Innate Immunity PDF

Innate Immunity Dr. Sneha Dokhale Assistant Professor BK Birla College (Autonomous), Kalyan  Innate Immunity The innate immune system is the body's first line of defense against germs entering the body. It responds in the same way to all germs and foreign substances, which is why it is so...

Innate Immunity Dr. Sneha Dokhale Assistant Professor BK Birla College (Autonomous), Kalyan  Innate Immunity The innate immune system is the body's first line of defense against germs entering the body. It responds in the same way to all germs and foreign substances, which is why it is sometimes referred to as the "nonspecific" immune system. It acts very quickly: For instance, it makes sure that bacteria that have entered the skin through a small wound are detected and destroyed on the spot within a few hours. The innate immune system has only limited power to stop germs from spreading.  Innate Immunity The major functions -  recruit immune cells to infection sites by producing chemical factors, including chemical mediators called cytokines  activate the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells  identify and remove foreign substances present in organs, tissues, blood and lymph, by specialized white blood cells  activate the adaptive immune system through antigen presentation  act as a physical and chemical barrier to infectious agents; via physical measures such as skin and chemical measures such as clotting factors in blood, which are released following a contusion or other injury that breaks through the first-line physical barrier  Innate Immunity https://video.mhhe.com/ watch/HwtdbDUc9MW2n 6t7Px3g6g?chapter=1  Innate Immunity Mechanical barrier retards entry of microbes. Skin Acidic environment (pH 3–5) retards growth of microbes. Anatomic Barriers Mucous Normal flora compete with microbes for attachment Membrane sites and nutrients. Mucus entraps foreign microorganisms. Cilia propel microorganisms out of body. Temperatur Normal body temperature inhibits growth of some e pathogens. Physiologic Fever response inhibits growth of some pathogens. Low PH Acidity of stomach contents kills most ingested Barriers microorganisms. Lysozyme cleaves bacterial cell wall. Interferon induces Chemical antiviral state in uninfected cells. Complement lyses. Toll- Mediators like receptors recognize microbial molecules, signal cell to secrete immunostimulatory cytokines. Collectins disrupt cell wall of pathogen. Phagocytic/ Various cells internalize (endocytose) and break down foreign macromolecules. Endocytic Barriers Specialized cells (blood monocytes, neutrophils, tissue macrophages) internalize Tissue damagekill, (phagocytose), andand infection digest induce leakage of vascular fluid, containing whole microorganisms. Inflammatory serum proteins with antibacterial activity, and influx of phagocytic cells Barriers into the affected area.  Anatomical Barriers The most obvious components of innate immunity are the external barriers to microbial invasion: the epithelial layers that insulate the body’s interior from the pathogens of the exterior world. These epithelial barriers include the skin and the tissue surfaces connected to the body’s openings: the mucous epithelial layers that line the respiratory, gastrointestinal, and urogenital tracts and the ducts of secretory glands such as the salivary, lacrimal, and mammary glands (which produce saliva, tears, and milk, respectively) Skin and other epithelia provide a kind of living “plastic wrap” that encases and protects the inner domains of the body from infection. They contribute to physical and mechanical processes that help the body shed pathogens and also generate active chemical and biochemical defenses by synthesizing and deploying molecules, including peptides and proteins that have or induce antimicrobial activity. Anatomic al Barriers  Epithelial Barriers Prevent Pathogen Entry into the Body’s Interior The skin, the outermost physical barrier, consists of two distinct layers: a thin outer layer, the epidermis, and a thicker layer, the dermis. The epidermis contains several tiers of tightly packed epithelial cells; its outer layer consists mostly of dead cells filled with a waterproofing protein called keratin. The dermis is composed of connective tissue and contains blood vessels, hair follicles, sebaceous glands, sweat glands, and scattered myeloid leukocytes such as dendritic cells, macrophages, and mast cells. The epithelial surfaces of the respiratory, gastrointestinal, and urogenital tracts and the ducts of the salivary, lacrimal, and mammary glands are lined by strong barrier layers of epithelial cells stitched together by tight junctions that prevent pathogens from squeezing between them to enter the body.  Epithelial Barriers Prevent Pathogen Entry into the Body’s Interior A number of nonspecific physical and chemical defense mechanisms also contribute to preventing the entry of pathogens through the epithelia in these secretory tissues. For example, the secretions of these tissues (mucus, urine, saliva, tears, and milk) wash away potential invaders and also contain antibacterial and antiviral substances. Mucus, the viscous fluid secreted by specialized cells of the mucosal epithelial layers, entraps foreign microorganisms; mucins, glycoproteins found in mucus, can prevent pathogen adherence to epithelial cells. In the lower respiratory tract, cilia, hairlike protrusions of the cell membrane, cover the epithelial cells. The synchronous movement of cilia propels mucus-entrapped microorganisms from these tracts. Coughing is a mechanical response that helps us get rid of excess mucus, with trapped microorganisms, that occurs in many respiratory infections. The flow of urine sweeps many bacteria from the urinary tract.  Epithelial Barriers Prevent Pathogen Entry into the Body’s Interior With every meal, we ingest huge numbers of microorganisms, but they have to fight the defenses in the gastrointestinal tract that begins with the antimicrobial compounds in saliva and in the epithelia of the mouth and includes the hostile mix of digestive enzymes and acid found in the stomach. If infection in the gastrointestinal tract does occur, vomiting and diarrhea help remove pathogens from the stomach and intestine. The mucus and acidic pH of vaginal secretions are important in providing protection against bacterial and fungal pathogens. In addition to these chemical barriers, some mucosal epithelial layers, such as in the intestine and reproductive tract, have beneficial commensal microorganisms (normal microbiota) that limit infection by pathogens.  Physiologic Barriers to Infection Include General Conditions and Specific Molecules The physiologic barriers that contribute to innate immunity include temperature, pH, and various soluble and cell associated molecules. Many species are not susceptible to certain diseases simply because their normal body temperature inhibits growth of the pathogens. Chickens, for example, have innate immunity to anthrax because their high body temperature inhibits the growth of the bacteria. Gastric acidity is an innate physiologic barrier to infection because very few ingested microorganisms can survive the low pH of the stomach contents. One reason newborns are susceptible to some diseases that do not afflict adults is that their stomach contents are less acid than those of adults.  Antimicrobial Proteins and Peptides Kill Would-Be Invaders To provide strong defense at these barrier layers, epithelial cells secrete a broad spectrum of antimicrobial proteins and peptides that provide protection against pathogens. The capacity of skin and other epithelia to produce a wide variety of antimicrobial agents on an ongoing basis is important for controlling the microbial populations on these surfaces, as breaks in these physical barriers from wounds provide routes of infection that would be readily exploited by pathogenic microbes if not defended by biochemical means. Antimicrobial Proteins Antimicrobi al Peptides  Cellular Innate Response Receptors and Signaling Several families of cellular pattern recognition receptors (PRRs) have essential roles in detecting the presence of a pathogen and activating innate immune responses that combat the infection. PRRs bind pathogen-associated molecular patterns (PAMPs) that trigger cellular responses. Some of these PRRs are expressed on the plasma membrane, where they bind and are activated by extracellular pathogens. Others are found inside our cells, either in endosomes/lysosomes where they bind PAMPs released by endocytosed pathogens, or in the cytosol, where they respond to PAMPs such as cytoplasmic bacteria and nucleic acids from replicating viruses. This range of PRR locations ensures that cells can recognize the PAMPs of virtually any pathogen, both extracellular and intracellular. Damage-associated molecular patterns (DAMPs) released by cell and tissue damage also can be recognized by both cell surface and intracellular PRRs.  Cellular Innate Response Receptors and Signaling Many cell types in the body express these PRRs, including all types of myeloid white blood cells (monocytes, macrophages, neutrophils, eosinophils, mast cells, basophils, dendritic cells) and subsets of three types of lymphocytes (B cells, T cells, and NK cells). PRRs are also expressed by some other cell types, especially those commonly exposed to infectious agents; examples include epithelial cells of the skin and mucosal and glandular tissues, vascular endothelial cells that line the blood vessels, and fibroblasts and other stromal support cells in various tissues.  Toll-Like Receptors Toll-like receptors (TLRs) were the first family of PRRs to be discovered and are still the best characterized in terms of their structure, how they bind PAMPs and activate cells, and the extensive and varied set of innate immune responses that they induce. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.  Toll-Like Receptors TLRs are membrane proteins that share a common structural element in their extracellular region called leucine-rich repeats (LRRs); multiple LRRs make up the horseshoeshaped extracellular ligand-binding domain of the TLR polypeptide chain. When TLRs bind their PAMP or DAMP ligands via their extracellular LRR domains, they are induced to dimerize, either as a homodimer (e.g., TLR3/3) or as a heterodimer (e.g., TLR2/1) TLRs exist both on the plasma membrane and in the membranes of endosomes and lysosomes; their cellular location is tailored to enable them to respond optimally to the particular microbial ligands they recognize. TLRs can bind via their LRR domains to a wide variety of conserved PAMPs from bacteria, including cell wall lipopolysaccharides (LPS) from gram-negative bacteria and peptidoglycans from gram-positive bacteria, as well as flagellin and bacterial nucleic acids. TLRs also recognize PAMPs from viruses (RNA, DNA, and protein), fungi (cell wall polysaccharides), and parasites (proteins and other components), as well as DAMPs from damaged cells and tissues. Toll-Like Receptors  Functions Toll-Like Receptors The binding of ligands to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity. Upon activation, TLRs recruit adaptor proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell to propagate the antigen-induced signal transduction pathway. These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events. Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity. If the ligand is a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons. Toll-like receptors have also been shown to be an important link between innate and adaptive immunity through their presence in dendritic cells.  C-Type Lectin Receptors The second family of cell surface PRRs that activate innate and inflammatory responses is the Ctype lectin receptor (CLR) family. CLRs are membrane receptors expressed variably on monocytes, macrophages, dendritic cells, neutrophils, B cells, and T-cell subsets. CLRs generally recognize carbohydrate components of fungi, mycobacteria, viruses, parasites, and some allergens (peanut and dust mite proteins). Humans have at least 15 CLRs that function as PRRs, most of which recognize one or more specific sugar moieties such as mannose, fucose and glucans. Binding of these PAMPs triggers a variety of distinct signaling pathways that activate transcription factors that induce the expression of inflammatory cytokines.  NOD-Like Receptors NLR is an acronym that stands for both NOD-like receptor and nucleotide oligomerization domain/leucine-rich repeat–containing receptor. The NLRs are a large family of cytosolic proteins activated by intracellular PAMPs and substances that alert cells to damage or danger (DAMPs and other harmful substances). They play major roles in activating beneficial innate immune and inflammatory responses, but, as we will see, some NLRs also trigger inflammation that causes extensive tissue damage and disease. The human genome contains approximately 23 NLR genes.  NOD-Like Receptors NLR is an acronym that stands for both NOD-like receptor and nucleotide oligomerization domain/leucine-rich repeat–containing receptor. The NLRs are a large family of cytosolic proteins activated by intracellular PAMPs and substances that alert cells to damage or danger (DAMPs and other harmful substances). They play major roles in activating beneficial innate immune and inflammatory responses, but, as we will see, some NLRs also trigger inflammation that causes extensive tissue damage and disease. The human genome contains approximately 23 NLR genes. In addition to inducing expression of genes encoding antimicrobial proteins and peptides, NOD1 and NOD2 contribute to the elimination of cytosolic bacteria by initiating autophagy, in which membrane from the endoplasmic reticulum surrounds the bacteria, forming an autophagosome, which then fuses with lysosomes, killing the bacteria.  Inflammation Represents a Complex Sequence of Events that Stimulates Immune Responses Tissue damage caused by a wound or by an invading pathogenic microorganism induces a complex sequence of events collectively known as the inflammatory response. A molecular component of a microbe, such as LPS, may trigger an inflammatory response via interaction with cell surface receptors. The end result of inflammation may be the marshalling of a specific immune response to the invasion or clearance of the invader by components of the innate immune system. In the first century AD, the Roman physician Celsus described the “four cardinal signs” of inflammation” as rubor (redness), tumor (swelling), calor (heat), and dolor (pain). In the second century AD, another physician, Galen, added a fifth sign: functio laesa (loss of function).  Major events of an inflammatory response An increase in the diameter of blood vessels—of nearby capillaries occurs as the vessels that carry blood away from the affected area constrict, Vasodilation resulting in engorgement of the capillary network. The engorged capillaries are responsible for tissue redness (erythema) and an increase in tissue temperature. Facilitates an influx of fluid and cells from the engorged Increased capillaries into the tissue. The fluid that accumulates (exudate) Capillary has a much higher protein content than fluid normally released Permeability from the vasculature. Accumulation of exudate contributes to tissue swelling (edema). The emigration of phagocytes is a multistep process that includes adherence of the cells to the endothelial wall of the blood vessels Influx of (margination), followed by their emigration Phagocytes between the capillary endothelial cells into the tissue (extravasation), and, finally, their migration through the tissue to the site of the invasion (chemotaxis). Inflammation  Mediators of Inflammation The events in the inflammatory response are initiated by a complex series of events involving a variety of chemical mediators whose interactions are only partly understood. Some of these mediators are derived from invading microorganisms, some are released from damaged cells in response to tissue injury, some are generated by several plasma enzyme systems, and some are products of various white blood cells participating in the inflammatory response. Among the chemical mediators released in response to tissue damage are various serum proteins called acute-phase proteins. The concentrations of these proteins increase dramatically in tissue-damaging infections.  Mediators of Inflammation C-reactive protein is a major acute-phase protein produced by the liver in response to tissue damage. Its name derives from its pattern recognition activity: C-reactive protein binds to the C- polysaccharide cell-wall component found on a variety of bacteria and fungi. This binding activates the complement system, resulting in increased clearance of the pathogen either by complement- mediated lysis or by a complement mediated increase in phagocytosis. One of the principal mediators of the inflammatory response is histamine, a chemical released by a variety of cells in response to tissue injury. Histamine binds to receptors on nearby capillaries and venules, causing vasodilation and increased permeability.  Mediators of Inflammation Another important group of inflammatory mediators, small peptides called kinins, are normally present in blood plasma in an inactive form. Tissue injury activates these peptides, which then cause vasodilation and increased permeability of capillaries. A particular kinin, called bradykinin, also stimulates pain receptors in the skin. This effect probably serves a protective role, because pain normally causes an individual to protect the injured area. Vasodilation and the increase in capillary permeability in an injured tissue also enable enzymes of the blood-clotting system to enter the tissue. These enzymes activate an enzyme cascade that results in the deposition of insoluble strands of fibrin, which is the main component of a blood clot. The fibrin strands wall off the injured area from the rest of the body and serve to prevent the spread of infection. Once the inflammatory response has subsided and most of the debris has been cleared away by phagocytic cells, tissue repair and regeneration of new tissue begins.  Phagocytosis Phagocytosis is one type of endocytosis, the general term for the uptake by a cell of material from its environment. In phagocytosis, a cell’s plasma membrane expands around the particulate material, which may include whole pathogenic microorganisms, to form large vesicles called phagosomes. Most phagocytosis is conducted by specialized cells, such as blood monocytes, neutrophils, and tissue macrophages. Most cell types are capable of other forms of endocytosis, such as receptor-mediated endocytosis, in which extracellular molecules are internalized after binding by specific cellular receptors, and pinocytosis, the process by which cells take up fluid from the surrounding medium along with any molecules contained in it. Phagocytosis Fever Fever  Adaptive Innate Immunity Immunity Hematopoietic Cells: Hematopoietic macrophages, dendritic Cells: T & B Cellular cells, mast cells, lymphocytes Elements neutrophils, eosinophils, NK Cells Non Hematopoietic Cells: epithelial cells (skin, mucous membrane etc.)  Adaptive Innate Immunity Immunity Complement Proteins, Immunoglobulins LPS binding proteins, C secreted by B Cells Humoral reactive proteins, anti Elements microbial peptides, mannose binding lectins  Adaptive Innate Immunity Immunity Fixed in genome Encoded in gene Rearrangement is not Rearrangement Receptor necessary necessary Characterist ics  Adaptive Innate Immunity Immunity Conserved Microbial Epitopes present Components on antigens Ligands Recognize d  Adaptive Innate Immunity Immunity TLR, NLR, Complement, B cell & T Cell Types of Killer cell immunoglobulin receptors like receptors Receptor s  Adaptive Innate Immunity Immunity Immediate Delayed by hours Respons e Time  Adaptive Innate Immunity Immunity None Responses are Responses are same with enhanced by Immunologi each exposure repeated antigen c memory exposure  Adaptive Innate Immunity Immunity Low High Risk of Autoreactivi ty