Innate Immunity Introduction

NONSPECIFIC DEFENSE RESPONSES - 1st & 2nd LINES OF DEFENSE

 [Nonspecific defenses are general attack responses; the response is the same, no matter who the "invader" is.]

 I.                The Body's First Line of Defense:  Structural, Mechanical, & Chemical Defense Responses on Internal & External Body Surfaces:

 A.   Skin & mucous membranes (epithelial surface tissues)

1.       Cells are tightly joined together, preventing bacteria from invading deeper tissues.

 2.      Sloughing of dead cells prevents microbial population from continually increasing. 

 3.      The protein, keratin, fills the cells in the outer layers of the epidermis.  These cells then contain little water, making the skin dry & inhospitable to many microbes. 

 4.      Ciliated, mucous membranes  (ex. in the respiratory tract) trap microbes, dust etc. in mucous & cilia move mucous toward mouth, where it is coughed up and swallowed.

 B.    Normal flora - Normal bacterial inhabitants of the skin, gut, & vagina - the "natives" outcompete the "foreigners" for resources.  Also, some normal bacteria produce acid from sugar fermentation, creating an acidic environment that keeps other populations in check (ex. lactic acid produced by bacteria in the vagina keep the yeast Candida albicans under control).

 In the vagina, low estrogen concentrations in prepubertal and postmenopausal women result in a decrease in bacterial numbers in the vagina; this can lead to vaginal yeast infections.  Yeast infections can also result from antibiotic treatments (broad spectrum antibiotics kill the pathogen and the normal flora) & douching.

 C.    Movement of body fluids dislodges microbes. Ex. urine, tears, saliva.  Peristalsis in digestive tract causes food & digestive juices to sweep microbes away.   (Urine itself is not microbiocidal!)

 D.   Secretions: 

 1.       Tears, perspiration, & saliva contain lysozyme, an enzyme that destroy the bacterial cell wall.  Lysozyme is especially destructive to G(+) bacteria because they lack an outer membrane.

 2.      Perspiration also contains high concentrations of salt, creating a hypertonic environment. 

3.      Bile, produced by the liver, also disrupts the bacterial cell wall.  Bile is secreted into the small intestine to aid in the digestion of lipids.  It passes from the small intestine into the colon in feces; the bacterium E. coli , which is part of the normal flora of the colon, is resistant bile.  Remember that bile salts are an important ingredient in some selective media that select for G(-) bacteria and against G(+) bacteria.

 4.      Hydrochloric acid produced in the stomach (pH of the stomach is 2!).

 5.      Fatty acids are contained in the oil secreted from oil glands in the skin.  It makes the skin slightly acidic.

 II.            The Body’s Second Line of Defense – What Happens Once the Microbes Get Past the Surface Defenses:          

     First a little about the types of white blood cells (called leukocytes): 

a.     macrophages - phagocytic

b.     eosinophils - phagocytic

c.      neutrophils - phagocytic

d.     basophils - release histamine; involved in the inflammatory response.

e.     lymphocytes - 3 types:  B cells, T cells, Natural Killer cells.                                                                        

(Be careful not to get the terms leukocyte and lymphocyte confused!)

A.   Natural Killer Cells - Type of lymphocyte (type of wbc); most lymphocytes are involved in specific defense responses (ex. B & T lymphocytes).  NK cells are unlike other lymphocytes in that they lack antibodies & antigen receptors (we’ll talk about these under the specific defenses); they are like a specific type of T lymphocyte called a killer T cell in that they release perforins [chemicals that cause lysis of the bacterium - they perforate or punch holes in the cell envelope of bacterium].

B.   Phagocytic White Blood Cells (Phagocytes) - Phagocytosis occurs in 3 phases:

                  (remember CAI)

1.    Chemotaxis - the chemical attraction of phagocytes to a particular location; chemotactic chemicals that attract phagocytes include bacterial toxins components of damaged tissue cells, complement proteins, & antibodies.

2.    Adherence or Attachment - Because of certain microbial defenses, adherence of the phagocyte cell membrane to the surface of the microbe may be difficult (for example some bacteria produce a slimy outer capsule that makes them slippery).  Opsonization of microbes by complement proteins and antibody facilitates phagocytosis.

 3.    Ingestion - The phagocyte engulfs the microbe with its cell membrane.  The engulfed microbe moves into the cytoplasm of the phagocyte inside a vesicle (sac); these vesicles fuse with lysosomes containing digestive enzymes; phagocytes include the wbc’s such as neutrophils, eosinophils, & macrophages; phagocytes circulate within blood vessels, & are also located in the lymph nodes, spleen, liver, kidneys, lungs, joints, skin, red bone marrow, & brain.

 Fever - When phagocytes ingest certain bacteria, the phagocytes secrete a type of interleukin, which circulates to the hypothalamus & causes it to secrete prostaglandins; these chemicals "reset" the hypothalamic thermostat at a higher temperature; temperature-regulating mechanisms (vasoconstriction, increased metabolism, shivering) act to bring the core body temperature to this new setting. [Aspirin, ibuprofen, & acetaminophen inhibit the synthesis of prostaglandins.]  A low grade fever has a beneficial effect on the body: 

1.)   It inhibits the growth of some microbes.

2.)   It increases the heart rate so that white blood cells, etc. are delivered to infection sites more rapidly.

3.)   B cell & T cell proliferation (division) increases.

4.)   Heat speeds up chemical reaction rates.

 High grade fevers are dangerous - they can denature the body's own enzymes & other proteins. 

 What’s low grade?  What is considered low grade in infants is much lower in adults.  This is due to a baby’s higher surface area to volume ratio.  Basically, a baby has more surface area compared to her volume than an adult does.  So, it’s easier for heat to reach the skin and dissipate into the air.  Heat does not dissipate as easily from an adult’s body (too much volume for it to move through) and so it does more damage to internal organs.

D.   Interferon (IFN) - Interferons are proteins that are produced by certain viral-infected cells (particularly macrophages).  Once interferons are released from viral-infected cells, they diffuse to neighboring uninfected cells & bind to their surface protein receptors.  This binding induces the uninfected cells to synthesize antiviral proteins that interfere with or inhibit viral replication.  In other words, interferons serve as a red flag to warn uninfected cells that there's a "stranger among us" & the uninfected cells take action to protect themselves. 

Certain interferons also enhance the activity of phagocytes & natural killer cells.

Certain interferons also inhibit cell growth & suppress tumor formation.  Ex.  Alpha-IFN is approved in the U.S. for treating Kaposi's sarcoma, a cancer that often occurs in patients infected with HIV; it is also used for treating genital herpes & hepatitis B & C.

E.    Complement System - When certain microorganisms invade the body, about 20 complement proteins in blood plasma & on cell membranes interact as a system.  When activated, these proteins "complement" or enhance certain immune, allergic, & inflammatory reactions; therefore, the complement system enhances the effectiveness of both nonspecific & specific defense responses.  Complement proteins respond to the binding of antibodies to the cell membrane of the invading microbe; the complement proteins are activated one after another in a "cascade" of reactions [one reaction catalyzes the next.]  These reactions have the following results:  (use the acronym COLA to remember them!)

1.    Chemotaxis - They act as chemotactic chemicals to attract phagocytes to the scene.

2.    Opsonization - Complement proteins bind to the surface of the microbe & then interact with receptors on phagocytes to promote phagocytosis.  In this way complement proteins give macrophages a "foot hold."

3.    Lysis - Other complement proteins kill the microbe by causing lysis.

4.    Activation of Inflammatory response (See below).

 F.    Inflammatory Response - Many cells, the complement system, & other substances take part in this response.  This response is a series of events that destroys invaders & restores damaged tissues to normal.  The 4 major symptoms of inflammation are (in latin) Rubor, Calor, Tumor, Dolor & Functio laesa, which are redness, heat, swelling,  pain & loss of function (think about what happens when a bee stings you or a cut gets infected).  Inflammation is a nonspecific defense - the response of a tissue to a cut is similar to the response that results from a burn, radiation, or microbial invasion.  The inflammatory response involves the following events: 

1.  Vasodilation & Increased Permeability of Blood Vessels -

¨       Vasodilation is an increase in diameter of the arterioles.  Arteriole dilation enables white blood cells & other substances to more easily penetrate the tissues. Increased permeability means that an increased amount of material is allowed to pass out of the blood vessels. 

¨       Blood vessels dilate & become more "leaky" due to the release of histamine by basophils, which are activated by the complement system.  Prostaglandins, released by damaged cells, intensify the effects of histamine.

¨       Within minutes after injury, dilation & increased permeability of blood vessels produces heat, redness, & swelling. 

¨       Warmth & redness occurs from the large amount of warm blood flowing through the area.  Temperatures will continue to rise due to the release of heat energy from chemical reactions (increased metabolic activity). 

¨       Fluid seeping from "leaky" capillaries causes swelling. 

¨       Pain can result from injury of nerve fibers, from irritation by toxins produced by microbes, from increased pressure due to swelling, or from prostaglandin release.

2.  Phagocytosis

¨       Fluid seeping from "leaky" arterioles causes local swelling & delivers more complement proteins to the tissues (remember, proteins are large molecules - they would normally stay in the blood vessels & couldn't get into the interstitial spaces between cells). 

¨       Phagocytes, following increased concentrations of complement proteins to affected tissues, engulf foreign invaders & damaged cells. 

¨       Eventually phagocytes die.  Within a few days a pocket of dead phagocytes & damaged tissue forms (called pus). 

3.  Tissue Repair

¨       Platelets initiate clotting mechanisms, help wall off the pathogen, & help repair tissues.