Immunology Notes PDF

Omar Shmoury BIOL 263 Chapter 1 Introduction (flag): Immunology is the study of the immune system. It surveys how the immune system, specifically its cells, mount a defense against pathogens, other non-self-entities, and cancer cells which are self-cells– becau...

Omar Shmoury BIOL 263 Chapter 1 Introduction (flag): Immunology is the study of the immune system. It surveys how the immune system, specifically its cells, mount a defense against pathogens, other non-self-entities, and cancer cells which are self-cells– because they are self-cells, they possess immunotolerance against the immune system so that they are rarely completely eradicated by the immune system. The immune system actively surveys the body for any invaders and usually efficiently dispatches the present threat. The reason for the active surveillance is because we are always exposed to microbes be that in our food, in the air, or when we encounter contaminated surfaces or infected people. Thus, we don’t get ill every time we get infected due to the effectiveness of the immune system. What are the key scientific questions in immunology? 1. What are the defensive strategies of the body against infection? This question is broader than molecules and cells. In other words, how do organisms protect themselves from infection? - Possessing a barrier between inner tissues and outer environment such as skin or cuticle (in plants). - Behavioral strategies such as wearing a mask or social distancing (avoidance). Organisms instinctively stay away from sick individuals. Honeybees, for instance, do not allow for the entry of sick individuals. - Elimination of the microbe/invader through the adaptive and innate immune systems. Two terms become important here: 1. Resistance: resistance is characterized by how fast an organism can eliminate the invader/microbe. It is a direct measure of the efficiency of an organism’s immune system. 2. Tolerance: is how much an organism can tolerate the damage inflicted by a microbe so that the greater the tolerance, the greater the chances for survival. 3. Tolerance is less studied than resistance and depends on a variety of factors such as the efficiency of tissue repair in the organism. It is not a direct measure of the efficiency of the immune system, but only the host’s capacity to handle the infection. Avoidance can be measured behaviorally. Resistance can be measured by surveying the quantity of the microbe over time. The viral titer progression is measured. The greater the decrease over time, the greater the resistance, but the initial dose of microbial contamination must be considered too. o We use a tissue sample from the relevant organ to measure the resistivity of the organism.  Tolerance is measured as a ratio of death to survival of an organism. We inject the organism with the microbe and follow how many of the group died. Thus, tolerance is determined by using survival curves. An individual who has been infected but has no symptoms likely has high tolerance and resistance. The titer count will decrease over time in this case. A host may be infected with a microbe that is still in a latent/lysogenic phase of the disease and so produce no symptoms. However, whether the microbe is transmissible or can infect other organisms during this phase depends on the microbe. 2. When infection does occur (when the avoidance strategies have failed), how does the body sense the invader, eliminate the invader, and cure itself? - The body recognizes the invader through specific receptors. The first of these receptors that has been discovered is the toll receptor. The determination of these receptors is believed to be nearly exhausted in the human genome. If we know all the receptors, then why do we not have all the vaccines? → There are a variety of factors including that we do not understand immunology very well. There are experimental differences concerning the model organisms that we use and the fact that we must first start with benchwork before transitioning to higher organisms. - After recognition, the body eliminates the invader through a variety of mechanisms. - The body then cures itself through mechanisms that are yet to be properly elaborated. However, the efficiency of this process directly affects tolerance. 3. What constitutes a protective immune response against a specific pathogen? What kinds of cells and factors do we need to protect ourselves from infection? Do we need an innate immune response with killer cells? We cannot properly and entirely provide an answer to these questions. When we manage to answer questions such as these, we will possess a more mature understanding of immunity. 4. Is the immune system elicited also against noninfectious agents (endogenous and exogenous)? Are these responses protective in nature? 1. The immune response is elicited against noninfectious exogenous agents such as allergens and noninfectious endogenous agents in the case of autoimmune responses. 2. We are not sure whether the responses against noninfectious exogenous agents are protective in nature and there are different views in the matter. Some find that allergic reactions can protect us from pollutants that can contribute to tumorigenesis. Additionally, because of the allergic reactions, there is increased surveillance that may lead to the elimination of cancerous cells.  3. Others argue against the latter remark, citing evidence that a prolonged immune response can lead to the formation of reactive oxygen species which can damage DNA and contribute to the formation of cancer cells. 4. There is yet to be any strong evidence supporting either stance. 5. Allergens differ significantly from other infectious agents so that it is not viable to suggest that they mimic microbial molecules. 6. There are receptors on the cells that can sense foreign enzymatic activity. Facts, figures, and debatable issues in immunology: - Our knowledge of immunology has aided us in the grafting of organs- MHC typing– yet we have failed, thus far, to combat the 5 major killers regarding infectious diseases (lower respiratory tract infections, diarrheal diseases, HIV, tuberculosis, and malaria). - We are yet to produce viable and effective vaccines against major, globally important pathogens. We fail not only because of the vaccine strategy, but also because the microbes mutate. Other reasons include that the microbes do not always produce immunological memory. The microbes are also highly diverse with a large degree of genetic polymorphism. Infection by some pathogens does not always lead to proper maturation of germinal regions of the lymph nodes, and we do not know why. - There is an increase in the number of people with allergies worldwide. We are not sure what is causing this rise, what is happening to the immune system, or whether human beings play a role in microbial ecology in this context. This relates to the hygiene hypothesis which states that if children are raised in a very hygienic environment, then they are prone to develop allergies when they grow. It appears that if the immune system is more often exposed to the microbial environment around the organism, then it will develop less sensitivity to allergens. It cues the system from a T-helper 2 to a T-helper 1 response because the T-helper 2 cells are responsible for an allergic response. We are far from understanding the details of this mechanism. - There exist interactions between the environment, microbiota (in the gut, in the lungs, and on the skin), and the immune system. We do not understand how the immune system distinguishes between these “good” microbiota and invaders and how these systems interact with each other. The immune system not only needs to determine pathogenic non-self-cells but also needs to distinguish between the “good” bacteria and the “bad” bacteria. Immune Responses: Innate: - The innate immune system is characterized by responses that are immediately available and non-specific for any individual organism. - Different examples of an innate response include: 1. Phagocytosis by macrophages (a process that takes only minutes to manifest entirely). 2. The release of anti-microbial peptides (peptides because they are short in sequence). These are chemical defenses of the cells. Some are constituently present and always secreted. Their function is to kill microbes. 3. Complement proteins are activated in a cascade after infection. It is an acellular system based on proteins and is part of the innate immune system. - The non-specificity means that innate immune cells will react to all entities that are termed invaders. This system, however, unlike in the adaptive system, does not lead to the manifestation of immunological memory. It is a response that is manifested pointedly in time. - The reaction time is not dynamic, it is the same across exposure to infections. - Cells of the innate immune response include Granulocytes, Macrophages, Dendritic cells, natural killer cells, and mast cells (allergic responses). The vast majority of immune cells are part of the innate immune system. Adaptive: - The adaptive response is characterized by lifelong protection against a specific pathogen due to immunological memory. It is termed the adaptive system because it develops over the lifetime of the individual as an adaptation to the infection of a pathogen. - This response confers immunological memory (the reason we get vaccines is to produce this memory but not all microbes generate this memory and we do not know why. Plasma cells continue to constitutively produce antibodies after the manifestation of immunological memory. Memory B and T cells will continue to circulate and, when the microbes are present once more, the B and T cells will reactivate and quickly eliminate the invader) - Adaptive immunity is not present in invertebrates. - The response is different between infections; that is, the dynamics of the response change; it will be much more reactive in the second exposure than in the first exposure. - Adaptive immunity deals with T and B lymphocytes where there is a wide variety of T-cell and B-cell receptors (because T-cells activate B-cells). - Antibodies are produced and target a very specific receptor on microbes or even microbial toxins. - Adaptive immunity evolves over time– it adapts. All blood cells originate from Hematopoietic stem cells Not all these cells mature in the bone marrow or blood. T-cells mature in the thymus. Mast cells are released from the blood as precursor cells and mature when they enter a specific tissue such a mucosal tissue. The Phases of the Immune Response (We don’t need to memorize this so far; we need to understand the differences between the innate and adaptive systems).  As long as the microbe is present, the innate immune response is present along with the eventual presence of the adaptive system. The function of dendritic cells is to alert the adaptive immune system (this process takes hours to start (we need at least 12 hours for the dendritic cells to find the T cells and a couple of days to mature). B cells also require T cells to mature. Memory T and B cells do not protect you in the first exposure, but they do so in future exposures to the specific microbe. Memory cells may form during the infection, but they need a lot of time to mature. Innate Immunity- The Frontline of Defense: The innate immune system is present in both vertebrates and invertebrates. Given the diversity of the latter and their success in habitation and colonization of many environments, it is clear that the innate immune system is efficient at dispatching threat especially considering that invertebrates lack an adaptive system. The innate immune system plays three major roles in vertebrates: 1. Innate reactions detect and destroy most of the microorganisms encountered in daily life. We are always exposed to microbes even when we do not exhibit any symptoms of infection. The reason for this lack of exhibition is due to the efficient elimination of microbes by the innate immune system 2. The innate immune system works in concert with the adaptive immune system to produce long-term immunological memory even when the infection is quickly dealt with by the innate system. It is only when the innate system fails to halt and draw back the progression of the microbe that the adaptive immune system– whose first exposure requires days to manifest due to the maturation of T and B cells– is in play. Both these systems work simultaneously together to kill the pathogen. 3. The innate immune system is responsible for the activation of the adaptive immune system– the swelling of lymph nodes is due to the prevention of movement of lymphocytes so that they will more likely contact T-cells, activate them, and tell them what kind of infection is present (as in: they orient the adaptive response). If the message from dendritic cells is not translated properly and does not orient the T cell response properly, then T-cells may create a response that is not efficient at dealing with the disease. Both systems act in concert, and they are not independent in function. The activation of the adaptive system enhances the activity of innate immune cells in the defense of the body. What Activates the Immune System? - The immune system is activated by inflammatory inducers. These indicate the presence of a pathogen or tissue damage. - The immune system is not only activated by microbes. It can be activated by allergens and other non-living entities through tissue damage. Thus, activation of the immune system occurs due to the presence of a pathogen or tissue damage. There are 2 types of inflammatory inducers: 1. PAMPs: Pathogen Associated Molecular Patterns. These are produced by microbes and are things like their cell wall components (lipopolysaccharides in gram negative bacteria). They are molecular patterns and are distributed over a wide range of cells that belong to a group of organisms. 2. DAMPs: Danger Associated Molecular Patterns. These are molecules that are present inside cells and that are released when cells are lysed (transcription factors). They signal for the activation of the immune system– such as uric acid which causes inflammation of the joints. Toxins are not PAMPs because they are indicative of specific types of bacteria– there are way too many toxins that belong to different species of bacteria. PAMPs are molecules that are indicative of the presence of a group of organisms → such as cell wall components (peptidoglycan, LPS) and viral RNA. Sensory cells detect inflammatory inducer molecules and secrete cytokines– small proteins that mediate communication between cells of the immune system and determine the kind of response (antibody or otherwise), the duration of the response, and may even have autocrine effects that involve the enhancement of the function of the cell that secretes these molecules. The release of cytokines also influences antimicrobial and antiviral protein (viruses are dealt with either through neutralization, or by killing infected cells) production by stromal cells at target tissues. Additionally, sensory cells may release other mediators that possess cytotoxic effects and that kill infected cells. Protection against pathogens relies on several levels of defense: 1. Avoidance (behavioral barriers) 2. Resistance (clearance of the microbe) 3. Tolerance (tissue resistance to damage) If the anatomic barriers are compromised or surpassed, complement cascades and antimicrobial proteins (such as lysozyme and lectins) as well as innate immune cells “combat” the pathogens whether through the function of the chemical defenses (step 2) or the phagocytosis performed by immune cells (steps 2 and 3 can take place in parallel and simultaneously). The cells of the adaptive system will be activated even when the innate immune system has already quelled the invasion. In circumstances where the innate system has not yet managed the threat, the adaptive system will have had substantial time to respond and aid in the protection against the threat. - The role of dendritic cells is not to destroy microbes, but it is to capture the antigens of invaders and to relay that to the adaptive system so that they can activate it and allow the cells of the adaptive system to proliferate and respond to the threat. - B cells and T cells are in constant circulation around the body. They travel through the lymphatic system and always enter and leave different lymph nodes around the body. - Dendritic cells don’t migrate too far around the location of infection. They travel to the closest lymph nodes and wait for the correct T cells to arrive from different nodes or from their circulation. - Once the T cell has found the dendritic cell, the adaptive response has begun. - Primary lymphoid tissues (the bone marrow and thymus) are involved in the development of the immune cells. The bone marrow contains the stem cells that produce the immune cells. The thymus is where T cells mature. - Secondary immune tissues are tissues where immune reactions occur. The spleen is a secondary immune organ that responds to bloodborne pathogens and initiates an  immune response. The liver is also exposed to bloodborne pathogens but does not possess the capacity to activate an adaptive immune response. Also see slides 12, 13, and 14 on the importance of vaccines and some history. Topic 1 Mucosal Immunity (flag): Mucosal tissues constitute epithelial surfaces that are covered in mucus or that are “moist.” These layers are present as linings of tubular structures in the body: the gastrointestinal tract, the urogenital tract, the respiratory tract. Many deaths worldwide are due to mucosal infections which reflects the importance of protecting these tissues. Not all microbes, however, are pathogenic. Many microorganisms that inhabit mucosal epithelia are commensal bacteria that are beneficial for us. These commensal bacteria inhabit the lungs, the intestines, the stomach, the esophagus, and the mouth. They are also present on the surface of the skin though the skin, but because it is a dry surface, it is not mucosal tissue, yet it continues to be an important barrier for protection. Thus, the immune system must learn not to target these commensal bacteria. These bacteria provide several advantages including the production of antibacterial proteins that prevent pathogenic bacteria from infecting the body.