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Innate Immune Response Kathy Huschle Northland Community and Technical College.

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1 Innate Immune Response Kathy Huschle Northland Community and Technical College

2 The Human Body we are made up of warm, moist, nutrient rich substances, an ideal environment for the housing of microorganisms –every drop of water we drink contains 100’s of bacteria –the air we breath introduces millions of bacteria daily to our lungs –every time we brush our teeth we drive microorganisms into our gums Bacteria on just brushed teeth

3 The Human Body despite this environment our body is relatively sterile (pathogen free) in most cases the presence of microorganisms are controlled by our defense mechanisms –innate immunity –adaptive immunity these 2 systems interact to keep out microorganisms, remove microorganisms if they get in, and combat them if they remain inside

4 Immunity immunity is the ability to ward off diseases through nonspecific and specific defenses our bodies normally have 2 defense mechanisms against pathogens –innate immunity nonspecific resistance that refers to all body defenses that protect the body against any kind of pathogen –adaptive immunity specific resistance that refers to defenses against specific microorganisms

5 Innate Immunity the protection provided by the innate immune system is one the human body is born with initially it was thought to be a very generalized system and was often referred to as the non-specific immune system

6 Innate Immunity recent research has determined that though the system will attack a variety of microbial pathogens, the system does rely on recognition of patterns of invading pathogens innate immunity is supplemented by the adaptive immune response which will be discussed in the next lecture

7 Innate Defenses Overview first-line defenses –physical barriers –antimicrobial substances –normal flora sensor systems –toll like receptors –complement –phagocytes inflammationinterferonsfever First-line Defenses

8 First Line Defenses: Physical Barriers skin and mucosa –body’s first line of defense –the function of defense is both mechanical and chemical

9 First Line Defenses: Physical Barriers skin and mucosa –mechanical function involves physical barriers that block entry or processes that remove microbes –chemical function include substances that the body makes that inhibit microbial growth or destroys microbes

10 First Line Defenses: Physical Barriers This figure is a representation of the human body. The purple represents skin, the pink the mucous membranes. You can easily visualize the complete protection offered our body by intact skin and mucous membranes

11 First-Line Defenses: Skin intact skin physically blocks the entrance of microorganisms made up of 2 distinct layers –dermis thick inner portion made up of tight connective tissue –epidermis outer layer of skin made up of many layers of epithelial cells the top layer of the epidermis contains dead cells embedded in a protective protein called keratin –keratin is a water-repelling protein

12 First-Line Defenses: Skin the presence of dead cells and keratin in the outer layers of our skin plays a major role in inhibiting any microorganisms from gaining a foot hold –microorganisms require water to survive: keratin repels water keratin and dead cells on the surface of skin

13 First-Line Defenses: Skin –viruses require a living host to invade: dead cells are obviously not suitable for viral invasion –the outer layer of cells are periodically shed which helps remove any microbes that may have found a home on the skin’s surface Dead skin cells

14 First-Line Defenses: Mucous Membranes mucous membranes line the internal spaces of organs and tubes that open to the outside, and also line the body cavities some examples of the location of mucous membranes

15 Mucous Membranes mucous membranes inhibit the entrance of microorganisms, but offer less protection than intact skin mucous, the sticky fluid found in mucous membranes, functions to keep the membranes moist Mucous secreting cells

16 Mucous Membranes –this moist environment enhances the presence of some microorganisms these microorganisms, if present in a large enough number, are often capable of penetrating the membrane –but on the other hand, the bathing of mucous membranes by mucosa can in some cases wash the microorganisms from the surfaces Esophagus

17 Mucous Membranes in the digestive tract, many microorganisms are directed towards elimination by a process called peristalsis

18 Mucous Membranes –peristalsis is the rhythmic contraction of the intestinal tract that moves food through the system –this process also enhances the removal of microorganisms Gastic gland in digestive tract secrete mucous

19 Mucous Membranes cilia line the respiratory tract –with a constant beating upward by the cilia, microorganisms are propelled away from the lungs to the throat where they are either swallowed or coughed away Trachial cell with cilia in green and mucousal glands in yellow Cilia actions removing debris

20 Mucous Membranes more penetrable than skin dry conditions thin mucous layer making them even more penetrable –this explains why we are more vulnerable to colds and respiratory infections during dryer winters cells of the mucous membranes are alive –high concentrations of viruses and pathogens can overwhelm them Bacteria in yellow on nasal epithelium in mauve

21 Mucous Membranes mechanical methods of microbial removal from mucous membranes –respiratory: coughing, sneezing, gagging –gastrointestinal: peristalsis, vomiting, defecation –genitourinary: urination

22 First Line Defenses: Antimicrobial many of the body fluids found in or on the skin or mucous membranes are antimicrobial –they can effectively limit ability of invading organisms to infect by inhibiting growth: bacteriostatic killing: bactericidal –examples include sweatlysozymeacidslactoferrin

23 First Line Defenses: Antimicrobial sweat has a high salt content –as it evaporates on our skin, it leaves behind a residue that is high in salt –a salty environment on the skin is not conducive to growth for most microorganisms Sweat gland cells

24 First Line Defenses: Antimicrobial lysozyme –an enzyme that is found in tears, saliva, sweat, and mucus –lysozyme degrades peptidoglycan which is found in bacterial cell walls particularly effective against Gram – cells –the degradation of the cell wall causes the organism to die from osmotic shock: it no longer has the rigid protection of the cell wall lysozyme

25 First Line Defenses: Antimicrobial acids –generally microorganisms require a neutral environment –the presence of acid kills or prevents the growth of most microorganisms vaginal tract has a pH of digestive tract has a pH of 1-2 Endoscopic view of digestive tract

26 First Line Defenses: Antimicrobial the presence of normal “friendly” microorganisms on the skin break down the sebum found in the skin –the break down of sebum releases fatty acids which make the skin more acidic, inhibiting the growth of invading microorganisms Sebum on skin

27 First Line Defenses: Antimicrobial blood and body fluids also contain antimicrobial chemicals –iron-binding proteins transferrin –found in blood and tissue fluids lactoferrin –found in saliva, mild and mucus Transferrin-HeLa cellsLactoferrin

28 First Line Defenses: Antimicrobial transferrin and lactoferrin –inhibit bacterial growth by reducing the amount of available iron bind the available iron so the pathogens can’t –the probability of contracting a STD during menstruation is increased due to increased amount of blood in the vaginal tract: more iron available for the invading microorganism

29 First Line Defenses: Fluid Flow the cleansing action of fluids also assists in the removal of microorganisms from mucous membranes –saliva dilutes the number of microorganisms and washes them from the surface of the teeth and the mucous membranes of the mouth bacteria in saliva

30 First Line Defenses: Fluid Flow –urinary tract the cleansing of the urethra by the flow of urine prevents colonization of microorganisms

31 First Line Defenses: Fluid Flow –eye production of tears by the lacrimal apparatus continually washes over the eyes lacrimal gland secretes tears: tears are drained by the nasalacrimal duct

32 First Line Defenses: Fluid Flow this continuous washing of the eyes with tears prevents microorganisms from settling on the surface of the eye

33 First Line Defenses: Microbial Barriers on a cellular basis, our body is made up of 90% microbial cells and only 10% “human” –most of the bacterial cells found in our body are associated with the gastrointestinal tract –S. aureus is prevalent on skin –Lactobacilli are prevalent in the vaginal tract S. aureus

34 First Line Defenses: Microbial Barriers this large number of microbial cells are indigenous (naturally occurring) and are referred to as normal microbita or normal flora microbial barriers play a key role in our immune system by inhabiting specific body surfaces

35 First Line Defenses: Microbial Barriers many of the normal flora found in various parts of the human body

36 First Line Defenses: Microbial Barriers normal flora are nonpathogenic –colonize body tissues thus preempting other microorganisms from colonizing –they are capable of producing antimicrobial substances that interfere with the growth of other microorganisms –they reduce the availability of oxygen –they compete for nutrients

37 First Line Defenses: Microbial Barriers the normal flora found in our body are a balanced complex –but an imbalance can lead to disease nonpathogenic normal flora are opportunistic and will take advantage of any opportunity to invade which can lead to disease opportunities that can lead to an imbalance can be injury or a depressed or non-functioning immune system

38 First Line Defenses: Microbial Barriers the process of acquisition of our normal flora begins during birth –the human fetus is sterile and through a successional process occurring in stages, acquires the microbiota necessary for survival –the first step of acquiring the normal flora for some newborns is the transfer of microorganisms from mother’s milk

39 Cells of the Immune System cells are capable of moving around the body through the circulatory system cells of the immune system are found in normal blood –develop in the bone marrow –increase in amounts during infection –leukocytes: white blood cells granulocytes mononuclear phagocytes lymphocytes stem cell is the common ancestor to all blood cells: red, white, and platelets

40 Granulocytes presence of large granules in their cytoplasm filled with biologically active chemicals critical to their function granulocytes differentiate into three types of cells –neutrophils –basophils –eosinophils granulocytes

41 Neutrophils neutrophils –professional phagocytes – 50% of the leukocytes found in the body are neutrophils these numbers increase during the presence of a bacterial infection

42 Neutrophils –chemical found in their granules assists in the degradation of engulfed material –often referred to as polymorphonuclear neutrophilic leukocyte or poymorphs (PMN) Neutrophil SEM pictogram of neutrophil Neutrophil in collagen

43 Neutrophils –have the ability to leave the blood, enter an infected tissue and destroy microbes and foreign particles –always present for protection and surveillance

44 Basophils the role of basophils is not particularly well understood –they are involved in allergic reactions and inflammation

45 Eosinophils important defense against parasites –capable of leaving the blood and infiltrating tissue –major function is to produce toxic proteins against parasites physically too small to ingest parasites, eosinophils are able to attach to the outer surface of a parasite and discharge a toxin that destroys them

46 Mononuclear Phagocytes 2 types of phagocytic cells arise from monocytes monocytes circulate in the blood after leaving the bone marrow

47 Mononuclear Phagocytes monocytes migrate to tissue and form: –macrophages also considered to be professional phagocytes abundant in spleen, liver, lymph nodes, lungs, peritoneal cavity macrophage

48 Mononuclear Phagocytes –dendritic cells scout phagocytes; highly mobile cells more involved with adaptive immune system which will be discussed later

49 Leukocyte Invasion

50 Lymphocytes cells that are players in the adaptive immune system –these cells are not phagocytes –occur in the lymphoid tissue of the lymphatic system; tonsils, spleen, red bone barrow, lymph nodes

51 Lymphocytes B cells –produce antibodies T cells –destroy infected/abnormal cells and coordinate the immune response Natural Killer cells (NK) –kill cells –are capable of recognizing a target and then destroying that cell B cell with bacteria T cell NK cells attacking

52 Cell Communication the function of the immunes system relies on cooperation between many factors –this cooperation relies on a method of communication between the players receive signals from environment send messages direct contact

53 Cell Communication surface receptors –proteins that bind signal molecules or specific chemical messengers –connect outside of the cell to the inside eyes and ears of the cell –allows cell to respond to what’s happening outside it’s cell wall –the response that is made is called chemotaxis movement made in response to a chemical

54 Cell Communication cytokines –proteins that bind to certain surface receptors –chemical messengers of the immune system –there are numerous types of cytokines that have various affects on the behavior of cells –please view the table 15-3 on page 380 in your textbook for examples of the many kinds of cytokines Interleukin L in red, human cells in green

55 Cell Communication adhesion molecules –“grab” other cells as they pass such as phagocytic cells –allow cells to make direct contact enabling delivery of cytokines to a cell Macrophage (A) using pseudopodia (B) to grab bacteria (C)

56 Sensor Systems responsible for detecting signs of tissue damage or microbial invasion within the blood or tissue recognize and respond to patterns associated with “danger” –toll-like receptors –complement system Macrophage roams and monitors lung tissue

57 Toll-Like Receptors a very recent discovery in the microbial world 10 different toll-like receptors have been discovered so far, each recognizing a specific or group of specific compounds associated with “danger” for the cell surface receptor proteins that are capable of recognizing microbial particles and activating immune cells against the source of these microbial particles

58 Complement glycoproteins found in blood that are responsible for –removal of invading pathogens –preventing and limiting bacterial infections –assisting in other defenses that protect Glycoprotein E

59 Complement Cytolysis complement system destroys microbes by cytolysis, inflammation or phagocytosis

60 Complement complement proteins act in a cascade; one reaction triggers another, triggers another, etc –this amplifies the effect as the reaction continues

61 Complement complement is activated by –classical pathway: antibody/antigen complex –alternative pathway –lectin pathway

62 Complement classical pathway –is initiated by an antigen-antibody reaction –this complex activates complement which ultimately initiates cytolysis, inflammation or opsonization

63 Complement alternative pathway –complement is activated by the contact between specific complement proteins and a pathogen –can be stopped by regulatory proteins which are found in host cells but are not associated with microbial surfaces

64 Complement lectin pathway –requires mannan-binding lectins (MBL) mannan is a substance that is found on microbial cells and not mammalian cells as a result of binding, the MBL acts as an opsonin (serum protein) to enhance phagocytosis

65 Complement activation of complement generally leads to –inflammation: contributes to vascular permeability –lysis of foreign cells assembles a membrane attack complex (MAC) –creates pores in the cell, disrupting cell integrity –most effective against Gram – cells because of the outer membrane of the Grams – cell –opsonizaion: the coating of microorganisms with serum particles to make them more susceptible to phagocytosis

66 Phagocytosis phagocytes are cells that engulf and digest they are capable of pattern recognition which is critical in the determination between self and non- self cells Macrophage attacking self

67 Phagocytosis there are six general steps in the process of phagocytosis which include –chemotaxis –recognition and attachment –engulfment –fusion of phagosome –destruction and digestion –exocytosis Macrophage ingesting M. pneumoniae

68 Phagocytosis chemotaxis –presence of a chemical stimuli from microorganisms, damaged mammalian tissue and complement –chemical stimuli recruits phagocytes to the site

69 Phagocytosis recognition and attachment –direct binding occurs with surface receptors –indirect binding occurs when a particle has been opsonized

70 Phagocytosis engulfment –engulfment of the particle forms a membrane- bound vacuole called a phagosome –this does not destroy the microorganism

71 Phagocytosis fusion with lysosome –within the phagocyte the phagosome fuses with a lysosome, which is vesicle filled with digestive enzymes –this fusion results in the formation of a phagolysosome Walking macrophage in lung ridding it of debris

72 Phagocytosis destruction and digestion –within the phagolysosome the microorganism is broken down with the aid of enzymes –this process generally takes minutes to kill most types of bacteria

73 Phagocytosis exocytosis –the vesicle containing the digested material joins with the plasma membrane –the vesicle is then expelled to the external environment

74 Phagocytosis types of phagocytes –macrophages scavengers and sentries of the system long lived: weeks to months are able to maintain their killing power by regenerating their lysosomes Macrophage in lung tissue ingesting bacteria

75 Phagocytosis –neutrophils rapid response team: quickly move to an area when needed extremely effective in the early stages of infection short life span:1-2 days have more killing power than the larger macrophages but do not last as long both are replaceable Stages in neutrophil development

76 Phagocytosis

77 Inflammatory Response generalized, coordinated response to –localize invading microorganisms (penetration of skin) –production of toxic compounds the inflammatory responses role is to –arrest the spread of infection –localize the response –restore tissue function

78 Inflammatory Response initiation of inflammatory response –microbial products such as LPS, flagella, bacterial DNA trigger –microbial surfaces can trigger the complement cascade which can trigger the inflammatory response –tissue damage can trigger Inflammation response in mice Notice swelling and reddness in mouse on the right

79 Inflammatory Response symptoms of inflammation includes –swelling – pain –reddening –elevated temp all of the above symptoms of inflammation are a result of the process of inflammation, which begins with –the dilation of blood vessels at the site of damage –leakage of fluid from those vessels allowing for the migration of leukocytes to the site

80 Inflammation Response redness is due to capillary dilation elevated temp is due to capillary dilation which brings heat to the site swelling is due to increased capillary permeability pain is due to lysis of the blood cells dilation of blood vessels –increases circulation –increase phagocytes

81 Inflammation increased blood flow –brings more phagocytic cells to the site –area of inflammation is walled off due to fibrin which is more prevalent due to vasodilatation –the blood clots formed around the area prevent the microbe and/or its toxin from spreading as a result, there may be a localized collection of inflammatory exudate or pus –dead microorganisms –dead phagocytic cells –debris –body fluids final stage of inflammation is repair of affected tissue

82 Inflammation Following infection or injury, mast cells release vasodilators that increase capillary permeability allowing plasma and leukocytes to leave the bloodstream and enter the tissue.

83 Inflammatory Response Step One Step Two

84 Inflammatory Response Step Three Step Four

85 Steps of Phagocytosis in the Inflammatory Response

86 Interferons a class of antiviral proteins produced by certain animal cells after viral stimulation principal function of interferons is to block replication of viral genetic material –blocks translation of viral mRNA –interferons do not block entry

87 Interferons non-specific protection against viral infection –response of interferons to one virus offers protection against other viruses –it only works with limited quantities: neighboring cells are protected, but not cells throughout the body Inhibition of SARS virus with interferons

88 Interferons interferons play a major role in the short-term acute infections such as the common cold and influenza the commercial production of interferons is being explored –not only for their antiviral properties but also as potential anticancer agents

89 Fever homoeothermic animals maintain a constant body temperature fever is a: –systemic response –abnormal increase in temp –strong indication of infectious disease, particularly those of bacterial origin Kevorkian painting entitled “Fever”. This is one of an original series of paintings (now lost) concerning various medical signs and symptoms. It depicts the great discomfort of intense bodily heat.

90 Fever fever –enhances natural defenses stimulates phagocytosis increases rate of enzyme reactions which enhances –degradation of microorganism –tissue repair –intensifies the action of interferons –reduces the blood iron concentration

91 Fever up to a certain point, fever is considered a defense against disease –for this reason, one should consult a physician before taking drugs to reduce a fever


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