Adaptive vs Innate Immunity PDF

13/11 ADAPTIVE VS INNATE IMMUNITY Through the adaptive response, pathogen-specific T-cells and B-cells can be created and, although the process takes several days, this allows immune memory to sometimes last a lifetime. Innate Immunity: -​ First line of defence -​ Broad defence mechanisms that...

13/11 ADAPTIVE VS INNATE IMMUNITY Through the adaptive response, pathogen-specific T-cells and B-cells can be created and, although the process takes several days, this allows immune memory to sometimes last a lifetime. Innate Immunity: -​ First line of defence -​ Broad defence mechanisms that come into play immediately or within hours of a pathogen’s appearance in the body. -​ These mechanisms include physical barriers such as skin, chemicals in the blood, and immune system cells that attack foreign cells in the body. -​ Alerts and activates the adaptive immune division. Adaptive Immunity: -​ Specific immune response. -​ The pathogen component first must be processed and recognized. Then the adaptive immune system creates an army of immune cells specifically designed to attack that component. -​ Includes "memory" making future responses against component more efficient -​ Regulates innate immune function 2 ways to study the immune system: 1.​ Take a pathogen, inject it into an animal, and see how the animal reacts.  2.​ Study cases of people with immunodeficiency diseases and check which genes are affected in order to understand their role and the immune system in general. Experiment 1: To determine whether the mutation affects the innate or adaptive immune system, the immune response of two mice is compared: a healthy mouse and a mouse with a mutation in the immune system. When a virus is injected: -​ Healthy mouse: It becomes ill for a few days, but eventually recovers. -​ Mutated mouse: It dies after 3 to 4 days. This result suggests that the mutation affects the innate immune system. Indeed, the adaptive immune system generally only begins to kick in after several days (beyond 3-4 days). The rapid death of the mutated mouse therefore indicates a problem with the innate immune system, which is the first line of defence against the virus. Experiment 2: For this experiment, a small amount of virus is injected into the mice, so that they can survive it. After 2-3 days, all mice, whether healthy or mutant, recover. Thirty days later, a lethal dose of the same virus is administered. It is observed that the healthy mice survive, while the mutant mice die. This result suggests two possibilities: -​ The mutation concerns the adaptive immune system: -​ The adaptive immune system is responsible for immunological memory. -​ In healthy mice, it allows a rapid and effective response during the second exposure to the virus, thus neutralising the lethal viral load. -​ In mutant mice, if the mutation affects adaptive immunity, they cannot develop this immunological memory. During the second exposure, they behave as if they were encountering the virus for the first time, failing to fight it effectively. -​ The mutation affects the innate immune system: -​ The innate immune system plays a role in recognizing and rapidly eliminating pathogens during the early stages of infection. Although it is not directly responsible for immunological memory, it can help to efficiently activate the adaptive system. -​ Innate immunity does not create long-lasting immunological memory, however, it is essential to reduce the initial viral load and provide warning signals (via cytokines such as IL-12, TNF-α) to activate adaptive immunity. -​ If the mutation affects innate immunity, mutant mice may have a weakened response upon second exposure, compromising their ability to control a high viral load, despite the presence of adaptive memory. Organs Involved in the Immune System 1.​ Bone marrow: -​ Location: In the long bones, ribs, breastbone, and pelvis. -​ Role: The bone marrow is the site of production of blood cells, including white blood cells (leukocytes) such as B lymphocytes, macrophages, and neutrophils. Mature B lymphocytes acquire their ability to produce antibodies there. 2.​ Thymus: -​ Location: Organ located behind the breastbone, above the heart. When we’re born, it is huge and covers the whole heart of the baby, and slowly in the first 3 years it is very active and by age 12 it's almost completely folded away. -​ Role: The thymus is the site of maturation of T lymphocytes. 3.​ Lymph nodes: -​ Location: Distributed throughout body, often grouped in neck, armpits, groin... -​ Role: Lymph nodes filter lymph and allow immune cells, such as B and T lymphocytes, to interact with the antigens present. They are key points of activation of the immune response. Diseases of the Immune System David Vetter, nicknamed "Bubble Boy," was a child with severe combined immunodeficiency (SCID), a rare genetic disorder that prevents the immune system from functioning properly. Because of this condition, his body was unable to fight off even mild infections, making him extremely vulnerable to pathogens. To protect him, he had to live his entire life in a sterile environment, often called a "bubble." There are also diseases that are related to an "overly" active immune system. Fortunately, these diseases affect fewer patients than immunodeficiency diseases. The innate immune system The immune system must be regulated, quite active, but must take breaks, so as not to lead to immunopathological illness and kill us. It requires precise modulation: -​ In general, the first step (immediate) is not sufficient. -​ Often, the second is. -​ The third is very effective, although sometimes not necessary. The activity of the innate system can be limited if pathogen can be eliminated quickly. Function of the immune system: 1.​ Detection: Differentiate self from foreign, and dangerous from non-dangerous. 2.​ Designation: Highlight the foreign origin to direct immune cells (using secondary messengers such as cytokines). Where is the virus in the body? In which tissue? 3.​ Recruitment: Mobilise effector cells (using chemokines and adhesion molecules). 4.​ Elimination: Destroy and eliminate pathogens and dead cells. 5.​ Recurrence Prevention: Ensure wound heals and maintain immunological memory First line of defence of the immune system Without these barriers, everything else would be useless. -​ Skin: layer of fat, then the epidermis, which prevents the entry of foreign substances. -​ Epithelium is made up of tight junctions that prevent pathogens from penetrating. It constitutes tears, saliva, cilia, microvilli, mucosa... -​ Lysozyme: antibiotics that affect peptidoglycans ( which constitutes the membrane of bacteria) found in tears, mucosa… created in goblet cellls -​ Defensins: Peptides created by the epithelium. Binds to the bacteria to kill it, or enters it to prevent it from breathing, etc … -​ Microflora: bacteria that live in symbiosis with us (in the intestine etc.) to provide us with substances that we cannot produce. Very important. Infection: Entry of dangerous pathogen into the body Inflammation: immune system response against this pathogen Initiation of the inflammatory response: Clinical manifestations: -​ Pain: increased vascular diameter -​ Redness and warmth: increased blood flow -​ Swelling: increased vascular permeability Role of inflammation: -​ Mechanism to return a tissue to its steady state -​ Prevent initial establishment of infection (reproduction of the pathogen in tissues, especially in blood): we decrease the permeability of blood vessels near affected tissue, while keeping the tight junctions of the epithelium a little more relaxed to allow the entry of immune cells. We block the exit, but we allow the entry. -​ Prevent the spread of infection from the site of invasion -​ Healing (healing wounds) -​ Recruit effector cells for help -​ Alert and mobilise B and T cells Even if it is painful, it is necessary to allow the immune system to function. Acute inflammation VS chronic inflammation: Inflammation can be triggered by immune recognition of infection or tissue damage (often beneficial). Inflammation can also be caused by hypersensitivity to environmental components or by autoinflammatory or autoimmune reactions (which can cause diseases). -​ Acute inflammation: Influx of white blood cells and fluids from the blood to fight infection and promote tissue repair. Immediate, short-lived inflammation necessary for the immune response. Happens even if there is no cut so no pathogens and it’s just a hit, we still need it so the area can be fixed. -​ Chronic inflammation: When the trigger of inflammation is not eliminated. Leads to tissue damage and loss of function (joint destruction, pulmonary fibrosis) Current approach: It is recommended to actively treat inflammation in certain chronic diseases in order to slow down or prevent the progressive loss of function of the affected tissues or organs. This aims to limit the long-term damage caused by persistent inflammation. Current research shows that inflammation plays an important role in common chronic diseases such as atherosclerosis, type 2 diabetes, neurodegeneration, and cancer. Infection is initiated by bacterial adherence and penetration of the epithelial barrier. Persistent local infection of tissues induces adaptive immune response Stages of Inflammation 1.​ Initial Barrier (First Line of Defense): -​ The skin and mucous membranes act as physical barriers to prevent the entry of pathogens. If this barrier is broken (e.g. injury), inflammation is triggered. 2.​ Sensing (Innate Immunity): -​ Sentinel cells (macrophages, mast cells) detect pathogens or tissue damage. This triggers the release of inflammatory mediators (e.g. histamine, cytokines). 3.​ Vascular Phase: -​ Blood vessels dilate (vasodilation) to increase blood flow to the affected area, causing redness and warmth. The vessel walls become more permeable, allowing the influx of plasma and immune cells, which causes swelling (edema). 4.​ Immune Cell Recruitment: -​ Neutrophils, then macrophages, are recruited to the site through chemical signals (chemokines). They phagocytose pathogens and release other signals to amplify the response. 5.​ Clearance and Repair: -​ Pathogens and dead cells are cleared. Macrophages orchestrate the resolution of inflammation by releasing anti-inflammatory cytokines and promoting repair of damaged tissues. Sensing: -​ Influenza virus: Virus mainly targets cells in the respiratory tract and causes symptoms such as fever and cough. -​ Helicobacter pylori (Bacteria): Spiral-shaped bacteria known to colonise the stomach and be linked to gastric ulcers and gastric cancer. -​ Plasmodium: Parasite responsible for malaria, transmitted by mosquitoes, infecting red blood cells and causing cyclic fevers. -​ Candida: Opportunistic fungus that can cause superficial or systemic infections, especially in immunocompromised individuals. -​ C. Elegans: Nematode often used as model in research, but not human pathogen -​ Ascaris: Parasitic worm that infects the human intestine, causing digestive disorders and sometimes serious complications if the infection is massive. All these pathogens have one thing in common: they are very different from what we find in our bodies. For example: -​ Flagellin, a protein that allows the bacteria to move with its flagellum, is not found in us, and allows the immune system to identify bacteria. -​ LPS, which is found in the bacterial membrane. -​ DNA: the DNA of pathogens is different from ours. For example, our DNA is methylated, unlike that of bacteria. PRR PRRs (Pattern Recognition Receptors) are receptors of the innate immune system that recognize molecular patterns specific to pathogens (PAMPs) or cellular damage (DAMPs). Upon detection, they trigger immune responses such as inflammation, phagocytosis and activation of adaptive cells, playing a key role in defence infections. Robert Koch: -​ German physician and microbiologist, pioneer of modern microbiology. -​ He discovered the pathogens responsible for diseases such as tuberculosis, cholera and anthrax, and formulated Koch's postulates, fundamental criteria for establishing a causal link between a microorganism and a disease. -​ He observed that even dead bacteria could cause toxic effects in mammals. -​ He discovered and named endotoxin, a molecule present in the wall of Gram-negative bacteria (lipopolysaccharides), which remains active after the death of the bacteria and causes severe inflammatory responses. Example: LPS (lipopolysaccharides) Components of the external membrane of Gram-negative bacteria, trigger an inflammatory response in the host: -​ Recognition of LPS: Macrophages detect LPS via Toll-like receptors (TLR4), which activates the transcription factor NF-κB. -​ Production of cytokines: This activation leads to the release of pro-inflammatory cytokines, including TNF-α, which amplifies the immune response. -​ Chain reaction: Cytokines stimulate other immune cells, leading to the production of inflammatory molecules such as NO (nitric oxide), PAF (platelet-activating factor), kinins and free radicals (O2⁻), while activating coagulation to limit the spread of the infection. This coordinated cascade aims to eliminate the pathogen but can cause tissue damage if excessive. Macrophages detect LPS through the Toll-like receptor 4 (TLR4), which binds to a complex containing LPS and accessory proteins such as CD14 and MD2. This interaction activates an intracellular signalling pathway, including NF-κB, to trigger an inflammatory response. Toll-like receptors (TLRs) Toll-like receptors (TLRs), crucial for innate immunity, detect pathogen-specific motifs (PAMPs), such as lipopolysaccharides (LPS) from Gram-negative bacteria, single-stranded RNA (ssRNA) from viruses, or fungal compounds. These receptors, located on the membrane or inside cells, activate signalling pathways via adaptors such as MyD88, leading to the expression of inflammatory cytokines (e.g. TNF-α) to fight infection. Endosomes have receptors to detect what is familiar to our body. Many pathogens exploit this system to enter the cell by endocytosis. TLR7 detects unmethylated DNA Other TLRs can detect single-stranded RNA. But yet, it is the structure of the mRNA TLRs, such as TLR7 and TLR8, detect pathogen single-stranded RNAs (ssRNAs), as these RNAs are found in endosomes after phagocytosis or viral infection. Unlike host messenger RNA (mRNA), these pathogenic RNAs often have specific motifs, such as uridine-rich sequences or secondary structures, that differentiate them from host RNAs TLRs are all transmembrane: -​ TIR: part in the membrane, which sends the signal inside the cell -​ LRR: part outside membrane, which binds to component that activates receptor Leucine-Rich Repeats (LRRs) are leucine-rich structural motifs found in many proteins, including Toll-like receptors (TLRs). These motifs form a horseshoe structure that facilitates interaction with specific ligands, like pathogen PAMPs. They play a key role in recognizing molecular patterns and activating immune responses. Process: -​ Ligand recognition: The convex surfaces of TLR1 and TLR2 have specific binding sites for lipopeptide lipid chains. -​ Dimerization: Once the lipopeptide is bound, the two TLRs approach and form a dimer, bringing their intracellular TIR (Toll/IL-1 Receptor) domains closer together. -​ Signalling: This dimerization activates intracellular signalling pathways, triggering an inflammatory response via the activation of factors such as NF-κB. TLR-2 and TLR-1 are heterodimers: together they form a structure composed of two different receptors. To be distinguished from homodimers. There is not a single cell in the body that does not contain TLRs, that is, a means of identifying a pathogen. This is not just about cells in the immune system. Apart from TLRs, there are other types of receptors that can identify pathogens.