Lymphatic System and Immunity

Introduction: Lymphatic System & Immunity

• The lymphatic system functions as a secondary circulatory system
• Lymphatic vessels collect excess tissue fluid from interstitial spaces, returning it to the blood
• Lacteals are specialized vessels that transport absorbed fats into circulation
• Lymph nodes are found along lymphatic vessels and contain lymphocytes
• Lymphocytes help defend the body against disease

Lymphatic Pathways

• Lymphatic pathways begin as lymphatic capillaries that merge into larger vessels
• Merge into lymphatic trunks that empty into veins in the thoracic cavity

Lymphatic Capillaries:

• Tiny, closed-ended tubular vessels extend into interstitial spaces parallel to blood capillaries
• Consist of endothelial cells, like blood capillaries
• Found all over the body, except in the central nervous system
• They receive tissue (interstitial) fluid through thin walls and slits between cells
• Tissue fluid is then called lymph

Lymphatic Vessels

• Lymphatic vessel walls are thinner than those of veins, but have the same 3 layers
• Lymphatic vessels have flap-like valves on the inside, similar to veins
• Larger lymphatic vessels pass through lymph nodes and then merge to form larger lymphatic trunks

Lymphatic Trunks and Collecting Ducts

• Lymphatic trunks drain lymph from the lymphatic vessels
• The trunks are named for the regions they drain
• Trunks empty into one of two collecting ducts: the thoracic or right lymphatic duct
• The right lymphatic duct drains the right side of the head and neck, right arm, and right thorax
• It empties into the right subclavian vein
• The thoracic duct is the larger collecting duct that drains the rest of the body
• It empties into the left subclavian vein

Tissue Fluid and Lymph

• Lymph is tissue fluid that has entered a lymphatic capillary

Tissue Fluid Formation

• Tissue fluid is made up of water and dissolved substances that leave blood capillaries by filtration and diffusion
• It's almost the same as blood plasma, but without large plasma proteins (too large to pass through capillary walls)
• Plasma proteins create plasma colloid osmotic pressure, which pulls fluid back into the capillaries
• Fluid that doesn't return to the capillaries becomes tissue fluid

Lymph Formation and Function

• Filtration from the plasma usually exceeds reabsorption, leading to tissue fluid formation
• Rising osmotic pressure in the tissues interferes with fluid return to the bloodstream
• Increasing tissue fluid hydrostatic pressure forces fluid ("flaps") into lymphatic capillaries, becoming lymph
• Most substances, including small proteins, return to blood via lymph
• Lymph transports foreign particles (bacteria and viruses) to lymph nodes for recognition and destruction

Lymph Movement

• Hydrostatic pressure of tissue fluid drives fluid into lymphatic capillaries, becoming lymph
• Muscular activity moves lymph through vessels, including skeletal muscle contraction, breathing movements, and smooth muscle contraction
• Valves prevent backflow
• Edema is the accumulation of lymph in interstitial spaces due to disrupted lymph flow
• This can happen during surgery that affects lymphatic vessels or tissues; an obstruction results in edema

Lymphatic Tissues and Organs

• Lymphatic tissue contains lymphocytes, macrophages, and other cells
• Unencapsulated lymphatic tissue associated with digestive, respiratory, urinary, and reproductive systems is called mucosa-associated lymphoid tissue (MALT)
• Tonsils, appendix, and Peyer's patches are compact masses of lymphatic nodules
• Encapsulated lymphatic organs include lymph nodes, thymus, and spleen

Lymph Nodes

• Lymph nodes are located in groups or chains along lymphatic vessels

Structure of a Lymph Node:

• Lymph nodes are bean-shaped
• Blood vessels, nerves, and efferent lymphatic vessels enter/exit at the indented hilum
• Afferent lymphatic vessels enter on the convex surface
• Lymph nodes have a connective tissue capsule that extends into nodules and sinuses
• Lymph nodes contain lymphocytes and macrophages that filter lymph
• Filtered lymph leaves the node through efferent lymphatic vessels

Locations of Lymph Nodes

• Lymph nodes are generally located in chains along larger lymphatic vessels
• They are NOT found in the central nervous system
• Major areas of concentration: cervical, thoracic, axillary, supratrochlear, abdominal, pelvic, and inguinal regions

Functions of Lymph Nodes

• Filter lymph and remove bacteria/cellular debris before return to blood
• Immune surveillance: monitor body fluids via lymphocytes and macrophages
• Act as centers of lymphocyte production
• Lymphocytes attack viruses, bacteria, and disease-causing cells that enter
• Macrophages engulf and destroy foreign particles, debris, and damaged cells

Thymus

• Soft, bi-lobed organ is located behind the sternum, anterior to the aorta
• It shrinks in size, being large in children and replaced by adipose/connective tissue in older adults
• Connective tissue capsule extends inward, dividing it into lobules
• Lobules contain lymphocytes that mature into T cells or T lymphocytes that leave to provide immunity
• Thymus secretes hormones called thymosins, influencing T lymphocyte maturation

Spleen

• Located in the upper left abdominal cavity, inferior to the diaphragm
• It is the largest lymphatic organ in the body
• It's similar to a large lymph node, but contains blood instead of lymph
• The Spleen is composed of white pulp (lymphocytes) and red pulp (red blood cells, macrophages, lymphocytes)
• Filters blood and removes damaged blood cells and bacteria

Body Defenses Against Infection

• Pathogens are disease-causing agents
• Presence and multiplication can produce an infection
• These can be bacteria, viruses, fungi, or protozoans
• There are two basic mechanisms of defense against pathogens:
  • Innate (nonspecific) defenses: guard against many pathogens and respond quickly
  • Adaptive (specific) defenses or immunity: respond against specific pathogens slower

Innate (Nonspecific) Defenses

• Species resistance refers to a species that is resistant to diseases that affect other species
• Based on factors like chemical environment and body temperature
• Absence of receptors for a particular pathogen can also prevent infection

Innate Defenses: Mechanical Barriers

• Prevent the entry of certain pathogens (physical separation)
• Examples include unbroken skin and mucous membranes
• Includes hair, mucus, and sweat
• Mechanical barriers represent the body's first line of defense
• The rest of the innate defenses are part of the second line of defense

Innate Defenses: Inflammation

• Inflammation is a tissue response to injury/infection
• Its function is to stop the spread of pathogens and infection
• Characterized by redness, swelling, heat, and pain

Major events of the inflammatory response include:

• Dilation of blood vessels increases blood volume (redness)
• Increased capillary permeability leads to edema and heat
• Attraction of white blood cells for phagocytosis
• Blood clotting & fibrin thread formation
• Fibroblasts secrete chemicals that produce a sac around the area to wall off infection; inhibits spread of infection

Innate Defenses: Chemical Barriers

• Chemicals kill many pathogens
• Acidic environment provided by HCl in gastric juice is lethal
• Enzymes (pepsin in stomach, lysozyme in tears) destroy others
• Interferons are hormone-like peptides secreted by lymphocytes and fibroblasts (viruses/tumor cells)
• Interferons block viral replication and slow tumor growth
• Complement is a group of plasma proteins in body fluids
• Complement stimulates inflammation, attracts phagocytes, and enhances phagocytosis/antibody action

Innate Defenses: Natural Killer (NK) Cells

• Small group of lymphocytes that are not T cells and B cells
• Defend against viruses and cancer cells by secreting cytolytic substances called perforins that lyse cell membranes

Innate Defenses: Phagocytosis

• Phagocytosis is the engulfment and digestion of pathogens/foreign debris
• Neutrophils and monocytes are most active phagocytes
• they leave the bloodstream by diapedesis at injury sites
• Phagocytes are attracted to the injured area by chemotaxis
• Neutrophils engulf smaller particles, while monocytes attack larger ones
• Monocytes give rise to macrophages - either free or fixed in tissues
• The mononuclear phagocytic system or reticuloendothelial system = neutrophils + monocytes + macrophages

Fever

• Occurs when body temperature resets to a higher point
• Fever provides a hostile environment for pathogens that reproduce best under normal human conditions
• Elevated body temperature causes the liver and spleen to take up iron
• Reduced iron levels in the blood keeps it from fungi/bacteria, which need iron for growth
• Phagocytic cells attack with more vigor when the temperature rises

Adaptive (Specific) Defenses or Immunity

• Immunity (adaptive immune defenses) is the body's response against specific pathogens, toxins, or metabolic products (third defense line)
• It's performed by lymphocytes and macrophages that recognize and remember specific foreign molecules
• Includes cellular and humoral immune response

Antigens

• Molecules evoke an immune response and can be proteins, polysaccharides, glycoproteins, or glycolipids
• Before birth, the body makes an inventory of "self" antigens
• The immune response is directed against "nonself" molecules, which are usually large, complex foreign molecules
• Small molecules called haptens are not antigenic by themselves, but combine with larger molecules to become antigenic

Lymphocyte Origins

• Red bone marrow releases undifferentiated lymphocyte precursors into circulation
• Lymphocytes are derived from hematopoietic stem cells residing in bone marrow
• About half go to the thymus to specialize into mature T cells or T lymphocytes
• T lymphocytes make up 70-80% of circulating lymphocytes, some settling in lymph nodes, spleen, or thoracic duct
• Other lymphocytes differentiate in red bone marrow to become B lymphocytes or B cells
• B lymphocytes represent 20-30% of circulating lymphocytes, settling in lymphatic organs (lymph nodes/spleen) and lining of intestines

A Comparison of T Cells and B Cells

• T cells originate in red bone marrow, differentiate in the thymus
• 70-80% of circulating cells, in lymphatic tissues
• T cells provide cellular immune response in which T cells interact with antigens or antigen-bearing agents, to destroy them
• B cells originate and differentiate in red bone marrow
• 20-30% of circulating cells, in lymphatic tissues
• B cells provide humoral immune in which B cells interact indirectly, producing antibodies that destroy antigens or antigen-bearing agents

T Cells and the Cellular Immune Response

• Lymphocytes require activation before responding to antigens
• T cell activation requires an encounter with an antigen-presenting cell (APC), such as B cell or macrophage
• Macrophages acting as APCs digest the pathogen and display antigenic fragments on their cell membranes
• Displayed pathogens are complexed with proteins encoded by the major histocompatibility complex (MHC)
• MHC proteins help T cells recognize displayed antigens
• Activated T cells interact with antigen-bearing cells and synthesize/secrete cytokines
• Cytokines enhance responses to antigens
• Some T cells secrete toxins, growth-inhibiting factors, or interferon
• Colony-stimulating factors are cytokines that stimulate white blood cell production in the red bone marrow

Types of T cells:

• Helper T cells stimulate B cells to produce antibodies against the displayed antigen
• Cytotoxic T cells patrol monitor recognizing/eliminating cancer cells and virus-infected cells
• Cytokines from helper T cells activate cytotoxic T cells, which create clones of themselves
• Cytotoxic T cells bind to antigen-bearing cells and release perforin to cut pores in the cell membrane, destroying the cells
• Memory T cells quickly respond to any future exposure to the same antigen

B Cells and the Humoral Immune Response

• A B cell may become activated and clone cells when it encounters a matching antigen
• Most B cells need helper T cells for activation
• Helper T cells release cytokines that activate B cells and stimulate proliferation
• Some B cells differentiate into plasma cells
• Plasma cells produce and secrete antibodies (immunoglobulins)
• Antibodies travel, inactivating and destroying antigens (humoral immune response) Other B cells become memory B cells, dormant but responsive to later antigens

B Cell Activities

• B cell encounters a matching antigen that fits its antigen receptors
• Alone or more often with helper T cells, the B cell is activated and proliferates
• Some B cells differentiate to become plasma cells
• Plasma cells synthesize and secrete antibodies (similar to antigen receptors)

T Cell Activities

• An antigen-presenting cell, like a macrophage, phagocytizes the antigen-bearing agent and digests them
• Antigens from the digested antigen-bearing agents are displayed on the membrane of the antigen-presenting cell
• A helper T cell becomes activated when encountering a displayed antigen (fits its antigen receptors)
• The activated helper T cell releases cytokines when encountering a B cell (previously combined with identical antigen)
• Cytokines stimulate B cell proliferation, enlarge clones Some of the newly formed B cells give rise to antibody-secreting plasma cells

Types of Antibodies

• 5 major types of antibodies (immunoglobulins)
• These constitute the gamma globulin fraction of plasma
• IgG, IgA, and IgM are the most abundant types

Types include

• Immunoglobulin G (IgG) defends against bacteria cells, viruses, and toxins, while also activating complement
• Immunoglobulin A (IgA): found in exocrine gland secretions (breast milk, saliva, tears, nasal fluid, gastric and intestinal juices, bile, urine)
• Immunoglobulin M (IgM): Activates complement and reacts with red blood cells during transfusions of mismatched blood
• Immunoglobulin D (IgD) is found on the surface of most B lymphocytes and functions in B cell activation
• Immunoglobulin E (IgE) is found on surfaces of basophils and mast cells and is associated with allergic reactions

Antibody Actions

• Antibodies react to antigens by
  • Direct attack by agglutination, precipitation, or neutralization, thus making antigens susceptible to phagocytosis
  • Activation of complement results in opsonization, chemotaxis, inflammation, agglutination, or lysis
  • Stimulation of Local Inflammation helps prevent the spread of pathogens

Immune Responses

• Primary: Activation of B or T cells during the first encounter with an antigen
  • Antibodies appear in plasma in 5-10 days
  • Antibodies (IgM, then IgG) are released into the blood and help destroy antigens for weeks
  • Some B cells remain as memory B cells
• Secondary: A rapid, long-lasting response to a later encounter; uses memory B cells and cytotoxic T cells
  • Memory B cells proliferate and antibodies appear in 1-2 days, remaining for months/years
  • Memory B cells can live for many years, providing long-term immunity

Practical Classification of Immunity

• Naturally acquired: obtained from natural events, like getting a disease
• Artificially acquired: obtained by injection
• Active immunity: obtained through antigen exposure; an immune response occurs in the person's body, and antibodies and memory B cells are produced (long- lasting)
• Passive immunity: receiving antibodies; no antigen contact, immune, or memory B cells (short-term)
• Naturally acquired active immunity through exposure to the antigen (primary immune response)
• Artificially acquired active immunity through use of vaccines (memory B cell formation)
• Naturally acquired passive immunity from antibodies passed from mother to fetus (lack of immune response and memory B cell formation)
• Artificially acquired passive immunity by injection of gamma globulins (short-term, no antigen exposure, immune response, or memory B cells)

Hypersensitivity

• Hypersensitivity reactions: Excessive response to harmless antigen
• Type 1 or immediate-reaction hypersensitivity (allergy):
  • Person becomes sensitized by producing IgE antibodies to allergen
  • During first exposure, IgE attaches to mast cells and basophils, which release histamine
  • Allergy mediators cause mucus production, vasodilation, bronchoconstriction, and inflammation
  • Occurs within seconds of exposure - Allergy mediators flood the body, resulting in anaphylaxis
• Antibody-dependent cytotoxic reactions (type II): involve formation of IgG (1-3 hours)
• Immune complex reactions (type III): involve IgG antibodies (1-3 hours, rheumatoid arthritis)
• Delayed-reaction hypersensitivity (type IV): results from exposure of skin (approximately 48 hours, poison ivy)

Transplantation and Tissue Rejection

• Transplantation replaces a nonfunctional, damaged, or lost body part
• The recipient's immune system recognizes and reacts with foreign antigens
• Rejection reaction is similar to cellular response
• Close matching of donor and recipient tissues reduces chances of rejection
• Immunosuppressive drugs reduce rejection, but individuals may be more susceptible to infection

Autoimmunity

• Autoimmune disorders are disorders in which the immune system turns against a body component
  • Immune system manufactures antibodies called autoantibodies and cytotoxic T cells
  • Autoantibodies damage the body's own tissues
  • Autoimmune disorders are from viral infection and certain reactions
  • Type 1 Diabetes mellitus: beta cells destroyed by autoantibodies