Innate Immunity
Immunity
• Ability to ward off a disease/ disease causing organism/ foreign material (pollen etc)
• Susceptibility: lack of resistance to a disease• INNATE IMMUNITY
– At birth– First and Second line of defense– Non-specific– No Memory
• ADAPTIVE IMMUNITY– Third line of defense– Specific– Memory response (to previous disease/ vaccination)
First line of defense
• Intact skin• Mucous membranes and their secretions• Normal microbiota
Second line of defense Third line of defense
• Specialized lymphocytes: T cells and B cells• Antibodies
• Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages• Inflammation• Fever• Antimicrobial substances
Figure 16.1 An overview of the body’s defenses.
Physical Barriers: First Line of Defense
• Skin– Epidermis
• Outer layer – thin• Layers of tightly packed epithelial cells• Outermost layers dead
– Keratin (Protein)– Sloughs off routinely
– Dermis• Inner layer – thick• Connective tissue
Bacteria enter through Skin ONLY when skin is damaged
Top layersof epidermiswith keratin
Epidermis
Dermis
Figure 16.2 A section through human skin.
Mucous Membranes
• Line respiratory, gastrointestinal, urogenital• Epithelial cells with inner connective tissue
– Goblet cells • Secrete mucus (glycoproteins)
– Prevents dessication, traps microbes, enzymes to kill microbes
• Mucus-coated nose hairs: Trap microbes• Ciliary escalator
– Ciliated cells of Lower Respiratory Tract– Mucus-coated dust/microbes pushed outward– Sneezing/ Coughing speed up process
• Epiglottis– Covering over larynx: prevents food and microbes getting in
Other Physical/Chemical Barriers• Tears
– Lacrymal Glands: Under upper eyelid– Constantly wash over eye; drain into lacrymal ducts– Lysozyme (breaks peptidoglycan walls of bacterial cell walls)
• Urine– Flushing mechanism prevents colonization– Contains uric acid, urea (makes pH ~6.5), lysozyme
• Saliva– Salivary Glands– Constantly washes over teeth and mouth– Contains Lysozyme
• Peristalsis– Movement of food by coordinated contractions– Defecation– Vomiting in response to microbial toxins
Lacrimal glands
Upper eyelid
Lacrimal canal
Nasolacrimalduct
Nose
Figure 16.3 The lacrimal apparatus.
Chemical Factors• Sebum: oils – protective layer on skin
– Low pH: unsatd. Fatty acids – inhibit path. Bacteria• Sweat
– Regulates body temperature– Flushes microbes, waste– Lysozyme
• Gastric Juice: HCl, mucus and enzymes– Low pH 1.5-3– Kills most microbes and toxins (except those of S. aureus and
Botulinum)• Some bacteria enter protected by food• H. pylori neutralizes acid and makes a niche for itself in stomach
• Vaginal Secretions: low pH
Normal Flora
• Competition/ Exclusion– Compete for nutrition – Alter environment to prevent pathogen growth
• Commensal– Where one benefits (normal flora), the other is
unaffected (host)– Opportunistic pathogens
• E. coli, S. aureus, S. epidermidis
Second Line of Defense
• Formed Elements in the Blood• Lymphatic System• Phagocytes• Inflammation• Fever• Antimicrobial Substances
Formed Element of Blood
• Platelets (for clotting)• Erythrocytes (Red Blood Cells)• Leukocytes (White Blood Cells)
– Granulocytes (visible granules)• Neutrophils• Basophils• Eosinophils
– Agranulocytes (granules not visible)• Monocytes• Dendritic Cells• Lymphocytes
Insert Table 16.1If possible, break into multiple slides
Table 16.1 Formed Elements in Blood (Part 1 of 2)
Insert Table 16.1If possible, break into multiple slides
Table 16.1 Formed Elements in Blood (Part 2 of 2)
• Percentage of each type of white cell in a sample of 100 white blood cells
Neutrophils 60–70%
Basophils 0.5–1%
Eosinophils 2–4%
Monocytes 3–8%
Lymphocytes 20–25%
Differential White Cell Count
The Lymphatic System• lymph : fluid• Lymph vessels • Lymph tissue (contain a large number of lymphocytes
T cells and B cells)• Red bone marrow• Lymph nodes: sites of activation for T cells and B cells • Tonsils/ Peyer’s patch• Spleen: monitor blood for microbes and secreted
products (toxins)• Thymus: T cell maturation
Rightlymphaticduct
Rightsubclavian vein
Leftsubclavianvein
Thoracic(leftlymphatic)duct
Tonsil
Thymus
Lymphatic vessel
Large intestine
Redbone marrow
Heart
Thoracic ductSpleen
Small intestine
Peyer’s patch
Lymph node
(a) Components of lymphatic system
Figure 16.5a The lymphatic system.
Phagocytosis
• Greek: Phagos (eat), cyte (cell)• Ingestion of a substance/ microbe by a cell• Phagocytes
– Cells that perform phagocytosis– Leukocytes and/or derivatives
SEM of a neutrophil phagocytosing
Aspergillus spores
Pseudopods
Bacterium
Macrophage
Figure 16.6 A macrophage engulfing rod-shaped bacteria.
Phagocytes
• Neutrophils: early during infection– First phagocytes at site of infection
• Monocytes– Morph into Macrophages when infection
progresses– Fixed v/s Wandering Macrophages
• Non-motile; Specifically present in tissues/ organs– Lymph nodes, bone marrow, spleen, liver
• Roaming through tissue, gather at site of inflammation
Phagocytosis: Mechanism
• Chemotaxis: attracted to site of infection– Cytokines (released from other WBCs)– Cell damage– Microbial products
• Adherence: attachment to microbial surface– Toll-like receptors (TLRs)– Pathogen associated Molecular Patterns (PAMPs)– Opsonins: proteins that coat microbe
• Ingestion: pseudopodia engulf microbe into phagosome• Digestion: fusion of phagosome with lysosome
– Enzymes digest microbe– Residual body excreted
Mechanism of Phagocytosis
PAMPs and TLRsTLRs in the plasma membrane of phagocytes attach to components commonly found on pathogens (PAMPs)
• LPS of gram (-) outer membrane• Peptidoglycan of gram (+) cell wall• DNA and RNA of viruses• Fungal and parasite components
Shown: Pattern Recognition Receptor of a TLR attaching to a pathogen’s PAMP
Inhibit adherence: M protein, capsules
Streptococcus pyogenes, S. pneumoniae
Kill phagocytes: Leukocidins Staphylococcus aureus
Lyse phagocytes: Membrane attack complex
Listeria monocytogenes
Escape phagosome Shigella, Rickettsia
Prevent phagosome–lysosome fusion
HIV, Mycobacterium tuberculosis
Survive in phagolysosome Coxiella burnettii
Microbial Evasion of Phagocytosis
Inflammation
• Damage to tissue: heat, infection, chemical• Four signs of inflammation:
– Heat (calor), swelling (tumor), redness (rubor), pain (dolor)– Loss of function in some cases
• Acute: intense– Infecting agent removed in short time– S. aureus (boil)
• Chronic: less intense, more destructive– Infecting agent cannot be removed– TB lesion in lungs
InflammationPurpose of inflammation:1. Destroy infectious agent
- Remove it and its byproducts from the body2. If #1 is impossible, confine the infectious agent and
byproducts; keep from spreading3. Repair or replace damaged tissue
Steps in the inflammatory response:4. Vasodilation & increased blood vessel permeability5. Phagocyte migration & phagocytosis6. Tissue repair
InflammationStage 1: Vasodilation & increased vessel permeability• Histamine
• released from injured cell granules (basophils, mast cells)• Kinins
• In plasma; attract phagocytic granulocytes to injured site• Prostaglandins
• From damaged cells • intensify the effects of histamine and kinins
• Leukotrienes• Damaged basophils, mast cells • increase vessel permeability; attach phagocytes to pathogens
• Cytokines • activated fixed macrophages• increase vasodilation and permeability
Clotting factors enter infection site; clot prevents spreadPUS: dead cells and body fluids; ABCESS: cavity after tissue breakdown
Histamine Vasodilation, increased permeability of blood vessels
Kinins Vasodilation, increased permeability of blood vessels
Prostaglandins Intensify histamine and kinin effect
Leukotrienes Increased permeability of blood vessels, phagocytic attachment
Chemicals Released by Damaged Cells
InflammationStage 2: Phagocyte migration and phagocytosis
• Phagocytes appear on the scene within ~1 hourMargination = cytokines alter blood vessel lining, cause phagocytes to stick to vessel walls at inflammation site
- Traverse vessel walls to get into affected area (= diapedesis), phagocytize invading microbes
• Granulocytes are first on scene; die off rapidly• Macrophages enter at a later stage
- larger and more phagocytic- Phagocytize destroyed tissue, granulocytes, remnants of
invaders
Inflammation
Margination
Diapedesis
Macrophage
Neutrophil
InflammationStage 3: Tissue repair• Dead or damaged cells are replaced in affected tissues• Repair capacity depends on tissue type
Stroma = supportive connecting tissue- Ex) capsule around the liver that encloses and protects
it; not involved in liver functionsParechyma = functioning portion of tissue- Ex) Hepatocyte cells of liver that perform the liver’s
functions
If parenchymal cells are active in repair = perfect reonstruction; if stroma cells are more active = scar
Bacteria enteringon knife
Epidermis
Dermis
Subcutaneoustissue
(a) Tissue damage
Bacteria
Blood vessel
Nerve
Figure 16.8a-b The process of inflammation.
Chemicals such as histamine, kinins, prostaglandins, leukotrienes, and cytokines (represented as bluedots) are released bydamaged cells.
(b) Vasodilation and increasedpermeability of blood vessels
Blood clot forms.
Abscess starts to form(orange area).
1
2
3
Insert Fig 16.8d
Scab
Blood clotRegenerated epidermis(parenchyma)
Regenerateddermis(stroma)
(d) Tissue repair
Figure 16.8d The process of inflammation.
Fever
Fever = abnormally high body temperature• a systemic response
Hypothalamus = brain region that controls body temp• Raises temp in response to cytokines by:
- blood vessel constriction- increased metabolism- shivering
• Maintained until cytokines (and infection) are eliminated• Heat loss by vasodilation and sweating
Drop in body temperature
Fever benefits:• Intensifies the effect of antiviral interferons• Increases production of transferrins
- decreases iron available to microbes• Increased speed of tissue repair
- speeds up all of the body’s reactions
Fever complications:• Increased metabolism effects:
- Tachycardia = rapid heart rate- Acidosis = increased acidity of blood/tissue- Seizures, delirium, coma- Death (temp above 112-114oF)
Fever
Antimicrobial Substances
Complement system = defensive system of >30 proteins produced in the liver that circulate the blood & tissues
• “Complements” the action of immune cells
Destroy microbes by:1. Cytolysis2. Inflammation3. Phagocytosis
• Act in a cascade with one reaction triggering another Activated by one of 3 possible pathways
The Complement Cascade
1. C3 splits into C3a and C3b
2. C3b coats the microbe to promote phagocyte attachment (opsonization)
3. C3b initiates formation of membrane attack complex (MAC) on invading cell
4. MAC causes cytolysis = bursting of invading cell due to inflow of extracellular fluid
5. C3a and C5a bind mast cells stimulate release of histamine increase blood vessel permeability• C5a also attracts phagocytes
Complement-induced cytolysis
before cytolysis after cytolysis
1. Antibodies bind antigens antigen-antibody complexes activate C1
2. Active C1 splits (activates) C2 and C4 into C2a, C2b, C4a, C4b
3. C2a and C4b combine and split C3 into fragments C3a and C3b Active fragments initiate the complement cascade
Complement activation: classical pathway
Steps:1. C3 combines with factor B, D and P
(complement proteins) on the surface of a microbe
2. C3 splits into C3a and C3b complement cascade
• No antibodies involved• Direct contact between
complement proteins and pathogen
Complement activation: alternative pathway
Lectins = proteins produced by the liver that bind carbohydratesMannose binding lectin (MBL) = binds mannose (in bacterial cell walls and some viruses)
Steps:1. MBL binds an invader2. Activates C2 and C43. C2a and C4b combine and
activate C3 complement cascade
Complement activation: The lectin pathway
InterferonsInterferons = class of cytokines produced by certain animal cells after viral stimulation
• Interfere with viral multiplication
Three types in humans:Alpha and Beta interferon = produced by infected host to induce antiviral protein synthesis in neighboring cells
• Oligoadenylate synthetase = degrades viral mRNA• Protein kinase = inhibits viral protein synthesis
Gamma interferon = produced by lymphocytes; induces neutrophils and macrophages to kill invaders; suppresses tumor cell proliferation
Interferons
Interferon complications:• Stable for only short time periods• Side effects of injection:
- Nausea, fatigue, vomiting, fever• Toxic in high concentrations
- heart, kidneys, liver, red bone marrow
Medical usage:• Limited or no effect on tumors in clinical trials• Alpha interferon some virus-associated disorders
• Kaposi’s sarcoma• Chronic Hepatitis B and C
Iron-binding proteinsHumans use iron in many ways:• component of cytochromes in the ETC• cofactor of many enzymes• component of hemoglobin
Iron-binding proteins = transport and store ironTransferrin = blood and tissue fluidsLactoferrin = milk, saliva, mucusFerritin = liver, spleen, red blood marrowHemoglobin = red blood cells
deprives pathogens of available iron!
Iron-binding proteinsSiderophores = proteins released into the medium by bacteria to capture iron from transport proteins• Forms iron-siderophore complex, recognized by
bacterial receptors and taken into cell• Splits iron from siderophore and utilizes it
Other mechanisms of obtaining iron:• Release toxins when iron is low
Kills host cells, releasing their ironEx) Strep pyogenes
• Hemolysins lysis of red blood cells• Hemoglobin broken down to capture iron
Antimicrobial PeptidesAntimicrobial peptides (AMPs) = short chains of amino acids synthesized on ribosomes• Synthesized by neutrophils when TLRs contact PAMPs
- Broad spectrum killing of bacteria, viruses, fungi- Attract other phagocytes- Sequester endotoxins
What makes them interesting?• Work together with other antimicrobials (synergy)• Stable over a wide range of pH• Microbes don’t develop resistance