Lecture 20: Innate Immunity (Nonspecific)

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Immunity

ability to ward off disease

Susceptibility

lack of resistance to a disease

Innate Immunity

• defenses against any pathogen (non-specific)

• rapid

• present at birth

• first and second lines of defense

  • first: keeps them on the outside or neutralizes them before infection

  • second: works to slow or contain the infection (proteins, fever, phagocytes)

Adaptive Immunity

• immunity or resistance to a specific pathogen

• slower to respond

• has memory component (faster and more effective response after initial exposure)

• third line of defense

  • lymphocytes (T and B cells) target specific pathogens

  • produces memory

  • antibodies

Skin

• made of dermis and epidermis

• shedding and dryness of the skin inhibits microbial growth by preventing microbes from attaching

• has a formidable barrier that is difficult to penetrate = first line of defense

• anything that breaks the skin (burns, stabs, etc) will permit microbes to enter the body (vulnerable)

Dermis

inner portion of the skin made of connective tissue

Epidermis

outer portion of the skin made of tightly packed epithelial cells containing keratin

Mucus membranes

• epithelial tissue layer that lines GI, respiratory, and genitourinary

• goblet cells in membrane produce mucus: traps microbes and prevents the tracts from drying out

  • ciliary escalator: transports microbes trapping in the mucus upward toward the throat

Lacrimal apparatus

• drains tears

• washes the eye

• prevents microorganisms from being able to settle on the surface of the eye

Epiglottis

prevents the microorganism form entering the lower respiratory tract

Earwax

prevents microbes from entering the ear

Urine

cleans the urethra with the flow

Vaginal secretions

move microorganisms out of the vaginal tract

Peristalsis, defecation, vomiting, and diarrhea

helps to expel microbes from the body

Sebum

• chemical factor

• forms a protective film made of unsaturated fatty acids that inhibit the growth of some pathogens

• lowers the pH from the secretion of fatty acids and lactic acid

Lysozyme

• chemical factor; enzyme

• perspiration: maintains body temperature, eliminates waste, and flushes microorganisms off the surface

• more effective on gram-positive because it breaks peptidoglycan walls

  • hydrolyzes chemical bonds between the sugars in the peptidoglycan

Gastric Juice

• chemical factor

• low pH of 1.2-3.0

• produced by the glands of the stomach

• mixture of HCl, enzymes, and mucus

• destroys most bacteria and toxins

Vaginal Secretions

• chemical factor

• low pH of 3-5

• glycogen → lactic acid → acidic pH

• inhibits microbes

Normal Microbiota

• competes with pathogens via microbial antagonism (competitive exclusion)

• advantage for space and nutrients

• produces substances harmful to pathogens

• can alter conditions that impact pathogen’s survival

• prevents overgrowth

Commensalism

when one organism benefits while the other (host) is unharmed

Probiotics

live microbial cultures administered to exert a beneficial effect

Prebiotics

chemicals (nutrients) that selectively promote the growth of beneficial bacteria

Hematopoiesis

• formed elements in the blood created from red bone marrow stem cells

• made of cells and cell fragments suspended in plasma:

  • erythrocytes (RBC), leukocytes (WBC), platelets

Granulocytes

leukocytes that show visible granules in the cytoplasm when under a light microscope

• neutrophils, basophils, and eosinophils

Neutrophils

• highly phagocytic and motile

• most active during early stages of an infection

  • increases WBC count

Basophils

• releases histamine

  • works in allergic responses and inflammation

Eosinophils

• phagocytic

• toxic against parasites and helminths

• too small to fully ingest, so they attach to the outer surface of the parasite and discharge peroxide ions to destroy them

Agranulocytes

leukocytes that do not show visible granules in the cytoplasm when under a light microscope

• monocytes, dendritic cells, and lymphocytes

Monocytes

• matures into macrophages in tissues where they are phagocytic

Dendritic cells

• found in the skin, mucous membranes, and thymus

• phagocytic

Lymphocytes

• T cells, B cells, NK cells

• both B and T cells play a role in adaptive immunity

Lymphoid System

• consists of: lymph, lymphatic vessels, structures and organs containing lymphoid tissue, red bone marrow, and thymus

• tissue: contains lymphocytes and phagocytic cells

• lymph: carries microbes to B and T cells so macrophages and dendritic encounter and destroy the pathogen

Chemotaxis

• first stage of phagocytosis

• chemical signals attract phagocytes to microorganisms

• includes: components of WBCs, damaged cells, and complement proteins

Adherence

• second stage of phagocytosis

• attachment of phagocyte to the surface of the microbes or other foreign material

• PAMPs: pathogen-associated molecular patterns

  • attach to toll-like receptors on phagocyte surfaces

  • ex. LPS, flagellin, peptidogycan, bacterial DNA, viral DNA, and RNA

• opsonization: increases chances of adherence

Opsonization

• when the microorganism is coated with serum proteins that make it easier for adherence

• opsonins: complement components and antibodies

Ingestion

• third stage of phagocytosis

• pseudopods: cytoplasmic projections on phagocyte

  • extends out and engulfs the microbes and particles

• engulfed microorganism are enclosed within a phagosome

  • have enzymes in membane which pump protons to reduce the pH to activate hydrolytic enzymes

Digestion

• fourth stage of phagocytosis

• when the lysosomes fuse with phagosomes = phagolysosome

  • lysosomes have enzymes and toxic products (oxidative burst)

• the microorganism is digested within phagolysosome

• results in the formation of residual which is removed via exocytosis

Inflammation

• a local defensive response triggered by damage to tissues

  • ex. microbial infection, physical agents, or chemical agents

• signs & symptoms = PRISH

• function:

  • eliminate injurious agent

  • limit effects of injurious agent

  • repair and replace tissue because of injurious agent

PRISH

• signs and symptoms of inflammation

P: pain
R: redness
I: immobility

S: swelling (edema)
H; heat

Phase One of Inflammation

• vasodilation: widening of blood vessels to increase blood flow

  • cause of redness and heat

• increased vascular permeability: allows defensive substances to pass through blood vessel walls

  • cause of swelling (edema) due to clotting

• both effects caused by vasoactive mediators released by damaged cells

  • additionally, cytokines released by macrophages

Phase Two of Inflammation

• phagocyte migration and phagocytosis

• margination occurs in response to the cytokines

• diapedesis occurs once phagocytes arrive

• then, phagocytosis begins

Margination

the sticking of phagocytes to the blood vessels near inflammation site in response to the cytokines

occurs as blood flow decreases

Diapedesis

when phagocytes squeeze between endothelial cells of blood vessels

Phagocytosis

once microorganisms are engulfed, they die and form pus, which is pushed out to the surface of the body

Phase Three of Inflammation

• tissue repair: begins during the active phase of inflammation, but cannot be completed until all harmful substances are removed or neutralized at injury site

• scars may be formed by fibroblasts

  • cytokines from macrophages also induce fibroblasts to produce collagen fibers

Fever

• abnormally high body temperature

  • normal: 37°C or 98.6°F

• caused by prostaglandins which reset hypothalamus to higher temperature

  • induced by cytokines

• high temperature maintained until the cytokines are fully eliminated

• chills are an indicator for rising body temperature (onset of fever)

  • as body temperature falls (crisis), vasodilation and sweating occur

Effects of a Fever

• benefits:

  • phagocytes and T cells work better at a slightly higher temperature because of enzyme reactions being sped up, which can stimulate immune protein production

  • intensifies effect or production of microbial substances (interferons or transferrins)

  • slow growth of pathogens

  • an increased metabolic rate speeds up repair process

• complications:

  • tachycardia (rapid heart rate), acidosis (increased metabolic rate → too much acid), dehydration, seizures (kids), delirium, or coma

  • body temperature greater than 44°- 46° C → fatal

Complement System

• system of over 30 serum proteins made by the liver to enhance the immune system in destroying microbes

• acts in a cascade in the process, complement activation

• part of the innate immune system, but can recruit the adaptive

• lack of such proteins = susceptibility to infection

• naming system:

  • proteins with uppercase = inactivated

  • proteins with lowercase = activated

    • C3a → inflammation

    • C3b → cytolysis & opsonization

Classical Pathway

• first complement system pathway

• initiated by antigen-antibody complexes → activated C1

• C1 → C2 & C4 → C2a + C4b → C3 → C3a & C3b

Alternative Pathway

• second complement system pathway

• activated spontaneously from the hydrolysis of C3 → combination with factors on microbe surface

• factors B, D, P + C3 → C3a & C3b

Lectin Pathway

• latest complement system pathway

• triggered by mannose-binding lectin (MBL) attachment to microbial carbohydrate (mannose)

  • macrophage ingest pathogens and release cytokines that stimulate lectin production in the liver → MBL production

• MBL + mannose → C2 & C4 → C2a + C4b → C3 → C3a & C3b

Cytolysis

• outcome of complement activation

• activated complement proteins create a membrane attack complex (MAC) that can lyse targeted cells

  • creating holes and placing transmembrane proteins to allow the flow of extracellular fluids into the pathogen to cause it to burst

    • host cells = resistant = plasma membrane proteins prevent attachment

    • gram-negative pathogens are susceptible due to few layers of peptidoglycan

    • gram-positive have many layers so very limited MAC effect

• C3b → C5 → C5a & C5b → C5b + C8 + C9 fragments → MAC

Opsonization

• outcome of complement activation

• promotes attachment of a phagocyte to a microbe

• when C3b binds to the surface of the microbe and then receptors of the phagocyte attach

Inflammation

• outcome of complement activation

• C3a & C5a bind to mast cells → release histamine, cytokines, and other inflammatory cytokines

  • C5a → good chemostatic factor → attracts phagocytes

Interferons

• cytokines produced by host cells and have antiviral activity (only effective for humans who created them, less for other species)

• not virus-specific; but host-specific

• IFN-a & IFN-b: produced by viral-infected host; causes uninfected neighboring cells to release AVPs

• IFN-y: made by immune cells to activate other immune cells, like macrophages and neutrophils to kill the bacteria

  • production is stimulated by IFN-a and IFN-b

Antiviral Proteins (AVPs)

• inhibit viral replication by disrupting various stages of replicate

• produced by IFN-a and IFN-b