Immune System - Shiur 1-2 PDF

06/11 Introduction Thucydides: A person who realised that people who get sick once from a disease don't get sick from the disease again and can even take care of sick people. Immune system: protection against pathogens (microscopic: bacteria, fungi, viruses, etc.). Difference between cancer and pa...

06/11 Introduction Thucydides: A person who realised that people who get sick once from a disease don't get sick from the disease again and can even take care of sick people. Immune system: protection against pathogens (microscopic: bacteria, fungi, viruses, etc.). Difference between cancer and pathogens: -​ Cancer and pathogens differ in their evolutionary impact. -​ Pathogens, which are often responsible for early infectious diseases, directly influence natural selection by favouring resistant individuals. -​ Cancer, linked to the accumulation of mutations with age, generally occurs after the reproductive period and has little impact on evolution, because it does not hinder gene transmission. The immune system plays an important role in tissue renewal and regeneration. Some immune cells, such as macrophages, actively participate in the repair of damaged tissues by eliminating dead cells and releasing chemical signals (cytokines, growth factors) that stimulate the proliferation of surrounding cells. This support function contributes to maintaining tissue homeostasis in addition to defence against infections. Functions of the immune system -​ Identify and eliminate a wide range of pathogens. -​ Prepare for the future: immune memory. -​ Do all this without harming the body tissues - self tolerance (heat, fever etc are not supposed to be too “aggressive” to harm us). Defence Lines Immune System First line of defence: -​ The skin and openings of the body (e.g. tears, eyelashes, acid secretions, etc.). -​ Most pathogens do not enter the body. However, the openings of the body are weak points, and many pathogens enter through these routes. Second line of defence: -​ Act against pathogens that manage to enter the body -​ White blood cells reach the areas where pathogens have entered. -​ The main response is inflammation, which focuses on the infected area. -​ Leukocytes = white blood cells. There are several types of white blood cells with a specific role for each: -​ NK cells (Natural Killer): Kill cells infected by viruses. -​ Phagocytic cells: Engulf pathogens like viruses/bacteria and destroy them, and sometimes even recycle the substances leftover -​ Granulocytes: release toxic substances that kill parasites and bacteria, for pathogens that are too large and therefore difficult to swallow. These cells are in the blood all the time and act when they are requisitioned. Third line of defence: -​ Specialised white blood cells (lymphocytes) participate in the response. These cells can distinguish between different types of pathogens. They are found in the blood vessel and don’t come out unless needed. -​ They create a specific response against each pathogen and develop a memory to recognize this pathogen and fight it in the future. -​ The soldiers: -​ B cells: Secrete antibodies that identify pathogens in a specific way by associating with them. They are secreted from the cell. -​ Cytotoxic T cells: Kill cells infected by viruses in a specific way. -​ The commanders: -​ Dendritic cells (in blue): Play key role in recognizing pathogens. They capture fragments of the antigens and take them to the immune system cells to alert them and coordinate the response. They act as messengers, providing precise information about the pathogen that has entered the body. They remain in the tissues without doing anything until a pathogen enters. There, they break down the pathogen to present its proteins on the surface of the cell, to inform the helper T cells. -​ Helper T cells (CD4 T cells) (in yellow): These cells receive information from dendritic cells about pathogens. Once activated, they coordinate the immune response by stimulating other immune cells, such as B lymphocytes (which produce antibodies) or cytotoxic T lymphocytes (which directly destroy infected cells). Immune Defence Process: 1.​ First line of defence intact: -​ Skin (epidermis, dermis, and hypodermis) and mucous membranes prevent pathogens from entering. -​ Macrophages and dendritic cells monitor tissues. 2.​ Barrier breakdown: -​ Injury or infection allows pathogens to enter. -​ Macrophages detect invaders and trigger an inflammatory response. 3.​ Arrival of additional white blood cells: -​ Blood vessels dilate to allow white blood cells to pass through. -​ Macrophages and dendritic cells phagocytose pathogens. 4.​ Activation of the third line of defence: -​ Dendritic cells take antigens to lymphocytes (activation of adaptive response). -​ B lymphocytes produce specific antibodies. -​ T lymphocytes destroy infected cells. 5.​ Immune memory: -​ Memory lymphocytes are trained for a rapid response in the event of a new infection by the same pathogen. Great Figures in Immunology 1.​ Edward Jenner (1749-1823): -​ Important physician during outbreak of Smallpox infection that killed 1-10% of people -​ He concluded that infection with cowpox, a mild disease in humans, offered protection against smallpox, a much more serious and often fatal disease. After inoculating a boy with pus from a cowpox lesion, Jenner observed that he did not develop smallpox when exposed to the smallpox virus. -​ This discovery led to the development of the first vaccine, laying the foundation for modern immunisation and demonstrating that controlled exposure to a less virulent pathogen could protect against serious disease. -​ He succeeded in completely eradicating the disease, something that has never been done again, even today with vaccines. -​ Vaccination: using cowpox to give cross-immunity to smallpox 2.​ Louis Pasteur (1822-1895): -​ A microbiologist who was one of the first to understand that diseases were caused by beings too small to be visible. -​ He developed vaccines; he used a weakened pathogen to give immunity to rabies, anthrax and cholera. -​ He understood that even dead bacteria could be used to vaccinate. This is called active vaccination (dead organisms, attenuated pathogens, attenuated toxins, DNA so that the cell can recreate the pathogen and learn to eliminate it) 3.​ Emil von Behring:  -​ Serotherapy involves using specific antibodies (antitoxins), extracted from the serum of an immunised individual or animal, to neutralise the toxins of pathogens such as diphtheria and tetanus. -​ This approach provides short-term protection because it does not stimulate the immune system to produce its own immune memory = Passive vaccination -​ Von Behring demonstrated the effectiveness of this technique in saving lives, earning him the Nobel Prize in Medicine in 1901. Active vs Passive Vaccination: Active vaccination involves introducing an antigen (an attenuated, killed, or part of a pathogen or toxin) into the body to stimulate the immune system to produce its own antibodies and memory cells. This provides long-lasting immunity, as the immune system "learns" to recognize and fight the pathogen if encountered again in the future. Passive vaccination, on the other hand, involves directly administering pre-made antibodies, immune serum, to a person. This provides immediate, short-term protection, as the body doesn’t produce its own immune response or memory cells. Passive vaccination is often used in cases of immediate need, such as exposure to certain toxins or diseases Targets of the Immune System Intracellular infections can be more severe because the pathogen hides within our cells, making it harder for the immune system to detect and eliminate them without harming our own tissue. These infections often require a strong cell-mediated immune response (e.g., T cells) to identify and destroy infected cells. Intracellular pathogens, such as viruses and some bacteria (like Mycobacterium tuberculosis), can persist in the body and lead to chronic or latent infections, which are challenging to treat. Extracellular infections are generally more accessible for the immune system to target, as the pathogens remain outside cells, where they can be neutralised by antibodies and other immune components. While extracellular pathogens can cause severe infections, especially in cases of overwhelming bacterial load (like sepsis), the body often has a better chance of eliminating them without extensive collateral damage. However, some extracellular pathogens produce toxins that can cause severe or life-threatening symptoms, even if the infection itself is easier to access. Obligatory parasite: organism that must live and reproduce within a host organism to survive Cells of the Immune System White blood cells = leukocytes Red blood cells = erythrocytes Platelets = thrombocytes All develop from a single stem cell: HSC. Found in bone marrow. Stem cell = can divide “infinitely” and specialise. Each immune cell includes several subtypes of cells. Phagocytes 1.​ Macrophages (Monocytes) -​ Phagocytic cells. -​ Difference between phagocytosis and endocytosis: endocytosis involves small particles or liquids (nm), phagocytosis involves large solid particles (um). Endocytosis is general (absorption), while phagocytosis is specialised for defence and cleaning. -​ Macrophages swallow microorganisms into the lysosome to break them down. Found in the tissues and when they detect a pathogen, activate -​ Monocytes leave the bloodstream and migrate to the tissues in response to infection or inflammation, then differentiate into macrophages -​ This process is triggered by tissue-specific signals. 2.​ Neutrophil -​ Granulocyte because it contains many vesicles (purple dots) and several nuclei. -​ Between 4 and 6 hours (very fast) response, it’s the first to penetrate the infected area by crossing the blood vessels. -​ It is very flexible (10 um, crosses spaces of 0.5 um). This is possible thanks to its nuclei which can stretch the DNA without it being afflicted. -​ It dies quickly and must be replaced quickly. -​ Doesn’t know how to present the proteins of the pathogen on the surface of the cell 3.​ Dendritic cells (Monocytes) -​ Originate from monocytes or myeloid progenitors. -​ Main role is capture of pathogens (phagocytosis). -​ Presentation of antigens to T lymphocytes to activate adaptive immunity -​ Mainly involved in the communication between innate and adaptive immunity. Granulocytes Perform exocytosis (secrete toxins to kill pathogens). They act outside the cell because toxins are very dangerous for it.  1.​ Eosinophils -​ Fight against multicellular parasites (helminths). -​ Release cytotoxic enzymes to destroy organisms too large to be phagocytosed. -​ Also involved in allergic responses and in the regulation of inflammation. Is activated during asthma due to allergens. As it secretes its toxins, it damages an enzyme in our lungs which helps with elasticity. 2.​ Basophils -​ Mediators of inflammation and allergic reactions. -​ Release molecules like histamine and leukotrienes to amplify inflammatory response -​ Participate in the defence against parasites, although indirectly. -​ Present in very small numbers in the blood. 3.​ Mast cell -​ Release of chemical mediators (histamine, heparin) during inflammatory and allergic responses. -​ Located in tissues, close to blood vessels and nerves, where they react quickly to allergens. -​ Responsible for symptoms of immediate allergic reactions (e.g. hives, anaphylactic shock). Lymphocytes 1.​ T cells -​ As we said earlier, we have the soldiers, who kill, and the T-helpers, who know how to be activated by macrophages and dendritic cells and they release proteins that direct the immune cells.  2.​ B cells -​ Contain B receptors on surface. When these detect something, they are activated, and secrete antibodies, which spread everywhere, and act as receptors themselves. 3.​ Natural killer cells -​ Kill infected cells. -​ Does not need another cell to ​ ​ ​ ​ “direct” it. SUMMARY CELLS: Immune system Divisions: The immune system is divided into two: -​ Innate immunity (‫)מולדת‬ -​ Includes NTC and phagocytes -​ Adaptive/Acquired immunity (‫)נרכשת‬ -​ Includes B and T cells Antigen: substance that activates the immune system. The antigen is injected and the concentration of antibodies that result is observed. First image: innate response Second image: adaptive response (B cells) We can see that the first reaction (innate) is much faster but less targeted. We have an innate reaction so we don’t die immediately. This is logical because adaptive immunity needs activation by innate immunity to act. This graph shows the difference between primary and secondary antigen immune responses -​ Primary Response (left side of the graph): When the body is first exposed to antigen A, there is a lag phase where no antibodies are present as the immune system prepares to respond. Antibody levels then gradually rise, peaking around day 16, and then decline. This response is relatively slow and weaker. -​ Secondary Response (right side of the graph): On day 64, both antigen A and a new antigen B are introduced. For antigen A, the immune system shows a rapid and stronger response with a high concentration of antibodies due to "immune memory" from the primary exposure. This is the secondary response, which is faster and more intense. For antigen B, however, the body goes through a new primary response, with a slower and weaker antibody increase.  -​ Cytokine Concentration: Cytokine levels (shown in yellow) increase in response to both primary and secondary exposures, supporting immune activity and signalling, but they are not as high as antibody levels in the secondary response to antigen A. The innate response provides initial, non-specific defence (mainly cytokine release), while the adaptive response builds a specific antibody response. Upon re-exposure to the same antigen, the adaptive response is much faster and stronger due to immune memory, whereas a new antigen triggers a slower, primary adaptive response. Adaptive immunity: Initial immune response (7-14 days): Activation of antibodies and T cells to fight infection. Protective immunity (14-35 days): Antibodies and effector cells persist, preventing visible reinfection. The system doesn’t go back to steady state. If we were to be reinfected during this time period, we wouldn’t even tell (inapparent reinfection). Not memory, protective! Immunological memory (after several months/years): Rapid and intense response in case of reinfection, often asymptomatic or mild. This is the adaptive immune response. An adaptive immune system must be able to do four things: -​ Recognize a wide range of pathogens. -​ Eliminate these pathogens once they are recognized. -​ Preserve host tissues (i.e. ensure self-tolerance). -​ Learn and maintain immunological memory. - Cytokine production (IFN-α, IFN-β, TNF-α, IL-12) (green line, day 1-3): these cytokines are rapidly produced by infected cells and innate immune cells to limit viral replication and activate other immune mechanisms. - NKC (blue line, day 2-5): NK cells kill infected cells in response to cellular stress signals, thus limiting the spread of the virus. - Cytotoxic T cell action (red line, day 5-10): Antigen-specific cytotoxic T lymphocytes (CTLs) take over and destroy infected cells in a targeted manner, effectively eliminating the virus. - Virus titer (yellow) - virus concentration in blood: concentration gradually decreases under combined effect of cytokines, NKC and T cells, until complete elimination.