Chapter 14: The Innate Immune Response

The Complement System

- Alternative pathway triggered when C3b binds to foreign cell surfaces (C3 unstable, so some C3b always present) - Lectin pathway: pattern recognition molecules (mannose-binding lectins, or MBLs) bind to mannose of microbial cells, interact with complement system components - Classical pathway: activated by antibodies bound to antigen, which interact with complement system

The Complement System

- Augments activities of adaptive immune system Proteins circulating in blood and bathing tissues Proteins named in order discovered: C1 through C9 Can split into fragments, e.g., C3 splits to C3a and C3b Activated by three different pathways that lead to formation of C3 convertase, which splits C3

The Cells of the Immune System

- Blood cells originate from hematopoietic stem cells Found in bone marrow - Induced to develop by colony-stimulating factors (CSFs) - Move around body, travel through circulatory systems - Always found in normal blood

Macrophages are scavengers and sentries

- Can become activated macrophages to increase power - One mechanism involves T cells - If insufficient, can fuse to form giant cells - Macrophages, giant cells, T cells form granulomas that wall off and retain organisms or material resistant to destruction - Prevent escape but interfere with normal tissue function - Tuberculosis and other diseases

Cytokines

- Chemokines: chemotaxis of immune cells - Colony-stimulating factors (CSFs): multiplication and differentiation of leukocytes - Interferons (IFNs): control of viral infections, regulation of inflammatory response - Interleukins (ILs): produced by leukocytes; important in innate and adaptive immunity - Tumor necrosis factor (TNF): inflammation, apoptosis

Phagocytes engulf and digest material, pathogens

- Chemotaxis: phagocytes recruited by chemoattractants (products of microorganisms, phospholipids from injured host cells, chemokines, C5a) - Recognition and Attachment: direct (receptors bind mannose) and indirect (binding to opsonins) - Engulfment: pseudopods surround, form phagosome

Pattern recognition receptors (TLRs, NLRs) trigger

- Detect PAMPs, DAMPs - Host cells release inflammatory mediators like cytokines, histamine, bradykinin. -inducers include microbes, tissue damage If blood vessels damaged, two enzymatic cascades activated; lead to coagulation and increased permeability

RIG-like receptors (RLRs) found in cytoplasm

- Detect viral RNA indicating infection, produce interferons Often has three phosphates at 5′ end (unlike cytoplasmic RNA, where capping hides phosphates) Often double-stranded - Interferons cause neighboring cells to express inactive antiviral proteins - Activated by dsRNA to degrade mRNA, stop protein synthesis, undergo apoptosis

Phagosome Maturation and Phagolysosome -

- Formation: endosomes fuse, lower pH; lysosomes bring enzymes - Destruction and Digestion: toxic ROS and nitric oxide produced; pH decreases; enzymes degrade; defensins damage membrane of invader; lactoferrin ties up iron - Exocytosis: vesicle fuses with cytoplasm, expels remains

Phagocytosis - Specialized attributes of neutrophils

- Neutrophils act as rapid response team: move into area and eliminate invaders - Critical role in early stages of inflammation - First to be recruited from bloodstream to site of damage -More powerful than macrophages, but short life span of 1-2 days in tissues - Die once granules used

The Cells of the Immune System

- Numbers increase during infections - Some reside in various tissues - Three general categories - Red blood cells (erythrocytes) carry O2 -Platelets (from megakaryocytes) involved in clotting - White blood cells (leukocytes) important in host defenses

Macrophages are scavengers and sentries

- Phagocytize dead cells, debris, destroy invaders - Live weeks or months; regenerate lysosomes - Always present in tissues; can call in reinforcements - TLRs on surfaces and in phagosomes detect invaders Cytokines produced in response

Lymphocytes

- Responsible for adaptive immunity - B cells, T cells highly specific in recognition of antigen - Generally reside in lymph nodes, lymphatic tissues - Natural killer (NK) cells lack specificity

Dendritic Cells

- Sentinel cells, function as "scouts" - Engulf material in tissues, bring it to cells of adaptive immune system for "inspection" - Usually develop from monocytes

Cell Communication

- Surface receptors - Adhesion molecules - Cytokines are "voices" of cell

The Inflammatory Response

- Tissue damage results in inflammation - Purpose is to contain site of damage, localize response, eliminate invader, and restore tissue function - Results in swelling, redness, heat, pain, sometimes loss of function

Pattern Recognition Receptors (PRRs)

- detects pathogen-associated molecular patterns (PAMPs), "see" signs of microbial invasion - Cell wall components (lipopolysaccharide, peptidoglycan, lipoteichoic acid, lipoproteins), flagellin subunits, viral RNA molecules - May be called MAMPs (for microbe-associated) - Some are DAMPs (for danger-associated), which indicate host cell damage

NOD-like receptors (NLRs)

- found in cytoplasm - Detect bacterial components indicating cell has been breached; some detect damage - Unleash series of events to protect host Some at expense of cell - Some NRLs join cytoplasmic proteins to form an inflammasome Activates inflammatory response

Surface receptors

- serve as "eyes" and "ears" of cell - Usually span membrane, connect outside to inside - Binding to specific ligand induces response

C3 Convertase

A complex formed by the three pathways of the complement system; it splits C3 and leads to additional steps of the complement system activation cascade.

Interferons (IFNs)

A group of cytokines that are important in the control of viral infections.

Colony-stimulating factors (CSFs)

A group of cytokines that are important in the multiplication and differentiation of leukocytes.

Chronic inflammation

A long-term inflammatory process that can last for years. Macrophages and giant cells accumulate, and granulomas form.

Ligand

A molecule that can bind to a given receptor; the binding causes a response by the cell.

Alternative pathway

A pathway of the complement system that is triggered by C3b binding to foreign cell surfaces. This pathway converges with the lectin pathway and the classical pathway to form C3 convertase.

Normal microbiota

A population of microorganisms that routinely grow on body surfaces of healthy humans. These provide protection to the host by covering binding sites, producing compounds toxic to other bacteria, and using up nutrients.

The Interferon response

A response that occurs when RIG-like receptors detect viral RNA; the cell synthesizes and secretes interferons, which then attach to the infected cell and neighboring cells and cause them to express "suicide enzymes", causing programmed cell death. Only the infected cells are killed. Uninfected cells remain functional but are prepared to undergo apoptosis if they become infected.

Complement system

A series of proteins that are always present in the blood and tissue fluids that act in combination with the adaptive immune defenses. They "complement" the function of antibodies. These proteins are numbered C1-C9.

Acute inflammation

A short-term inflammatory phase marked by a prevalence of neutrophils.

Natural killer (NK) cells

A type of lymphocyte (WBC) that lacks specificity in its mechanism of antigen recognition.

Toll-like receptors (TLRs)

A type of pattern recognition receptor that is anchored in the membranes of sentinel cells such as macrophages, dendritic cells, and cells that line sterile body sites. They can "see" microbial compounds that orginated outside of the cell

Adaptive immunity

Adaptive immunity develops throughout life: antigens cause response, system produces antibodies to bind. Can also destroy host cells Protection provided by host defenses that develop throughout life; involves B cells and T cells.

Transferrin

An iron-binding protein found in blood and tissue fluids that inhibits microbial growth.

Lactoferrin

An iron-binding protein in saliva, mucous, milk and some types of phagocytes that inhibits microbial growth.

Fever

An oral temperature of above 37.8 degrees C. Fever inhibits growth of bacteria that prefer 37 degrees C; the slowed growth rate due to fever allows more time for other defenses to destroy invaders. Fever also increases the rate of enzymatic reactions, which in turn enhances inflammatory response, etc.

First-line defense physical barriers

Barriers first encountered by microbes: skin and mucous membranes.

First-line defenses

Barriers that separate and shield the interior of the body from the surrounding environment; the initial obstacles microbes must overcome to invade the tissues.

Inflammatory response in the complement system

C3a and C5a induce changes that contribute to local vascular permeability and attract phagocytes, and cause mast cells to release pro-inflammatory cytokines.

Lysis of foreign cells in the complement system

C5b combines with complement proteins C6, C7, C8 and C9 to form membrane attack complexes (MACs) that insert into cell membranes. MACs create pores in the cell membrane, disrupting the integrity of the cell.

Mast cells

Cells that are similar to basophils in appearance and function, but are found in tissues instead of blood; they are important in inflammatory response and allergic reactions.

Phagocytes

Cells that specialize in engulfing and digesting microbes and cell debris. These are cells that eat

Chemotaxis in the process of phagocytosis

Chemoattractants cause phagocytic cells to be recruited to the site of infection or tissue damage;chemoattractants include products of microorganisms, phosopholipids released by injured host cells, chemokines, and the complement system component C5a.

Granulomas

Concentrated groups formed by macrophages, giant cells, and T cells, that wall off and retain organisms and other material that cannot be destroyed; these prevent the microbes from escaping to infect other cells but simultaneously harm the host because they interfere with normal tissue function. This is part of the disease process in TB.

Tumor necrosis factor (TNF)

Cytokine that has a role in killing tumor cells; it also helps initiate the the inflammatory response and triggers the process known as "cell suicide", a programmed cell death known as apoptosis.

Pyrogens

Cytokines and other substances released by macrophages when they detect microbial products; the cytokines are carried through the bloodstream to the brain, where they act as messages that the body has been invaded. The body then sets its thermostat to a higher temperature setting.

Pro-inflammatory cytokines

Cytokines that act together to generate a response.

Chemokines

Cytokines that are important in chemotaxis of immune cells.

Interleukins (ILs)

Cytokines that are produced by leukocytes and have diverse, often overlapping, functions. Important in both innate and adaptive immunity.

NOD-like receptors (NLRs)

Cytoplasmic proteins that detect bacterial components, allowing the cell to recognize when its own border has been breached; some also detect signs of cell damage.

RIG-like receptors (RLRs)

Cytoplasmic proteins that detect viral RNA, due to two differing characteristics from normal cellular RNA.

Pattern recognition

Detection of molecules associated with invading microbes or tissue damage.

Opsonization in the complement system

Enhances phagocytosis caused by coating of a particle with an opsonin. C3b binds to microbial cells, functioning as an opsonin.

Lysozyme

Enzyme that degrades peptidoglycan; found in tears, saliva and mucous; also found within the body in phagocytic cells, blood, and the fluid that bathes tissues.

Peroxidase enzymes

Enzymes that break down hydrogen peroxide to produce reactive oxygen species; found in saliva, milk, body tissues, and inside phagocytes.

Endogenous pyrogens

Fever-inducing cytokines, made by the body.

Phagocytosis

Kill microbes via phagocytosis Can release contents of granules along with DNA to form neutrophil extracellular traps (NETs), which ensnare microbes, allow enzymes and peptides from granules to destroy

Dendritic cells

Leukocytes that are differentiated from monocytes; they collect antigen from the tissues and then bring it to lymphocytes that gather in the secondary lymphoid organs. They function as "scouts" that engulf material in the tissues and then bring it to the cells of the adaptive immune system for "inspection".

Lymphocytes

Leukocytes that are responsible for adaptive immunity and are found in lymphoid tissues and circulation. Two major groups- B cells and T cells, which are very specific in their recognition of antigen.

Macrophages

Leukocytes that phagocytize and digest engulfed materials; they are differentiated monocytes that are found in tissues and are named based on the tissue they are found in. They also function as an important sentinel cell.

Monocytes

Leukocytes that phagocytize and digest engulfed materials; they circulate in the bloodstream but will differentiate into either macrophages or dendritic cells when they migrate into the tissue.

Activated macrophages

Macrophages that have increased their otherwise limited killing power. This involves the assistance of certain T cells and is an example of the cooperation between innate and adaptive defenses.

Phagolysosome

Membrane-bound vacuole generated when a phagosome fuses with lysosomes. It is a phagosome that matures to develop antimicrobial properties.

Phagosome

Membrane-bound vacuole that contains the material engulfed by a phagocyte.

Danger-associated molecular patterns (DAMPs)

Microbial patterns that indicate host cell damage and are recognized by certain pattern recognition receptors.

Opsonin

Molecule such as the complement system component C3b and certain antibody classes that binds to invading particles, making it easier for phagocytes to engulf them.

Antigen

Molecule that reacts specifically with an antibody or lymphocyte.

Adhesion molecules

Molecules on the surface of cells that allow those cells to "grab" other cells.

Neutrophil extracellular traps (NETs)

Neutrophils that release the contents of their granules along with DNA. The DNA ensnare microbes, allowing the granule contents (enzymes and peptides) that accumulate within the NET to destroy them.

Lectin pathway

Pattern recognition molecules called mannose-binding lectins (MBLs) bind to microbial invaders; this pathway converges with the alternative pathway and the classical pathway to form C3 convertase.

Giant cells

Phagocytes that fuse together if activated macrophages fail to destroy microbes.

Cytokines are "voices" of cell

Produced by cell, diffuse to others, bind to appropriate cytokine receptors to induce changes such as growth, differentiation, movement, cell death Act at low concentration; effects local, regional, systemic

Apoptosis

Programmed cell death; does not trigger an inflammatory response. Macrophages are signaled that the remains of the cell should be engulfed without the events associated with inflammation.

Pyroptosis

Programmed cell self-destruction that triggers an inflammatory response, maybe due to the pattern recognition receptors in a macrophage being triggered.

Inflammasone

Protein complex in macrophages that activates a potent proinflammatory cytokine, thereby initiating an inflammatory response. NOD-like receptors can create these complexes with other proteins in the cytoplasm.

Exogenous pyrogens

Pyrogens that are introduced from other sources, such as microbial products.

Erythrocytes

Red blood cells; carry O2 in the blood.

Defensins

Short antimicrobial peptides produced by neutrophils and epithelial cells that insert into bacterial membranes, forming pores that damage cells.

First-line defense antimicrobial substances

Substances located on the skin and mucous membranes that inhibit or kill microorganisms.

Inflammation

Swelling, redness, heat and pain. A response to tissue damage that attempts to contain a site of damage, localize response, eliminate the invader, and restore tissue function.

Classical pathway

This pathway is triggered by antibodies binding to microbial invaders, it converges with the alternative pathway and the lectin pathway to form C3 convertase.

Cytokine receptor

Type of surface receptor that binds to a cytokine.

Granulocytes

White blood cells that contain cytoplasmic granules filled with biologically active chemicals. Types- neutrophils, eosinophils, and basophils.

Mononuclear phagocytes

White blood cells that make up the mononuclear phagocyte system (MPS). These include monocytes, macrophages, and dendritic cells.

Leukocytes

White blood cells; important in all host defenses; can be divided into four broad groups- granulocytes, mononuclear phagocytes, dendritic cells, and lymphocytes.

Adhesion molecules

allow cells to adhere to other cells E.g., endothelial cells can adhere to phagocytic cells, allow them to exit bloodstream

Toll-like receptors (TLRs)

are anchored in membranes of sentinel cells e.g., macrophages, dendritic cells, cells lining sterile body sites

Pattern-recognition receptors (PRRs)

found on sentinel cell surfaces and within their cytoplasm and recognize groups of compounds unique to microbes

Inflammatory response

innate response coordinate leading to inflammation, with the purpose of containing a site of damage by localizing the response, eliminating the invader, and restoring tissue function.

Hematopoietic stem cell

A cell type found in the bone marrow that all blood cells originate from.

Inflammatory mediators

A collective term for various pro-inflammatory cytokines and chemicals such as histamine and bradykinin (increases blood vessel permeability). Inducers include: microbes and tissue damage.

Pathogen-associated molecular patterns (PAMPs)

Generic microbe-associated patterns that are detected by pattern recognition receptors. They are found on all microbes, not just pathogens.

Eosinophils

Granulocytes (WBCs) that participate in inflammatory reaction and immunity to some parasites. Also contain antimicrobial substances and histaminase, an enzyme that breaks down histamine.

Basophils

Granulocytes (WBCs) that release histamine and other inflammation-inducing chemicals from the granules. Involved in allergic reactions and inflammation.

Neutrophils

Granulocytes WBC that phagocytize and digest engulfed materials. Most numerous and important in the innate defenses.

Antibody

Immunoglobulin protein produced by the body in response to a substance; it reacts specifically with that substance.

Innate immunity

Innate immunity is routine protection. Although considered non-specific, involves recognition of specific molecules. Involves host defenses - anatomical barriers, sensor systems that recognize patterns associated with microbes or tissue damage, phagocytic cells, and the inflammatory response.

Surface receptors

The "eyes" and "ears" of a cell; they are proteins that are all over the plasma membrane. They connect the inside and outside of a cell. specific

Cytokines

The "voices" of a cell; they are small regulatory proteins that cells produce to affect the behavior of other cells. Binding to a cytokine receptor will induce a change in the cell such as growth, differentiation, movement, or cell death.

Hematopoiesis

The formation and development of blood cells.

Phagocytosis

The series of steps by which phagocytes engulf and digest material, including invading organisms. The steps are: chemotaxis, recognition and attachment, engulfment, phagosome maturation and phagolysosome formation, destruction and digestion, and exocytosis.