1. Central Lymphoid tissue Lymphoid tissue - The central lymphoid tissue (also known as primary) is composed of bone morrow and thymus. Bone Morrow - The major site of hematopoiesis in humans. - Hematopoiesis is facilitated by a certain types of stromal cells as well as production of soluble mediators. - All blood cells are derived from the bone morrow. Also, all blood cells are found in bone morrow except for mature T-lymphocytes, which are not present in the bone morrow. - The only cell type that matures (differentiates) in the bone morrow is the B-lymphocyte. B-lymphocytes near the periphery of the bone morrow are immature. They start maturation as they move from the periphery towards the center. That means the most mature cells are found in the center of the bone morrow. - During maturation, Cells may die because of the stress related to the process. For example, some cells are Auto-reactive and therefore should be deleted. - Growth factors, Cytokines, reticular stromal cells are involved in the maturation process of B-lymphocytes Thymus - Largest in size at birth. (in relative size to the body) - It continues to grow till puberty then regresses after that. In adults it is composed of a strip of atrophic tissue. - T-lymphocytes that are generated in the thymus during childhood are sufficient to perform the function of T-lymphocytes throughout the life of a person. - There s evidence suggesting that the removal or involution of the thymus doesn t affect the health of a person significantly. Examples: Removing the thymus early in life due to thymoma doesn t prevent mounting an immune response against foreign antigens. Meaning that they have a sufficient reserve of T-cells to perform the function. Digeorge syndrome: a syndrome characterized by either having a hypoplastic (partial absence) or aplastic (complete absence) thymus. People with an aplastic thymus receive a thymus transplant. But people with a hypoplastic thymus, spontaneous improvement in the function of the thymus occur. 1
- These 2 examples could indicate that there are other sites that may potentially replace the thymus for maturation of T-lymphocytes. - T-cells are divided to two major groups: 1. Alpha-Beta T-cells. (For most T-cells) 2. Gamma-Delta T-cells. - This division is based on the structure of the receptor that recognizes antigens. This receptor is known as TCR (T-Cell receptor), which is composed of 2 chains. Either Alphabeta or Gamma-Delta - Gamma-Delta T-cells do NOT mature in the thymus. Also indicating that there are other sites than the thymus where T-cells can mature. - It is a capsulated gland located in the anterior mediastinum - The thymus is composed of lobes; trabeculae divide the lobes into lobules. - Peripheral T-cells are the least mature, maturation takes place as they move towards the center. - Composed of three areas: 1. The subcapsular zone: least mature cells (progenitor cells) 2. Cortex: maturing cells 3. Medulla: Mature cells - Cells that just enter the thymus are in the subcapsular zone. They leave the bone morrow, travel throw blood and reach the subcapsular zone. As they move towards the medulla, they become mature T-cells. - Only 5% of progenitor cells survive the maturation process. Leaving the thymus as mature T-cells. This is because the process of maturation is very selective and stressful, killing most of the cells. - since most cells die before reaching the medulla, it appears lighter in color than the cortex 2
- The thymus contains epithelial cells and macrophages (dendritic cells), those are very important for the differentiation and selection of T-lymphocytes. - There are two processes of selection for T-lymphocytes in the thymus: 1. Negative selection: Removes all auto-reactive T-lymphocytes Many of our self antigens are present in the thymus, on the surface of MHC+ cells (antigen presenting cells). Macrophages are the professional antigen presenting cells in the body; they have MHC molecules (major histocompatibility complex) that are usually associated with self antigens. Any T-cells that recognize a self antigen is immediately killed by apoptosis 2. Positive selection T-Cells that survive negative selection go through positive selection. Those surviving cells are educated to recognize any antigen that is presented with an MHC molecule. If they fail this selection they ll also die. Cells that survive those selection processes leave the thymus as Naïve-mature T-cells. - Those Mature cells that leave the thymus either Carry CD8 or CD4 surface proteins, but not both. CD8 are Cytotoxic T cells, and CD4 are Helper T Cells. - Note that before selection; some cells might be double positive (carrying both CD8 and CD4.) But during selection they become single positive. -If they interact with MHC class 1, they become CD8 cells -If they interact with MHC class 2, they become CD4 Cells - Now that T-cells and B-cells left the central lymphoid tissue as mature cells, they populate the peripheral lymphoid tissue. 3
2. Peripheral Lymphoid Tissue: While the peripheral lymphoid tissue (secondary) is composed of Lymph nodes, spleen and the mucosa-associated lymphoid tissue (MALT) Spleen - Most important peripheral lymphoid tissue - Has 25% of body s lymphocytes - Located in the upper left abdominal quadrant - It functions as a filter of blood from microbes and dead cells, dead cells are buried in the spleen - Main site for response for blood borne antigens and T-independent antigens; antigens that get to the bloodstream generate an immune response in the spleen. - Note that antigens can be introduced to the body subcutaneously, intramuscularly, intravenously or orally. - Antigens Divided to T-independent and T-dependent antigens. T-dependent antigens require T-cell help to generate an immune response, these are usually proteins. T-independent antigens don t require T-cell help, and they re usually polysaccharides. For an antigen to generate an immune response, it usually must go through processing and presentation. Proteins are usually engulfed by macrophages, then they are digested and processed, then they re presented as epitopes to T-cells, then an immune response taken place Some antigens like polysaccharides are composed of identical repeating units, and they do not need processing. So the antigen is already in a form that induces a response from B-Lymphocytes* Those T-cell independent antigens induce the release of IgM only. No memory cells are generated against these antigens. No memory means that if you are exposed to the same antigen again, the same primary response takes place (no secondary response) T-cell Dependent antigens generate memory cell, so a 2 nd exposure would mount a secondary immune response. 4
- The spleen Composed of red pulp (RBCs and macrophages) and white pulp (lymphocytes) T Cells: Periarteriolar lymphoid sheaths (PALS). B cells: Primary (resting) and secondary (activated) follicles. Marginal zones: T cells, B cells, and macrophages. - Note that B cells are in follicles in both the spleen and lymph nodes. - Also note that active follicles have a germinal center (circled follicle), while resting follicles do not (in square). Everything is shown in this drawing. Here s an empty space for notes, drawings, thoughts, scribbles, poems or short stories 5
Lymph Nodes - Clusters of bean shaped organs distributed all over the body - Concentrate lymphocyte borne antigens for presentation to T-cells - Composed of: 1. Cortex, containing B cells 2. Paracortex, containing T cells 3. Medulla, Containing T & B Cells and macrophages (like marginal zone of the spleen) - Lymphocytes enter lymph nodes from the blood stream. - T lymphocytes in particular leave lymphatic & blood vessels and enter lymph nodes via specialized high endothelial venules (HEVs) where they mount a response. - Usually antigens are brought to lymph nodes by the lymphatic drainage or blood stream. And the immune response is attended by the proliferation of lymphocytes. - That causes an enlargement of lymph nodes. Known as lymphadenopathy. - Things like infections or sutures could cause lymphadenopathy. For example, infection of tonsils causes enlargement of cervical lymph nodes. - That happens of you are exposed to only 1 antigen. Now imagine if you are exposed to a huge number of antigens that are present in our environment, in this case there will be no place for homing to accommodate those lymphocytes that can be generated, that s why they re activated only upon exposure to an antigen, and selection of a clone will result in proliferation and enlargement of a lymph node. - This is a picture showing the structure of a lymph node: 6
Mucosa associated lymphoid tissue (Malt) - Present in the GI & respiratory tract. Known as GALT and NALT. They re also present in the Skin and genitourinary tracts. - These sites contain specialized epithelial cells (M-Cells) that engulf antigens and can present antigens. - Those sites are rich in IgA producing cells. Remember that IgA can be found in serum or in secretion. Secretory IgA can be found in saliva, lacrimal secretions, GI secretions, genitourinary tract. Note that for IgA to be secreted it has to cross the epithelial barrier, as it is crossing the barrier; the epithelial cells attach a Secretory piece. That piece prevents digestions of the antibody, it is believed that the piece also plays a role in oral tolerance** - 90% of lymphocytes in MALT are T-lymphocytes. 50% of these are CD8 of the Gamma- Delta receptor. - They can directly recognize an antigen, without MHC, and they secrete cytokines that can suppress the immune response against food antigens, resulting in Oral Tolerance. *** Skin - I don t know if it is part of the peripheral lymphoid tissue or not. - The major physical barrier. - Contains: 1. Dendritic cells. 2. T cells (intraepidermal) mainly CD8+ of gamma-delta type. 3. Dermis full of macrophages and T cells. - If you are allergic to certain antigens, like rubber or Ivy, it s due to an immune response in the skin. Indicating there s enough cells to produce such an immune response in the skin. - Immune response in skin manifests as an erythema. 7
Lymphoid trafficking and homing: - Lymphocytes (T Lymphocytes in particular), circulate through the body, when they re needed, chemotactic stimuli attract Lymphocytes and lead them to leave circulation and move to tissues. - A lymphocyte makes a tour of the body (Blood once or twice daily ensuring antigen contact. - The source of such chemotactic stimuli is usually foreign micro organisms, for example, if you have an infection, the organism secretes substances that attract those lymphocytes. - Those lymphocytes that circulate in the blood and leave it to tissues are mostly naïve mature T cells, meaning they are not specific for an antigen, they look for an antigen as they re circulating, if they don t find an antigen, eventually they die. - The process of circulation and homing are regulated by a collection of integrins, addressins and selectins, which work by receptor mediated mechanisms. - The process of lymphocyte extravasation goes through 4 steps. 1. Primary adhesion to endothelium. (in response to chemotactic stimuli) 2. Lymphocyte activation. 3. Secondary adhesion (arrest). 4. Transmigration/chemotaxis. Lymphocytes are originally in the blood vessel, the chemotactic signal is detected, and lymphocytes start to express certain molecules on their surface that interact with endothelial cells, the lymphocyte becomes arrested and then it starts diapedeses (squeezing between endothelial cells), and leave the vascular bed to the tissue, where they mount an immune response locally at the tissue site. Below is a picture illustrating the entire process, read it carefully. A clearer version is in the slides. 8
* I m not sure if its B or T, it s very hard to hear it. It s on 19:35 of the record if you want to check yourself. **oral tolerance is basically the prevention of mounting an immune response to oral antigens present in the GI. This protects from mounting an inflammation against food. M cells are believed to play a role in oral tolerance. ***there s a slide that if I put here will be too small to notice anything; it shows MALT and its parts. Including the Secretion of IgA and attaching the secretory piece. Done by Owen Madaeen 9