Definitions

Immunity refers to various defense mechanisms that the body uses to protect against environmental agents that are foreign to the body - microorganisms, pollen, insect venom, transplanted organs, etc. The cells and specialized molecules responsible for immunity constitute the immune system. An immune response is a coordinated effort by the cells of the immune system to eliminate foreign invaders and minimize the damage they cause. Substances capable of triggering an immune response (usually proteins or complex polysaccharides) are called antigens. Immunity can be either innate or acquired.

1. Innate Immunity - (Also called natural immunity) Some of the defense mechanisms of the immune system are active at birth, prior to exposure to infectious microbes or foreign substances, and serve as an immediate first line defense. Innate immune mechanisms are important for limiting the effects of acute infection and delaying the spread of microorganisms within tissues. One disadvantage of innate immunity is the fact that it is nonspecific - i.e., it cannot discriminate one foreign substance from another. Innate immune responses are uniform regardless of the nature of the antigenic stimulus. Further, innate responses are not enhanced by repeat exposure to the foreign substance, and they cannot adapt to microbial counter-strategies designed to evade them.

2. Acquired Immunity - Other immune responses are present in a dormant form at birth and are only activated after exposure to environmental antigens later in life. Unlike innate immunity, a brief delay occurs between the introduction of an antigen and acquired immune responses. However, acquired immune responses are highly specific to particular antigens and attacks on a microorganism can be varied making it difficult for microbes to completely evade immune defenses. The responses of acquired immunity are also increased in magnitude and speed by repeat exposure to an antigen. From the evolutionary standpoint, the development of acquired specific immunity is a more recent event. It is present in vertebrates but not invertebrates

Overview of Innate Immunity - Innate immunity is the first line of defense against infectious agents. It is nonspecific. It does not require prior contact with the infectious agent to be effective.

1. Exterior Defenses - Preventing microorganisms from gaining access to the body.
   1. Mechanical barriers - skin, mucous membranes of nasopharynx, lining of respiratory, GI and GU tracts.

   2. Low (acidic) pH of sweat, sebaceous secretions and stomach.

   3. Secretion of mucous by GI, GU, and respiratory tracts to trap microorganisms. The "washing" action of tears, saliva, and urine. Some of these secretions also contain non-specific inhibitors of bacterial growth such as lactoferrin, or lysozymes capable of degrading bacterial walls. The cough, sneeze, and vomiting reflexes also serve to rid the body of noxious or irritating substances.

   4. Competitive antagonism between normal bacterial flora within the aerodigestive tracts and the skin and potential pathogens.

   
   

2. Inflammation - The inflammatory response is one of the body's most important innate defense mechanisms. It is a non-specific physiologic reaction of vascular connective tissue to injury and microbial invasion. The inflammatory process can be divided into two sequential steps: (1) a Vascular Phase - dilation and increased permeability of blood vessels with the accumulation of fluid and cells at the site of injury; (2) a Cellular Phase - the activation of specialized blood and connective tissue cells that destroy or wall off injurious agents and clear debris so that tissue repair can take place.

   Circulating blood cells important to inflammation include neutrophils, basophils, eosinophils, lymphocytes, monocytes, and platelets. Other connective tissue cells involved in inflammation are mast cells, macrophages, and fibroblasts.

   Inflammation can be an acute process lasting from minutes to days, or it can be chronic. In the skin, inflammation is recognized by the presence of redness, swelling, heat, and pain. The inflammatory response is closely intertwined with acquired immunity, hemostasis, and the process by which tissues repair themselves following injury. Without inflammation and repair, infections would go unchecked and wounds would never heal.

   1. Inflammation is mediated by chemical factors at the site of tissue injury. The vascular and cellular phases of the inflammatory response are dependent on a series of chemical mediators, acting together or in sequence, that are released or activated by microbial invasion and tissue injury. Some of these substances are present in the plasma. Others are released by mast cells, macrophages, platelets, and some white blood cells.

      Plasma derived mediators of inflammation:

      1. Complement - A family of over 20 complex proteins which are synthesized mainly in the liver and circulate in the plasma and other extracellular fluids in an inactive form. When complement is exposed to microorganisms, or other foreign substances, a series of enzymatic chain-reactions occur which convert them into biologically active molecules. Complement can be activated by direct contact with various components of microorganisms, as well as by antigen-antibody complexes.

         Nomenclature of the Complement System: Components of complement present in the plasma are numbered C1 thru C9. When a specific complement molecule is enzymatically split during the process of activation, the larger fragment gets the designation "b" and the smaller "a". E.g., activation of the C3 component of complement yields C3a + C3b. The remaining components of complement are co-factors involved in the regulaton of C1-C9 activation (e.g., properdin P, factors B and D, C3 convertase, etc.)

         Biologic Functions of Activated Complement: Figure 1. - Complement

         • Anaphylatoxins: Three forms of activated complement, C3a, C4a, and C5a, cause the release of potent vasodilators from mast cells initiating the vascular phase of inflammation.

         • Opsonization: The C3b component of activated complement has the ability to bind to the surface of some bacteria. The complement coated bacteria are then more easily engulfed and destroyed by white blood cells and macrophages. The coating of bacteria is called opsonization, and the engulfment of these bacteria is called phagocytosis. Some bacteria have evolved a defense against opsonization by surrounding themselves with a mucopolysaccharide capsule. These "encapsulated" bacteria are more resistant to phagocytosis.

         • Chemotaxis: C3a and C5a are also important to the cellular phase of inflammation because they attract WBC's and macrophages to sites of injury. At the site of tissue injury, complement ads in activating phagocytic cells to clear infectious organisms.

         • Membrane Lesions: Several components of activated complement (C5b, C6, C7, C8, C9) combine on the surface of some microorganisms to form pore-like structures called Membrane Attack Complexes (MAC's). Large numbers of membrane attack complexes literally punch holes in the surface of microorganisms leading to cell rupture and death.

         • Certain components of activated complement are directly toxic to some microorganisms.

      2. Kinins - These are a group of plasma proteins that form a potent vasodilator called bradykinin. Precursors of bradykinin include prekallikrein and high-molecular weight kinogen (HMWK). They are converted to bradykinin by activated Hageman Factor which is formed when tissues are injured. (Hageman Factor is Factor XII in the intrinsic pathway of the coagulation cascade) Bradykinin also contributes to the pain that frequently accompanies inflammation.

      Cell derived mediators of inflammation: Some of these substances are pre-formed by inflammatory cells and can be immediately released at the site of injury. Others are synthesized after cells have been exposed to an injurious agent.

      1. Histamine and Serotonin - These substances are stored in the cytoplasmic granules of mast cells, basophils, and platelets. They are potent vasodilators that augment the inflammatory response by increasing vascular permeability.

      2. Nitric Oxide - Reactive nitrogen intermediates such as nitric oxide are produced by endothelium (cells lining blood vessels) and phagocytic cells such as macrophages. This substance is a potent vasodilator.

      3. Prostaglandins and Leukotrienes - This family of compounds are synthesized from arachidonic acid - a twenty carbon fatty acid, found in most cell membranes. Prostaglandins and leukotrienes are produced mainly by WBC's and injured cells. They exert their effects locally before being rapidly degraded. Prostaglandins are vasodilators and also produce fever and pain. Some leukotrienes act as chemotactic agents, others contribute to increased vascular permeability.

      4. Cytokines - An important group of small molecular weight polypeptides that are produced by lymphocytes, macrophages, and other connective tissue cells. The physiologic function of cytokines is to regulate growth and differentiation of blood, lymphoid, and connective tissue cells. They also help to coordinate many aspects of innate and acquired immunity as well as wound healing and hemostasis.

         From the standpoint of inflammation, two important cytokines are Interleukin-1 (IL-1), and Tumor Necrosis Factor (TNF). They help activate leukocytes and other inflammatory cells and increase vascular permeability within injured tissues. Both also help induce the fever, fatigue, and decreased appetite associated with inflammation. TNF and IL-1 play an important role in the pathogenesis of rheumatoid arthritis. Drugs that interfere with these cytokines are proving useful in the management of this disease.

      
      

   2. Stages of Acute Inflammation:

      Vascular Phase of Inflammation Figure 2.

      1. Vasoconstriction - Immediately following tissue injury, there is a brief period of localized vasoconstriction.

      2. Complement activation and mediator release - Tissue injury, or the presence of microorganisms, activates complement. C3b molecules formed in this process bind to microbes and injured tissue (opsonization). C3a and C5a trigger the release of histamine and serotonin from nearby mast cells. Tissue injury also triggers the formation of bradykinin and initiates the synthesis of prostaglandins and leukotrienes.

      3. Vasodilation - Histamine, and the other vasoactive mediators of inflammation, then cause relaxation of smooth muscle in arteriolar and capillaries walls. Vessels dilate increasing blood flow to injured tissues. This is manifested by redness (hyperemia) and heat near the site of injury.

      4. Increased vascular permeability - With vasodilation, the endothelial cells lining blood vessels contract slightly creating gaps between the cells that allow plasma to escape into surrounding tissues. Plasma delivers antibodies and other antimicrobial substances to the site of injury. Fibrinogen from plasma also clots and serves as a temporary barrier to bacterial invasion.

      
      Cellular Phase of Inflammation Figure 3.

      1. Adhesion - As blood vessels dilate, the velocity of blood flow slows allowing circulating white blood cells (WBC's) to accumulate on the inner surface of vessel walls. This process is called margination.

      2. Diapedesis and chemotaxis - The WBC's then begin to squeeze between the contracted endothelial cells and migrate in an ameba-like fashion into the extravascular space (a process called diapedesis). Once in tissue, the WBC's are attracted by activated complement and and begin to migrate towards the site of injury or infection. WBC's apparently have surface receptors for chemotactic agents which cause them to move in the direction of increasing concentrations of the chemotactic substance.

         Initially, the first group of cells to arrive at the site of injury are polymorphonuclear leukocytes (neutrophils). Later, mononuclear cells (macrophages) become more numerous. In certain parasitic infections, eosinophils predominate. In viral infection, lymphocytes rather than neutrophils usually predominate.

      3. Phagocytosis - When WBC's arrive at the site of tissue injury or microbial invasion they become very active and begin engulfing bacteria (or other foreign or substances) that have been opsonized by complement or antibodies. As noted above, the coating of bacteria by complement allows phagocytic cells to attach themselves to the invader to facilitate ingestion. Many bacteria are not recognized by WBC's and macrophages unless they have been opsonized.
         • Bacterial killing - After bacteria have been phagocytosed, WBC's and macrophages greatly increase their consumption of oxygen and accelerate their metabolism of glucos (the "respiratory burst"). A byproduct of this process is the generation of oxygen-derived free radicals such as superoxide and hydrogen peroxide which are extremely toxic to bacteria. Although phagocytes have a number of diverse killing mechanisms - such as hydrolytic enzymes, lysozyme, and lactoferrin - the oxygen-dependent mechanisms are the most effective.

         • Bacterial degradation - Following bacterial killing, hydrolytic enzymes are released from lysosomes present in phagocytes in order to enzymatically degrade the microorganism.

      
      

   3. Systemic effects of acute inflammation: Inflammation is frequently associated with systemic signs and symptoms. These include fever, fatigue, decreased appetite, and leukocytosis (increased WBC count >15,000/ml). The systemic effects of inflammation are mediated primarily by interleukin-1, tumor necrosis factor, and prostaglandins - all of which are secreted by inflammatory cells. Fever may also be induced by certain constituents in the cell wall of dead bacteria called pyrogens.

      Acute inflammation is commonly accompanied by increased concentrations of several plasma proteins such as C-reactive protein, alpha-2 macroglobulin, and fibrinogen (collectively called acute phase proteins). Although the precise function of these proteins is largely unclear, when measured in the laboratory, they can serve as markers for inflammation. These proteins also cause erythrocytes suspended in a capillary tube to aggregate and rapidly settle out. This is the basis for the erythrocyte sedimentation rate (ESR), a nonspecific indicator of inflammation. Finally, prolonged or widespread inflammation can deplete complement leading to decreased levels of certain components of complement in the serum.

      
      

   4. Consequences of acute inflammation: The acute inflammatory response may have one of four outcomes depending on whether or not injury results in significant tissue loss or the inflammatory stimulus is rapidly removed: (1) resolution (2) healing, (3) suppuration, or 4) chronic inflammation.
      1. Resolution - The complete removal of the agent or microorganism that triggered the inflammatory response. Includes the removal of any injured (necrotic) host cells. This is the ideal outcome for acute inflammation. It is more likely if cellular damage has been minimal.

      2. Healing
         • Regeneration - The replacement of damaged or lost tissue by normal tissue of a similar type. Only occurs in tissues that contain cells capable of dividing (e.g., epithelal tissues such as the epiderms of the skin).

         • Repair - Scar formation, fibrosis. Replacement of damaged or lost tissue by collagen fibers (scar tissue). This is the healing mechanism for those tissues that cannot regenerate (dermis, nerve, muscle, etc.).

      3. Suppuration and abscess formation - If there has been a large amount of cellular necrosis, or if there is a great deal of bacterial contamination, exudates and dead leukocytes (pus) can accumulate forming an abscess. In time, connective tissue walls off the abscess and limits its spread. Resolution and healing cannot take place until adequate drainage of the abscess has been provided. Careful debridement and irrigation of wounds prior to closure can reduce the risk of infection significantly.

      4. Chronic Inflammation - Normally, the acute inflammatory response to cellular injury has subsided by the time tissue healing begins. If tissue destruction is prolonged, inflammation and attempts at healing occur at the same time. This produces the picture of chronic inflammation.
         • Histologically, chronic inflammation is characterized by tissue destruction and an accumulation of macrophages and lymphocytes.

         • Another manifestation of chronic inflammation is the presence of granulomas - localized, compact masses of scar tissue and transformed macrophages called epithelioid cells. Granuloma formation is characteristically associated with infections such as tuberculosis, leprosy, syphilis, cat scratch disease, and schistosomiasis. Fungal infections, silicosis, sarcoid disease, and many autoimmune disesaes are also associated with granulomas.

         • Yet another manifestation of chronic inflammation is the ulcer. This is a local defect or excavation in the surface of a tissue or organ which is produced by the shedding of inflammatory necrotic tissue. Ulcers are commonly encountered on the oral mucosa, gastrointestinal and genitourinary tracts, and subcutaneous tissues of the lower extremities (especially in patients with peripheral vascular disease or diabetes).

         Factors that favor the development of chronic inflammation include: (1) Persistent or recurrent infection - or a limited ability to destroy certain intracellular microorganisms such as mycobacteria. (2) Prolonged exposure of tissues to potentially toxic material (e.g., asbestosis, silicosis, talc). (3) Exaggerated host immune responses - (e.g., tuberculosis, sarcoidosis, rheumatoid arthritis, lupus, etc.).

   
   

3. Innate Anti-Viral Defense Mechanisms
   1. Natural Killer (NK) Cells - A special subset of large granular lymphocytes that have a limited ability to seek out and destroy host cells infected by viruses. Since viruses are not free-living organisms, and require a host cell in order to replicate, destroying infected host cells interrupts their life cycle.
      1. NK cells appear to function by releasing proteins (e.g., perforin) into the infected host cell which damages cell membranes and degrades DNA.

      2. NK cell killing is non-specific. NK Cells are not directed against specific viral antigens; rather, they can target any virally infected cell.

      3. NK cells may also have some activity against certain malignant tumors.

   2. Alpha Interferon - When the cells of the body are infected by a virus, they respond by synthesizing a protein called alpha interferon and releasing it into the near-by extracellular environment. Neighboring cells take up the interferon and become resistant to further infection by the virus.
      1. The anti-viral effect of alpha interferon is believed to be due to its ability to induce the synthesis of enzymes in the host cell which either degrade viral RNA, or interfere with the ability of viruses to synthesize proteins and nucleic acids required for replication. Alpha interferon also seems to enhance the killing potential of NK cells.