Chapter 16- Innate Immunity- Nonspecific Defenses of the Host

Which of the following is NOT a chemical factor that helps the skin to be relatively resistant to infection?

A. Acidic pH
B. Sebum
C. Compliment proteins
D. Lysozyme

Compliment proteins

Which of the following statements about sebum is NOT true?

A. Accutane limits acne by preventing its formation.
B. It is secreted by sebaceous glands.
C. It has antimicrobial properties.
D. Its metabolism can result in acne.
E. It raises the pH of the skin.

It raises the pH of the skin.

Which of these cells do NOT have phagocytic activity?

A. Lymphocytes
B. Neutrophils
C. Eosinophils
D. Macrophages

Lymphocytes

Which type of leukocyte is the most abundant in blood?

Neutrophils

Neutrophils, basophils, and eosinophils are collectively referred to as __________.

Granulocytes

The ID50 for many pathogens is significantly smaller when testing with gnotobiotic animals compared to animals with normal microbiota. This is likely because of __________.

Microbial antagonism

Which of the following statements concerning lysozyme is FALSE?

A. It is an enzyme.
B. It is found in many different body fluids.
C. It breaks down peptidoglycan.
D. It is an organelle in white blood cells.

It is an organelle in white blood cells.

The respiratory system is protected against harmful microbes by all of the following EXCEPT __________.

A. Ciliated cells
B. Mucus-coated hairs
C. The epiglottis
D. The ciliary escalator
E. The lacrimal apparatus

The lacrimal apparatus

Which term best describes the symbiotic relationship between humans and most of the normal microbiota that live on our human skin?

Commensalism

One remarkable finding on a patient’s laboratory workup is a marked eosinophilia. This might be suggestive of __________.

Either a parasitic infection or an allergic (hypersensitivity) reaction

When blood cells are removed from blood, the remaining liquid is referred to as __________.

Serum

The epidermis __________.

Contains the protein keratin.

Which of the following is the correct order of events after tissue damage during the process of inflammation?

Vasodilation; margination; diapedesis; phagocytosis

Which of the following does NOT accurately describe innate immunity?

A. It includes the first and second lines of defense.
B. It includes defenses present at birth.
C. It includes inflammation, fever, and phagocytosis.
D. It produces strong, long-lasting memory responses.

It produces strong, long-lasting memory responses.

Which of these molecules or structures is/are NOT associated with innate immunity?

Antibodies

Which of the following is an INCORRECT statement about antimicrobial peptides (AMPs)?

A. The modes of action of AMPs include inhibiting cell wall synthesis; forming pores in the plasma membrane, resulting in lysis; and destroying DNA and RNA.
B. AMPs have a narrow spectrum of antimicrobial activities.
C. AMPs are also very stable over a wide range of pHs.
D. AMPs are on the most important components of the innate immune system.

AMPs have a narrow spectrum of antimicrobial activities.

__________ are involved in detecting foreign invaders. They do so by binding to pathogen- associated molecular patterns (PAMPs) on the surface of the pathogen.

Toll-like receptors

The process of coating bacteria with serum proteins to promote attachment of phagocytes is called __________.

Opsonization

Which of the following statements is NOT true of inflammation?

A. Many neutrophils can be found at the site of chronic inflammation.
B. Granulocytes that have died are commonly engulfed by macrophages.
C. Inflammation can be triggered by microbial infection, burns, exposure to chemicals, or trauma.
D. Histamine released by damaged host cells can result in vasodilation.
E. Vasodilation causes redness in affected tissues.

Many neutrophils can be found at the site of chronic inflammation.

Which answer is NOT true of the inflammatory process?

A. The area becomes red because of a decrease in capillary diameter.
B. Swelling occurs because of vasodilation and increased capillary permeability.
C. Edema occurs.
D. Kinins cause increased capillary permeability.
E. Leukotrienes cause increased capillary permeability.

The area becomes red because of a decrease in capillary diameter.

Which answer is NOT true for adherence of a phagocyte to a microbe?

A. Antibody molecules attached to the microbe will limit adherence.
B. Complement molecules attached to the microbe can enhance adherence.
C. Adherence is a critical step in phagocytosis.
D. The M protein of Streptococcus pyogenes limits adherence.
E. A capsule limits adherence.

Antibody molecules attached to the microbe will limit adherence.

__________ are inflammatory molecules that are usually found in blood in an inactive form. Once activated, they help to attract neutrophils to the injured area.

Kinins

Which answer is true for bacterial destruction by phagocytosis?

Myeloperoxidase in lysosomes is involved in the formation of HOCl.

The stage of phagocytosis in which the phagocyte’s plasma membrane attaches to the surface of the microbe is called __________.

Adherence

Which of these structures are NOT part of the mononuclear phagocytic system?

A. Lymphocytes
B. Kupffer’s cells
C. Microglial cells
D. Wandering macrophages
E. Alveolar macrophages

Lymphocytes

Histamine causes all of the following reactions. Which occurs first?

A. Vasodilation
B. Redness
C. Pain
D. Swelling

Vasodilation

When attracted to an infected area, macrophages can leave the bloodstream by squeezing through the endothelial cells lining a blood vessel. What is this process called?

Diapedesis

What is the correct name for the fluid that is collected from the body by lymphatic capillaries?

Interstitial fluid

Your lab partner slipped on his way to class and scraped his arm on the concrete. You make a smear of the fluid from his scrape and observe large nucleated cells. These cells are most likely __________.

Neutrophils

Which of the following describes the correct chronological order of events in phagocytosis?

Chemotaxis, adherence, ingestion, digestion

Edema is defined as a collection of fluid in an area of the body. What is the physiological change that causes edema?

Increased permeability of blood vessels

The presence of a capsule and the M protein of Streptococcus pyogenes are both involved in __________.

Helping bacteria resist phagocytosis

Which of the following occurs first, setting in motion the remaining events?

A. Toll-like receptors (TLRs) on macrophages and dendritic cells attach to pathogen-associated microbial patterns (PAMPS) on invading microorganisms.
B. The macrophages and dendritic cells release cytokines.
C. Antimicrobial peptides (AMPs) are produced and damage microbes in a variety of ways.
D. Additional dendritic cells are attracted to the infection site by AMPs.
E. Adaptive immune responses are initiated.

Toll-like receptors (TLRs) on macrophages and dendritic cells attach to pathogen-associated microbial patterns (PAMPS) on invading microorganisms.

Complement components C5 through C9 form plasma membrane channels in cellular microbes referred to as the __________.

Membrane attack complex

Mucous membranes are a part of

Innate defense

B cells interact directly with

Helper T cells.

Which of the following defense systems would be involved in eliminating virally-infected cells?

T lymphocytes

Antibodies interact with which innate defenses?

Phagocytosis and the complement system

Which cells directly attack abnormal cells in the body?

Cytotoxic T cells

Mycobacterium tuberculosis is an intracellular pathogen of humans. After being ingested by a macrophage, it prevents formation of the ___________ by preventing fusion of the phagosome with the ___________________.

Phagolysosome, lysosome

In which intracellular compartment would you expect most of the digestive enzymes involved in pathogen destruction to be found?

Lysosome

In macrophages and dendritic cells (so-called antigen-presenting cells) some small parts of the phagocytosed particle are presented to other cells of the immune system. If you were to draw an arrow leading to "antigen presentation" as described above, from which word would it extend?

Digestion

If one is examining a blood smear from a patient with a parasitic worm infection, which of the following leukocytes would be found in increased numbers (as opposed to a blood smear from a normal patient NOT infected with worms)?

Eosinophils

What direct effect do histamines and leukotrienes have on capillaries?

They allow capillary walls to open and become leaky.

Diapedesis is

The migration of phagocytes through blood vessels to the site of tissue damage.

Why is vasodilation important to tissue repair?

It allows for an increased delivery of oxygen, nutrients, and phagocytes to the site of damage.

Pus is comprised of

Dead phagocytes.

Which of the following can release histamines?

Cells from damaged tissues and the complement pathway

Which of the complement pathways employs properdin?

Alternative pathway

In the classical pathway, which of the following directly activates cellular responses?

C3a, C5a, and C5bC6C7

Antibodies from cellular immune responses are used in

The classical pathway.

Which of the complement pathways was discovered first?

The classical pathway.

Which of the following are functions of lectins?

They act as opsonins for phagocytosis, they attach to carbohydrates on some bacterial and viral surfaces, and they activate C2 and C4.

How does cytolysis occur via the complement pathway?

Formation of the MAC in invading cells, killing them.

Which complement protein is used as an opsonin?

C3b

If a person lacked the ability to form C5, what direct result of complement could still occur?

Opsonization

If a person could not form C2, which result of complement would be affected?

Cytolysis, chemotaxis, inflammation, and opsonization

What complement result involves the use of phagocytes?

Chemotaxis and opsonization

Which of the following is an event that ultimately results in activation of complement C3 by splitting it into C3a and C3b?

Interaction of mannose-binding lectin with mannose molecules on a bacterium

Which of the following are best described as short chains of amino acids that are very stable and can have a variety of different antimicrobial activities, such as forming pores in bacterial plasma membranes and inhibiting cell wall synthesis?

Antimicrobial peptides

________________ is/are always present in an individual’s blood. However, in the absence of infection, it is in an inactive form.

Kinins

You note that the body temperature of one of your patients is starting to increase. As a result, you can infer that all of the following may be occurring in this patient EXCEPT __________.

Dilation of blood vessels.

Which statement regarding the lymphatic system is true?

Lymphatic capillaries possess one-way valves. These valves permit the uptake of fluid from the body but do not allow the fluid to flow back out of the capillaries into the intracellular spaces.

What is a first-line defense?

Keeps pathogens on the outside or neutralize them before the infection begins. Skin, mucous membranes, and certain antimicrobial substances are part of these defenses.

What is a second-line defense?

Slow or contain infections when first-line defenses fail. Include proteins that produce inflammation, fever that enhances cytokine activity, and phagocytes and NK cells, which attack and destroy cancer cells and virus-infected cells.

What is a third-line defense?

Includes lymphocytes that target specific pathogens for destruction when the second-line defenses don’t contain infections. Includes a memory component that allows the body to more effectively respond to that same pathogen in the future.

Basophil

Participates in innate immunity; granulocyte; releases histamines that cause inflammation

Eosinophil

Participates in innate immunity; granulocyte; kills parasites with oxidative burst

Mast cell

Participates in innate immunity; agranulocyte; kills infected cells (often virus-infected) via cytolysis or apoptosis

Neutrophil

Participates in innate and adaptive immunity; granulocyte; phagocytizes bacteria and fungi

Monocyte

Participates in innate and adaptive immunity; agranulocyte; precursor to macrophages, some of which are fixed in certain organs while other wander tissues, causing inflammation. All perform phagocytosis.

Dendritic cell

Participates in innate and adaptive immunity; many surface projections; in skin, respiratory, and intestinal mucosa, phagocytes bacteria and presents antigens to T cells.

Natural killer (NK) cell

Participates in innate and adaptive immunity; agranulocyte (lymphocyte); kills cancer cells and other virus-infected cells.

Plasma cell, B cell

Participates in adaptive immunity; agranulocyte (lymphocyte); recognizes antigens and produces antibodies

T cells (helper T cells, cytotoxin T lymphocyte, regulatory T cell)

Participates in adaptive immunity; agranulocyte (lymphocyte) -Th cells secrete cytokines; they are CD4+ cells that bind MHC class II molecules on antigen-presenting cells (APCs) -CTLs recognize and kill specific "non self" cells; they are CD8+ cells that bind to MHC class I molecules -Treg cells are CD4+ cells that destroy cells that do not correctly recognize "self" cells

What is the purpose of a white blood cell count?

Measure the number of leukocytes found in the blood. Abnormal blood cell counts give healthcare providers important clues for diagnosing infections and other conditions

Differential white blood cell count

Breaks down the white blood cell count further, identifying percentage of eosinophils, basophils, neutrophils, monocytes, and lymphocytes in a sample of 100 WBCs.

What factors can cause a high white blood cell count?

High WBC count means the patient is producing higher than average number of leukocytes. Typically occurs when the patient battles a bacterial infection. May also stem from autoimmune disorders that result in too much inflammatory response and from leukemia (cancer of the blood). Some drugs can cause high WBC counts as a side effect (asthma medications and heparin, an anticoagulant).

What factors can cause a low white blood cell count?

Low WBC counts means that the patient has fewer leukocytes than expected. Particularly, a low neutrophil count is instructive. Even bacteria that generally live in the mouth and digestive track without being pathogenic may result in disease when the patient’s neutrophil count drops below 500 neutrophils per cubic mm of blood. May result from viral infections or pneumonia. May also be caused from autoimmune diseases, certain cancers, and radiation and other cancer treatments. Numerous drugs may also cause low WBC counts (antibiotics, diuretics, anticancer medications.

Immunity or resistance

Ability to ward off disease caused by microbes or their products and to protect against environmental agents such as pollen, chemicals, and animal dander. Two types: innate and adaptive.

Susceptibility

Lack of immunity

Innate immunity

Refers to defenses that are present at birth. Always available to provide rapid responses to protect against disease. Does not involve recognition of a specific microbe and has no memory response. First line defenses include skin and mucous membranes. Second line defenses include natural killer cells, phagocytes, inflammation, fever and antimicrobial substances. Responses represent immunity’s early-warning system and are designed to prevent microbes from gaining access into the body and to help eliminate those that do gain access.

Adaptive immunity

Based on a specific response to a specific microbe once a microbe has breached the innate immunity defenses. Adjusts to handle a particular microbe. Slower to respond, but has a memory component that allows the body to more effectively target the same pathogens in the future. Involves lymphocytes called T cells (T lymphocytes) and B cells (B lymphocytes).

Toll-like receptors (TLR)

Responses of the innate system are activated by protein receptors in the plasma membranes of defensive cells. TLRs attach to various components commonly found on pathogens called PAMPs. Transmembrane protein of immune cells that recognizes pathogens and activates an immune response directed against those pathogens.

Pathogen-associated molecular patterns (PAMPs)

Molecules present on pathogens and not self.

Cytokines

Proteins that regulate the intensity and duration of immune responses. Released when TLRs encounter PAMPs of microbes. Secreted by activated fixed macrophages and bring about vasodilation and increased permeability.

Skin

Body’s largest organ in terms of surface area and weight; extremely important component of the first line of defense. Contains dermis and epidermis.

Dermis

Skin’s inner, thicker portion. Composed of connective tissue.

Epidermis

Outer, thinner portion in direct contact with the external environment. Consists of many layer of continuous sheets of tightly packed epithelial cells with little or no material between the cells. Top layer of epidermal cells is dead and contains keratin. Periodic shedding of the top layer helps remove bacteria at the surface. Dryness of skin is a major factor in inhibiting microbial growth.

Keratin

Protein found in hair, nails, and epidermis.

What bacteria are most likely to cause infection, especially when the skin is broken?

Staphylococci that normally inhabit the epidermis, hair follicles, and sweat and oil glands of the skin.

Endothelial cells

Type of epithelial cell; line the blood and lymphatic vessels and are not closely packed like those of the epidermis, allowing defensive cells to move from blood into tissues during inflammation, but also permits microbes to move into and out of blood and lymph.

Mucous membranes

Consist of an epithelial layer and underlying connective tissue layer. Important component of first line of defense. Line the entire gastrointestinal, respiratory, and genitourinary tracts. Epithelial layer secretes mucous.

Mucus

Secreted by the epithelial layer of mucous membranes. Slightly viscous glycoproteins produced by goblet cells of the mucous membrane. Prevents tracts from drying out. Traps many of the microorganisms that enters tracts.

How do pathogens survive on the moist secretions of the body?

Penetrate the membrane with toxic substances, prior injury by viral infection, or mucosal irritation, if the microorganism is present in sufficient numbers.

Lacrimal apparatus

A group of structures that manufactures and drains tears. Lacrimal glands, located toward the upper, outermost portion of each eye socket, produce tears and pass them under the upper eyelid. Tears then pass toward the corner of the eye near the nose and into two small holes that lead through the lacrimal canals to the nose. Tears are spread over the surface of the eyeball by blinking. Normally, teats evaporate or pass into the nose as fast as they are produced. Continual washing action helps keep microorganisms from settling on the surface of the eye. If an irritating substance or large numbers of microorganisms come in contact with the ye, lacrimal glands secrete heavily and tears accumulate more rapidly than they can be carried away. Excessive production is a protective mechanism because the excess tears dilute and wash away the irritating substance or microorganisms before infection can occur.

Saliva

Produced by salivary glands and uses a cleansing action similar to that of tears. Dilutes numbers of microorganisms and wash them from the surface of the teeth and mucous membrane of the mouth. Helps prevent colonization by microbes. Contains the enzyme salivary amylase that digests starch along with lysozyme, urea, and uric acid, all substances that inhibit microbial growth. Slightly acidic (6.55-6.85) and contains an antibody lgA that prevents attachment of microbes so they cannot penetrate mucous membranes.

Hairs

Mucous membrane of the nose has mucus coated hairs that filter inhaled air and trap microorganisms, dust, and pollutants.

Cilia

Cells of the mucous membrane of the lower respiratory tract are covered with cilia.

Ciliary escalator

By moving synchronously, cilia propel inhaled dust and microorganisms that have been trapped in mucus upward toward the throat. Keeps mucus blanket moving toward the throat at a rate of 1-3 cm per hour. Coughing and sneezing speed up the process.

Epiglottis

Microorganisms are prevented from entering the lower respiratory tract by this small lid of cartilage, which covers the larynx during swallowing.

Earwax (cerumen)

Located within the external ear canal along with hairs to prevent microbes, dust, insects, and water from entering the ear. Serves as physical barrier and chemical protectant. Mixture of secretions from glands producing earwax as well as from the sebaceous glands, which produce sebum. Secretions are rich in fatty acids, giving the ear a low pH (3-5), which inhibits the growth of many pathogenic microbes. Contains many dead cells from the lining of the ear canal.

Urine

Cleansing of the urethra prevents microbial colonization in the genitourinary tract. When urine output is disrupted, it may cause a UTI. Contains lysozyme and has an acidic pH of 6.

Vaginal secretions

Moves microorganisms out of the female body. Glycogen produced by vaginal epithelial cells is broken down into lactic acid by L. acidophilus, creating an acidic pH (3-5) that inhibits microbes. Cervical mucus also has some antimicrobial activity.

Peristalsis

Series of coordinated contractions that propels food along the gastrointestinal tract. Helps to expel microbes.

Defecation

Mass peristalsis of large intestinal contents into rectum. Helps to expel microbes.

Vomiting and diarrhea

In response to microbial toxins, muscles of the gastrointestinal tract vigorously contract,, which may also rid the body of microbes.

Sebum

Produced by sebaceous (oil) glands within the skin. Prevents hair from drying and becoming brittle. Forms a protective film over the surface of the skin. Contains unsaturated fatty acids, which inhibits the growth of certain pathogenic bacteria and fungi. Low pH of the skin (3-5) is caused in part by the secretion of fatty acids and lactic acid.

Perspiration

Produced by the sweat glands of the skin. Helps maintain body temperature, eliminates certain wastes, and flushes microorganisms from the surface of the skin. Contains lysozyme.

Lysozyme

Enzyme capable of breaking down cell walls of Gram-positive bacteria and Gram- negative bacteria to a lesser extent. Breaks chemical bonds on peptidoglycan, which destroys cell walls. Found in tears, saliva, nasal secretions, tissue fluids, and urine.

Gastric juice

Produced by the glands of the stomach. Mixture of hydrochloric acid, enzymes, and mucus. High acidity (1.2-3) is sufficient to destroy bacteria and most bacterial toxins, except those of Clostridium botulinum and Staphylococcus aureus. Many enteric pathogens are protected by food particles and can enter the intestines through the GI tract. H. pylori neutralizes stomach acid, allowing bacterium to grow in the stomach.

Normal microbiota

Help prevent the overgrowth of pathogens and may be considered components of innate immunity.

Microbial antagonism

Normal microbiota prevent pathogens form colonizing the host by competing with them for nutrients (competitive exclusion) by producing substances the are harmful to the pathogens, and by altering conditions that affect the survival of the pathogens, such as pH and oxygen availability.

Commensalism

One organism uses the body of a larger organism as its physical environment and may make use of the body to obtain nutrients. One organism benefits while the other is unaffected. Most commensal microbiota are found on the skin and GI tract. Majority have highly specialized attachment mechanisms and precise environmental requirements for survival. Normally, they are harmless, but may cause disease if environmental conditions change.

Probiotics

Live microbial cultures applied to or ingested that are intended to exert a beneficial effect. May be administered with prebiotics.

Prebiotics

Chemicals that selectively promote growth of beneficial bacteria. Ex. lactic acid bacteria (LAB) prevents colonization, alleviate diarrhea, prevent surgical wound infection, and inhibit the growth of certain pathogens.

Plasma

Contained within blood

Formed elements

Cells and cell fragments suspended within plasma. Include erythrocytes (RBCs), leukocytes (WBCs), and platelets. Created in red bone marrow by stem cells through hematopoiesis.

Hematopoiesis

Process by which formed elements are created within the red bone marrow by stem cells. Begins when a pluripotent stem cell develops into myeloid stem cells and lymphoid stem cells. From these two cells, all of the formed elements develop.

What are the two main categories of leukocytes and why are they so called this?

Granulocytes and agranulocytes; based on their appearance under a light microscope

Granulocytes

Presence of large granules in their cytoplasm that can be seen with a light microscope after staining. Differentiated into three types of cells based on how the granules stain: neutrophils, basophils, and eosinophils.

Neutrophils or polymorphonuclear leukocytes (PMNs) or polymorphs

Stain pale lilac with a mixture of acidic and basic dyes. May be called polymorphonuclear due to their nuclei, which contain two to five lobes. Highly phagocytic and motile, and active in the initial stages of infection. Have the ability to leave blood, enter an infected tissue, and destroy microbes and foreign particles.

Basophils

Stain blue-purple with the basic dye methylene blue. Release substances, such as histamine, that are important in inflammation and allergic responses.

Eosinophils

Stain red or orange with the acidic dye eosin. Somewhat phagocytic and have the ability to leave the blood. Major function is to produce toxic proteins against certain parasites, such as helminths. Physically too small to ingest and destroy helminths, they can attach to the outer surface of parasites and discharge peroxide ions that destroy them. Number increases significantly during certain parasitic worm infections and hypersensitivity (allergy) reactions.

Agranulocytes

Also have granules in their cytoplasm, but these are not visible under the light microscope after staining. Three different types: monocytes, dendritic cells, and lymphocytes.

Monocytes

Not actively phagocytic until they leave circulating blood, enter body tissues, and mature into macrophages.

Macrophages

Mature monocytes. As blood and lymph that contain microorganisms pass through organs with macrophages, these organisms are removed by phagocytosis. Dispose of worm out blood cells.

Lymphocytes

Proliferation of these cells is one factor responsible for the swelling of lymph nodes during infection. Include natural killer cells, T cell, and B cells.

Dendritic cells

Believed to be derived from the same precursor cells as monocytes. Have long extensions that resemble the dendrites of nerve cells. Especially abundant in the epidermis of the skin, mucous membranes, thymus, and lymph nodes. Destroy microbes by phagocytosis and initiate adaptive immunity responses.

Natural killer (NK) cells

Found in blood, spleen, lymph nodes, and red bone marrow. Have the ability to kill a wide variety of infected body cells and certain tumor cells. Attack body cells that display abnormal or unusual plasma membrane proteins. Binding of NK cells to target cells causes the release of vesicles containing toxic substances. Some granules contain perforin.

Perforin

Released from granules of NK cells. Protein which inserts into the plasma membrane of the target cell and creates channels (perforations) in the membrane.Cytolysis occurs as a result.

Cytolysis

Perforin creates perforations within the plasma membrane of target cells. Extracellular fluid flows into the target cell and the cell bursts.

Granzymes

Released from granules of NK cells. Protein-digesting enzymes that induce target cell to undergo apoptosis (self-destruction). Kills infected cells but not the microbes inside the cells. Released microbes, which may or may not be intact, can be destroyed by phagocytes.

T cells and B cells

Not usually phagocytic, but play a key role in adaptive immunity. Occur in lymphoid tissues of the lymphatic system and circulate in blood.

Leukocytosis

During many kinds of infections, especially bacterial infections, total number of WNCs increases as a protective response to combat the microbes. Ex. meningitis, infectious mononucleosis, appendicitis, pneumococcal pneumonia, gonorrhea.

Leukopenia

Decease in leukocyte count. May be related to either impaired WBC production or the effect of increased sensitivity of WBC membranes to damage by compliment, antimicrobial serum proteins.Some diseases may also cause this. Ex. brucellosis, salmonellosis, rickettsial infections.

Lymphatic system

Consists of lymph (fluid), lymphatic vessels (vessels), lymphoid tissue (contained within structures and organs), and red bone marrow (stem cells develop into blood cells)

Lymphoid tissue

Contains large numbers of lymphocytes: T cells, B cells, and phagocytic cells that participate in immune responses.

Lymph nodes

Sites of activation of T cells and B cells. Contain reticular fibers, which trap microbes, and macrophages and dendritic cells, which destroy microbes by phagocytosis. Located at intervals along lymphatic vessels; kidney bean shaped.

Lymphatic capillaries

Lymphatic vessels begin as capillaries located in spaces between cells. Permit interstitial fluid derived from blood plasma to flow into them, but not out. Converge to form larger lymphatic vessels. Vessels, like veins, have one-way valves to keep lymph flowing in one direction.

Thoracic (left lymphatic) and right lymphatic duct

All lymph eventually passes into these ducts and then into their respective subclavian veins, where the fluid is then called blood plasma. Plasma moves through the cardiovascular system and ultimately becomes interstitial fluid between tissue cells, and another cycle begins.

Tonsils

Lymphoid tissue located in the throat

Lymphoid tissues and organs

Scattered throughout the mucous membranes that line the GI, respiratory, urinary, and reproductive tracts. Protect against microbes that are ingested or inhaled. Multiple large aggregations of these tissues are located throughout the body: tonsils and Peyer’s patches.

Peyer’s patches

Lymphoid tissue located in the small intestine

Spleen

Contains lymphocytes and macrophages that monitor the blood for microbes and secreted products, such as toxins.

Thymus

Serves as a site for T cell maturation; contains dendritic cells and macrophages.

Phagocytosis

Ingestion of a microorganism or other substance by a cell. Involved in clearing away debris, such as dead body cells and denatured proteins, and is a means by which cells in the human body counter infection as part of the second line of defense.

Phagocytes

Cells that perform phagocytosis; all are types of WBCs or WBC derivatives. When an infection occurs, granulocytes (especially neutrophils) and monocytes migrate to infected area.

What happens when monocytes migrate to infected areas of the body?

Monocytes enlarge and develop into actively phagocytic macrophages, which can leave the blood and migrate into tissues where they enlarge and develop into macrophages.

Fixed macrophages (histiocytes)

Resident in certain tissues and organs of the body. Found in the liver (Kupffer’s cells), lungs (alveolar macrophages), nervous system (microglial cells), bronchial tubes, spleen (splenic macrophages), lymph nodes, red bone marrow, and the peritoneal cavity surrounding abdominal organs (peritoneal macrophages).

Free (wandering) macrophages

Motile; roam tissues and gather at all sites of infection or inflammation.

Mononuclear phagocytic (reticuloendothelial) system

Various macrophages of the body constitute this system.

Which WBC dominates the bloodstream during the initial phase of a bacterial infection?

Granulocytes (especially neutrophils); actively phagocytic and is indicated by their increased number in a differential white blood cell count.

Which WBC dominates the bloodstream when an infection progresses?

Macrophages; scavenge and phagocytize remaining living bacteria and dead or dying bacteria. Increased number of monocytes (which develop into macrophages) is reflected in a differential white blood cell count.

What are the four main phases of the mechanism of phagocytosis?

1. Chemotaxis 2. Adherence (includes opsonization) 3. Ingestion 4. Digestion

Chemotaxis

Chemical attraction of phagocytes to microorganisms.

What are some chemotactic chemicals that attract phagocytes?

Microbial products, components of WBCs, damaged tissue cells, peptides derived from a complement (a system of host defense proteins)

Adherence

Attachment of a phagocyte’s plasma membrane to the surface of the microorganism or other foreign material. Facilitated by the attachment of pathogen-associtated molecular patterns (PAMPs) of microbes to receptors, such as toll-like receptors (TLRs) on the surface of phagocytes.

What does the binding of PAMPs to TLRs initiate?

Phagocytosis and induces the phagocyte to release specific cytokines that recruit additional phagocytes.

Opsonization

Coating process where microorganisms can be more readily phagocytized if they are first coated with certain serum proteins that promote attachment of the microorganisms to the phagocyte.

Opsonins

Proteins that include some components of the complement system and antibody molecules.

Ingestion

Follows after adherence. Plasma membrane of the phagocyte extends pseudopods that engulf the organism.

Pseudopods

An projection extended from the plasma membrane of a phagocyte

Phagosome or phagocytic vesicle

Sac surrounding the microorganism once it is surrounded by the pseudopod and the pseudopods meet and fuse. Membrane of a phagosome has enzymes that pump protons (H+) into the phagosome, reducing the pH to 4. At this pH, hydrolytic enzymes activate.

Digestion

Phagosome pinches off from the plasma membrane and enters the cytoplasm, where it contacts lysosomes that contain digestive enzymes and bactericidal substances.

Phagolysosome

On contact, the phagosome and lysosome membranes fuse to form a single, larger structure. Contents of the phagolysosome brought in by ingestion are digested in the phagolysosome.

What lysosomal enzymes directly attack microbial cells?

-Lysozyme: hydrolyzes peptidoglycan in bacterial cell walls. -Lipases, proteases, ribonuclease, and deoxyribonuclease hydrolyze other macromolecular components of microorganisms. -Contain enzymes that can produce toxic oxygen products, such as superoxide radical (O2-), hydrogen peroxide (H2O2), nitric oxide (NO), singlet oxygen (1O2-), and hydroxyl radical (OH).

Oxidative burst

Produces toxic oxygen products. Other enzymes can make use of these products in killing enzymes.

Residual body

After enzymes have digested the contents of the phagolysosome brought into the cell by digestion, the phagolysosome contains indigestible material. This body moves toward the cell boundary and discharges its wastes outside the cell.

How do microbes evade phagocytosis?

-M proteins and capsules inhibit adherence -Heavily encapsulated organisms can be phagocytized only if the phagocyte traps the microorganism against a rough surface (blood vessel, clot, connective tissue fiber) from which the microbe cannot slide away. -S. aureus produces leukocidins that may kill phagocytes by causing the release of the phagocyte’s own lysosomal enzymes into its cytoplasm. -Streptolysin has a similar effect (from streptococci). -Secretion of pore-forming toxins that lyse phagocyte cell membranes once inside cell phagocyte. -Some have ability to survive inside of phagocytes (low pH requirement, escape abilities, prevention of fusion with phagosomes, etc. -Biofilms are more resistant to phagocytosis because phagocytes cannot detach bacteria from biofilm prior to phagocytosis.

Inflammation

Occurs in response to damage to the body’s tissues (burns, infection, chemical agents, physical agents); local defensive response and another component in second line of defense.

What are the stages of inflammation?

-Vasodilation and increased permeability -Phagocyte migration and phagocytosis -Tissue repair

What are the four signs and symptoms that characterize inflammation?

Redness, pain, heat, and swelling. Sometimes a fifth is loss of function, which depends on the extent of damage.

What are the functions of inflammation?

-Destroy injurious agent (if possible) and to remove it and its by-products from the body -If destruction is not possible, to limit the effects on the body by confining or walling off the injurious agent and its by-products -To repair or replace tissue damaged by the injurious agent or its by-products

Acute inflammation

If the cause of the inflammation is removed in a relatively short period of time, the inflammatory response is intense.

Chronic inflammation

If the cause of inflammation is difficult or impossible to remove, the inflammatory response is longer lasting but less intense (although overall more destructive).

Acute-phase proteins

In response to TNF-∂ in the blood, the liver synthesizes this group of proteins. Other acute-phase proteins are present in the blood in inactive form and are converted to an active form during inflammation. Include both local and systemic responses and include proteins such as: -C-reactive protein -mannitose-binding lectin -several specialized proteins (fibrinogen for blood clotting, kinins for vasodilation)

Tumor necrosis factor-alpha (TNF-∂)

During the early stages of inflammation, microbial structures (flagellin, LPS, bacterial DNA) stimulate TLRs of macrophages to produce cytokines, such as TNF-∂.

What mechanism amplified inflammatory response?

All cells involved in inflammation have receptors for TNF-∂ and are activated by it to produce more of their own TNF-∂. Excessive production can lead to rheumatoid arthritis and Crohn’s disease.

Vasodilation

Dilation of blood vessels; responsible for the redness (erythema) and heat associated with inflammation. Occurs immediately after tissue damage in the area of the damage.

Increased permeability

Occurs immediately after tissue damage; permits defensive substances normally retained in the blood to pass through the walls of blood vessels and enter the injured area. Permits fluid to move from the blood into tissue spaces and is responsible for edema.

Edema

Caused by increase in permeability; accumulation of fluid.

What causes the pain of inflammation?

Nerve damage, irritation of toxins, pressure of edema.

What causes vasodilation and increased permeability of blood vessels?

Caused by a number of chemicals released by damaged cells in response to injury, such as histamine. Helps deliver clotting elements of blood into the injured area.

Histamine

Chemical present in many cells of the body, especially in mast cells in connective tissue, circulating basophils, and blood platelets. Released in direct response to the injury of cells that contain it and in response to stimulation by certain components of the complement system. Phagocytic granulocytes attracted to the site of injury can also produce chemicals that cause its release.

Kinins

Group of substances that cause vasodilation and increased permeability of blood vessels. Present in blood plasma and, once activated, play a role in chemotaxis by attracting phagocytic granulocytes, chiefly neutrophils, to the injured area.

Prostaglandins

Substances released by damaged cells that intensify the effects of histamine and kinins and help phagocytes move through capillary walls. Associated with the pain related to inflammation.

Leukotrienes

Substances produced by mast cells and basophils; cause increased permeability of blood vessels and help attach phagocytes to pathogens

Mast cells

Cells especially numerous in the connective tissue of the skin and respiratory system and in blood vessels.

Pus

A mixture of dead cells and body fluids usually found in a cavity formed by the breakdown of body tissues.

Abscess

Focus of infection that includes a localized cavity containing pus. Ex. pustules and boils.

T/F: Blood clots that form around the site of activity prevent the microbe (or its toxins) from spreading to other parts of the body.

True

What drugs help to alleviate pain by inhibiting prostaglandin production? What are side effects of these medications?

Aspirin and ibuprofen; interfere with the stomach’s ability to protect itself from acidic gastric juices, therefore long-term side effects include ulcers, stomach upset, and heartburn. Can also be used to reduce fever.

How long does it take for phagocytes to appear at the site of injury once the process of inflammation is initiated?

About an hour.

Margination

Sticking process in response to local cytokines. As blood flow gradually decreases, phagocytes (neutrophils and monocytes) begin to stick to the inner surface of the endothelium (lining) of blood vessels. Cytokines alter cellular adhesion molecules on cells lining blood vessels, causing phagocytes to stick at the site of inflammation. This process is also involved in red bone marrow, where cytokines can release phagocytes into circulation when needed.

Diapedesis

Migration resembling ameboid movement; can take as little as two minutes. Collected phagocytes begin to squeeze between endothelial cells of the blood vessel to reach the damaged area. Phagocytes then begin to destroy invading microorganisms by phagocytosis.

Chemokines

Cytokines that are chemotactic for phagocytes and T cells and thus stimulate both the inflammatory response and an adaptive immune response.

What ensures the availability of a steady stream of neutrophils?

Production and release of additional granulocytes from red bone marrow.

What happens to monocytes as the inflammatory response continues?

Monocytes follow granulocytes into the infected area. Once they are contained in the tissue, they undergo changes in biological properties and become free macrophages. Granulocytes predominate in early stages of infection but tend to die off rapidly. Macrophages enter during a later stage of infection once granulocytes have accomplished their function. They are several times more phagocytic than granulocytes and are large enough to phagocytize tissue that has been destroyed, granulocytes that have been destroyed, and invading microorganisms.

What happens after granulocytes or macrophages engulf large numbers of microorganisms and damaged tissues?

They eventually die. Pus forms, and its formation usually continues until the infection subsides.

What causes can make phagocytosis less functional in response to certain conditions?

-With age, there is a decline in efficiency of phagocytosis. -Kidney or heart transplant recipients have impaired innate defenses. -Radiation depress innate immune responses by damaging red bone marrow. -Diseases such as AIDS and cancer depress innate defenses. -Individuals are born without the ability to produce phagocytes.

What is tissue repair? When does tissue repair begin?

Process by which tissues replace dead or damaged cells. Begins during the active phase of inflammation but cannot be completed until all harmful substances have been removed or neutralized at the site of injury. Ability to regenerate or repair depends on type of tissue.

How is a tissue repaired?

When its stroma or parenchyma produces new cells.

Stroma

Supporting connective tissue. If repair cells of the stroma are more active, scar tissue is formed.

Parenchyma

Functioning part of the tissue. If repair cells of the parenchyma are more active, a perfect or near-perfect reconstruction of the tissue occurs.

Fibrosis

Cytokines released by activated macrophages induce fibroblasts in tissue stroma to synthesize collagen fibers. Fibers aggregate to form scar tissue.

Fever

Abnormally high body temperature; a component of the second line of defense. Most frequent cause is infection from bacteria (and their toxins) or viruses.

What role does the brain have in fever production?

Hypothalamus is called the body’s thermostat (normally set at 37ºC). Certain substances affect hypothalamus by setting it at a higher temperature.

How does phagocytosis react with the hypothalamus to play a role in inducing fever?

When phagocytes ingest Gram-negative bacteria, LPS of the cell wall are released. Since LPS is an endotoxin, it causes the phagocytes to release cytokines interleukin-1 along with TNF-∂. These cytokines cause the hypothalamus to release prostaglandins that reset the hypothalamic thermostat at a higher temperature, causing a fever. The body will remain at this temperature until all of the cytokines are eliminated.

Shivering

To adjust to the new thermostat setting, the body responds by constricting blood vessels, increasing the rate of metabolism, and shivering, all of which increases body temperature.

Chill

Even though body temperature is high, skin remains cold. This is a definite sign that body temperature is rising. When the body reaches the temperature of the thermostat, the chill disappears.

Crisis

As the infection subsides, heat-losing mechanisms, such as vasodilation and sweating, go into operation. Skin becomes warm and person begins to sweat. This phase of the fever indicated body temperature is falling.

Fever is considered a defense against disease. What mechanisms of the body occur in response to a fever in order to help fight disease?

-Interleukin-1 steps up the production of T cells. -High body temperature intensifies the effect of antiviral interferons. -High body temperature increases production of transferrins that decrease available iron to microbes. -High temperature speeds up body’s reactions and may help body tissues repair themselves more quickly.

What are the complications of a fever?

-Tachycardia; may compromise older people with cardiopulmonary disease -Increased metabolic rate; may produce acidosis -Dehydration -Electrolyte imbalances -Seizures in young children -Delirium -Coma -Death if the body temperature rises about 44-46ºC (112-114ºF)

Complement system

Consists of over 30 proteins produced by the liver that circulate in blood serum and within tissues throughout the body. So named because it "completes," or assists, cells of the immune system in destroying microbes. Not adaptable and never changes throughout a person’s lifetime, therefore part of the innate immune system, but can be recruited into action by the adaptive immune system.

How do proteins of the complement system destroy microbes?

Cytolysis, opsonization, and inflammation. Prevents excessive damage to host tissues. Inactive until split into fragments (products), which activates them. Activated fragments carry out destructive actions.

How are complement proteins designated?

Uppercase C and numbered 1-9 for the order in which they were discovered. Activated fragments are indicated by lowercase a and b.

Cascade

Complement proteins act in a cascade, where one reaction triggers another, which in turn triggers another. More product is formed with each succeeding reaction in the cascade, amplifying the effects.

Complement activation

Cascade of complement proteins that occurs during infection. May occur in three pathways that end with the activation of C3.

Classical pathway

First discovered. Initiated when antibodies bind to antigens: -Antibodies attach to antigens, forming antigen-antibody complexes. Antigen-antibody complexes bind to and activate C1. -Activated C1 activates C2 and C4 by splitting them. C2 splits into fragments C2a and C2b, and C4 is split into C4a and C4b. -C2a and C4b combine and together activate C3 by splitting it into C3a and C3b fragments. C3a participates in inflammation and C3b functions in cytolysis and opsonization.

Alternative pathway

Discovered after the classical pathway; does not involve antibodies. Activated by contact between certain complement proteins and a pathogen. -C3, constantly present in blood, combines with complement proteins called factor B, factor D, and factor P (properdin) on microbe’s surface. Complement proteins are attracted to microbial cell surface material (mostly lipid-carbohydrate complexes of certain fungi and bacteria). -Once the complement proteins combine and interact, C3 splits into fragments C3a and C3b. C3a participates in inflammation and C3b functions in cytolysis and opsonization.

Lectin pathway

Most recently discovered. When macrophages ingest bacteria, viruses, and other foreign matter by phagocytosis, they release cytokines that stimulate the production of lectins. -Mannose-binding lectin (MBL) binds to the carbohydrate mannose. Binds to many pathogens because MBL molecules recognize a distinctive pattern of carbohydrates that includes mannose, which is found in bacterial cell walls and on some viruses. -As a result of binding, MBL functions as an opsonin to enhance phagocytosis and activates C2 and C4. -C2a and C4b activate C3. C3 splits into fragments C3a, which participates in inflammation, and C3b, which functions in cytolysis and opsonization.

Lectins

Produced by the liver in response to the release of cytokines; proteins that bind to carbohydrates.

What does the activation of the complement system (the activation of C3) lead to?

Cytolysis, opsonization, inflammation.

Cytolysis as a result of complement activation

Involves the membrane attack complex (MAC): -Activated C3 splits into C3a and C3b -C3b splits C5 into C5a and C5b -Fragments C5b, C6, C7, and C8 bind together sequentially and insert into the plasma membrane of the invading cell. C5b-C8 act as a receptor that attracts a C9 fragment. Additional C9 fragments are added to from a transmembrane channel.

Membrane attack complex (MAC)

C5b-C8 an the multiple C9 fragments form the MAC. Creates a hole in the pathogen’s cell membrane and makes trans-membrane channels, allowing for flow of extracellular fluid into the pathogen, causing it to burst.

How do host cells protect against cytolysis?

Plasma membranes of the host cell contain proteins that protect against lysis by preventing MAC proteins from attaching to their surfaces.

Why are Gram-negative bacteria more susceptible to cytolysis? Why are Gram-positive bacteria less susceptible?

-Only have one or very few layers of peptidoglycan to protect plasma membrane from the effects of complement. -Have many layers of peptidoglycan, which limit complement’s access to the plasma membrane. Said to be MAC-resistant.

Opsonization as a result of complement activation

Immune adherence, promotes attachment of a phagocyte to a microbe. Enhances phagocytosis: -C3 splits into activated C3a and C3b. -C3b binds to the surface of a microbe, and receptors on phagocytes attach to C3b.

Inflammation as a result of complement activation

-Activated C3 splits into C3a and C3b. -C3a and C5a bind to mast cells and cause them to release histamine and other chemicals that increase blood vessel permeability during inflammation. C5a also functions as a very powerful chemotactic factor that attracts phagocytes to the site of infection.

How is the complement system regulated?

Once activated, destructive capabilities usually cease quickly to minimize destruction of host cells. This is accomplished by various regulatory proteins in the host’s blood and on certain cells. Regulatory proteins are present in higher concentrations than complement proteins. They bring about the inhibition or breakdown of activated complement. ex. CD59 prevents C9 assembly to form MAC.

How can the complement system cause disease?

Inherited deficiencies: -C1, C2, or C4 deficiencies cause collagen vascular disorders that can result in anaphylaxis -C3 deficiency results in increase susceptibility to recurrent infections with pyogenic (pus-producing) microbes -C5-C9 deficiencies result in increased susceptibility to N. meningitides and N. gonorrhoeae infection -Implicated in Alzheimer’s disease, asthma, arthritis, multiple sclerosis, etc.

How do some bacteria evade the complement system?

Capsules: -Sialic acid discourages opsonization and MAC formation -Inhibit C3b and C4b and cover C3b to prevent contact with phagocyte receptor -Lengthen O-polysaccharide of LPS to prevent MAC formation -Enzyme release that breaks down C5a, which serves as a chemotactic factor that attracts phagocytes

Interferons (IFNs)

Cytokines that help counter virus-infected host cells. Proteins produced by certain animal cells, such as lymphocytes and macrophages. Different cells produce different interferons. Play a major role in acute infections. In humans, they are produced by fibroblasts in connective tissue, lymphocytes, and other leukocytes. Each type has a slightly different effect on the body. all are small proteins with molecular weights of about 15,000-30,000. They are stable at low pH and resistant to heat.

Alpha interferon (IFN-∂), beta interferon (IFN-ß), and gamma interferon (IFN-y)

-IFN-∂ and IFN-ß principally interfere with viral multiplication and are produced by virus-infected host cells only in very small quantities. Both are host-cell-specific but not virus-specific. react with plasma or nuclear membrane receptors, inducing uninfected neighboring cells to manufacture mRNA for the synthesis of antiviral proteins (AVPs)s)*. -IFN-y produced by lymphocytes and induces neutrophil and macrophages to kill bacteria. Causes macrophages to produce nitric oxide that appears to kill bacteria as well as tumor cells by inhibiting ATP production. Increases the expression of class I and class II molecules and increases oxygen expression.

Antiviral proteins (AVPs)

Proteins are enzymes that disrupt various stages of viral multiplication. Ex. oligoadenylate synthetase degrades viral mRNA; protein kinase inhibits protein synthesis.

What are some complications to the use of interferons?

-Stable for short periods of time, therefore have limited effect. -When injected, have side effects such as nausea, vomiting, fatigue, headache, weight loss, and fever. -High concentrations are toxic to the heart, liver, kidneys, and red bone marrow. -Have no effect on viral multiplication in cells already infected, and some viruses have resistance mechanisms that inhibit antiviral proteins. -Some viruses do not induce production of sufficient amounts of interferon in host cells following viral stimulation.

Recombinant interferons (rIFNs)

Interferons produced with recombinant DNA techniques. Important because: -they are pure -they are plentiful

Iron-binding proteins

Molecules, such as transferrin, lactoferrin, ferritin, and hemoglobin, whose job is to transport and store iron. These molecules cause the concentration of free iron in the body to be low. They deprive most pathogens of the available iron.

Transferrin

An iron-binding protein found in blood and tissue fluids.

Lactoferrin

An iron-binding protein found in milk, saliva, and mucus.

Ferritin

An iron-binding protein found in the liver, spleen, and red bone marrow.

Hemoglobin

An iron-binding protein located within RBCs;

Siderophores

In order to survive in the human body, many pathogenetic bacteria obtain iron by secreting there proteins. They compete to take iron away from iron-binding proteins by binding it more tightly. Once the iron-siderophore complex is formed, it is taken up by siderophore receptors on the bacterial surface and brought into the bacterium.

Antimicrobial peptides (AMPs)

An important component to innate immunity; short peptides that consist of a chain of about 12-50 amino acids synthesized on ribosomes. They have a broad spectrum of antimicrobial activities against bacteria, fungi, viruses, and parasites. Synthesis is triggered by protein and sugar molecules on the surface of microbes. Cells produce AMPs when chemicals in microbes attach to TLRs.

What are the modes of action of AMPs?

-Inhibiting cell wall synthesis -Forming pores in the plasma membrane, resulting in lysis -Destroying DNA and RNA

What are some of the AMPs produced in humans?

-Dermcidin produced by sweat glands -Defensins and cathelicidins produced by neutrophils, macrophages, and epithelium -Thrombocidin produced by platelets

Why are scientists interested in working with AMPs?

-Broad spectrum of activity -Shown synergy with other antimicrobial agents -Stable over a wide range oh pH -Microbes do not develop resistance even when exposed to them for a long period of time

How do AMPs participate in other immune functions?

-Sequester LPS shed from Gram-negative bacteria -Vigorously attract dendritic cells, which destroy microbes by phagocytosis and initiate an adaptive immune response -Recruit mast cells, which increase blood vessel permeability and vasodilation, causing inflammation