The Establishment of Disease

Fig. 18.7

Lecture 24 Resistance to Disease

{Hosts defense barriers} •  A. Nonspecific Resistance- Chapter 20

(Innate immune Response) – The body defenses that protects the body

against any kind of pathogen. •  B. Specific Resistance- Chapter 21

(Acquired immune Response) – The body acquires these defenses against

specific microorganisms. •  [Note: up to 10% of our genes may help

build or operate body defenses. ]

Relationship - Host Resistance and Disease

Fig. 19.1

Innate

Acquired

Nonspecific Resistance

•  First Line of Defense Mechanical barriers and –  Intact skin – Mucus membranes and their secretions

Chemical barriers – Acidity in GI and vaginal tracts – Defensins, lysozyme, interferons

Microbiological Barriers – Normal microbiota

Skin •  Skin tough

environment for microbial growth –  Skin consists of two

distinct layers of cells: dermis(inner) and epidermis (outer).

–  Top layer of epidermal cells is dead and contains a protective protein called keratin.

Skin continued

•  Dry, except for moist areas like underarms and genital areas

•  Antimicrobial compounds are produced by the skin – Sebaceous (oil) gland produce an oily

substance called sebum. • Sebum unsaturated fatty acid and

lactic acid • Lactic acid - keep skin pH between 3

and 5. • Sebum prevents hair from drying and

becoming brittle.

Skin continued

•  Sweat glands produce perspiration which contains lysozyme and other enzymes that destroys the cell walls (peptidoglycan) of bacteria.

•  Skin has high salinity (saltiness).

Mucous membranes

•  Mucous membrane consists of an epithelial layer and an underlying connective tissue layer. – Less protection than the skin – Epithelial layer secretes a fluid call

mucus that prevent epithelial cells from drying out.

–  Mucins are the protein components of the mucus protecting the internal epithelial layers of our body.

Mucous membranes continued

•  Mucus layer in respiratory trap the bacteria

•  Ciliary epithelial cells move mucus blanket toward the throat - " ciliary escalator”

Normal microbiota

•  Normal microbiota prevent the colonization of pathogens by competitive exclusion.

•  Normal microbiota - coated surfaces prevent pathogenic microbes from colonizing

Normal microbiota

•  Normal microbiota change the body’s environment.

•  Examples: – A. The female vagina area is normally

acidic. • This low pH prevents growth of

Canidida albicans - (Yeast infections). • Normal microbiota (Lactobacillus

species) ferments glycogen excreted in vagina to lactic acid.

Normal microbiota

•  Example: B. E. coli in large intestine.

• E. coli secretes proteins called bacteriocins - kills non-E. coli organisms.

• Results: They prevent the growth of Salmonella and Shigella.

Sites were bacteria are normally found.

Fig. 19.4

Interferons

•  Interferons (IFNs) are antiviral proteins produced in response to viral infections.

•  Three types of human interferon: – !-interferon – !- interferon – !- interferon

Interferon puts cells

in an antiviral

state

Fig. 20.10

Interferons

•  The mode of action of !-interferon and !- interferon is to induce uninfected cells to produce antiviral proteins that prevent viral replication.

•  !- interferon activated neutrophils to kill bacteria.

•  Note: interferons are host-cell specific but not virus-specific.

Nonspecific Resistance

•  Second Line of Defense – Phagocytic white blood cells –  Inflammation and fever – Natural Killer Cells – Complement system – Recognition of pathogen-associated

molecular patterns (PAMPs)

Phagocytic white blood cells

•  Phagocytosis is the ingestion of microorganisms or particulate matter by a cell.

•  Cells perform this function are called phagocytes. – Types of white blood cells and

derivatives of white blood cells.

Leukocytes (white blood cells)

•  Leukocytes (white blood cells) are divided into three categories: –  Granulocytes

•  large granules in their cytoplasm that can be seen under a light microscope after staining

•  neutrophils* –  stain pale lilac with a mixture of acidic and basic

dyes. •  basophils

–  stain blue-purple with basic dye methylene blue •  eosinophils*

–  stain red or orange with acidic dye eosin.

Agranulocytes

•  Agranulocytes: – Monocytes

• differentiate into Macrophages* •  * - phagocytes that are activated by

bacterial components (LPS, lipid A) and cytokines.

•  Lymphocytes: • key role in specific immunity.

Dendritic cells

•  Dendritic cells: –  Dendritic cells are present in tissues that are in

contact environment, mainly the skin (where they are often called Langerhans cells) and the inner lining of the nose, lungs, stomach and intestines.

–  Their main function is to process antigen material and present it on the surface to other cells of the immune system

–  Once activated, they migrate to the lymphoid tissues where they interact with T cells and B cells to initiate the adaptive immune response.

Leukocytes (White Blood Cells)

Leukocytes (White Blood Cells)

•  During many infections the number of leukocytes increase. Called leukocytosis.

•  Some infections are characterized by decrease in leukocytes - leukopenia.

The Lymphatic System

•  From the blood capillaries, some plasma filters into the surrounding tissue and enter the lymph capillaries. –  It is now called lymph.

•  Lymph returns to blood by larger vessels- lymphatics.

•  At certain point in the lymphatic system there are lymph nodes, through with the lymph flows. – Swollen lymph nodes are called buboes.

Relationship Cardiovascular and Lymphatic

System

The Human

Lymphatic System

Fig. 20.2

Actions of Phagocytic Cells

•  Blood - granulocyte most active phagocytotic cell is the neutrophils.

•  Tissue migration - involves monocytes that enlarge and develop into actively phagocytotic macrophages.

Phagocytotic Macrophages •  Types:

– wandering macrophages –  fixed macrophages (histiocytes)

located in certain tissues and organs of the body. •  Liver lungs •  nervous system bronchial tubes •  spleen lymph nodes •  red bone marrow •  peritoneal cavity surrounding abdominal

organs.

Mechanism of Phagocytosis

Mechanism of Phagocytosis

•  1. Chemotaxis •  Process by which phagocytes are attracted

to microorganisms. •  Microbe substances, tissue damage,

complement (will discuss later) will attract phagocytes.

Mechanism of Phagocytosis continued

•  2. Adherence –  Attachment of the phagocyte's plasma

membrane to surface of microorganism (or foreign material).

•  Can be inhibited by capsule polysaccharide, M protein of Streptococcus.

–  Adherence may be facilitated by antibodies and complement proteins binding. As group proteins are call opsonins

–  opsonization •  protein coating of the microbe with serum proteins.

Mechanism of Phagocytosis continued

•  3. Ingestion – Pseudopods of phagocytes engulf the

microorganism, – Microorganism enclosed in a

phagocytic vesicle (phagosome)

Mechanism of Phagocytosis

Fig. 19.5

Mechanism of Phagocytosis continued

•  4. Digestion – Phagosome enter the cytoplasm – Phagosome and lysosome fuse into

larger - phagolyosome. – Microorganisms are killed by lysosomal

enzymes and oxidizing agents. – Residual body containing indigestible

material moved toward cell boundary and discharge its waste outside the cell.

Mechanism of Phagocytosis

Fig. 19.5

Mechanism of Phagocytosis continued

•  Notes: the lysosomal enzymes do not kill all microorganisms – Some bacteria have enzymes that lyse

phagolysosomes •  Listeria monocytogenes •  Shigella flexneri

– Other bacteria prevent the fusion of phagosome with a lysosome or the acidification of digestive enzymes. •  Mycobacterium tuberculosis

Inflammation

•  Inflammation is a bodily response to cell damage –  It is characterized by redness, pain,

heat, swelling and sometimes the loss of function.

– Signs of inflammation: •  Ruber – red color from blood accumulation. •  Calor – warmth from heat of blood. •  Tumor – swelling from accumulation of

fluid. •  Dolor – pain from injury to the local nerves.

Inflammation •  Benefits

–  (1) It functions to destroy the injurious agent, if possible, and to remove it from the body.

–  (2) If destruction is not possible, it functions to limit the effects on the body by confining or walling off the injurious agent.

–  (3) If functions to repair or replace the tissue damaged by the injurious agent or its by-products.

Process of inflammation:

•  Divide into three stages: – Vasodilation and increased permeability

of blood vessels – Phagocyte migration and phagocytosis – Tissue repair

Vasodilation and increased permeability of blood vessels

•  Vasodilation is an increase in the diameter of blood vessels. –  At the site of tissue damage, chemical

mediators are produced. •  For example histamine

•  Results: –  Increase blood flow – Redness and heat associated with

inflammation.

Vasodilation and increased permeability of blood vessels

•  Increased permeability permits defensive substance in the blood to pass through the walls of the blood vessel and enter the injured area.

– Responsible for swelling (edema) of inflammation.

Vasodilation and increased permeability of blood vessels

•  Also delivers clotting elements of blood into injured area – Blood clots prevent microbe (or its

toxins) from spreading to other parts of body.

– Results in collection of pus - mixture of dead cells and body fluids.

– This focus of infection is called an abscess or boil.

Phagocyte migration and phagocytosis

•  Within an hour after the process of inflammation, phagocytes (granulocytes and macrophages) appear. – 1st, phagocytes stick to inner surface of

the lining of the blood vessels. • called margination.

– 2nd phagocytes begin to squeeze between the endothelial cells of the blood vessels to reach the damaged area. • Migration by amoeboid movement

call emigration.

Phagocyte migration and phagocytosis

– 3rd, after phagocytes engulf large number of microorganisms they eventually die. • Becomes part of pus at wound site.

Process of Inflammation

Inflamation

Fig. 20.6

Fever •  Fever is a systemic, (overall) response of

the body to injury. •  Fever is an abnormally high body

temperature produced in response to bacterial or viral infection.

–  A chill (shivering) indicates a rising body temperature,

–  Crisis (sweating) indicates that the body's temperature is falling.

•  Fever-producing substances are called pyrogens. –  Pyrogens produced by activated

macrophages, bacteria and viruses.

Fever example •  Bacterial endotoxins (LPS) induces

interleukin-1 production by macrophages.

•  Mechanism: ! Macrophage produces interleukin-1. ! Interleukin-1 released into bloodstream. ! Travels to hypothalamus of the brain. ! Interleukin-1 induces hypothalamus to

produce prostaglandins. ! Prostaglandins resets the body’s

thermostat to a higher temperature. ! Produces fever.

Natural Killer Cells

•  Natural killer cells a third type of lymphocyte.

•  They are cytotoxic lymphocytes that lyses cells displaying foreign antigens and do not display class I Major HistoCompatibility antigens (MHC proteins).

•  They kill virus-infected cells and tumor cells. – Proliferation stimulated by interleukin-2

Natural Killer Cells Fig. 19.7

The Complement System

•  Serum is the liquid remaining after blood plasma is clotted.

•  Complement system consists of ~30 serum proteins that activate one another to destroy invading microorganisms. – Complement is nonspecific because it

can be activated in response to any foreign cell.

The Complement System continued

•  Activated by: –  (1) The immune reaction of antibodies

to antigens. (Classical Pathway) –  (2) The direct interaction of certain

proteins with bacterial cell wall polysaccharides. (Alternative Pathway)

–  (3) The binding mannose-binding lectin to mannose residues on the pathogen surface (Lectin Pathway)

The Complement System continued

•  Key C3 convertase activation results in : –  Inflammation

• C3a and C5a • binds to mast cells, basophils and

platelets to trigger the release of histamine.

• C5a also functions as chemotactic factor that attracts phagocytes to the site of complement activation.

The Complement System continued

•  Key C3 convertase activation results in : – Cell lysis

•  Transmembrane channel formed by membrane attract complex C5a,C6- C9

– Opsonization •  C3b coat microorganisms and promote

attachment of phagocyte - opsonization.

The Complement System

Fig. 20.8

Pattern-Recognition Receptors on Phagocytes

• Pathogen-asociated molecular patterns (PAMPs)

• Includes bacteria carbohydrates, LPS,nucleic acid, peptidoglycan, lipotechoic acids N-formylmetionine and others. • TLR binding triggers synthesis and secretion of cytokines and other activation of host defense programs involved in both innate or adaptative immune responses. Arrays of transmembrane

proteins known as toll-like receptors (TLRs).