Immunopharmacology PDF

IMMUNOPHARMACOLOGY  What is immunity Important definitions Innate immunity Adaptive immunity Overview: Every day humans encounter potentially harmful disease causing organisms, or “pathogens”, like bacteria or viruses. Yet most of them are still able to function properly and live li...

IMMUNOPHARMACOLOGY  What is immunity Important definitions Innate immunity Adaptive immunity Overview: Every day humans encounter potentially harmful disease causing organisms, or “pathogens”, like bacteria or viruses. Yet most of them are still able to function properly and live life without constantly being sick. That’s because the human body requires a multilayered immune system to keep it running smoothly.  Self vs. Non-self: How does the body know? In order to be effective, the immune system needs to be able to identify which particles are foreign, and which are a part the body. Self refers to particles, such as proteins or molecules, that are a part of or made by the body. They could be circulating in blood or attached to different tissues. self particles should not be targeted and destroyed by the immune system which is not reactive to self particles (tolerance). Non-self refers to particles that are not made by body (foreign bodies) and are recognized as potentially harmful. Non-self particles can be bacteria, viruses, parasites, pollen, dust, and toxic chemicals. The non-self particles could be infectious or pathogenic or antigenic.  Important definitions: ANTIGEN: Is anything that causes an immune response, it could be entire pathogens, like bacteria, viruses, fungi, and parasites, or smaller proteins that pathogens express.  CYTOKINES are molecules that are used for cell signaling, or cell-to-cell communication. Cytokines are similar to chemokines, wherein they can be used to communicate with neighboring or distant cells about initiating an immune response. Cytokines are also used to trigger cell trafficking, or movement, to a specific area of the body. CHEMOKINES are a type of cytokines that are released by infected cells. Infected host cells release chemokines in order to initiate an immune response, and to warn neighboring cells of the threat.  The immune system (Immunity): Defined as the body’s response to disease and injury or it is how body protects itself against infectious diseases caused by microorganisms; bacteria, viruses, protozoa, fungi, and parasitic organisms, such as helminth worms. It consists of two systems: 1. Innate immune system: a first line defence that provides a rapid, general, response when alerted by certain typical signals of infection. 2. Adaptive immune system: a persistent immune memory that is able to develop highly specific responses to target infection with extraordinary accuracy. Both systems work in close co-operation and, to an important extent, the adaptive immune system relies upon the innate immune system to alert it to potential targets and shape its response to them.  Innate (non specific) immunity: Is the kind of immunity that we have born with, it involves: initial barriers that are considered first line of defence and they keep harmful materials from entering the body; o Skin (physical barrier), eyelashes, cilia o Saliva and tears, that contain molecules that can neutralise bacteria. o Mucosal tissues (e.G. Lungs & airways, and the gut) are coated with mucus that is able to trap potential infectants. o Cough reflex o Stomach acid o Innate cellular immunity = Phagocytic cells ; immune cells that can respond to infectants that breach these physical defences o Innate humoral immununity = complement system & substances called interferon and interleukin-1 How does innate immunity recognize pathogens? Innate immune recognition (also known as pattern recognition) is based on the detection of molecular structures that are unique to microorganisms. Pattern recognition is unusual in that each host receptor (PRR) has a broad specificity and can potentially bind to a wide range of molecules that have a common structural motif or pattern. The targets of PRRs are sometimes referred to as pathogen-associated molecular patterns (PAMPs), although they are present on both pathogenic and non-pathogenic microorganisms. PAMPs are often components of the cell wall, such as bacterial lipopolysaccharide & peptidoglycan and fungal β-glucan. The detection of these structures by the innate immune system can signal the presence of microorganisms. An important aspect of pattern recognition is that PRRs themselves do not distinguish between pathogenic microorganisms and symbiotic (non-pathogenic) microorganisms, because the ligands of the receptors are not unique to pathogens. Yet, despite humans being colonized by trillions of symbiotic bacteria, homeostasis is somehow maintained under normal conditions. Furthermore, innate immune recognition of symbiotic microorganisms has an important role in maintaining intestinal homeostasis, and dysregulation of these interactions can lead to the development of inflammatory bowel disease and other disorders. The recognition of viruses also partly follows this principle. However, because all viral components are synthesized within host cells, the main targets of innate immune recognition in this case are viral nucleic acids. Discrimination between self and viral nucleic acids occurs on the basis of specific chemical modifications and structural features that are unique to viral RNA and DNA, as well as on the cellular compartments where viral (but not host-derived) nucleic acids are normally found. Nevertheless, this discrimination is not perfect and can fail under certain conditions, which can result in the development of autoimmune diseases. PRRs and their functions: There are several functionally distinct classes of PRR ,The best characterized class is Toll-like receptors (TLRs). TLRs are transmembrane receptors that recognize viral nucleic acids and several bacterial products like lipopolysaccharide. The full range of TLR functions in antimicrobial defense has not yet been determined, but TLRs are known to elicit inflammatory and antimicrobial responses after activation by their microbial ligands.  Cells of the Innate Immune System ❑Phagocytes, or Phagocytic cells: Phagocyte means “eating cell”, which describes what role phagocytes play in the immune response. Phagocytes circulate throughout the body, looking for potential threats, like bacteria and viruses, to engulf and destroy. Neutrophils: are phagocytic cells that are also classified as granulocytes because they contain granules in their cytoplasm. These granules are very toxic to bacteria and fungi and cause them to stop proliferating or die on contact. Neutrophils are typically the first cells to arrive at the site of an infection because there are so many of them in circulation at any given time. Monocytes: Are the largest cell types and they are classified as mononuclear Agranulocytes with a kidney shaped nucleus. made in the bone marrow and travels through the blood to tissues in the body where it becomes a macrophage or a dendritic cell.  Slide Title Macrophages: Macrophages, are efficient phagocytic cells that can leave the circulatory system by moving across the walls of capillary vessels. The ability to roam outside of the circulatory system is important, because it allows macrophages to hunt pathogens with less limits. Macrophages can also release cytokines in order to signal and recruit other cells to an area with pathogens. Dendritic cells: Dendritic cells are antigen-presenting cells that are located in tissues, and can contact external environments through the skin, the inner mucosal lining of the nose, lungs, stomach, and intestines. Since dendritic cells are located in tissues that are common points for initial infection, they can identify threats and act as messengers for the rest of the immune system by antigen presentation. Dendritic cells also act as bridge between the innate immune system and the adaptive immune system. Mast cells: Mast cells are found in mucous membranes and connective tissues, and are important for wound healing and defense against pathogens via the inflammatory response. When mast cells are activated, they release cytokines and granules that contain chemical molecules to create an inflammatory cascade. Mediators, such as histamine, cause blood vessels to dilate, increasing blood flow and cell trafficking to the area of infection. The cytokines released during this process act as a messenger service, alerting other immune cells, like neutrophils and macrophages, to make their way to the area of infection, or to be on alert for circulating threats.  Eosinophils are granulocytes target multicellular parasites. Eosinophils secrete a range of highly toxic proteins and free radicals that kill bacteria and parasites. The use of toxic proteins and free radicals also causes tissue damage during allergic reactions, so activation and toxin release by eosinophils is highly regulated to prevent any unnecessary tissue damage. While eosinophils only make up 1-6% of the white blood cells, they are found in many locations, including the thymus, lower gastrointestinal tract, ovaries, uterus, spleen, and lymph nodes.  Basophils: Basophils are also granulocytes that attack multicellular parasites. they release histamine, much like mast cells. The use of histamine makes basophils and mast cells key players in mounting an allergic response. Natural Killer cells: Natural Killer cells (NK cells), do not attack pathogens directly. Instead, they destroy infected host cells in order to stop the spread of an infection. Infected or compromised host cells can signal natural kill cells for destruction through the expression of specific receptors and antigen presentation.  The complement system The complement system (complement cascade) is a mechanism that complements other aspects of the immune response. Typically, the complement system acts as a part of the innate immune system, but it can work with the adaptive immune system if necessary. The complement system plays a critical role in inflammation and defense against some bacterial infections. Complement may also be activated during reactions against incompatible blood transfusions, and during the damaging immune responses that accompany autoimmune disease. The complement system is made of a variety of proteins that, when inactive, circulate in the blood. When activated, these proteins come together to initiate the complement cascade, which starts the following steps: Opsonization:is a process in which foreign particles are marked for phagocytosis. All of the pathways require an antigen to signal that there is a threat present. Opsonization tags infected cells and identifies circulating pathogens expressing the same antigens. Chemotaxis: Chemotaxis uses cytokines and chemokines to attract macrophages and neutrophils to the site of infection, ensuring that pathogens in the area will be destroyed. Cell Lysis: Lysis is the breaking down or destruction of the membrane of a cell. The proteins of the complement system puncture the membranes of foreign cells, destroying the integrity of the pathogen. Destroying the membrane of foreign cells or pathogens weakens their ability to proliferate and helps to stop the spread of infection. Agglutination: Agglutination uses antibodies to cluster and bind pathogens together. By bringing as many pathogens together in the same area, the cells of the immune system can mount an attack and weaken the infection. Classical Pathway: This pathway involves complement components C1, C2 and C4. The pathway is triggered by antibody-antigen complexes binding to C1, which itself has three subcomponents C1q, C1r and C1s. The pathway forms a C3 convertase, C4b2a, which splits C3 into two fragments; the large fragment, C3b, can covalently attach to the surface of microbial pathogens and opsonise them; the small fragment, C3a, activates mast cells, causing the release of vasoactive mediators such as histamine. Alternative Pathway: This pathway involves various factors, B, D, H & I, which interact with each other, and with C3b, to form a C3 convertase, C3bBb, that can activate more C3, hence the pathway is sometimes called ‘the amplification loop’. Activation of the loop is promoted in the presence of bacterial and fungal cell walls, but is inhibited by molecules on the surface of normal mammalian cells. Mannose-binding Lectin Pathway This pathway is activated by the binding of mannose-binding lectin (MBL) to mannose residues on the pathogen surface. This in turn activates the MBL-associated serine proteases, MASP-1 and MASP-2, which activate C4 and C2, to form the C3 convertase, C4b2a. Lytic Pathway All the pathways shares the final step by splitting of C5 and attachment of C5b to a target which binds sequentially to C6, C7, C8 and C9 to form membrane-attack complex (MAC), when inserted into the outer membrane of some bacteria, can contribute to their death by lysis. Adaptive immunity The adaptive immune system, also called acquired immunity, uses specific antigens to strategically mount an immune response. Unlike the innate immune system, which attacks only based on the identification of general threats, the adaptive immunity is activated by exposure to pathogens, and uses an immunological memory to learn about the threat and enhance the immune response accordingly. The adaptive immune response is much slower to respond to threats and infections than the innate immune response, which is primed and ready to fight at all times. Cells of the adaptive immune system Unlike the innate immune system, the adaptive immune system relies on fewer types of cells to carry out its tasks: B cells and T cells. Both B cells and T cells are lymphocytes that are derived from specific types of stem cells, called multipotent hematopoietic stem cells, in the bone marrow. After they are made in the bone marrow, they need to mature and become activated. Each type of cell follows different paths to their final, mature forms. B cells After formation and maturation in the bone marrow (hence the name “B cell”), the naive B cells move into the lymphatic system to circulate throughout the body. In the lymphatic system, naive B cells encounter an antigen, which starts the maturation process for the B cell. B cells each have one of millions of distinctive surface antigen-specific receptors that are inherent to the organism’s DNA. For example, naive B cells express antibodies on their cell surface, which can also be called membrane-bound antibodies. When a naive B cell encounters an antigen that fits or matches its membrane- bound antibody, it quickly divides in order to become either a memory B cell or an effector B cell, which is also called a plasma cell. B cells also express a specialized receptor, called the B cell receptor (BCR) which assist with antigen binding, as well as internalization and processing of the antigen, also they play an important role in signaling pathways. Memory B cells express the same membrane-bound antibody as the original naive B cell, or the “parent B cell”. Plasma B cells produce the same antibody as the parent B cell, but they aren’t membrane bound. Instead, plasma B cells can secrete antibodies. Secreted antibodies work to identify free pathogens that are circulating throughout the body. After the antigen is internalized and processed, the B cell can initiate signaling pathways, such as cytokine release, to communicate with other cells of the immune system. T cells Once formed in the bone marrow, T progenitor cells migrate to the thymus (hence the name “T cell”) to mature and become T cells. While in the thymus, the developing T cells start to express T cell receptors (TCRs) and other specific type of receptors called CD4 and CD8 receptors ( either CD4 or CD8, not both) Unlike antibodies, which can bind to antigens directly, T cell receptors can only recognize antigens that are bound to certain receptor molecules, called Major Histocompatibility Complex class 1 (MHCI) and class 2 (MHCII). These MHC molecules are membrane-bound surface receptors on antigen-presenting cells, like dendritic cells and macrophages. CD4 and CD8 play a role in T cell recognition and activation by binding to either MHCI or MHCII. T cell receptors have to undergo a process called rearrangement, causing the nearly limitless recombination of a gene that expresses T cell receptors. The process of rearrangement allows for a lot of binding diversity. This diversity could potentially lead to accidental attacks against self cells and molecules because some rearrangement configurations can accidentally mimic a person’s self molecules and proteins. Mature T cells should recognize only foreign antigens combined with self-MHC molecules in order to mount an appropriate immune response. In order to make sure T cells will perform properly once they have matured and have been released from the thymus, they undergo two selection processes: 1.Positive selection ensures MHC restriction and ability of cell to bind MHCI and MHCII. In order to pass the positive selection process, cells must be capable of binding only self-MHC molecules. If these cells bind nonself molecules instead of self- MHC molecules, they fail the positive selection process and are eliminated by apoptosis. 2.Negative selection tests for self tolerance and the binding capabilities of CD4 and CD8 specifically. The ideal example of self tolerance is when a T cell will only bind to self-MHC molecules presenting a foreign antigen. If a T cell binds, via CD4 or CD8, a self-MHC molecule that isn’t presenting an antigen, or a self-MHC molecule that presenting a self-antigen, it will fail negative selection and be eliminated by apoptosis. After positive and negative selection, we are left with three types of mature T cells: Helper T cells express CD4, and help with the activation of TC, B cells, and other immune cells. Cytotoxic T cells express CD8, and are responsible for removing pathogens and infected host cells. T regulatory cells express CD4 and another receptor, called CD25. T regulatory cells help distinguish between self and nonself molecules, and by doing so, reduce the risk of autoimmune diseases. Immunological memory Because the adaptive immune system can learn and remember specific pathogens, it can provide long-lasting defense and protection against recurrent infections. When the adaptive immune system is exposed to a new threat, the specifics of the antigen are memorized so we are prevented from getting the disease again. The concept of immune memory is due to the body’s ability to make antibodies against different pathogens. A good example of immunological memory is shown in vaccinations. A vaccination against a virus can be made using either active, but weakened or attenuated virus, or using specific parts of the virus that are not active. Both attenuated whole virus and virus particles cannot actually cause an active infection. By getting a vaccination, you are exposing your body to the antigen required to produce antibodies specific to that virus, and acquire a memory of the virus, without experiencing illness. Some breakdowns in the immunological memory system can lead to autoimmune diseases. Molecular mimicry of a self‐antigen by an infectious pathogen, such as bacteria and viruses, may trigger autoimmune disease due to a cross-reactive immune response against the infection. One example of an organism that uses molecular mimicry to hide from immunological defenses is Streptococcus infection. Thank you