… The epidermis also contains intra epidermal lymphocytes. These are CD8+ Tc cells and bear T cell receptors (TCRs) which have limited diversity. The dermis also contains CD4+ and CD8+ cells with few macrophages. It is believed that intraepidermal T cells, Langerhans cells as well as CD4+ and CD8+ T cells are the cells that combat ags that enter through the skin and generate effective immune responses.