The Lymphatic System

• The immune and lymphatic structures and systems work in concert.
• The functions of the lymphatic, heart, and blood vessels are interdependent.

Relationship to Circulatory System

• The lymphatic system returns excess interstitial fluid to the cardiovascular system.
• It works in concert with venous circulation.

Components of the Lymphatic System

• Lymph
• Lymph vessels
• Lymphatic tissues
• Lymph nodes and nodules
• Spleen
• Thymus gland
• Red bone marrow
• Tonsils

Functions of the Lymphatic System

• Facilitates movement of fluid
• Removes excess fluid, proteins, and waste products
• Filters and destroys foreign material
• Initiates immune response
• Absorbs lipids from the GI tract

Lymph

• Lymph is mostly water and plasma.
• Excess interstitial fluid enters lymph capillaries and is returned to the blood via lymphatic vessels.
• Maintaining blood volume and BP is an important factor of lymph.
• Lymph contains leukocytes, proteins, electrolytes, urea, creatinine, and other waste products.

Lymphatic Vessels

• Lymphatics have thinner walls than veins, which causes them to collapse more easily under pressure.
• Lymph is initially absorbed at the capillary level.
• It is then channeled through small vessels (pre-collectors) and then larger vessels (collectors).
• Collectors have smooth muscle and valves.
• Larger vessels merge into trunks and then ducts.
• The right lymphatic duct drains lymph from the upper right quadrant.
• The thoracic duct drains all the rest.
• Cisterna chyli collects lymph from the abdomen and drains it into the thoracic duct.
• Lymphatic ducts return lymph fluid to subclavian veins.

Movement of Lymph

• Movement of lymph fluid occurs through diffusion and filtration
• Additional mechanisms include:
  • Nerve stimulation
  • Mild stimulation of dermal tissue
  • Arterial pulsation adjacent to lymph vessel
  • Muscle contraction adjacent to lymph vessels (skeletal muscle pump)
  • Abdominal/thoracic cavity pressure (respiratory pump)
• The lymphangion is the functional unit of a lymph vessel and is the portion of the vessel between adjacent valves.
• Lymphangions contain smooth muscle in the walls and have an intrinsic pumping mechanism triggered by pressure in the vessel.

Lymph Nodes

• Lymph nodes are encapsulated and measure 1-2 cm in diameter
• Lymph nodes are found in groups along lymph vessel pathways
• Lymph enters via afferent lymph vessels and leaves via efferent vessels
• Lymph nodes filter lymph
  • Bacteria and foreign materials are phagocytized by macrophages
  • Plasma cells develop from B lymphocytes exposed to pathogens in lymph and produce antibodies

Lymph Nodules

• Lymph nodules range from a fraction of a millimeter to several millimeters in size and do not have a capsule.
• They are located just beneath the epithelium of mucous membranes within the respiratory, digestive, urinary, and reproductive tracts.
• Examples of types of lymph nodules:
  • Tonsils: lymph nodules in the pharynx
    • Palatine, pharyngeal (adenoid), and lingual tonsils form a ring of lymphatic tissue around the pharynx.
  • Peyer's patches: lymph nodules in the small intestine.

Spleen

• Located in upper left quadrant (ULQ) of abdominal cavity just below the diaphragm and behind stomach
• Produces RBCs in the fetus
• Function after birth: filters blood that flows through it
• Contains plasma cells, which produces antibodies in response to foreign antigens
• Contains monocytes and fixed macrophages that phagocytize pathogens or foreign material in blood
  • Monocytes may enter circulation when tissue is damaged and needing cleanup and repair.
• Stores platelets and destroys platelets when they are no longer needed.

Thymus

• The thymus is located inferior to the thyroid and gets smaller as we age.
• Stem cells of the thymus produce T lymphocytes (T cells).
• Thymic hormones and other cells give rise to the "immunological competence" of T cells.
• Immature T cells are "introduced" to the cells and organic molecules of the body.
• T-cells develop self-recognition and self-tolerance.

Components of the Immune System

• Lymphoid structures and tissues
• Locations of immune cell development
  • Bone marrow: origination of all immune cells
  • Thymus: maturation of T lymphocytes
• Immune cells
  • Leukocytes
  • Macrophages

Innate Vs. Adaptive Immunity

• Innate Immunity:
  • Non-specific response.
  • Includes anatomical and physiological barriers, phagocytic and other defensive cells, chemical secretions, and the inflammatory process.
  • Efficiency does not increase with repeated exposure.
• Adaptive Immunity:
  • Specific response.
  • Carried out by lymphocytes and macrophages
  • Includes cell-mediated and antibody-mediated processes.
  • Becomes more efficient with repeat exposure.

Elements of the Immune Response: Antigens

• "Self" antigens are cell surface antigens found on cell membranes.
  • The HLA complex is a group of genes coding for the production of specific proteins that help the immune system distinguish the body’s own proteins from foreign substances
  • Normally, the immune system ignores self cells/antigens due to self recognition and self-tolerance.
• The immune system recognizes specific non-self antigens as foreign.
  • Specific response to that antigen develops.
  • Memory cells are produced to respond quickly to the antigen when encountered again.

Major Cells of the Immune Response

• Leukocytes
  • Mast cells: release histamine and other chemical mediators in inflammatory response
  • Neutrophils: phagocytosis; active in inflammatory process
  • Basophils: play major role in allergic reactions; release histamine; bind to IgE
  • Eosinophils: involved in allergic responses; phagocytosis; antiparasitic and bactericidal activity
  • Monocytes: circulate in blood; mature into macrophages upon migration into tissues in response to infection/inflammation
  • Macrophages: phagocytosis; process and present antigens to lymphocytes for immune response
  • Dendritic cells: phagocytosis; antigen presenting cells
  • Lymphocytes: T cells, B cells, and NK cells

Cells of the Immune System: Macrophages

• Macrophages are located throughout the body.
• They initiate immune response
• They develop from monocytes
• Engulf Foreign Material
  • They also process and display foreign antigen material on their cell membranes.
    • Lymphocytes respond to the display, triggering immune response.
• Macrophages secrete chemicals like monokines and interleukins.

Cells of the Immune System: Lymphocytes

• Lymphocytes
  • T Lymphocytes
    • Arise from bone marrow stem cells and differentiate and mature in the thymus. -Play a major role in cell-mediated immunity
      • Cytotoxic T killer cells
      • Helper T cells
      • Memory T cells
      • Regulatory T cells
    • Cytotoxic T-Cells: Bind to antigen and release cytotoxic enzymes/chemicals.
    • Helper T-Cells: Regulate all the cells of the immune system via secretion of "messenger" cytokines, primary task is to activate B-cells and cytotoxic T cells
    • Memory T-Cells: Remain in lymph nodes for years, respond if exposed to same antigen in the future.
    • Regulatory T-Cells: Suppress Immune response when no longer needed.
  • B lymphocytes (B cells)
    • Responsible for production of antibodies (immunoglobulins)
    • Mature in bone marrow, then proceed to spleen and lymphoid tissue
    • Most involved in fighting bacteria and viruses that are outside of cells
    • Plasma cells produce antibodies
    • B memory cells can quickly form a clone of plasma cells
  • Natural killer cells
    • Distinct from T cells and B cells
    • Destroy tumor cells, cells infected with viruses, and other foreign cells without the need for prior exposure
    • Localized to infected tissue in response to cytokines

Adaptive Immunity

• Cell-mediated immunity (CMI)
  • Lymphocytes are programmed to attack non-self cells.
  • Develops when T cells with protein receptors on cell surface recognize antigens on target cells → destroy invading antigens.
    • Programmed T cells reproduce and then creates more cells to battle the antigen.
• Antibody-mediated (humoral) immunity
  • Antibodies are produced to protect the body
  • B cells become plasma cells after exposure to antigens

Antibodies

• Antibodies are also known as immunoglobulins.
• They are found within general circulation and lymphoid tissues.
• There are 5 major classes of immunoglobulins.
• The major classes of immunoglobulins are based on the constant region structure and immune function
  • Constant region: attaches to macrophages and other effector cells, related to type/class of immunoglobulin
  • Variable region: unique set of a.a.'s that binds to a specific antigen

Major Classes of Antibodies

• IgG:
  • Most abundant antibody in the circulation.
  • Found in blood & extracellular fluid.
  • Includes antiviral, antibacterial and antitoxin antibodies.
  • Crosses placenta, creates passive immunity in newborns.
• IgM
  • Bound to B lymphocytes in the circulation.
  • Usually, 1st to increase in immune response.
  • Doesn't require helper T cells.
  • Involved in the ABO blood type incompatibility reaction.
• IgA
  • Provides localized defense.
  • Found in secretions such as tears, saliva and mucous membranes and colostrum.
• IgE
  • Binds to mast cells or basophils in the skin and mucous membranes, involved in allergic response.
  • Causes release of histamine and other chemical mediators.
  • Results in inflammation.
• IgD
  • Attached to B cells.
  • Activates B cells and assists them in leaving bone marrow.

Complement System

• The complement System is a group of inactive proteins circulating in blood composed of C1 to C9
• It can be activated in innate and adaptive immune response.
• When an antigen-antibody complex binds with C1 it sets off a cascade
• Ultimately causes cell damage & further inflammation when activated

Acquired (Adaptive) Immunity

• A 2 Step Process
  • Primary Response
    • Occurs with 1st exposure to antigen
    • Antigen is recognized & processed, subsequent antibody production or sensitization of T lymphocyte occurs
    • 1-2 weeks before antibody level reaches full efficacy
  • Secondary Response
    • Repeat exposure to same antigen
    • More rapid response, with efficacy in 1-3 days

Acquired (Adaptive) Immunity: Passive Natural Immunity

• IgG transferred from mother to fetus
  • across placenta or through breast milk
  • Protection of infant for the first few months of life or until weaned

Acquired (Adaptive) Immunity: Passive Artificial Immunity

• Injection of antibodies
• Short-term protection

Acquired (Adaptive) Immunity: Active Natural Immunity

• Natural exposure to antigen
• Development of antibodies

Acquired (Adaptive) Immunity: Active Artificial Immunity

• Antigen purposefully introduced to body
• Stimulation of antibody production
• Immunizations

Types of Acquired Immunity

Body defenses

• 1st Line of Defense: Non-specific, mechanical barriers
  • Unbroken skin & mucous membranes
  • Secretions (tears, saliva & gastric juices) have enzymes to help break down bacteria, etc.
• 2nd Line of Defense: Non-specific
  • Phagocytosis: process by which bacteria, cell debris & foreign material are engulfed and destroyed
  • Inflammation: sequence of events meant to limit effects of injury or harmful event in the body
• 3rd Line of defense: Specific defense
  • Antibody mediated or cell-mediated immunity

Physiology of Inflammation

• Protective mechanism
• Normal defense mechanism
• Signs and symptoms serve as a warning
• A problem may be hidden within the body
• The inflammatory process is the same, regardless of cause
• Inflammation is not the same as infection
• However, infection may cause inflammation
  • The medical terminology for inflammation ends with "-itis."

Common Causes of Inflammation

• Direct physical damage
  • Cut, sprain, etc.
• Caustic chemicals
  • Acid, drain cleaner, etc.
• Ischemia or infarction
• Allergic reactions
• Extremes of heat or cold
• Foreign bodies
  • Splinter, glass, etc.
• Infection

Acute Inflammation

• Chemical mediators affect blood vessels & nerves in damaged area
  • Vasodilation: relaxation of smooth muscles causing increased diameter of arterioles
  • Hyperemia: increased blood flow in the area
  • Increase in capillary permeability
    • Allows plasma proteins to move into interstitial space along with more fluid
      • Dilutes toxic material at site
      • Fibrinogen forms fibrin mesh to localize the injurious agent; blood clotting will "wall-off" area
  • Chemotaxis to attract leukocytes
    • Movement of a substance or cell in response to a chemical stimulus

Local Effects of Inflammation

• Cardinal Signs of Inflammation
  • Redness: caused by increased blood flow to the damaged area
  • Warmth or heat: caused by increased blood flow to the damaged area
  • Swelling (edema): shift of protein and fluid into the interstitial space
  • Pain: increased pressure of fluid on nerves; release of chemical mediators (e.g., bradykinins)
  • Loss of function: may develop if cells lack nutrients; edema & pain interfere with motion

Systemic Effects of Inflammation

• More general manifestations of inflammation
  • Mild fever (pyrexia): common if inflammation is extensive
    • Release of pyrogens (fever producing substances released by WBC or macrophages)
    • More severe fever may occur if infection is also present
  • Malaise: generalized feeling of being unwell
  • Fatigue
  • Headache
  • Anorexia: lack of appetite

Chemical Mediators in the Inflammatory Response

Changes in the Blood Values with Inflammation

Chronic Inflammation

• May follow acute inflammation if the cause is not completely resolved
• Can occur secondary to chronic irritation (smoking, long-term autoimmune conditions, etc.)
• Chronic inflammation differs from acute inflammation due to the following:
  • Less swelling & exudate
  • Presence of more lymphocytes, macrophages, & fibroblasts
  • Continued tissue destruction
  • More fibrous scar tissue
  • Granuloma may develop around a foreign object
    • Granuloma: small mass of cells with necrotic center, covered by connective tissue

Potential Complications of Inflammation

• Complications will depend upon the site and cause of inflammation.
• Typical complications related to inflammation:
  • Infection
  • Muscle spasm
  • Ulcerations
  • Immune suppression

Types of Healing

• Resolution is the type of healing that occurs when there is minimal tissue damage where damaged cells recover and tissue returns to normal within a short time period i.e mild sunburn.
• Regeneration occurs in damaged tissues in which cells are capable of mitosis.
  • Some types of cells are constantly replicating (epithelial cells), but others don't replicate at the same rate.
  • Some types of tissue have a greater potential for regeneration.
  • Nearby cells may proliferate to replace the damaged cells/tissue with identical cells.
• Replacement: Functional tissue is replaced by scar tissue (fibrous tissue)
  • Occurs with extensive tissue damage or when cells are incapable of mitosis in cells such as cardiac tissue, and brain tissue.
  • Loss of tissue function occurs and chronic inflammation & infection tend to lead to more scarring.

The Healing Process

• 1st (primary) intention:
  • Healing of a wound in which edges are closely re-approximated
    • Occurs readily when wound is clean, free of foreign material & not necrotic
    • Normal healing process for smaller cuts/wounds or in post-op procedure with presence of sutures or steri-strips.
    • This process tends to result in thinner scars
• 2nd intention:
  • Occurs when there is a large break in the tissue and edges cannot be approximated
    • Often has more inflammation and a longer healing period
    • The process leads to more scar formation
  • Begins when the clot forms and seals the area. Granulation tissue: highly vascularized, appears moist & pink or red, and contains new capillary buds.
    • After 3-4 days foreign material & cell debris have been removed by phagocytes, monocytes & macrophages. -Granulation tissue grows into the “gap” from nearby connective tissue.
  • Very fragile and easily broken down by microorganisms or stress on the tissue.

Healing Process Steps

• Granulation tissue fills in wound area; nearby epithelial cells undergo mitosis.
  • New cells extend across wound from outside edges moving inward
• Fibroblasts enter area & begin forming collagen.
• Fibroblasts & macrophages produce growth factors which stimulate more fibroblasts, epithelial cell proliferation & migration, development of new blood vessels (angiogenesis)
• Cross-linking & shortening of collagen fibers promotes formation of tight, strong scar
• Capillaries in the area decrease and scar color gradually fades, scar tissue normally takes 12-18 months to fully mature

Factors Promoting Healing

• Younger age
• Effective circulation
• Adequate hemoglobin
• Clean, undisturbed wound/tissue
• Absence of repetitive or further trauma to the site
• Good nutrition: protein, and vitamins A & C

Factors Delaying Healing

• Smoking
• Poor circulation
• Advanced age
• Chronic disease
• Anemia
• Prolonged use of steroids
• Chemotherapy treatment
• Infection
• Recurrent irritation or excessive bleeding
• Dehydration
• Poor nutrition