Nonspecific Defenses of the Host

 

Introduction

 

1. The ability to ward off disease through body defenses is called resistance.
2. Lack of resistance is called susceptibility.
3. Nonspecific resistance refers to all body defenses that protect the body against any kind of pathogen.
1. First Line of Defense

                                                    i.     Skin

                                                   ii.     Mucous membranes

2. Second line of defense

                                                    i.     Inflammation

                                                   ii.     Phagocytosis

                                                 iii.     Complement

                                                 iv.     Interferons

                                                  v.     Fever

4. Specific resistance (immunity) refers to defenses (antibodies) against specific microorganisms.
1. Third line of defense

                                                    i.     Immunity                                                                                      

 

Skin and Mucous Membranes

 

Mechanical Factors                                                                              

  

1.     The structure of intact skin and the waterproof protein keratin provide resistance to microbial invasion.

2. Some pathogens, if present in large numbers can penetrate mucous membranes. 
3. The lacrimal apparatus protects the eyes from irritating substances and microorganisms.
4. Saliva washes microorganisms from teeth and gums.
5. Mucus traps many microorganisms that enter the respiratory and gastrointestinal tracts; in the lower respiratory tract, the ciliary escalator moves mucus up and out.
6. The flow of urine moves microorganisms out of the urinary tract, and vaginal secretions move microorganisms out of the vagina.

    

Chemical Factors

 

1. Sebum contains unsaturated fatty acids, which inhibit the growth of pathogenic bacteria.  Some bacteria commonly found on the skin can metabolize sebum and cause the inflammatory response associated with acne.
2. Perspiration washes microorganisms off the skin.
3. Lysozyme is found in tears, saliva, nasal secretions, and perspiration.
4. The high acidity (pH 1.2-3.0) of gastric juice prevents microbial growth in the stomach.
5. Transferrins bind iron.
6. Normal microbiota prevent the growth of many pathogens.

 

    

Normal Microbiota and Nonspecific resistance

 

1.     Normal microbiota change the environment, which can prevent the growth of pathogens. 

 

 

 

Phagocytosis

 

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

2.     Phagocytosis is performed by phagocytes, certain types of white blood cells or their derivatives.

 

Formed Elements in Blood

 

1.     Blood consists of plasma (fluid) and formed elements (cells and cell fragments).

2.     Leukocytes (white blood cells) are divided into three categories: granulocytes (neutrophils, basophils, and eosinophils), lymphocytes, and monocytes. 

3.     During many infections, the number of leukocytes increases (leukocytosis); some infections are characterized by leukopenia (decrease in leukocytes).

4.     Phagocytes are activated by bacterial components (for example, lipid A) and cytokines.

 

Actions of Phagocytic Cells

 

1.     Among the granulocytes, neutrophils are the most important phagocytes.

2.     Enlarged monocytes become wandering macrophages and fixed macrophages.

3.     Fixed macrophages are located in selected tissues and are part of the mononuclear phagocytic system.

4.     Granulocytes predominate during the early stages of infection, whereas macrophages predominate as the infection subsides.

 

The Mechanism of Phagocytosis

 

1.     Chemotaxis is the process by which phagocytes are attracted to microorganisms.

2.     The phagocyte then adheres to the microbial cells; adherence may be facilitated by opsonization – coating the microbe with serum proteins. 

3.     Pseudopods of phagocytes engulf the microorganism and enclose it in a phagocytic vesicle to complete ingestion.

4.     Many phagocytized microorganisms are killed by lysosomal enzymes and oxidizing agents.

 

Microbial Evasion of Phagocytosis

 

1.     Some microbes are not killed by phagocytes and can even reproduce in phagocytes. 

2.     Evasion mechanisms include M protein, capsules, leukocidins, membrane attack complexes, and prevention of phagolysosome formation

 

Inflammation

 

1.     Inflammation is a bodily response to cell damage; it is characterized by redness, pain, heat, swelling and sometimes the loss of function.

2.     Functions:

a.     To destroy and remove pathogens and debris.

b.     To confine pathogens; prevent spread of infection.

c.     To repair or replace damaged tissue (sets stage for wound repair).

 

Vasodilation and Increased Permeability of Blood Vessels

 

1.     The release of histamine, kinins, and prostaglandins causes vasodilation and increased permeability of blood vessels.

a.     Histamine causes vasodilation, increases vascular permeability, and is chemotactic for eosinophils.

b.     Kinins cause clotting, vasodilation, increased vascular permeability, and pain.

                                                    i.     Factor XII (Hageman Factor) is activated by endotoxin, uric acid, calcium pyrophosphate, and basement membrane proteins (collagen).

                                                   ii.     XIIa activates Factor XI to initiate clotting and cleaves prekallikrein to kallikrein.

                                                 iii.     Kallikrein converts plasminogen to plasmin, HMW kininogen to bradykinin, and cleaves C5 to release C5a and C5b.

                                                 iv.     C5a stimulates inflammation

c.     Arachidonic acid metabolites

                                                    i.     Cyclooxygenase products

1.     Prostaglandins:

2.     PGE₂ increases vascular permeability, sensitizes to pain, and is pyrogenic.

3.     PGI’s cause vasodilation.

4.     Thromboxanes cause vasoconstriction.

                                                   ii.     Lipooxygenase products

1.     Leukotrienes are produced by mast cells, basophils, macrophages, and eosinophils.

2.     LTB4 (SRS-A) is chemotactic, causes vasoconstriction, and increases endothelial stickiness.

3.     LTC and LTD cause bronchoconstriction, allergy, increase vascular permeability.

2.     Blood clots can form around an abscess to prevent dissemination of the infection.

 

Phagocyte Migration and Phagocytosis

 

1.     Phagocytes have the ability to stick to the lining of the blood vessels (margination).

2.     They also have the ability to squeeze through blood vessels (emigration).

3.     Pus is the accumulation of damages tissue and dead microbes, granulocytes, and macrophages.

 

Tissue Repair

 

1.     A tissue is repaired when the stroma (supporting tissue) or parenchyma (functioning tissue) produces new cells.

2.     Stromal repair by fibroblasts produces scar tissue.

 

Fever

 

1.     Fever is an abnormally high body temperature produced in response to a bacterial or viral infection.

2.     Bacterial endotoxins and interleukin-1 can induce fever.

3.     A chill indicates a rising body temperature; crisis (sweating) indicates that the body’s temperature is falling.

 

Antimicrobial Substances

 

The Complement System

 

1.     The complement system consists of a group of serum proteins that activate one another to destroy invading microorganisms.  Serum is the liquid remaining after blood plasma is clotted.

2.     Classical Pathway

a.     C1 binds to antigen – antibody complexes.

b.     C2 and C4 associate and this acts as C3 convertase.

c.     C3 is cleaved to C3a and C3b

d.     C3a stimulates inflammation

e.     C3b opsonizes and cleaves C5 to produce C5a and C5b

f.      C5a stimulates inflammation

g.     C6, C7, C8, and C9 associate to form the MAC, which causes cell lysis. 

3.     Alternative Pathway

a.     Factor B, factor D, factor P, and C3b bind to certain cell wall polysaccharides (i.e. peptidoglycan) to activate C3b.

b.     C3 undergoes autolysis to provide C3b, which is very unstable and has a short half-life.

c.     Factor B stabilizes the C3b.

d.     Factor D cleaves factor B to produce a C3b-factorBb molecule; this acts as C3 convertase.

e.     Properdin, Factor P, stabilizes the C3b-factorBb C3 convertase.

4.     The Lectin Pathway

a.     Phagocytosis by macrophages induces release of chemicals that stimulate the liver to produce carbohydrate binding proteins (lectins).

b.     One such lectin, mannose-binding lectin (MBL) binds to mannose on bacterial cells walls and on some viruses.

c.     MBL opsonizes and activates C2 and C4 to activate C3.

5.     C3 activation can result in cell lysis, inflammation, and opsonization.

6.     Complement is deactivated by host-regulatory proteins and water.

7.     Complement deficiencies can result in an increased susceptibility to disease.

 

Interferons

 

1.     Interferons (IFNs) are antiviral proteins produced in response to viral infection.

2.     There are three types of human interferon:  alpha-IFN, beta-IFN, and gamma-IFN.  Recombinant interferons have been produced.

3.     The mode of action of alpha-IFN and beta-IFN is to induce uninfected cells to produce antiviral protein (AVPs) that prevent viral replication.

4.     Interferons are host-cell-specific but not virus-specific.

5.     Gamma-IFN activates neutrophils and macrophages to kill bacteria.

6.     Gamma IFN also activates Th1 cells, which stimulate cell mediated reactions.

7.     Lack of gamma-IFN results in activation of Th2 cells, which are humoral mediators

8.     Very high levels of gamma-IFN stimulates NK cells and CTLs.