Immune System

• Defends against microbes and parasites• Removes dead and damaged cells and

tissues• Allergies and autoimmune diseases• Chronic inflammation and heart disease

and cancer • Transplant tissue rejection• Septic shock and anaphylactic shock

Immune Defenses: Found in all life forms

Pathogens attack all life forms

How can a bacteria defend itself from a virus?

Restriction enzymes

Immune Systems: Required for Multicellular lifeSome immune defenses shared by plants and

humans

Immune System and History• Infectious disease causes 1/3 of deaths

today

• Infectious disease is a major factor in history…for example…the population of Native Americans fell 95% after the Spanish landed in North America…They had no resistance to “Old World” diseases. What would the world be like today if they….like the Central Africans…. had been able to resist invasion by Europeans?

Immune System and History

• The ancient Greeks were almost destroyed by a plague that had symptoms that match no known disease today….they said the plague followed the Nile River from central Africa

• Can new plagues appear today?

Infectious Diseases Constantly Evolving and Invading new

Hosts HIV Monkey Pox

Immune SystemsInnateFastRecognizes many

microbe molecules

Stable genes in DNA genome

Responds in same way every time

Specific or AdaptiveSlowerTargets highly specific

molecular features (antigens)

Variable genes in DNA genome

Has “memory” and responds differently to repeated infection

Innate Defenses-Physical barriers-External chemical and

microbial barriersMucusNormal bacteriaDefensins and

lysozyme

-Internal moleculesComplement

----Phagocytic cellsMacrophagesMonocytesNeutrophilsNatural Killer cells

----Inflammation and fever

Innate Defenses: Physical Barriers

Epithelial cell layers---skin---respiratory---gastrointestinal---urinary and vaginal

Epithelial cells bind to form barriers layers

Figure 19-40 Molecular Biology of the Cell (© Garland Science 2008)

Innate DefensesChemical barriers: Mucus

Some epithelial layers secrete highly hydroscopic molecules to form mucus barriers to trap and wash away bacteria and viruses

Innate DefensesChemical barriers: Mucus

• During pregnancy the cervix forms a mucus plug as a barrier to maintain a sterile uterus

Innate DefensesChemical and microbial barriers

Vaginal mucus secretions select a community of bacteria that cause the female reproductive tract to be highly acid…this limits the growth of pathogens

The ears, skin, oral and respiratory cavities intestines have similar communities of protective bacteria

Innate DefensesChemical barriers

Many epithelial tissues secrete antibacterial molecules

LysozymeDissolves bacterial cell walls…found in

tears

DefensinsNaturally produced antibiotic peptides

DefensinsLarge family of antibiotic peptides found

from plants to humansAlso found as venoms in some poisonous

snakes

Perhaps dozens of human genes…not all active

…..difficult to study as the different defensins overlap in functions

Defensins• Insert into membranes and form pores• May have intra-cellular cell toxic

functions • Found in storage granules of leukocytes

(White blood cells) …released by to kill other cells

• Toxic to bacteria, fungi and some viruses• Some monkeys resistant to HIV have

been reported to have defensins that kill HIV

Some Viruses have cell-like membranes

Defensins: Cationic and hydrophobic sides

• Believed to form membrane pores

• May not function well in Cystic Fibrosis patients due to altered ion channels

• A future topical microbiocide?

Non Specific Defenses:Complement

• Complement: Proteins produced in liver

• Classical pathway….complements

function of antibodies • Alternative and Lectin

pathway….Recognizes and

binds to bacterial and fungal membranes

• Stimulates function of other parts of immune systems

• Attracts Phagocytes by chemotaxis

• Coats bacteria and facilitates phagocytosis: Opsonization

• Destroys target cell Membrane Attack Complexes

Complement Activation

Complement: Membrane Attack Complex

Complement: Membrane Attack Complex

Complement: Membrane Attack Complex

Phagocytes

Phagocytes

Greek phagein: To eatInnate immune system cells designed to

devour and destroy:…extracellular matrix material for tissue

remodling…foreign cells and microbes…abnormal cells (old Red Blood Cells)…can become highly active “Respiratory

Burst”

Phagocytes

Macrophages: Found as resident cells within tissues:

……Microglial cells: found in CNS…..Kupffer cells: found in Liver …..Dust Cells: lung alveolar macrophages

Phagocytes: Kupffer cellsLiver specific

macrophages engulf bacteria, debris and damaged RBCs.

One of two functional cell types in liver---will phagocytose India Ink

Phagocytosis1. Chemotaxis and adherence to microbe2. Surround and ingest (eat) microbe3. Formation of phagosome4. Fusion with lysosomes to form

phagolysome5. Digestion/destruction of microbe by

enzymes and molecules produced by enzymes

NO, HOCL, H2O2, Hydroxyl radicals

6. Processing or discharge of digest

Phagocytes: Monocytes• Monocytes are produced by bone

marrow stem cells• Migrate into blood and follow signals

released at infection sites• Differentiate into macrophages at

sites of infection• Bone marrow production increases

during infection when more macrophages are needed

Phagocytes: NeutrophilsNeutrophils: also known as Polymorphonuclear leukocytesProduced by bone marrow stem cellsTravel in blood: attracted to sites of

infectionFirst additional cells to arrive at infection

siteFast acting….but live for short timeDead neutrophils make up most of Pus

Innate Immune System Recognition of Microbes

• Complement bind to bacteria and fungi and their binding stimulates phagocytosis by macrophages

• Many cell surface receptors for bacterial and fungal molecules… Toll Like Receptors (TLR)

• Several families of internal sensors of microbes... NOD family most well known

NOD proteins also found in plants and insects

Natural Killer Cells• Natural Killer Cell are produced from

bone marrow stem cells• Have cell surface receptors that scan

cells for abnormal cells and evidence of intracellular infection by bacteria and viruses

• Kill cells showing evidence of infection• Also stimulates macrophages

Natural Killer CellsImmunological Surveillance

• Natural Killer cells (NK cells) Attack cells with abnormal membrane molecules OR when MHC I of the adaptive immune sys. disappears

Destruction of:--bacteria, fungus and some enveloped

virus--infected cells--cancerous cells

Natural Killer cells Cell Killing

1. NK cells contact and recognizes abnormal cell2. Golgi apparatus moves like “turret of a tank” and vesicles of Perforins released towards cell3 Perforins diffuse into target cell membrane

and form complexes and create pores4 Target cell membrane leaks and dies5 Also, adds proteins to attacked cell that

stimulates apoptosis

NK cells: Perforin

Innate Immune System Inflammation

• Damaged cells release prostaglandins and various proteins, potassium ions

• The body interprets the altered interstitial fluid composition as an infection or wound.

and responds with inflammation

Innate Immune System: Inflammation

• Inflammation: designed to signal infection is underway and to limit the infection

• Factors released from dying cells can trigger

Mast cells release of histamine as signaling molecule for inflammation:

Cascade of signals: prostaglandins play a major role in promoting inflammation

Inflammation• Dilation of blood vessels: swelling• Capillary permeability increases• Phagocytes attracted to area• Fibrin from blood clot cascade forms

fibers around wound area to trap bacteria• Chemokines released

Inflammation• Chemokines released to act to attract

phagocytes following chemokine concentration gradient

• Locally, blood vessel endothelial cells respond to inflammation factors by expressing glycoproteins in cell surface: Selectins

• Remotely, bone marrow reserves respond by releasing neutrophils and monocytes

Emigration from blood: Monocytes and Neutrophils

The leukocytes begin to stick to blood vessel walls and “roll” along: margination

Local presence of chemokines causes theleukocytes to adhere tightly and begin

migrating thru enlarged capillary pores: diapedesis

Leukocytes migrate to site of chemokine release

InflammationRole in many diseases

• Chronic inflammation may have roles in heart many diseases including heart disease,cancer and autoimmune diseases

• Aspirin blocks prostaglandin synthetase …. some doctors in US recommend a child’s aspirin every day for those at risk of heart disease or colon cancer

• C-Reactive protein used as a measure of systemic inflammation

Inflammation:Endometriosis

• Endometriosis: the most common cause of female sterility in the developed world

• Believed to result from abnormal inflammation response in the endometrium lining of uterus

• Why would the uterus have such sensitivity to inflammation?

• How has this sensitivity been used in medicine?

Septic Shock

• Septic shock, or sepsis, results from the massive release of endotoxins such as LPS

• (Lipopolysccharide)• These compounds are recognized

throughout the body as a sign of infection: This results in a systemic inflammation response of vasodilatation and loss of fluid from capillaries

• The death rate of sepsis is about 50% results from circulatory collapse

Lipopolysccharide-LPS-Endotoxin

Anaphylaxis• Anaphylaxis results from a systemic

response to a circulating antigen such as a drug one has become allergic to

• The response is similar to septic shock but can happen very, very quickly after taking a medicine or getting a sting from an insect

• Can quickly cause death from circulatory collapse: Anaphylactic shock

Innate Immune SystemInterferons

• Small protein signal molecule released by virally infected cells responding to presence of dsRNA or unmethylated CpG DNA

• Acts as hormone to normal cells and by 2nd messenger system triggers expression of over 300 genes….to make them poor viral hosts

• Generally shuts down cellular viral production antiviral

• Can lead to infected cell apoptosis

Interferon:Dicer: RNA interference

• Cells respond interferon by production of the protein Dicer

• Dicer degrades dsRNA into small fragments of about 21-25 nucleotides

• Then, it degrades any mRNA these fragments will bind to

• This system has been used to great effect to silence genes by adding small RNAi molecules

Innate Immune SystemInterferon

• Currently used as drug for Hepatitis B and C

• Also used for some cancers

• Mixed success…sometimes doesn’t help

• Toxic to cells with prolonged use

Innate Immune System Fever

• Fever: a metabolically elevated body temperature

• Can be induced by the hypothalamus• Often induced by pyrogens such as

lipopolysaccharides or (LPS). • The body recognizes the presence of this

molecule as a sign of bacterial infection and fever begins as part of the non-specific immune response

Innate Immune System Fever

• Increased leukocytes mobility and phagocytosis

• Enhanced effects of the specific immune responses

• Cells move faster and enzymatic reactions are quicker @ higher temperatures

• Some pathogens may not function well at high temp. i.e. soil dwelling bacteria

Fever:Metabolic functions are temperature

sensitive

Figure 22–24

Body Responses to Bacterial Infection