The Innate Immune Response

Chapters 15 and 19

Nester 4th. Ed.

Anjum Odhwani, MD MPH

Public Health MP 3304

Definition of Immunology

The branch of science that is devoted to the study of many mechanisms the body uses to defend itself against invading organisms or microbes.

Types of Defense Mechanisms

Non-specific (Innate immunity) Specific (adaptive immunity)- Immune

Response

One branch of immunity

Non-specific immunity– found in most of the humans and animals – inborn, innate, natural – already in place before the organism

enters the host– directed against any organism that tries to

invade a host

Mechanisms involved in Non-specific immunity Tissue barriers

– Mechanical – Chemical

Non-specific antimicrobial substances Acute inflammation Phagocytosis Fever Changes in iron metabolism

First – line defense

Physical barriers Normal flora Antimicrobial substances

Innate Immunity Mechanical Barriers that prevent entry of

microorganisms (Fig 15.1-15.3)– Skin

• Most difficult barrier• Physically prevents microbes from

accessing the tissues• Skin is tough and durable• Outer layer Keratin constantly slough

off• Arid environment• Sweat high in salt and lysozyme• Sebum (fatty acid)

Epithelial barriers

Innate Immunity Mechanical Barriers that prevent entry

of microorganisms (Fig 15.1-15.3) Mucous membranes

– Constantly bathed with mucus and other secretions

– Propel microbes • Ciliated epithelium• Peristalsis• Urine flushes organisms

Anatomical barriers

Figure 15.1

Innate Immunity

Chemical Barriers (Figure 15.3)– Acid mantle

• urine, stomach acid and vaginal pH

First-line defense mechanisms in humans

Innate Immunity

Normal flora (resident flora)– Covers binding sites– Compete– Consume resources– Produce toxins e.g. Propionibacterium,

Lactobacillus species in vagina– Stimulate host defense mechanism

Normal flora

Establishment– fetus has no normal flora– acquire some at birth– acquire some in food– acquire some from other people– colonization

Normal flora

Importance of Normal Flora

Prevent growth of other organisms– by taking up space - commensals– by competing for nutrients– by preventing attachment

Importance of Normal Flora Prevent growth of other organisms

– by making products that are toxic to other organisms• lipid catabolic by-products e. g.

Propionibacterium (sebaceous secretion to fatty acid)

• Colicins (E. coli synthesis protein toxic to other organisms)

• Lactic acids (lactobacillus in vagina acidic environment)

Importance of Normal Flora

Prevent the growth of other organisms– by stimulating immunity

• an immune response to one organism may help against a similar organism

Providing a useful function– degrading cellulose for nutrients

– making vitamins (biotin, panthothenic acid (B5), folic acid and Vitamin K)

Normal flora

– Types of symbiotic relationships• Mutualism

– An association in which both partners benefit e.g. intestinal bacteria synthesize vit K and vit B

• Commensalism– An association in which one partner benefits

but other remains unharm• Parasitism

– An association in which one organism, the parasite derives benefit at the expense of the other organism, the host

Normal Flora Can Change

How?– increased perspiration– acidity of the stomach (Alteration of the acid barrier

of the stomach by disease, surgery, drugs or antacids)

– ingestion of antibiotics– meat diet vs. vegetarian diet (People living on

the high carbohydrate diet have significantly fewer Bacteroides and more Enterococci in their faeces)

– changes in peristalsis (e.g. diarrhea)

Innate Immunity Non-specific antimicrobial factors Antimicrobial substances found in

saliva, tears, mucus and skin– Lysozyme– Peroxidase– Lactoferrin– Interferons

Innate Immunity

Non-specific antimicrobial factors– Lysozyme

• Found in tears, saliva, mucus, in phagocytic cells, blood and fluid that bathes tissues

• Enzyme that degrades peptidoglycan• Gram-positive bacteria peptidoglycan is

exposed• Gram-negative peptidoglycan not

exposed

Innate Immunity Non-specific antimicrobial factors

– Lactoferrin and transferrin• Found in saliva, mucus, milk, blood and

tissue fluids• Iron binding protein• Major element for growth of the

organism• Sequester iron from the organisms

Innate Immunity Non-specific antimicrobial factors

Peroxidase• Found in saliva, milk, body tissues and

phagocytes• Peroxidases are a group of enzymes that

catalyze oxidation-reduction reactions

• H2O2 + peroxidase + Cl = yields chlorine and hypochlorite (bleach)

• H2O2 + catalase yields H2O and O2

• Catalase (+) organisms are more resistant to peroxidase

• Catalase –negative organisms are sensitive to perxidase killing

Innate Immunity Non-specific antimicrobial factors

– Defensins• Short antimicrobial peptides• Found on mucus membranes and

within phagocytic cells (macrophages and neutrophils)

• Insert themselves into bacterial membranes and form pores

• Distrupt the integrity of bacterial membrane

Interferon

Innate Immunity Non-specific antimicrobial factors

– Interferons• Group of glycoproteins (control viral

infection) See Figure 15.11• Inhibits protein synthesis in cells near

virally infected cells• Prevent viral replication• Are species specific with regards to host

Cells and Tissues Involved in Defense Mechanisms

Cells are mainly the leukocytes– Figure 15.4– Table 15.2– Non-specific are the granulocytes,

monocyte/macrophages and null cells (natural killer cells)

– Specific are the lymphocytes

Cells and Tissues Involved in Defense Mechanisms

Tissues – lymphoid tissues (dense accumulation of

lymphocytes e.g. Peyer’s

patches)

– Lymphoid organ (spleen, lymph nodes, tonsils, bone marrow, adenoids and appendix)

Professional phagocytes

Professional phagocytes

Cells and Tissues Involved in Defense Mechanisms Acute bacterial infection Neutrophils ↑ Inflammation and allergic reaction Basophils ↑ Eosinophils ↑ Allergic reaction and parasitic

infestation Eosinophils ↑

Cell Communication

Trauma or invasion Communicate to immediate

environment and to other cells How do they communicate?

– Surface Receptors (eyes and ears)– Cytokines (Voice)– Adhesion molecules (hands)

Cell Communication

Surface receptors– Are integral membrane proteins– Bind specific compound or compounds– Molecule binds to a particular receptor is

called a ligand for that receptor– Internal portion of the receptor becomes

modified– Elicit response (chemotaxis)

Cell Communication Cytokines

– Low molecular weight proteins– Made by certain cells

• lymphokine (cytokines made by lymphocytes)

• monokine (cytokines made by monocytes)

• chemokine (cytokines with chemotactic activities)

• interleukin (cytokines made by one leukocyte and acting on other leukocytes).

Cell Communication Cytokines

– Communicate with other cells (chemical messengers)

– Short-lived– Very powerful– Act at extremely low concentration– Act locally, regionally or systemically

Cell Communication Cytokines

– Cytokines binds to cytokine receptors• Induce a change such as growth

(different kind of leukocytes, precursors of blood cell and mast cells)

• Differentiation (different leukocytes)

• Movement

• Cell death

Cell Communication Cytokines

• See Table 15.3• Chemokines• Colony stimulating factors• Interferons• Interleukins• Tumor necrosis factor

Direct immature leukocytes into the appropriate maturation pathway

Cell Communication

Cytokines: Groups of cytokines work together– Chemokines

• 50 different varieties• Chemotaxis of immune cells

– Colony-stimulating factors (CSFs)• multiplication and differentiation of

leukocytes

Cell Communication Cytokines

– Interferons (IFNs)• Glycoproteins• Control viral infections• Gamma-interferon helps regulate the

function of the cells involved in inflammatory response (phagocytes)

• Modulates certain responses of adaptive immunity

Cell Communication

Cytokines– Interleukins (ILs)

• Produced by leukocytes• At least 18 interleukins been studied• Innate and adaptive immunity

– Tumor necrosis factors (TNFs)• TNF- alpha produced by macrophages

plays an instrumental role in initiating the inflammatory response

• Programmed cell death or appoptosis (destroy self-cells without eliciting inflammation)

Cell Communication

Cytokines– Groups of cytokines work together

• Pro-inflammatory cytokines contributes to inflammation (TNF-alpha, IL-1, IL-6)

• Promotion of antibody responses (IL-4, IL-5, IL-10 and IL-14)

• Promotion of T cell activity (IL-2, and INF-gamma)

Cell Communication

Adhesion molecules– Allow cells to adhere to other cells– Ex. Endothelial cells bind to phagocytic

cells grab cells– Slow down phagocytic cell movement– Allow cells to adhere to other cells and

deliver cytokines or other compounds

Cell Communication Sensor Systems

– Present within blood and tissues– Senses tissue damage and microbial

invasion– Either directly destroy the microbes – Or recruit other components of the host

defenses E.g. Toll-like receptors Complement system

Sensor systems

Toll-like Receptors (TLRs) Figure 15-6 At least 10 TLRs identified Each recognizes a distinct compound or

groups of compounds E.g. TLR-2 recognizes peptidoglycan TLR-4 is triggered by lipopolysacchride

Sensor systems

Toll-like Receptors (TLRs) Other bacterial structures or compounds that

activate these receptor Flagellin Bacterial nucleotides What do they do?

Sensor systems

Toll-like Receptors (TLRs)– What do they do?– Transmit signals to the nucleus of the

host cells to alter the expression of certain genes

– E.g. – Lipopolysaccharide → triggers a TLRs of

monocytes and macrophages → chemokines attracts additional phagocytes

Sensor Systems• The Complement System (Figure 15.7 and

15.8)– Series of about 20 proteins

• Circulate in the blood and tissue fluids• C1 through C9 are the major components of

this system• Routinely circulate in an inactive form• once activated a cascade of events occurs• one event triggers the next event• Activated forms have specialized functions to

quickly remove and destroy the offending material

Compliment system

Regulatory proteins halt the process inactivate C3b

Regulatory proteins are not associated with microbial surfaces

C3a and C5a→induce changes in endothelial cells and mast cells →↑ vascular permeability

C5a attracts phagocytes

C3b binds to foreign material called opsonized, C3b called opsonins

Membrane attack complex

Sensor Systems Complement (continued)

– Two pathways of activation• Classical pathway part of specific immunity• Alternate pathway part of innate immunity

– Final common pathway• Ultimate function is lysis of a bacteria by the

membrane attack complex• C3a and C5a are the anaphylatoxins

Sensor Systems Complement System

– Classical pathway inflammation• Antigen-antibody complexes red

flag portion of the antibody interact with complement component in turn C3a and C5a induce changes in endothelial cells increase permeability associated with inflammation

• C5a is a potent chemoattractant

Sensor Systems Complement System

– Alternative pathway • C3b binds to foreign material is said opsonized

(prepared for eating)

• Phagocytes more easily destroy C3b coated cells as they have C3b receptors

• C3a and C3b cause phagocytes to produce more receptors for C3b

Sensor Systems Complement System

– Lactin pathway Lysis of foreign cells

• Mannan-binding lectins (MBLs), a polymer of mannose found on microbial cells MBL binds to a surface and interact with compliment component initiating classical pathway C5b, C6, C7, C8 and C9 forms doughnut shaped structure called membrane attack complex (MAC) creates pores in membrane, disrupting the integrity of the cell

Complement System C3a and C5a→induce changes in endothelial

cells and mast cells →↑ vascular permeability C5a attracts phagocytes C3b binds to foreign material called

opsonized C3b called opsonins Regulatory proteins halt the process

inactivate C3b Regulatory proteins are not associated with

microbial surfaces

Phagocytosis

Innate Immunity Phagocytosis (Figure 15.9)

– Chemotaxis- phagocytic cells are recruited

– Recognition and adhesion• Direct: mannose sugar found on the surface

of certain bacteria and yeast• Indirect: binding opsonized (C3b)

– Engulfment• phagocyte engulf the invader forming a

membrane-bound vacuole called phagosome

Innate Immunity

• Phagocytosis • Fusion of the phagosome with lysosome• Phagosome transported towards lysosome

forming phagolysosome

• Lysosome a membrane bound body filled with

various digestive enzymes

Innate Immunity• Phagocytosis • Destruction and digestion

• Oxygen dependent mechanisms oxidized sugars via TCA cycle

• Highly toxic oxygen by-products such as superoxide, hydrogen peroxide and hydroxyl radicals are produced

• Once oxygen is depleted fermentation anaerobic metabolism starts

• Metabolic pathway switches to lactic acid production lowering pH

• Enzymes degrade bacterial cell wall and other components of cells

Innate Immunity

Phagocytosis Exocytosis

– Digested material is expelled to external environment

Innate Immunity

Neutrophils – First to arrive during an immune response– Involved in inflammation– Inherently have more killing power than

macrophages

Innate Immunity Macrophages

– Located throughout the body (Kupffer cells, alveolar macrophages, etc.)

– Produce cytokines– Interact with T helper cells – activated

macrophages– Help form granulomas (Macrophages, Giant

cells and T-helper cells)

Innate Immunity

Inflammation-A coordinated response to invasion or damage– Types of inflammation– Cardinal signs of acute inflammation– Factors that initiate the inflammatory

response– Process of acute inflammation– Outcomes of inflammation

Innate Immunity

Inflammation– Definition

• When a tissue have been damaged, such as when an object penetrates the skin or when microbes produce toxic compound, a coordinated response called the inflammatory response, or inflammation occurs

– Types of inflammation• Acute

– Immediate and short lived response (neutrophils)• Chronic

– Delayed and long lived response (macrophages, giant cells, T cells forms granulomas)

Innate Immunity

Signs of inflammation– Swelling– Redness– Heat– Pain– Loss of function (sometimes present)

Intension of the inflammatory process– limit damage and restore function

Innate immunity Inflammation

– Factors that initiate the inflammatory response

• Microbial products– Lipopolysaccharide, flagellin, bacterial

DNA trigger toll-like receptors

Innate immunity Factors that initiate the inflammatory

• Microbial cell surface– Trigger complement cascasde

» leading to production of C3a and C5a» Stimulate changes associated with

inflammation– Complement component also induces

mast cells to release various proinflammatory cytokines

Innate immunity Factors that initiate the

inflammatory• Tissue damage

– Activate two enzymatic cascades

»Coagulation cascade results in blood clotting and catch microbe in a clot too

»Bradykinin increases vascular permeability, dilates blood vessels, contracts non-vascular smooth muscle, and causes pain

The inflammatory process

The inflammatory process

Innate Immunity The acute inflammatory response

(Figure 15.10)– Two components

• Vascular component–Vasodilation- produces redness and

heat–Increased vascular permeability -

produces swelling

Innate Immunity

The acute inflammatory response (Figure 15.10)– Two components

• Cellular component–Cell recruitment–Phagocytosis

Innate immunity

Inflammation– Outcomes of acute inflammation

• Resolution• Abscess formation• Scarring• Chronic inflammation

Innate immunity

Inflammation– Systemic response is life threatening– Enzymes and toxic products within

phagocytic cells can damage healthy tissues

– Inflammation in brain and spinal cord can be life threatening

Innate immunity Septic shock: Gram-negative bacteria → endotoxins→

proinflammatory cytokines →activate complement cascade and clotting cascade →results in rapid decrease in blood pressure → shock

Clot plugs the capillaries of vital organs e.g. liver, lung, brain etc cutting blood supply

Innate immunity Apoptosis

– Mechanism of eliminating dead self-cells without evoking an inflammatory response

– Cell suicide– Dying cells undergo changes

• Shape changes• Enzyme cut the DNA• Portions of the cells bud off• Cell shrink

Innate Immunity

Fever– one of the strongest indications of

infectious disease– the hypothalamus regulates our normal

body temperature in a narrow range• 98.6ºF or 37 ºC

– central temperature receptors and peripheral temperature receptors

Innate Immunity

Fever – Cytokines and other fever-inducing

substances are called pyrogens

– Fever-inducing cytokines body makes it e.g. IL-1 and TNF (endogenous pyrogens)

– Bacterial endotoxins, cell wall Lipoplysaccharide are (exogenous pyrogens)

Innate Immunity Fever

– microorganisms can cause the body to respond by changing the “set point”• components of microorganism attach to

phagocytic cells• phagocytic cells release interleukin-1• interleukin-1 travels via the blood to the

hypothalamus• the hypothalamus responds by raising

body temperature

Innate Immunity Fever

– inhibits pathogens by:• increasing body temperature above the

optimal temperature for growth of microorganisms

–enzymes are inactivated• activating and speeding a number of

body defenses–there are many examples

Innate Immunity

Fever– Examples of beneficial effects of fever

• enhance inflammation• increase killing by phagocytes• release of chemo-attractants of

neutrophils• activation and replication of lymphocytes• increase production of antibody and

interferon• decrease host’s ability to absorb iron