Lymphatic and Immune Systems

• The lymphatic and immune systems are vital for body defenses and overall health.

Lymphatic System Overview

• It returns excess interstitial fluid to the cardiovascular system.
• It works together with the venous circulation system.
• Functions of the lymphatic system, heart and blood vessels are interdependent.
• The function is to facilitate fluid movement, remove excess fluid/proteins/waste, filter foreign material, initiate immune response, and absorb lipids from the GI tract.

Components of the Lymphatic System

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

Lymph Details

• Lymph is mostly water/plasma.
• It consists of excess interstitial fluid that enters lymph capillaries.
• It is returned to the blood via lymphatic vessels.
• It's important in blood volume and blood pressure maintenance.
• Other components include leukocytes, proteins, electrolytes, urea, creatinine and other waste products.

Lymphatic Vessels

• Thinner walls than veins, collapse more easily under pressure.
• Lymph is first absorbed at the capillary level.
• It's channeled through small vessels (pre-collectors), 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 remaining lymph.

Lymphatic Movement

• Lymph fluid moves through diffusion and filtration.
• Additional factors include nerve stimulation and abdominal/thoracic cavity pressure (respiratory pump).
• Mild stimulation of dermal tissue, arterial pulsation adjacent to lymph vessel, and muscle contraction adjacent to lymph vessels (skeletal muscle pump) are factors.
• A lymphangion is the functional unit of lymph vessel, a portion of the vessel between adjacent valves.
• It contains smooth muscle in walls with pressure triggering an intrinsic pumping mechanism.

Lymph Nodes

• These are encapsulated structures, 1-2 cm in diameter.
• Found in groups along lymph vessel pathways.
• Lymph enters via afferent vessels, leaves via efferent vessels.
• They 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

• They range from fractions of a mm to several mms in size.
• They lack a capsule.
• Located beneath the epithelium of mucous membranes in respiratory, digestive, urinary, & reproductive tracts.
• Examples include tonsils (lymph nodules in pharynx) and Peyer's patches (lymph nodules in small intestine).
• Palatine, pharyngeal (adenoid), and lingual tonsils form a ring of lymphatic tissue around the pharynx.

The Spleen

• Located in the upper left quadrant of the abdominal cavity
• RBC production in the fetus
• Functions after birth: filters blood, contains plasma cells and fixed macrophages
• Contains plasma cells producing antibodies in response to foreign antigens.
• Monocytes may enter circulation when tissue needs cleanup/repair.
• Storage and destruction of platelets when they are no longer needed is a function.

The Thymus

• It's located inferior to the thyroid and it gets smaller with age.
• Stem cells produce T lymphocytes (T cells).
• Thymic hormones and other cells give rise to "immunological competence" of T cells.
• Immature T cells are "introduced" to the cells & organic molecules of body.
• They develop self-recognition & self-tolerance.

Immune System Components

• Lymphoid structures and tissues
• Locations of immune cell development in bone marrow and thymus
• Bone marrow is responsible for the origination of all immune cells.
• The thymus is responsible for the maturation of T lymphocytes.
• Immune cells include leukocytes and macrophages.

Innate vs. Adaptive Immunity

• Innate Immunity: non-specific response, includes anatomic/physiological barriers, phagocytic/defensive cells, chemical secretions/inflammatory processes.
  • Efficiency doesn't increase with repeated exposure.
• Adaptive Immunity: specific response carried out by lymphocytes/macrophages.
  • Includes cell/antibody-mediated processes, becoming more efficient with repeat exposure.

Elements of Immune Response: Antigens (Self)

• Cell surface antigens are found on cell membranes.
• The HLA complex is a group of genes coding for production of specific proteins.
• This helps the immune system distinguish body's own proteins from foreign substances.
• Typically, the immune system ignores self cells/antigens due to self-recognition & self-tolerance.

Elements of Immune Response: Antigens (Non-Self)

• The immune system recognizes specific non-self antigens as foreign and mounts a specific response.
• Memory cells are produced to respond quickly to the antigen when encountered again.

Major Cells of Immune Response: Leukocytes

• Mast cells, neutrophils, basophils, eosinophils, monocytes, macrophages, dendritic cells, and lymphocytes.
• Mast cells release histamine and other chemical mediators during an inflammatory response.
• Neutrophils function in phagocytosis.
• Basophils play a major role in allergic reactions, release histamine, and bind to IgE.
• Eosinophils are involved in allergic responses, phagocytosis, and defense against parasites.
• Monocytes circulate in blood, mature into macrophages upon entering tissues.
• Macrophages phagocytize/process antigens for lymphocytes.

More about Immune Cells

• Dendritic cells are phagocytic and act as antigen-presenting cells.
• Lymphocytes are T cells, B cells, and NK cells.
• Macrophages present throughout the body initiate immune responses.
  • Macrophages can engulf foreign material and display foreign antigen material on their cell membranes.
  • They secrete chemicals and develop from monocytes.
  • Lymphocytes respond to the display, thus triggering an immune response and secrete chemicals like monokines and interleukins.

Cells of the Immune System: Lymphocytes

• T Lymphocytes (T Cells): arise from bone marrow stem cells, differentiate and mature in the thymus.
  • Play a major role in cell-mediated immunity.
  • Includes: Cytotoxic T killer cells, Helper T cells, Memory T cells, and Regulatory T cells.
• Cytotoxic T killer cells: bind to antigen and release cytotoxic enzymes/chemicals.
• Helper T cells are able to regulate all the cells of the immune system via cytokines.
  • The primary task is to activate B cells & cytotoxic T cells.
• Memory T cells: remain in lymph nodes for years, responding if exposed to same antigen in the future.
• Regulatory T cells can suppress immune response when no longer needed.
• B Lymphocytes (B Cells): responsible for producing antibodies (immunoglobulins).
  • They mature in bone marrow, then proceed to spleen and lymphoid tissue.
  • Most involved in fighting bacteria/viruses outside of cells. Plasma cells produce antibodes.
  • B memory cells can quickly form clone of plasma cells.
• Natural killer cells are distinct from T and B cells.
  • They destroy tumor cells, cells infected with viruses, and other foreign cells without prior exposure.
  • Localized to infected tissue in response to cytokines.

Types of Adaptive Immunity

• Cell-mediated immunity (CMI) means lymphocytes are programmed to attack non-self cells.
  • Develops when T cells with protein receptors on cell surface recognize antigens on target cells, destroying invading antigens.
  • "Programmed" T cells reproduce, creating more cells to battle the antigen.
• Antibody-mediated (humoral) immunity means antibodies are produced to protect the body.
  • B cells become plasma cells after exposure to antigens.

Antibodies

• They're also known as immunoglobulins, found within general circulation, and are found in lymphoid tissues.
• There are 5 major classes determined by constant region structure & immune function.
• The constant region attaches to macrophages and other effector cells based on type/class of immunoglobulin.
• The variable region has a unique set of amino acids that binds to a specific antigen.
• IgG is the most abundant antibody in circulation found in blood & extracellular fluid.
  • It includes antiviral, antibacterial and antitoxin antibodies.
  • Crosses placenta, creates passive immunity in newborns.
• IgM is bound to B lymphocytes in the circulation and is usually the first to increase in immune response.
  • It doesn't require helper T cells and Involved in the ABO blood type incompatibility reaction.
• IgA provides localized defense, found in secretions, tears, saliva, mucous membranes, and colostrum.
• IgE binds to mast cells or basophils in skin & mucous membranes, involved in allergic response.
  • It causes release of histamine and other chemical mediators leading to inflammation.
• IgD are attached to B cells and activates B cells and assists them in leaving bone marrow.

Complement System

• It includes a group of inactive proteins circulating in blood designated C1 to C9.
• It's activated in innate and adaptive immune responses.
• When an antigen-antibody complex binds with C1, it sets off a cascade of reactions causing cell damage and further inflammation when activated.

Acquired (Adaptive) Immunity

• A two-step process:
  • Primary response: occurs with first exposure to antigen.
  • The antigen is recognized/processed, with subsequent antibody production or sensitization of T lymphocyte.
  • This process takes 1 to 2 weeks before antibody level reaches full efficacy.
  • Secondary response: exposure to the same antigen.
  • This is a more rapid response and efficacy in one to three days.
• Passive natural immunity is IgG transferred from mother to fetus across the placenta or through breast milk.
  • This provides protection to the infant for the first few months of life or until weaned.
• Passive artificial immunity involves the injection of antibodies for short-term protection.
• Active natural immunity occurs through natural exposure to an antigen.
• Active artificial immunity involves the purposeful introduction of antigen and involves immunizations.

The Inflammatory Response

• The 1st line of defense are nonspecific mechanical barriers such as unbroken skin and mucous membranes.
  • Secretions (tears, saliva, and gastric juices) contain enzymes to help break down bacteria, etc.
• The 2nd line of defense is nonspecific.
  • Phagocytosis is the process of engulfing and destroying bacteria, cell debris, and foreign material.
  • Inflammation is a sequence of events to limit the effects of injury or harmful event in body.
• The 3rd line of defense is specific and antibody mediated or cell-mediated immunity.

Physiology of Inflammation

• It's a protective, normal defense mechanism.
• Signs and symptoms serve as a warning, but the problem might be hidden within the body.
• The specific inflammatory process is the same, regardless of cause.
• Inflammation is not the same as infection, but infection may cause inflammation.

Common Causes of Inflammation

• Direct physical damage, such as a cut or sprain.
• Exposure to caustic chemicals like acid or drain cleaner.
• Ischemia or infarction.
• Allergic reactions.
• Extremes of heat or cold.
• Foreign bodies such as a splinter or glass.
• Infection.

Acute Inflammation

• Chemical mediators affect blood vessels & nerves in damaged area.
• Vasodilation occurs due to relaxation of smooth muscles, causing the diameter of arterioles to relax.
• This causes hyperemia: increased blood flow in the area.
• Increase in capillary permeability allows plasma proteins to move into interstitial space with more fluid.
  • Dilution of toxic material at site
• Fibrinogen forms fibrin mesh to localize the injurious agent.
• Blood clotting occurs.
• Chemotaxis attracts leukocytes: movement of a substance or cell in response to a chemical stimulus.

Local Effects of Inflammation

• Cardinal signs: redness, warmth (heat), swelling (edema), pain, and loss of function.
• Redness and warmth result from increased blood flow to the damaged area.
• Swelling (edema) is due to the shift of protein and fluid into the interstitial space.
• Pain is related to increased pressure of fluid on nerves, as well as chemical mediators (bradykinins).
• Loss of function may develop if cells lack nutrients; edema/pain interfere with motion.

Systemic Effects of Inflammation

• General responses include mild fever (pyrexia), common if inflammation is extensive.
• Release of pyrogens causes fever which is related to fever-producing substances released by WBC or macrophages)
• More severe fever may occur if infection is also present.
• Malaise: Generalized feeling of being unwell is a symptom.
• Other symptoms include fatigue, headache, anorexia (lack of appetite).

Chemical Mediators in the Inflammatory Response

• Histamine: immediate vasodilation & increased capillary permeability to form exudate.
• Chemotactic factors: Attract leukocytes to site.
• Platelet activating factor(PAF): Activates neutrophils; platelet aggregation.
• Cytokines (interleukins, lymphokines, tumor necrosis factor, etc): Increase plasma proteins, increase ESR, induce fever, chemotaxis, leukocytosis.
• Leukotrienes: Later response with vasodilation & increased capillary permeability, chemotaxis.
• Prostaglandins: Can cause increased capillary permeability, and trigger pain and/or fever.
• Kinins (bradykinin): Vasodilation & increased capillary permeability, triggers pain and chemotaxis.
• Complement system: Vasodilation & increased capillary permeability, chemotaxis, increased histamine release.

Changes in Blood Values with Inflammation

• Leukocytosis: increased number of WBCs, especially neutrophils.
• The differential count shows the proportion of each type of WBC altered, dependent upon the cause of inflammation.
• High plasma proteins: increased fibrinogen and prothrombin.
• A positive C-reactive protein is not normally present in blood, but appears with acute inflammation and necrosis in 24–48 hours.
• Increased ESR (SED rate): Related to increased plasma proteins which cause an increase in rate at which RBCs settle in a sample.
• Cellular enzymes: Released from necrotic cells and tissue fluids & blood.

Chronic Inflammation

• It may follow acute inflammation if the cause is not completely resolved.
• It can occur secondarily to chronic irritation related to smoking and long-term autoimmune conditions.
• It features less swelling and exudate and the presence of more lymphocytes, macrophages, & fibroblasts.
• Continued tissue destruction and more fibrous scar tissue occur.
• A granuloma (small mass of cells with necrotic center covered by connective tissue) may develop around a foreign object.

Potential Complications of Inflammation

• Complications depend upon site and cause of inflammation.
• Typical complications related to inflammation include infection.
  • This can occur due to microorganisms which can more easily penetrate edematous tissues.
  • Some microbes resist phagocytosis.
  • Inflammatory exudate provides an excellent medium for microorganisms.
• Skeletal muscle spasm which may be initiated by inflammation as a protective response to pain.
• Ulcers are related to cell necrosis and lack of cell regeneration causing erosion of the tissue.
  • This can lead to perforation of viscera or scarring.
• Suppressed immune system further increases infection risk.

Types of Healing

• Resolution occurs when there is minimal tissue damage: Damaged cells recover, tissue returns to normal in a short amount of time. Example: mild sunburn.
• Regeneration occurs in damaged tissues in which cells are capable of mitosis .
  • Some cell types are constantly replicating (epithelial cells), but others don't replicate at the same rate.
  • Nearby cells may proliferate to replace 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 (cardiac & brain tissue).
  • Loss of tissue function occurs, and chronic inflammation/infection tend to lead to more scarring.

The Healing Process: Primary Intention

• In this case, healing occurs when wound edges are closely re-approximated.
  • It occurs readily when the wound is clean, free of foreign material and not necrotic.
  • Normal healing process for smaller cuts/wounds or in post-op procedure with presence of sutures or steri-strips.
  • This tends to result in thinner scars.

The Healing Process: Secondary Intention

• Occurs when there is a large break in tissue and edges cannot be approximated.
• The process often has more inflammation, longer healing period, and more scar formation.

The Healing Process

• Healing begins when a clot forms and seals the area.
• After 3-4 days, foreign material & cell debris is removed by phagocytes, monocytes & macrophages.
• Granulation tissue grows into "gap" from nearby connective tissue.
  • Granulation tissue is highly vascularized and appears moist/pink/red. It contains new capillary buds.
  • This tissue is fragile and can easily be broken down by microorganisms or stress.
• Granulation tissue fills in wound area, nearby epithelial cells undergo mitosis as new cells extend across the wound from outside edges moving inward.
• Fibroblasts enter area and begin forming collagen as fibroblasts/macrophages produce growth factors.
• This will stimulate more fibroblasts, epithelial cell proliferation/migration, and development of new blood vessels (angiogenesis).
• Cross-linking & shortening of collagen fibers promotes formation of tight, strong scar.
• Capillaries in area decrease & scar color gradually fades.
• It takes between 12-18 months for scar tissue 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, 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