Chapter 14 Key Concepts

Define the complement system

A series of proteins that circulate in blood and the fluid that bathes the tissues. Circulate in inactive form, but presence of microbial invaders starts a cascading reaction that activates the system, which works to remove and destroy the invader. 'Complements' the adaptive immune system's antibodies.

Compare and contrast acute inflammation with chronic inflammation

Acute: a short-term inflammatory response characterized by an abundance of neutrophils. Once infection is controlled, neutrophils stop entering the area and macrophages clean up damage by ingesting debris. Chronic: occurs when the body's defenses cannot limit the infection. Can last for years. Macrophages and giant cells accumulate, and granulomas (small areas of inflammation) form.

Describe the characteristics and roles of surface receptors, cytokines, and adhesion molecules in innate immunity.

All allow cells to communicate with one another. Surface receptors: the eyes and ears of the cell. Proteins that span the cytoplasm. The specific molecule that binds to it is called a ligand. Ligands bind and modify the internal part of the receptor, triggering a response by the cell. Cytokines: the 'voice' of the cell. Transmitted from cell to cell via cytokine receptors, binding results in a change in the cell growth, differentiation, movement, etc. Act in low concentrations. Include many different kinds: chemokines, colony-stimulating factors, interferons, interleukins, and tumor necrosis factors. Act together or in sequence to generate a response. Example: TNFs and ILs work together to contribute to inflammation.

Compare and contrast chemokines, colony stimulating factors (CSFs), interferons (IFNs), Interleukins (ILs) and tumor necrosis factor (TNF).

All are types of cytokines. Chemokines: important in chemotaxis. Special chemokine receptors allow cells to sense the location where they are needed, such as an area of inflammation. CSFs: important in the multiplication and differentiation of leukocytes (white blood cells). Direct immature cells into maturation pathways when more leukocytes are needed. IFNs: Discovered because of their antiviral effects. Have many roles in host defenses and regulatory mechanisms. Can stimulate some cells and inhibit others. ILs: Produced by leukocytes/white blood cells. Have diverse functions and are important in both innate and adaptive immunity. TNF: Kills tumor cells. Helps initiate the inflammatory response and triggers one type of 'cell suicide'/programmed cell death called apoptosis.

Describe the three pathways that lead to complement system activation and the three outcomes of activation.

All three pathways converge when C3 convertase is formed. C3 convertase then splits C3 leading to additional steps. Alternative pathway: quickly and easily triggered, providing early warning signs of invader. Triggered when C3b binds to foreign cell surfaces→ other proteins attach → eventually forms c3 convertase. Lectin pathway: involves pattern recognition molecules called mannose-binding lectins (MBLs). Mannose is a type of carbohydrate found on some microbial cells, particularly bacteria and fungi. Once MBL attaches to mannose on cell surface, it interacts with complement system components and begins to form a C3 convertase. Classical pathway: requires antibodies. When antibodies bind to an antigen, they interact with the same complement system component involved in the lectin pathway and form a C3 convertase.

Define antigen and antibodies

Antigen: substance that causes the immune response. Antibody: proteins that bind specifically to antigens, targeting them for destruction or removal by other host defenses. Can also destroy the body's own cells that are infected with the virus or other invader.

Compare and contrast apoptosis and pyroptosis.

Apoptosis: programmed cell death that does not trigger an inflammatory response. Pyroptosis: If PRRs in macrophage's cytoplasm are triggered, the cell may initiate pyroptosis, a programmed cell death that triggers an inflammatory response. Sacrifices infected macrophages so that they cannot play host to an invader and recruits various immune system components to the region.

How can C3b be a product of complement activation, but also trigger the alternative pathway?

C3 is unstable and splits into C3a and C3b at a low rate, even when complement system has not been activated. So, some C3b is always present to trigger alternative pathway when needed.

Outline the 6 steps of phagocytosis.

Chemotaxis: phagocytic cells are recruited to site of infection or tissue damage by chemicals (secreted from injured host cells, chemokines, C5a, etc). Recognition and attachment: Phagocytic cells use receptors to bind directly or indirectly (through opsonins like C3b) to microbes. Engulfment: Phagocyte sends out pseudopods that surround and engulf the material, then bring it into the cell enclosed in a phagosome. Releases toxins to destroy material that is too large to engulf. Phagosome maturation and phagolysosome formation: phagosome develops antimicrobial capabilities (increased acidity, etc). Eventually fuses with enzyme-filled lysosomes, forming a phagolysosome. Destruction and digestion: O2 consumption increases, allowing an enzyme within the phagolysosome to produce toxic reactive oxygen species (ROS). Another enzyme makes nitric oxide, which reacts with ROS to produce even more toxins. pH is further lowered by proton pumps. Special proteins and enzymes damage microbe components. Lactoferrin binds iron. Exocytosis: the phagolysosome releases undigested debris into the outside of the cell by fusing with phagocytes cytoplasmic membrane.

Describe the first line defense normal microbiota

Competitive exclusion: normal microbiota prevent pathogens from adhering to host cells by covering binding sites that might otherwise be used for attachment and consuming nutrients that could otherwise support the growth of pathogens. Toxins: Cutibacterium (skin) degrade lipids, releasing fatty acids that inhibit pathogen growth. E. coli (GI tract) synthesize colicins, proteins that are toxic to bacteria. Lactobacillus (vagina) produce lactic acid, creating an acidic pH that inhibits growth.

Define Microbe-associated molecular patterns (MAMPs)

Components of certain groups of microbes (peptidoglycan, flagellin subunits, LPS, etc) that can be detected by pattern recognition receptors (PRRs) on host cells.

Describe the characteristics and role of granulocytes

Contain cytoplasmic granules filled with various compounds important for the cells' protective function. Three types: neutrophils, basophils, and eosinophils. Named based on staining types. Neutrophils--stain poorly. Most numerous (over half of white blood cells) and important granulocytes. Engulf and destroy bacteria and other materials. Granules contain enzymes and antimicrobial substances that destroy engulfed materials. Also called PMNs. Basophils--stain dark purple-blue with methylene blue. Contain histamine, which increases blood vessel permeability during inflammation. are involved in allergic reactions and inflammation. Similar to Mast cells, except mast cells are found in tissue, not blood. Eosinophils--stain red with acidic dye eosin. Important in ridding the body of parasitic worms. Also involved in allergic reactions. Granules contain histaminase (breaks down histamine) and antimicrobial substances.

Describe the inflammatory process, focusing on the factors that initiate the response and the outcomes of inflammation.

Factors that initiate inflammatory response include microbes and tissue damage, both of which cause host cells to release inflammatory mediators (including histamine and inflammatory cytokines, TNF, etc.). --Microbes: PRRs detect MAMPs and produce TNF and other mediators. TNF induces liver to synthesize proteins that facilitate phagocytosis and complement activation. Microbial surfaces also trigger complement activation. --Tissue damage: when cells detect DAMPs, they release inflammatory mediators. When blood vessels are injured, two pathways are initiated--one to clot blood, and one to increase blood vessel permeability. Outcomes of inflammation. If inflammation is limited, damage is minimal. However, some of the most severe effects of infection result from the inflammatory response.

Describe the induction and outcomes of fever.

Fever results from macrophages releasing pro-inflammatory cytokines in response to microbial components. Cytokines tell the brain to increase body temperature, which can prevent microbes with lower optimum temperatures from growing. Fever also enhances several processes, including phagocytic activity multiplication of lymphocytes, release of substances that attract neutrophils, production of interferons and antibodies, and release of leukocytes into the blood from bone marrow. Likely due to increased rate of chemical reactions. Fever-inducing substances are called pyrogens. Cytokines are endogenous pyrogens, while microbial components like LPS are exogenous pyrogens.

Describe the characteristics and role of mononuclear phagocytes

Mononuclear phagocytes make up the mononuclear phagocyte system (MPS). Includes monocytes and macrophages. Monocytes: circulate in blood, differentiate into either macrophages or dendritic cells. Macrophages: form of monocytes that have gained special properties. Important type of sentinel cell found in nearly all body tissues, particularly in spleen, lymph nodes, lungs, and abdominal cavity. Dendritic cells: Sentinel cells that function as scouts. Egulf material in tissues and bring it to the cells of the adaptive immune system for 'inspection'. Most develop from monocytes.

Compare and contrast the roles of macrophages and neutrophils.

Neutrophils: SWAT team. Granular white blood cells. Make up 50-70% of whie blood cells. More killing power, but live only a few days. Mature in bone marrow. They are the first to attack bacteria at the site of infection. They do not reside in connective tissue. Macrophages are large white blood cells that engulf foreign particles in the body when activated. Can be both 'killers'/M1 or 'healers' M2. Form 'giant cells' if they fail to destroy microbes. Make up only 2-8% of white blood cells. Mature in tissues, reside in connective tissue. Live for weeks to months by continuously regenerating their lysosomes.

Describe adhesion molecules and their importance

On the surface of cells, allow cells to grab other cells. For example, when phagocytic cells in blood are needed in tissues, endothelial cells that line the blood vessel synthesize adhesion molecules that bind to passing phagocytic cells. This slows the phagocytes and allows them to leave the bloodstream. Also make delivery of cytokines from one cell to another easier.

Describe the three outcomes of the complement system once C3 convertase has been formed.

Opsonization: C3b binds to microbial cells as opsonins that phagocytes can attach to, making the microbe easier to bind to and engulf. Inflammatory response: C5a is a potent chemoattractant, drawing phagocytes to the area where complement system has been activated. C3a and C5a contribute to vascular permeability associated with inflammation. Lysis of foreign cells: C5b combines with complement proteins C6, C7, C8, and C9 to form membrane attack complexes that insert into cell membranes.

Describe the function and role of PRRs and where they are found on/in cells

PRRs are sensors that alow the body's cells to 'see' signs of microbial invasion. Can detect microbe-associate molecular patterns (MAMPs) and damage associated molecular patterns (DAMPs). Found on many different cells--for example, macrophages, dendritic cells, virally infected cells, etc. Due to this variety, PRR immune responses can be tailored to the category of the pathogen and the situation. They are found in three locations: on cell surface (toll-like receptors/TLRs), in endosomes and phagosomes (a specialized toll-like receptor/TLR) and free-floating in the cytoplasm (rig-like receptors/RLRs and NOD-like receptors/NLRs).

Describe the characteristics and role of lymphocytes

Responsible for adaptive immunity. Two major groups: B cells and T cells, very specific in their recognition of antigens. Reside in lymph nodes and other lymphatic tissues. Another type of lymphocytes are innate lymphoid cells (ILCs), which lack the antigen specificity of B cells and T cells and are found in mucous membranes. Include Natural Killer (NK) cells.

Describe the first-line defense physical barriers

Skin: Dermis contains tightly woven fibrous connective tissue. Epidermis is composed of layers of epithelial cells that become flat towards the surface. Outermost cells are dead and filled with keratin, which is water repellant and makes skin dry. Cells flake off, taking microbes with them. Mucous membranes: Line the digestive tract, respiratory tract, and genitourinary tract. Constantly bathed in mucous or other secretions that wash microbes from the surface. Respiratory tract is lined with ciliated cells, which move materials away from the lungs and throat -- mucociliary escalator.

Describe the first-line defense antimicrobial substances (include the terms lysozyme, peroxidase, lactoferrin, AMPs)

Sweat: inhibits all but salt-tolerant microbes Lysozyme: degrades peptidoglycan, in tears, saliva, and mucous. Also found within the body in phagocytic cells, blood, and fluid that bathes tissues. Peroxidases: use hydrogen peroxide to form antimicrobial compounds. Less effective against microorganisms that produce catalase because they can convert hydrogen peroxide to water and oxygen before peroxidases can use it. Found in saliva, milk, tissues, and phagocytes. Lactoferrin: an iron-binding protein in saliva, mucus, milk, and some phagocytes. A similar compound, transferrin, is in blood and tissue fluids. Bind with iron and make it unavailable to microorganisms (except for microorganisms that can capture iron from the host). Antimicrobial peptides (AMPs): short chains of amino acids that have antimicrobial activity. A group of peptides called defensins are very important in protecting epithelial borders. Insert into microbial membranes, forming pores that damage cells. Produced by epithelial cells and phagocytes. Vitamin D plays a role in regulating AMPs.

Define leukocytes

White blood cells.

Describe the naming systems for complement system proteins

9 major proteins numbered C1-C9. When complement protein is split into two fragments, those fragments are distinguished by adding a lowercase letter to each name. (ex: C3a and C3b).

Outline the three general components of the innate defenses. Include the terms sentinel cells, PRRs, complement system, IFN, phagocytes, and inflammatory response.

First-line defenses: prevent microbes and other foreign material from entering the body's tissues. Include the physical barriers provided by the skin and mucous membranes, along with the antimicrobial substances that bathe them. Normal microbiota residing on these surfaces also provide protection. Sensor systems: allow immune response to recognize when the first-line defenses have been breached. Any microbe that passes through the first-line defenses and into tissue is perceived by the immune system as an invader. Sentinel cells serve as lookouts, recognizing microbes by their unique components such as peptidoglycan using a special group of receptors called Pattern Recognition Receptors (PRRs). The sensor that circulates in blood and tissue fluids is called the complement system. Circulate in an inactive form, but become activated in response to certain stimuli. Innate Effector Actions: eliminate invaders when one or more sensors detects an invading microbe. Interferons (IFNs) are produced when a sensor recognizes a virus. IFNs warn nearby cells about the virus, these cells shut down their biosynthetic activity -- depriving the virus of a mechanism to replicate. Phagocytes are recruited to the site of invasion or damage. They specialize in engulfing and digesting microbes or cell debris through phagocytosis. Some phagocytes also serve as sentinel cells. The inflammatory response is a coordinated response that results when various sensor systems detect infection or tissue damage. Results in cells that line blood vessels to allow fluids to leak out into tissues. Fevers are another response to sensor systems, and can interfere with the growth of some pathogens.

Name the three broad groups of white blood cells

Granulocytes, mononuclear phagocytes, and lymphocytes

Define innate immunity and adaptive immunity

Innate immunity is the routine protection present at birth. Germ-line encoded, meaning that it is passed from one generation to the next. Includes anatomical barriers and some chemicals. Vertebrates also have adaptive immunity, which develops throughout their life as a result to the exposure to microbes or other certain types of foreign material and substantially increases a host's ability to defend itself.

Describe the role of different kinds of pattern-recognition receptors (TLRs, NLRs, and RLRs), and the interferon response in the host defenses.

TLRs/toll-like receptors: some are on cell surface facing outwards, while others are on endosomal and phagosomal membranes facing inwards. Allow cell to detect invaders in surrounding environment. Many different kinds, each recognizing a specific component of a microbe. NLRs and RLRs are both cytoplasmic pattern recognition receptors/PRRs. --NLRs are cytoplasmic proteins that detect microbial components or signs of cell damage. Combine with other proteins in the cytoplasmic membrane to form an inflammasome, which triggers inflammation by activating a pro-inflammatory cytokine. --RLRs detect viral RNA and are found in most cell types. Very important warning system for viral infections. Differentiate viral and normal RNA by looking for strandedness (viral DNA is often double-stranded) and if the RNA has a cap (viral RNA often lacks a cap on 5' end). Interferon response: When cytoplasmic PRRs detect viral RNA, the cell synthesizes and secretes an interferon (IFN) that induces nearby cells to develop an antiviral state, causing cells to express inactive antiviral proteins (iAVPs) that can be activated by double-stranded viral RNA. Once activated, iAVPS degrade mRNA and stop protein synthesis, leading to cell apoptosis. Only infected cells will undergo this process.