Lecture 7 - Antigen Presenting Cells and Autoimmunity PDF

Antigen presenting cells and autoimmunity Immunology Course Lecture 7 Definitions  Effector Cells : Are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.  Effector cells :are short-lived, an...

Antigen presenting cells and autoimmunity Immunology Course Lecture 7 Definitions  Effector Cells : Are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.  Effector cells :are short-lived, and die when antigen (Ag) is eliminated  Definitions  Antigen-presenting cell (APC): An antigen-presenting cell (APC) is a special type of immune cell that shows pieces of harmful invaders (called antigens) on its surface. It does this by attaching the antigen to a molecule called MHC (Major Histocompatibility Complex). This helps other immune cells recognize and respond to the invader.  APCs can be divided into two groups: 1. Professional APCs – These are cells whose main job is to present antigens, like dendritic cells, macrophages, and B cells. They are very efficient at this. 2. Non-professional APCs – These are cells that can present antigens but only do so in specific situations, like when there’s an infection. They are less specialized for this role compared to professional APCs.  Definitions  Professional APCs (antigen-presenting cells) are called "professional" because they are highly skilled in two important tasks: 1. Displaying antigens on their surface for T cells to see. 2. Providing extra signals that are necessary to fully activate naïve T cells (T cells that have never encountered an antigen before).  Naïve lymphocytes are immune cells, either B- lymphocytes or T-lymphocytes, that haven’t yet encountered a foreign invader (antigen). They are like "rookie" immune cells waiting to be activated.  Once these naïve lymphocytes interact with an antigen, they become effector cells, which are fully equipped to fight and defend the body from the threat. APC professional and non-professional  Professional APCs Non-professional APCs - Dendritic cells − Fibroblasats (skin) - Macrophages − Thymic epithelial cells - B cells − Thyroid epithelial cells − Glial cells (brain) − Pancreatic beta cells − Vascular endothelial cells  Dendritic Cells (DCs)  Dendritic Cells (DCs) have specialized forms based on their location and function in the immune system:  Langerhans cells: These dendritic cells are found in the skin and mucosal epithelium. Their role is to capture antigens from the skin and mucous surfaces, and then migrate to lymph nodes to trigger an immune response.  Interdigitating cells: When dendritic cells travel to lymphoid tissues (like lymph nodes) and interact with T cells, they are known as interdigitating cells. They help activate T cells by presenting them with antigens.  Follicular dendritic cells (FDCs): These cells are located in the primary and secondary follicles of the B cell areasin lymph nodes and the spleen. They are involved in presenting antigens to B cells to aid in antibody production. Unlike other dendritic cells, follicular dendritic cells are specialized for interacting with B cells rather than T cells.  Germinal center dendritic cells (GCDC): These dendritic cells are found in the germinal centers within lymphoid follicles, where they assist in B cell maturation and the selection of high-affinity antibodies, helping form memory B cells. Dendritic Cells (DCs).. Cont..  Dendritic Cells (DCs).. Cont..  Interdigitating Cells: Rich in MHC II molecules – These cells have a high amount of MHC class II, which is crucial for presenting antigens to T cells. Found in the thymus – Interdigitating cells present antigens to T cells to help with their activation and development, especially in the thymus (an important organ for T-cell development).  Follicular Dendritic Cells (FDCs): Present antigens to B cells – FDCs interact with B cells in the lymph nodes and spleen, helping B cells recognize and respond to antigens. Non-migratory cells – Unlike other dendritic cells, FDCs stay in place and do not travel to other parts of the body. Lack MHC Class II – Unlike most antigen-presenting cells, FDCs do not express MHC II molecules. Instead, they bind antigens using complement receptors (like CD21 and CD35). Express Fc receptors – FDCs have Fc receptors that allow them to bind antibodies and help B cells in recognizing antigens.  Dendritic Cells (DCs).. Cont..  Germinal Center Dendritic Cells (GCDCs): Migrating cells – Unlike FDCs, GCDCs can move and are involved in B cell maturation in germinal centers (where B cells refine and improve their antibodies). Antigen processing by (APC) dendritic cells  Antigen processing by (APC) dendritic cells  Epithelial tissues contain professional antigen-presenting cells (APCs), such as dendritic cells (DCs). In the skin, these dendritic cells are known as Langerhans cells. Dendritic cells are also present in T cell-rich areas of secondary lymphoid organs (like lymph nodes), where they play a key role in activating T cells.  When an antigen (Ag) binds to Toll-like receptors (TLRs) on the surface of dendritic cells in the epithelium, it triggers an immune response. This interaction results in the production of inflammatory cytokines, such as Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1), which promote inflammation and enhance the immune response.  This process is crucial for initiating immune defenses, as dendritic cells serve as the bridge between detecting antigens in peripheral tissues and activating T cells in lymphoid organs.  Antigen processing by (APC) dendritic cells  Once dendritic cells are activated by a combination of cytokines and TLR signals, several key changes occur: 1. Activation of dendritic cells – Cytokines and TLRs trigger dendritic cell activation, initiating the immune response. 2. Loss of adhesiveness – Activated dendritic cells lose their adhesiveness to epithelial tissue, allowing them to migrate from the site where they encountered the antigen. 3. Expression of specific surface receptors – Upon activation, dendritic cells express specific receptors that respond to chemoattracting cytokines (chemokines) produced in the T cell zones of lymph nodes. 4. Migration to lymph nodes – Dendritic cells are directed to the lymph nodes by chemokines, where they interact with T cells, presenting the processed antigen and helping to activate the adaptive immune response.  This process ensures efficient movement of dendritic cells from the infection site to lymph nodes, where they trigger a targeted immune response by presenting antigens to T cells.  Antigen processing by (APC) dendritic cells  Dendritic Cell Migration and Maturation: Chemokines guide dendritic cells to lymph nodes, where they mature into antigen- presenting cells (APCs) during migration. As they mature, dendritic cells express MHC and co-stimulatory molecules, essential for interacting with and activating T cells. Once matured, they present antigens to T cells, triggering a targeted immune response.  Macrophage Dendritic Cell B cell Low levels. Always Expressed. MHC-II Expression Induced by Bacteria and/or Always Expressed. Inducible upon Cytokines Activation Extracellular Antigen Antigen type and Intracellular & binds Extracellular Antigens: Extracellular Antigens: to specific Ig presentation by presentation via MHC-II presentation via MHC- receptors: MHC I & II presentation via MHC-II Low levels. Low levels. Co-Stimulation Always expressed Induced by Bacteria and/or Inducible upon (B7 expression) at high Levels Cytokines Activation Lymphoid tissue Lymphoid tissue Lymphoid tissues. Location Connective tissue Connective tissue Blood Body Cavities Epithelium  Function of the Professional APCs  Efficient internalization of antigens – Professional APCs, such as dendritic cells, macrophages, and B cells, are highly efficient at capturing antigens. They do this through processes like phagocytosis (engulfing large particles) or endocytosis (taking in smaller particles or molecules).  Displaying the antigen – After internalizing the antigen, the APC processes it and displays a fragment of the antigen on its surface. This fragment is bound to a class II MHC molecule on the APC membrane.  Recognition by T cells – T cells recognize and interact with the antigen-class II MHC complex displayed on the APC. This interaction is essential for the activation of T cells.  Co-stimulatory signal – In addition to presenting the antigen, the APC produces a co-stimulatory signal. This signal is necessary to fully activate the T cell, ensuring the T cell can properly respond to the antigen and trigger an immune response. Autoimmunity  Autoimmunity  Autoimmunity is a condition where the immune system fails to properly distinguish between the body's own cells (self) and foreign invaders (non-self). As a result, the immune system mistakenly attacks healthy tissues, leading to various autoimmune diseases. Prevalence: Around 5% to 7% of adults are affected by autoimmune diseases. Gender prevalence: Two-thirds of those affected are women. Range of diseases: There are more than 40 autoimmune diseases in humans, where the immune system's malfunction plays a significant role.  Autoimmune diseases can affect various organs and tissues, leading to conditions like rheumatoid arthritis, lupus, and multiple sclerosis, among others.  Causes 1. Release of sequestered antigens: 1. Some antigens in the body are hidden (sequestered) from the immune system in tissues like the brain, eyes, or testes. Normally, the immune system doesn't encounter these antigens. However, if these tissues are damaged (due to injury or infection), the hidden antigens are released and recognized as foreign, which can trigger an autoimmune response. 2. Immune stimulation: 1. Overstimulation of the immune system, often due to infections or chronic inflammation, can lead to an abnormal response where the immune system begins to target the body's own tissues, mistakenly treating them as harmful invaders.  These causes can lead to the breakdown of the immune system's ability to differentiate between self and non-self, resulting in autoimmune diseases. Mechanisms of autoimmunity 1. Antigen released from hidden locations: Some antigens are normally hidden from the immune system in areas like the brain, eyes, or testes. When these tissues are damaged (due to trauma or infection), the antigens are released and the immune system mistakenly attacks them, as it treats them as foreign. 2. Antigen generated by molecular changes: Some proteins or molecules in the body can undergo structural changes (e.g., due to environmental factors, mutations, or infections) and may be recognized as foreign by the immune system, triggering an autoimmune response. 3. Molecular mimicry: In some cases, the immune system encounters foreign antigens (such as from infections) that closely resemble the body's own proteins. As the immune system fights the infection, it may mistakenly attack similar-looking "self" molecules, leading to autoimmunity. For example, some bacterial or viral antigens may closely mimic human tissue antigens.  Mechanisms of autoimmunity 4. Alteration in antigen processing: Defects in how antigens are processed and presented to the immune system can lead to improper recognition. This can cause the immune system to attack normal cells, thinking they are harmful. 5. Infection: Certain infections can disrupt the immune system’s tolerance to self- antigens, either through molecular mimicry, by releasing hidden antigens, or by causing chronic inflammation that leads to immune dysregulation. 6. Genetic factors: Genetic predisposition plays a significant role in autoimmunity. Certain genes associated with the immune response, particularly MHC (Major Histocompatibility Complex) genes, can increase the likelihood of developing autoimmune diseases. These genetic factors can make the immune system more prone to reacting against self-antigens.  These mechanisms interact and contribute to the development of over 40 different autoimmune diseases, with a combination of genetic susceptibility and environmental triggers playing key roles.  Additional Factors: 7. Lymphocyte abnormalities: Abnormal B or T cells contribute to self-reactivity. 8. Failure of central tolerance: Self-reactive lymphocytes fail to be eliminated in the thymus or bone marrow. 9. Overcome of peripheral tolerance: Peripheral tolerance mechanisms fail to control self-reactive lymphocytes. 10.Polyclonal lymphocyte activation: Non-specific activation of lymphocytes, including self-reactive ones, can lead to autoimmunity.  Effects of autoimmunity  Tissue destruction: Immune cells attack and destroy healthy tissues.  Antibodies block normal function: Autoantibodies interfere with normal cellular processes, leading to dysfunction.  Antibodies stimulate inappropriate function: Autoantibodies can abnormally stimulate cells, causing excessive or inappropriate activity.  Antigen-antibody complexes affect function: Immune complexes (antigen-antibody) deposit in tissues, leading to inflammation and impaired organ function. References  Goldsby R.A., T. J. Kindt, BA. Osborne. Kuby Immunology, Fourth edition, 2003. W. H. Freeman & Co., New York.  Janeway, C., Travers, P. Walport, M., and Capra, J., ImmunoBiology, Fifth edition, 2001. Garland Publishing, Inc., NY.