IS - Comprehensive Notes PDF

# Introduction to the Immune System ## Antigen Presentation Antigen presentation is the process by which immune cells display antigens on their surface to be recognized by T-cells. This is essential for initiating immune responses. There are three main antigen-presenting cells (APCs): dendritic ce...

# Introduction to the Immune System ## Antigen Presentation Antigen presentation is the process by which immune cells display antigens on their surface to be recognized by T-cells. This is essential for initiating immune responses. There are three main antigen-presenting cells (APCs): dendritic cells, macrophages, and B-cells. ## T-Cell Help T-cells are crucial white blood cells in immunity. Helper T-cells (CD4+) aid other immune cells, particularly B-cells, in producing antibodies. Antibodies are proteins that specifically target pathogens. ## Gene Rearrangement and Clonal Selection Gene rearrangement allows B-cells and T-cells to generate a diverse array of antigen receptors. Clonal selection occurs when a specific immune cell with the right receptor proliferates (multiplies) to target and destroy pathogens. ## Key Immunological Questions * **Why Don't Antibodies Attack Self?** The immune system avoids attacking the body's own tissues (self) through mechanisms of tolerance. The major histocompatibility complex (MHC), or human leukocyte antigen (HLA), encodes proteins that help present self and non-self antigens to T-cells. If T-cells recognize a self-antigen, they do not activate, preventing self-attack. * **What is Self?** Self is represented by the body's own proteins and is encoded by MHC molecules. MHC molecules are present on the surface of almost all cells and help the immune system differentiate between the body's proteins and foreign invaders (non-self). T-cells generally ignore self-antigens, maintaining self-tolerance. ## MHC and HLA Tolerance ### MHC Proteins MHC proteins display peptide fragments (antigens) on the surface of cells for T-cell recognition. They act like a “conveyor belt,” transporting protein fragments to the cell surface. T-cells continuously scan MHC proteins to detect infection or abnormalities. * **MHC Class I**: Found on most body cells, presents intracellular antigens (such as viral peptides) to cytotoxic T-cells (CD8+). * **MHC Class II**: Found on specialized antigen-presenting cells like dendritic cells, macrophages, and B-cells. They present extracellular antigens (such as bacteria) to helper T-cells (CD4+). ## Cytotoxic T-Cells and Immune Response ### CD8+ Cytotoxic T-Cells These T-cells specialize in identifying and eliminating infected or cancerous cells. They recognize antigens presented by MHC Class I molecules on the surface of infected or abnormal cells. ### Mechanism Cytotoxic T-cells use the T-cell receptor (TCR) to detect foreign peptides presented by MHC Class I molecules. Once they recognize an infected cell, they release toxic substances like perforins and granzymes, causing the target cell to die. ## Helper T-Cells and Antibody Production ### CD4+ Helper T-Cells Helper T-cells are essential for coordinating the immune response. They recognize antigens presented by MHC Class II molecules on APCs, particularly dendritic cells, and activate other immune cells, such as B-cells, to produce specific antibodies. ### Dendritic Cells and Antigen Presentation Dendritic cells process and present antigens on MHC Class II molecules to helper T-cells, enabling T-cells to activate B-cells. ## Immune Tolerance ### Central Tolerance Central tolerance is the elimination of self-reactive immature T-cells and B-cells during their development. This process occurs in the thymus for T-cells and the bone marrow for B-cells. * **T-Cell Central Tolerance**: In the thymus, T-cells that strongly recognize self-antigens are eliminated to prevent autoimmune reactions. * **B-Cell Central Tolerance**: In the bone marrow, B-cells that react to self-antigens are removed to avoid autoimmune diseases. ### Peripheral Tolerance Even though central tolerance removes most self-reactive cells, some may escape. Peripheral tolerance mechanisms, such as regulatory T-cells, prevent these escaped cells from becoming active and attacking the body's own tissues. ## Autoimmune Diseases and HLA Associations Certain HLA types are linked to autoimmune diseases, where the immune system mistakenly attacks the body's tissues: * **HLA-B27**: Associated with ankylosing spondylitis, a type of arthritis that affects the spine. * **HLA-DR3 and DR4**: Linked to diseases like rheumatoid arthritis, Type 1 diabetes, and multiple sclerosis. * **HLA-DQ2 and DQ8**: Strongly associated with celiac disease, where the body reacts to gluten. ## Positive and Negative Selection of T-Cells ### Positive Selection T-cells that moderately recognize MHC molecules survive and continue to mature. This ensures that T-cells can interact with MHC molecules and mount an immune response. ### Negative Selection T-cells that bind too strongly to self-antigens during development are eliminated. This prevents the survival of potentially harmful T-cells that could cause autoimmune diseases by attacking the body's tissues. ## B and T-Cell Diversity and Peripheral Tolerance ### Diversity of B and T-Cells The immune system generates a large variety of B and T-cells, each with a unique receptor for recognizing different antigens. This diversity is achieved through VDJ recombination, a process that shuffles gene segments to create various antigen receptors. ### Peripheral Tolerance Peripheral tolerance ensures that any self-reactive immune cells that escape central tolerance do not become active, primarily through mechanisms like regulatory T-cells. ## HIV Case Study and MHC Variability ### HIV Controllers A small group of people, known as “elite controllers,” can manage HIV infection without needing antiretroviral therapy. These individuals possess specific variations in their MHC genes, such as HLA-B*57, which help them control the virus more effectively. ### MHC and Population Diversity MHC genes are highly variable between individuals, which benefits populations by creating diverse immune responses. This diversity enhances a population's ability to survive different infections. However, it also complicates organ transplants because MHC differences between individuals can lead to tissue rejection. ## Lymphoid Organs and Pathogen Detection ### Lymphoid Organs Lymph nodes and the spleen act as central hubs where immune cells such as B and T-cells interact with antigens and each other. * **Lymph Nodes**: Filter antigens from lymphatic fluid. Dendritic cells bring antigens from tissues to the lymph nodes, where they present them to T-cells. * **Interaction of B and T-Cells**: Antigen-presenting cells (APCs) bring antigens to lymph nodes, where B-cells and T-cells interact and coordinate a targeted immune response. ## Mechanism of B-Cell and T-Cell Interaction For an effective immune response, B-cells and helper T-cells must recognize the same antigen. When a B-cell captures and processes an antigen, it presents it on MHC Class II. A helper T-cell recognizes this antigen and produces cytokines, which stimulate the B-cell to proliferate and produce antibodies. * **Memory B-Cells**: Some activated B-cells differentiate into memory cells that persist for years and respond rapidly if the same pathogen is encountered again. ## Phagocytosis and Antigen Processing ### Dendritic Cells and Phagocytosis Dendritic cells engulf pathogens through phagocytosis, process their proteins into peptides, and load them onto MHC Class II molecules. This is crucial for initiating an adaptive immune response. ## Immunoglobulin Gene Rearrangement and Antibody Production ### Isotype Switching B-cells initially produce IgM antibodies. Through isotype switching, they can switch to producing different types of antibodies (IgG, IgA, IgE), each suited for specific immune functions. * **IgG**: The most common antibody, responsible for neutralizing pathogens and tagging them for destruction (opsonization). * **IgA**: Plays a crucial role in mucosal immunity (found in the gut and respiratory tract). * **IgE**: Involved in allergic reactions and defense against parasitic infections. ## Immune System Evolution and HLA Diversity MHC/HLA diversity provides evolutionary advantages by ensuring that populations can respond to a wide range of antigens, thus protecting against various pathogens. This genetic variability is also a key factor in how some individuals, like HIV elite controllers, can manage infections more effectively. ## Cancer Immunology and CAR T-Cell Therapy ### CAR T-Cell Therapy CAR T-cell therapy is a revolutionary cancer treatment where a patient's T-cells are genetically modified to express receptors that target specific tumor antigens. These modified T-cells recognize and kill cancer cells more effectively. ### Living Drugs CAR T-cells are referred to as “living drugs” because they are biological therapies made from the patient's own cells, which are engineered to fight cancer.