Lymphatic System Summary
The lymphatic system maintains homeostasis by draining & circulating interstitial fluid as well as providing the mechanisms for defense against disease.
Damage or disease is warded off by using:
- Innate immunity present at birth – early warning system
- Adaptive immunity – specific recognition & response to a microbe after innate immunity breach using the white blood cells of lymphocytes (T Cells & B Cells)
- Some blood plasma filters into interstitial fluid which then filters into lymphatic vessels to form LYMPH
- Blood Plasma contains nutrients, gases, and hormones
- The porous nature of capillaries using overlapping cell walls ensure that larger proteins & molecules can be collected
- Lymph is circulated around the body in one direction and then returned to the blood
- Transports fat & some vitamins from lacteals in the small intestine in the form of chyle
- Moved using skeletal muscles & pressure gradients. Valves prevent backflow
- Starts as lymphatic capillaries, they transport lymph around the body passing through lymph nodes
- Unite to form lymph trunks that drains into ducts and finally into veins
The principal trunks are:
- Lumbar – Lower limbs, pelvis, kidneys, adrenal glands & abdominal wall
- Intestinal – Stomach, intestines, pancreas, spleen & part of liver
- Bronchomediastinal – Thoracic wall, lung & heart
- Subclavian – Upper Limbs
- Jugular – Head & Neck
Thoracic Duct –
- Left side of the head neck, and chest, the left upper limb
- and the entire body inferior to the ribs.
Lumbar, intestinal, left jugular, left subclavian, left bronchomediastinal
Right lymphatic duct –
Receives lymph from the upper right side of the body.
- right jugular
- right subclavian
- right bronchomediastinal trunks
(surrounded by capsule)
Where stem cells divide and become immunocompetent
Red Bone Marrow
- B cells & pre-T cells form
- B Cells Mature
- Covered by capsule
- 2 lobes divided into lobules by trabeculae
- Outer Cortex and inner medulla
- Matures Pre T- Cells sent from red bone marrow
- T Cells mature in cortex and enter medulla
- Dendritic cells assist maturation process
- Epithelial cells educate pre-T cells
- Mature T cells migrate to nodes, spleen and other lymphatic tissues
each is surrounded by a connective tissue capsule
- Covered by capsule
- Scattered throughout body
- Lymph nodes act as a filter that traps & destroys slowed foreign substances
- Divided into compartments by trabeculae, alongside fibers & fibroblasts forms a supporting framework(Stroma) & route for blood vessels
- Parenchyma (functioning part) divided into superficial cortex and a deep medulla
- Outer cortex contains egg-shaped aggregates of B cells called lymphatic nodules (follicles)
- Secondary lymphatic nodules form in response to an antigen. Contains germinal center
- In GC, Follicular dendritic cells present antigen resulting in B Cells producing antibody-producing plasma cells & memory B cells
- Inner cortex contains T Cells that migrate to antigen site
- Medulla contains B cells(plasma cells) that produces antibodies
- Surrounded by a serous membrane(visceral peritoneum) & a capsule
- Stroma formed by trabeculae, fibers & fibroblasts
- Parenchyma contains white pulp(lymphocytes) & red pulp (blood filled sinuses) & splenic cords(RBC, plasma & other cells)
- B cells & T cells in white pulp carries out immune functions & destruction
- Red Pulp destroys old blood cells, stores blood & produces blood(fetal)
- Egg shaped with no capsule( not an organ)
- Some in nodes
- Rest scattered throughout lamina of mucus membranes that line tracts & airways
- Referred to as mucosa-associated lymphatic tissue (MALT)
- Contain lymphocytes and macrophages that protect against bacteria & other pathogens
- Can be solitary, but many in clusters such as:
- Tonsils in mucosa of pharynx
- Peyer’s patches in mucosa that lines the ileum of the small intestine
- Appendix attached to large intestine
- First line of defense – physical & chemical
- Second line – Internal defences
First line of defense
- First line of defense – skin & mucous membranes
- Skin – physical barrier – sheds to remove microbes
- Mucous membranes – lines cavities – traps microbes
- Cilia – traps & filters – propels towards throat
- Coughing, sneezing, swallowing(gastric juice)
- Lacrimal apparatus produces: Tears(spread by blinking) – washes irritants – contains lysozyme that breaks down some bacteria
- Lysozyme also present in: saliva, perpiration, nasal secretions & tissue fluids
- Saliva – washes teeth & mouth and reduces microbes
- Urethra cleansing
- Vaginal secretions & defecation and vomiting also expel microbes.
- Sebaceous glands produce oil called sebum(fatty acids) – protects skin by inhibiting bacteria & fungi growth
- Perspiration helps flush microbes
- Gastric juice destroys microbes
Second line of defense
- Internal antimicrobial substances
- Natural killer cells
Antimicrobial substances –
- interferons – diffuse to uninfected cells – proteins stop viral replication
- complement – plasma proteins enhance immune reactions
- iron-binding proteins – reduces iron to inhibit bacteria growth
- antimicrobial proteins(AMPs) – kills microbes – attracts additional cells
Natural killer cells
- Kills wide variety of cells
- Attacks abnormal plasma membrane protein cells
- Releases granules – Perforin & granzymes
- Perforin(protein) – creates channels that fluid flow in to causing it to burst
- Granzymes(enzymes) – induces cell to self destruct
- Kills cells but not the microbes
- Ingest microbes
- Macrophages(enlarged monocytes) – wandering & fixed
- Migrate to infected area
- 5 phases:
- chemotaxis – chemically stimulated movement to site of damage
- adherence – attachment to microbe
- ingestion – projections(pseduopods) – engulf & fuse – sac
- digestion – merge with lysozyme – breaks down & degrades microbe. Forms lethal oxidants(oxidative burst)
- killing – lysozyme, enzymes & oxidants kill
- Responds to tissue damage
- redness, pain, heat & swelling
- disposes of microbes, toxins & foreign material to prevent spread
- prepares site for repair
- Vasodilation & blood vessel permeability increase – more blood & proteins(antibodies & clotting factors producing fibrin mesh)
- Produces heat, redness, edema & pain
- phagocyte movement – Phagocytosis occurs
- tissue repair
- Bacterial toxins elevate body temp
- Intensifies interferons, inhibits microbe growth & speeds repair
- Specificity for particular antigens
- Memory for previous antigen encounters
- Maturation causes immunocompetence
- Proteins insert into plasma membranes of B cells & T cells – some are antigen receptors
- Helper T Cells – CD4 T Cells – Aid both types of immunity
- Cytotoxic T Cells – CD8 T Cells – Cell- mediated immunity – attacking cells
- Plasma Cells – Secrete Antibodies – Antibody mediated immunity – Outside cells – AKA humoral immunity
- Memory B Cells – Remember antigens
- Correct antigen receptors needed
- Mixed group of cells attend – CD4, CD8 & B cells
- Both immunity types often occur – inside & outside cells
- Upon spotting an antigen, cells proliferate (divide) & differentiate (specialize) during clonal selection – creates:
- Effector (E) – Die out after response
- Memory (M) – Live long lives
Helper T cell (CD4) clones create:
- Helper T cells(E)
- Memory T cells(M)
Cytotoxic T cell (CD8) clones create:
- Cytotoxic T cells(E)
- Memory Helper cytotoxic T cells(M)
B Cell clones create:
- Plasma cells(E)
- Imunogenicity – Ability to provoke antibody response
- Reactivity – How effective antibodies are against it
- Entire microbes or parts (Epitopes) of microbes may act as antigens
- Enter via: Bloodstream, MALT entrapment, skin(into lymph nodes via vessels
- A Hapten needs to attach to larger molecules to provoke immune response
- Autoimmune disorders cause failure to spot friend (self) from foe (nonself)
Major Histocompatibility Complex Antigens(MHC)
- Self-antigens located in plasma membranes
- AKA Human leukocyte antigens(HLA) – Unique
- Marks the surface of cells(not RBC)
- Help T cells recognize that an antigen is foreign, not self
- Class I- Built into the plasma membranes (not RBC)
- Class II – On the surface of antigen-presenting cells
- Exogenous antigens – outside body cells
- Requires antigen-presenting cells (APCs)
- Dendritic, macrophages, B cells: located strategically
- Migrate to tissues after processing to present the antigen to T Cells
- Self cells are ignored, only foreign cells are processed
- Ingestion – Phagocytosis or endocytosis
- Digestion – Enzymes split antigens into short peptide fragments
- Synthesis – MHC-II molecules are created at the ER
- Packaging – Packed into vesicles
- Fusion – Peptide fragments & MHC-II molecules merge & fuse
- Binding – Peptides bind to MHC-II
- Insertion – Antigen–MHC-II complexes are inserted into plasma membrane
- Migration to lymphatic tissue to present antigen to T cells
- Killing time!
- Endogenous antigens – inside body cells
- All Cells can process & present endogenous antigens
- Digestion – Enzymes split antigens into short peptide fragments
- Synthesis – MHC-I molecules are created at the ER
- Binding – Peptides bind to MHC-I
- Packaging – Packed into vesicles
- Insertion – Antigen–MHC-I complexes are inserted into plasma membrane
- Cell Needs Help – Go kill Em!
- Many cells secrete small protein hormones called cytokines.
- Cytokines stimulate or inhibit cell functions
- Most T-Cells are inactive & require two signals to activate
- The first signal is antigen recognition
- Antigen receptors (TCRs) & additional CD4 or CD 8 proteins (Co-receptors) recognize and bind to specific antigens presented in antigen- MHC complexes to maintain TCR-MHC coupling
- The second signal is co-stimulation
- Some co-stimulators are cytokines, others are paired plasma membrane molecules( 1 on T cell, 1 on APC)
- Activation is achieved once both signals are received, if only one is used, inactivity is caused (anergy)
Helper T cells Activation
- CD4 cells recognize exogenous antigens with MHC II on APCs
- CD4’s and APC’s interact, costimulation occurs and the T cell acitvates
- Clonal selection occurs- active helper T-cells & memory helper T-cells are created
- Helper T-cells produce interleukin-2(IL-2)
- IL-2 is the main trigger for T-Cell proliferation(division) & enhances all cell activation and proliferation. It can act as a co-stimulator
Cytotoxic T Cells Activation
- CD8 cells recognize antigens with MHC-I on body & tumour cells as well as transplant cells
- Activation requires costimulation by IL-2 or other cytokines
- The IL-2 comes from active helper T-Cells bound from the same antigen
- So maximum activation requires antigen presentation from MHC-I(body cells) & MHC-II(helper T) molecules
- Clonal selection occurs- active cytotoxic T-cells & memory cytotoxic T-cells are created
- Cytotoxic T-cells attack!
- Memory cytotoxic quickly proliferate and differentiate into more cells in the future if they spot the same antigen
- Cytotoxic T cells are the soldiers & are specialized whereas NKC’s are generalized
- Kill using either:
- Granzymes that trigger apoptosis(self destruction)
- Perforin that creates channels, fluid flows in and causes cytolysis(cell bursting). Granulysin enter channels creating membrane holes.
- Cancerous cells display tumor antigens
- Can then recognize as nonself
- Killed by cytotoxic T cells, macrophages & natural killer cells
- Unlike T-Cells that seek out & destroy antigens, B-Cells stay put in lymph tissue
- B-Cells activate when they spot a foreign antigen
- Clonal selection occurs, creating plasma cells & memory cells
- Plasma cells(effector) circulate in lymph & blood to reach the invasion site
- Antigen binds to B-Cell receptor(BCR)
- Can respond to unprocessed antigens, but work better with processed ones
- Processing occurs when: Antigen broken down into peptide fragments & combined with MHC-II complex – moved to membrane
- Helper T-Cells recognize the Antigen-MHC-II complex, so costimulated using IL-2(& other cytokines)
- Clonal selection occurs resulting in plasma & memory B cells
- Plasma cells secrete antibodies, then die, antibodies travel to invasion site
- Memory B cells quickly proliferate and differentiate into more cells in the future if they spot the same antigen
- Clone B cells can only secrete the identical antibody of the initial B cell
- So if a different antigen turns up, a different predestined B-cell is required to counter it(through gene segment combinations)
- Combines specifically with the epitope of the antigen
- Antibodies are globulins(glycoproteins)
- Four polypeptide chains
- Two chains are heavy chains – 450 amino acids – Forms the stem region
- Two chains are light chains – 220 amino acids
- A disulfide bond connects the two
- Two disulfide bonds links the flexible mid-region of the heavy chains called the hinge region
- Antibodies can form a T shape or Y shape
- The tips of the H & L chains are the variable regions containing the antigen binding sites (bivalent)
- The remainder of the H & L chains are the constant regions responsible for the antigen-antibody reaction
- 5 antibody classes: IgM, IgG, IgA, IgD, IgE
- Neutralize – blocks toxins & prevents virus attachment
- immobilize – stops movement
- agglutination(clumping) – Easier to ingest
- activate complement – Initiates classical pathway
- & enhance phagocytosis – Attracts phagocytes
- Defensive system
- Liver proteins in blood plasma
- Destroys microbes
- Inactive C1–C9 complement proteins activate when split by enzymes
- Act in a cascade resulting in amplified starting with C3
- C3 is inactive, C3a & C3b are active
- The active fragments carry out the destructive actions
- Due to the presence of long-lasting antibodies & lymphocytes(from clonal selection)
- Immune responses are much quicker second time around
- Measured by antibody titer – amount of antibody in serum
- Primary response – slow rise in antibodies – Igm, IgG etc
- Secondary response – Future encounters increase the antibody titer – More successful
- Primary and secondary responses occur during microbial infection
- Immunological memory provides the basis for immunization by vaccination against certain diseases
THE LYMPHATIC SYSTEM, DISEASE RESISTANCE, AND HOMEOSTASIS
The lymphatic system contributes to homeostasis by draining interstitial fluid as well as providing the mechanisms for defense against disease
Maintaining homeostasis in the body requires continual combat against harmful agents in our internal and external environment. Despite constant exposure to a variety of pathogens (PATH-o¯-jens) disease producing microbes such as bacteria and viruses—most people remain healthy. The body surface also endures cuts and bumps, exposure to ultraviolet rays, chemical toxins, and minor burns with an array of defensive ploys.
Immunity or resistance is the ability to ward off damage or disease through our defenses. Vulnerability or lack of resistance is termed susceptibility.
The two general types of immunity are:
- (1) innate
- (2) adaptive
Innate (nonspecific) immunity refers to defenses that are present at birth. Innate immunity does not involve specific recognition of a microbe and acts against all microbes in the same way. Among the components of innate immunity are the:
- First line of defense (the physical and chemical barriers of the skin and mucous membranes)
- Second line of defense (antimicrobial substances, natural killer cells, phagocytes, inflammation, and fever)
Innate immune responses represent immunity’s early warning system and are designed to prevent microbes from gaining access into the body and to help eliminate those that do gain access.
Adaptive (specific) immunity refers to defenses that involve specific recognition of a microbe once it has breached the innate immunity defenses. Adaptive immunity is based on a specific response to a specific microbe; that is, it adapts or adjusts to handle a specific microbe.
Adaptive immunity involves lymphocytes (a type of white blood cell) called T lymphocytes (T cells) and B lymphocytes (B cells). The body system responsible for adaptive immunity (and some aspects of innate immunity) is the lymphatic system. This system is closely allied with the cardiovascular system, and it also functions with the digestive system in the absorption of fatty foods.
Explore mechanisms that provide defenses against intruders and promote the repair of damaged body tissues.
LYMPHATIC SYSTEM STRUCTURE AND FUNCTION
- List the components and major functions of the lymphatic system
- Describe the organization of lymphatic vessels
- Explain the formation and flow of lymph
- Compare the structure and functions of the primary and secondary lymphatic organs and tissues
The lymphatic system (lim-FAT-ik) consists of a fluid called lymph, vessels called lymphatic vessels that transport the lymph, a number of structures and organs containing lymphatic tissue (lymphocytes within a filtering tissue), and red bone marrow.
The lymphatic system assists in circulating body fluids and helps defend the body against disease-causing agents.
Most components of blood plasma filter through blood capillary walls to form interstitial fluid. After interstitial fluid passes into lymphatic vessels, it is called lymph (LIMF clear fluid).
The major difference between interstitial fluid and lymph is location: Interstitial fluid is found between cells, and lymph is located within lymphatic vessels and lymphatic tissue.
Lymphatic tissue is a specialized form of reticular connective tissue that contains large numbers of lymphocytes(agranular white blood cells)
Two types of lymphocytes participate in adaptive immune responses:
- B cells
- T cells
Functions of the Lymphatic System
The lymphatic system has three primary functions:
- Drains excess interstitial fluid. Lymphatic vessels drain excess interstitial fluid from tissue spaces and return it to the blood
- Transports dietary lipids. Lymphatic vessels transport lipids and lipid-soluble vitamins (A, D, E, and K) absorbed by the gastrointestinal tract
- Carries out immune responses. Lymphatic tissue initiates highly specific responses directed against particular microbes or abnormal cells.
Lymphatic Vessels and Lymph Circulation
Lymphatic vessels begin as lymphatic capillaries. These capillaries, which are located in the spaces between cells, are closed at one end.
Just as blood capillaries converge to form venules and then veins, lymphatic capillaries unite to form larger lymphatic vessels, which resemble small veins in structure but have thinner walls and more valves.
At intervals along the lymphatic vessels, lymph flows through lymph nodes, encapsulated bean-shaped organs consisting of masses of B cells and T cells.
- In the skin, lymphatic vessels lie in the subcutaneous tissue and generally follow the same route as veins
- Lymphatic vessels of the viscera generally follow arteries, forming plexuses (networks) around them.
Tissues that lack lymphatic capillaries include avascular tissues (such as cartilage, the epidermis, and the cornea of the eye), the central nervous system, portions of the spleen, and red bone marrow.
Lymphatic capillaries have greater permeability than blood capillaries and thus can absorb large molecules such as proteins and lipids. Lymphatic capillaries are also slightly larger in diameter than blood capillaries and have a unique one-way structure that permits interstitial fluid to flow into them but not out.
The ends of endothelial cells that make up the wall of a lymphatic capillary overlap.
When pressure is greater in the interstitial fluid than in lymph, the cells separate slightly, like the opening of a one-way swinging door, and interstitial fluid enters the lymphatic capillary. When pressure is greater inside the lymphatic capillary, the cells adhere more closely, and lymph cannot escape back into interstitial fluid. The pressure is relieved as lymph moves further down the lymphatic capillary.
Attached to the lymphatic capillaries are anchoring filaments, which contain elastic fibers. They extend out from the lymphatic capillary, attaching lymphatic endothelial cells to surrounding tissues. When excess interstitial fluid accumulates and causes tissue swelling, the anchoring filaments are pulled, making the openings between cells even larger so that more fluid can flow into the lymphatic capillary.
In the small intestine, specialized lymphatic capillaries called lacteals (LAK-te¯-als; lact- milky) carry dietary lipids into lymphatic vessels and ultimately into the blood. The presence of these lipids causes the lymph draining from the small intestine to appear creamy white; such lymph is referred to as chyle. Elsewhere, lymph is a clear, pale-yellow fluid.
Lymph Trunks and Ducts
As you have already learned, lymph passes from lymphatic capillaries into lymphatic vessels and then through lymph nodes. As lymphatic vessels exit lymph nodes in a particular region of the body, they unite to form lymph trunks.
The principal trunks are:
The lumbar trunks drain lymph from the lower limbs, the wall and viscera of the pelvis, the kidneys, the adrenal glands, and the abdominal wall.
The intestinal trunk drains lymph from the stomach, intestines, pancreas, spleen, and part of the liver.
The bronchomediastinal trunks (brong-ko¯- me¯-de¯-as-TI¯-nal) drain lymph from the thoracic wall, lung, and heart.
The subclavian trunks drain the upper limbs.
The jugular trunks drain the head and neck.
Lymph passes from lymph trunks into two main channels:
- the thoracic duct
- the right lymphatic duct
and then drains into venous blood.
The thoracic duct is about 38–45 cm long and begins as a dilation called the cisterna chyli (sis-TER-na KI¯-le¯; cisterna cavity or reservoir) anterior to the second lumbar vertebra.
The thoracic duct is the main duct for the return of lymph to blood. The cisterna chyli receives lymph from the:
- right and left lumbar trunks
- intestinal trunk
In the neck, the thoracic duct also receives lymph from the:
- left jugular
- left subclavian
- left bronchomediastinal trunks
Therefore, the thoracic duct receives lymph from the:
- Left side of the head neck, and chest, the left upper limb
- and the entire body inferior to the ribs.
The thoracic duct in turn drains lymph into venous blood at the junction of the left internal jugular and left subclavian veins.
The right lymphatic duct is about 1.2 cm long and receives lymph from:
- right jugular
- right subclavian
- right bronchomediastinal trunks
Thus, the right lymphatic duct receives lymph from the upper right side of the body.
From the right lymphatic duct, lymph drains into venous blood at the junction of the right internal jugular and right subclavian veins.
Formation and Flow of Lymph
Most components of blood plasma, such as nutrients, gases, and hormones, filter freely through the capillary walls to form interstitial fluid, but more fluid filters out of blood capillaries than returns to them by reabsorption. The excess filtered fluid-about 3 liters per day drains into lymphatic vessels and becomes lymph.
Because most plasma proteins are too large to leave blood vessels, interstitial fluid contains only a small amount of protein. Proteins that do leave blood plasma cannot return to the blood by diffusion because the concentration gradient (high level of proteins inside blood capillaries, low level outside) opposes such movement. The proteins can, however, move readily through the more permeable lymphatic capillaries into lymph. Thus, an important function of lymphatic vessels is to return the lost plasma proteins and plasma to the bloodstream.
Like veins, lymphatic vessels contain valves, which ensure the one-way movement of lymph. As noted previously, lymph drains into venous blood through the right lymphatic duct and the thoracic duct at the junction of the internal jugular and subclavian veins.
Thus, the sequence of fluid flow is:
- blood capillaries (blood)
- interstitial spaces (interstitial fluid)
- lymphatic capillaries (lymph)
- lymphatic vessels (lymph)
- lymphatic ducts (lymph)
- junction of the internal jugular and subclavian veins (blood).
The relationship between the lymphatic system & the cardiovascular systems form a very efficient circulatory system.
The same two “pumps” that aid the return of venous blood to
the heart maintain the flow of lymph.
- Skeletal muscle pump. The “milking action” of skeletal muscle contractions compresses lymphatic vessels (as well as veins) and forces lymph toward the junction of the internal jugular and subclavian veins
- Respiratory pump. Lymph flow is also maintained by pressure changes that occur during inhalation (breathing in).
Lymph flows from the abdominal region, where the pressure is higher, toward the thoracic region, where it is lower. When the pressures reverse during exhalation (breathing out), the valves in lymphatic vessels prevent backflow of lymph. In addition, when a lymphatic vessel distends, the smooth muscle in its wall contracts, which helps move lymph from one segment of the vessel to the next.
Lymphatic Organs and Tissues
The widely distributed lymphatic organs and tissues are classified into two groups based on their functions.
Primary lymphatic organs
are the sites where stem cells divide and become immunocompetent (im-u¯-no¯-KOM-pe-tent), that is, capable of mounting an immune response.
The primary lymphatic organs are the:
- Red bone marrow (in flat bones and the epiphyses of long bones of adults) and the thymus.
- Pluripotent stem cells in red bone marrow give rise to mature, immunocompetent B cells and to pre-T cells.
- The pre-T cells in turn migrate to the thymus, where they become immunocompetent T cells.
Secondary lymphatic organs and tissues
are the sites where most immune responses occur.
- lymph nodes
- the spleen
- lymphatic nodules (follicles)
The thymus, lymph nodes, and spleen are considered organs because each is surrounded by a connective tissue capsule.
Lymphatic nodules, in contrast, are not considered organs because they lack a capsule.
The thymus is a bilobed organ located in the mediastinum between the sternum and the aorta.
An enveloping layer of connective tissue holds the two lobes closely together, but a connective tissue capsule separates the two. Extensions of the capsule, called trabeculae (tra-BEK-u¯-le¯ little beams), penetrate inward and divide each lobe into lobules.
Each thymic lobule consists of a deeply staining outer cortex and a lighter-staining central medulla. The cortex is composed of large numbers of:
- T cells
- Scattered dendritic cells
- Epithelial cells
- and macrophages.
Immature T cells (pre-T cells) migrate from red bone marrow to the cortex of the thymus, where they proliferate and begin to mature.
Dendritic cells (den-DRIT-ik; dendr-a tree), which are derived from monocytes, and so named because they have long, branched projections that resemble the dendrites of a neuron, assist the maturation process. Dendritic cells in other parts of the body, such as lymph nodes, play another key role in immune responses.
Each of the specialized epithelial cells in the cortex has several long processes that surround and serve as a framework for as many as 50 T cells. These epithelial cells help “educate” the pre-T cells in a process known as positive selection.
Additionally, they produce thymic hormones that are thought to aid in the maturation of T cells.
Only about 2% of developing T cells survive in the cortex. The remaining cells die via apoptosis (programmed cell death).
Thymic macrophages help clear out the debris of dead and dying cells. The surviving T cells enter the medulla.
The medulla consists of widely scattered:
- Mature T cells
- Epithelial cells
- Dendritic cells
Some of the epithelial cells become arranged into concentric layers of flat cells that degenerate and become filled with keratohyalin granules and keratin. These clusters are called thymic (Hassall’s) corpuscles. Although their role is uncertain, they may serve as sites of T cell death in the medulla.
T cells that leave the thymus via the blood migrate to lymph nodes, the spleen, and other lymphatic tissues, where they colonize parts of these organs and tissues.
Because of its high content of lymphoid tissue and a rich blood supply, the thymus has a reddish appearance in a living body. With age, however, fatty infiltrations replace the lymphoid tissue and the thymus takes on more of the yellowish color of the invading fat, giving the false impression of reduced size.
However, the actual size of the thymus, defined by its connective tissue capsule, does not change. In infants, the thymus has a mass of about 70 g (2.3 oz). It is after puberty that adipose and areolar connective tissue begin to replace the thymic tissue. By the time a person reaches maturity, the functional portion of the gland is reduced considerably, and in old age the functional portion may weigh only 3 g (0.1 oz).
Before the thymus atrophies, it populates the secondary lymphatic organs and tissues with T cells. However, some T cells continue to proliferate in the thymus throughout an individual’s lifetime, but this number decreases with age.
Located along lymphatic vessels are about 600 bean-shaped lymph nodes.
They are scattered throughout the body, both superficially and deep, and usually occur in groups. Large groups of lymph nodes are present near the mammary glands and in the axillae and groin.
Lymph nodes are 1–25 mm (0.04–1 in.) long and, like the thymus, are covered by a capsule of dense connective tissue that extends into the node. The capsular extensions, called trabeculae (tra-BEK-u¯-le¯), divide the node into compartments, provide support, and provide a route for blood vessels into the interior of a node.
Internal to the capsule is a supporting network of reticular fibers and fibroblasts. The capsule, trabeculae, reticular fibers, and fibroblasts constitute the stroma (supporting framework of connective tissue) of a lymph node.
The parenchyma (functioning part) of a lymph node is divided into a superficial cortex and a deep medulla.
The cortex consists of an outer cortex and an inner cortex. Within the outer cortex are egg-shaped aggregates of B cells called lymphatic nodules (follicles).
A lymphatic nodule consisting chiefly of B cells is called a primary lymphatic nodule.
Most lymphatic nodules in the outer cortex are secondary lymphatic nodules, which form in response to an antigen (a foreign substance) and are sites of plasma cell and memory B cell formation. After B cells in a primary lymphatic nodule recognize an antigen, the primary lymphatic nodule develops into a secondary lymphatic nodule.
The center of a secondary lymphatic nodule contains a region of light staining cells called a germinal center.
In the germinal center are:
- B cells
- Follicular dendritic cells (a special type of dendritic cell)
- and macrophages
When follicular dendritic cells “present” an antigen, B cells proliferate and develop into antibody-producing plasma cells or develop into memory B cells.
Memory B cells persist after an initial immune response and “remember” having encountered a specific antigen. B cells that do not develop properly undergo apoptosis (programmed cell death) and are destroyed by macrophages.
The region of a secondary lymphatic nodule surrounding the germinal center is composed of dense accumulations of B cells that have migrated away from their site of origin within the nodule.
The inner cortex does not contain lymphatic nodules. It consists mainly of:
- T cells and
- Dendritic cells
that enter a lymph node from other tissues.
The dendritic cells present antigens to T cells, causing their proliferation. The newly formed T cells then migrate from the lymph node to areas of the body where there is antigenic activity.
The medulla of a lymph node contains B cells, antibody producing plasma cells that have migrated out of the cortex into the medulla, and macrophages. The various cells are embedded in a network of reticular fibers and reticular cells.
Lymph flows through a node in one direction only. It enters through several afferent lymphatic vessels (AF-er-ent; afferent to carry toward), which penetrate the convex surface of the node at several points. The afferent vessels contain valves that open toward the center of the node, directing the lymph inward.
Within the node, lymph enters sinuses, a series of irregular channels that contain branching reticular fibers, lymphocytes, and macrophages.
From the afferent lymphatic vessels, lymph flows into the subcapsular sinus (sub-KAP-soo-lar), immediately beneath the capsule. From here the lymph flows through trabecular sinuses (tra-BEK-u¯-lar), which extend through the cortex parallel to the trabeculae, and into medullary sinuses, which extend through the medulla.
The medullary sinuses drain into one or two efferent lymphatic vessels (EF-er-ent; efferent to carry away), which are wider and fewer in number than afferent vessels. They contain valves that open away from the center of the lymph node to convey lymph, antibodies secreted by plasma cells, and activated T cells out of the node. Efferent lymphatic vessels emerge from one side of the lymph node at a slight depression called a hilum (HI¯-lum) or hilus. Blood vessels also enter and leave the node at the hilum.
Lymph nodes function as a type of filter. As lymph enters one end of a lymph node, foreign substances are trapped by the reticular fibers within the sinuses of the node. Then macrophages destroy some foreign substances by phagocytosis, while lymphocytes destroy others by immune responses.
The filtered lymph then leaves the other end of the lymph node. Since there are many afferent lymphatic vessels that bring lymph into a lymph node and only one or two efferent lymphatic vessels that transport lymph out of a lymph node, the slow flow of lymph within the lymph nodes allows additional time for lymph to be filtered.
Additionally, all lymph flows through multiple lymph nodes on its path through the lymph vessels. This exposes the lymph to multiple filtering events before returning to the blood.
The oval spleen is the largest single mass of lymphatic tissue in the body, measuring about 12 cm (5 in.) in length.
It is located in the left hypochondriac region between the stomach and diaphragm. The superior surface of the spleen is smooth and convex and conforms to the concave surface of the diaphragm.
Neighboring organs make indentations in the visceral surface of the spleen:
- the gastric impression (stomach)
- the renal impression (left kidney)
- and the colic impression (left colic flexure of large intestine).
Like lymph nodes, the spleen has a hilum. Through it pass the splenic artery, splenic vein, and efferent lymphatic vessels.
A capsule of dense connective tissue surrounds the spleen and is covered in turn by a serous membrane, the visceral peritoneum.
Trabeculae extend inward from the capsule. The capsule plus trabeculae, reticular fibers, and fibroblasts constitute the stroma of the spleen.
The parenchyma of the spleen consists of two different kinds of tissue called white pulp and red pulp.
White pulp is lymphatic tissue, consisting mostly of lymphocytes and macrophages arranged around branches of the splenic artery called central arteries.
The red pulp consists of blood filled venous sinuses and cords of splenic tissue called splenic (Billroth’s) cords. Splenic cords consist of red blood cells, macrophages, lymphocytes, plasma cells, and granulocytes. Veins are closely associated with the red pulp.
Blood flowing into the spleen through the splenic artery enters the central arteries of the white pulp.
Within the white pulp, B cells and T cells carry out immune functions, similar to lymph nodes, while spleen macrophages destroy blood-borne pathogens by phagocytosis.
Within the red pulp, the spleen performs three functions related to blood cells:
- (1) removal by macrophages of ruptured, worn out, or defective blood cells and platelets;
- (2) storage of platelets, up to one-third of the body’s supply; and
- (3) production of blood cells (hemopoiesis) during fetal life.
Lymphatic nodules (follicles) are egg-shaped masses of lymphatic tissue that are not surrounded by a capsule.
Because they are scattered throughout the lamina propria (connective tissue) of mucous membranes lining the gastrointestinal, urinary, and reproductive tracts and the respiratory airways, lymphatic nodules in these areas are also referred to as mucosa-associated lymphatic tissue (MALT).
Although many lymphatic nodules are small and solitary, some occur in multiple large aggregations in specific parts of the body.
Among these are the tonsils in the pharyngeal region and the aggregated lymphatic follicles (Peyer’s patches) in the ileum of the small intestine. Aggregations of lymphatic nodules also occur in the appendix.
Usually there are five tonsils, which form a ring at the junction of the oral cavity and oropharynx and at the junction of the nasal cavity and nasopharynx. The tonsils are strategically positioned to participate in immune responses against inhaled or ingested foreign substances.
The single pharyngeal tonsil (fa-RIN-je¯-al) or adenoid is embedded in the posterior wall of the nasopharynx. The two palatine tonsils (PAL-a-tı¯n) lie at the posterior region of the oral cavity, one on either side; these are the tonsils commonly removed in a tonsillectomy. The paired lingual tonsils (LIN-gwal), located at the base of the tongue, may also require removal during a tonsillectomy.
DEVELOPMENT OF LYMPHATIC TISSUES
Lymphatic tissues begin to develop by the end of the fifth week of embryonic life. Lymphatic vessels develop from lymph sacs that arise from developing veins, which are derived from mesoderm.
The first lymph sacs to appear are the paired jugular lymph sacs at the junction of the internal jugular and subclavian veins. From the jugular lymph sacs, lymphatic capillary plexuses spread to the thorax, upper limbs, neck, and head.
Some of the plexuses enlarge and form lymphatic vessels in their respective regions. Each jugular lymph sac retains at least one connection with its jugular vein, the left one developing into the superior portion of the thoracic duct (left lymphatic duct).
The next lymph sac to appear is the unpaired retroperitoneal lymph sac (ret-ro¯ -per-i-to¯-NE¯ -al) at the root of the mesentery of the intestine. It develops from the primitive vena cava and mesonephric (primitive kidney) veins. Capillary plexuses and lymphatic vessels spread from the retroperitoneal lymph sac to the abdominal viscera and diaphragm.
The sac establishes connections with the cisterna chyli but loses its connections with neighboring veins.
At about the time the retroperitoneal lymph sac is developing, another lymph sac, the cisterna chyli (sis-TER-na KI¯-le¯), develops inferior to the diaphragm on the posterior abdominal wall. It gives rise to the inferior portion of the thoracic duct and the cisterna chyli of the thoracic duct. Like the retroperitoneal lymph sac, the cisterna chyli also loses its connections with surrounding veins.
The last of the lymph sacs, the paired posterior lymph sacs, develop from the iliac veins. The posterior lymph sacs produce capillary plexuses and lymphatic vessels of the abdominal wall, pelvic region, and lower limbs. The posterior lymph sacs join the cisterna chyli and lose their connections with adjacent veins.
With the exception of the anterior part of the sac from which the cisterna chyli develops, all lymph sacs become invaded by mesenchymal cells (me-SENG-kı¯-mal) and are converted into groups of lymph nodes.
The spleen develops from mesenchymal cells between layers of the dorsal mesentery of the stomach. The thymus arises as an outgrowth of the third pharyngeal pouch.
- Describe the components of innate immunity
- Innate (nonspecific) immunity includes the external physical and chemical barriers provided by the skin and mucous membranes
- It also includes various internal defenses, such as antimicrobial substances, natural killer cells, phagocytes, inflammation, and fever
First Line of Defense: Skin and Mucous Membranes
The skin and mucous membranes of the body are the first line of defense against pathogens. These structures provide both physical and chemical barriers that discourage pathogens and foreign substances from penetrating the body and causing disease.
With its many layers of closely packed, keratinized cells, the outer epithelial layer of the skin—the epidermis—provides a formidable physical barrier to the entrance of microbes.
In addition, periodic shedding of epidermal cells helps remove microbes at the skin surface. Bacteria rarely penetrate the intact surface of healthy epidermis. If this surface is broken by cuts, burns, or punctures, however, pathogens can penetrate the epidermis and invade adjacent tissues or circulate in the blood to other parts of the body.
The epithelial layer of mucous membranes, which line body cavities, secretes a fluid called mucus that lubricates and moistens the cavity surface. Because mucus is slightly viscous, it traps many microbes and foreign substances.
The mucous membrane of the nose has mucus-coated hairs that trap and filter microbes, dust, and pollutants from inhaled air. The mucous membrane of the upper respiratory tract contains cilia, microscopic hairlike projections on the surface of the epithelial cells. The waving action of cilia propels inhaled dust and microbes that have become trapped in mucus toward the throat. Coughing and sneezing accelerate movement of mucus and its entrapped pathogens out of the body. Swallowing mucus sends pathogens to the stomach, where gastric juice destroys them.
Other fluids produced by various organs also help protect epithelial surfaces of the skin and mucous membranes. The lacrimal apparatus (LAK-ri-mal) of the eyes manufactures and drains away tears in response to irritants.
Blinking spreads tears over the surface of the eyeball, and the continual washing action of tears helps to dilute microbes and keep them from settling on the surface of the eye.
Tears also contain lysozyme (LI¯-so-zı¯m), an enzyme capable of breaking down the cell walls of certain bacteria. Besides tears, lysozyme is present in:
- nasal secretions
- tissue fluids
Saliva, produced by the salivary glands, washes microbes from the surfaces of the teeth and from the mucous membrane of the mouth, much as tears wash the eyes. The flow of saliva reduces colonization of the mouth by microbes.
The cleansing of the urethra by the flow of urine retards microbial colonization of the urinary system. Vaginal secretions likewise move microbes out of the body in females. Defecation and vomiting also expel microbes.
For example, in response to some microbial toxins, the smooth muscle of the lower gastrointestinal tract contracts vigorously; the resulting diarrhea rapidly expels many of the microbes.
Certain chemicals also contribute to the high degree of resistance of the skin and mucous membranes to microbial invasion. Sebaceous (oil) glands of the skin secrete an oily substance called sebum that forms a protective film over the surface of the skin. The unsaturated fatty acids in sebum inhibit the growth of certain pathogenic bacteria and fungi.
The acidity of the skin (pH 3–5) is caused in part by the secretion of fatty acids and lactic acid. Perspiration helps flush microbes from the surface of the skin. Gastric juice, produced by the glands of the stomach, is a mixture of hydrochloric acid, enzymes, and mucus. The strong acidity of gastric juice (pH 1.2–3.0) destroys many bacteria and most bacterial toxins. Vaginal secretions also are slightly acidic, which discourages bacterial growth.
Second Line of Defense: Internal Defenses
When pathogens penetrate the physical and chemical barriers of the skin and mucous membranes, they encounter a second line of defense:
- internal antimicrobial substances
- natural killer cells
There are four main types of antimicrobial substances that discourage microbial growth:
- iron-binding proteins
- antimicrobial proteins
Lymphocytes, macrophages, and fibroblasts infected with viruses produce proteins called interferons (in-ter-FE¯ R-ons), or IFNs.
Once released by virus-infected cells, IFNs diffuse to uninfected neighboring cells, where they induce synthesis of antiviral proteins that interfere with viral replication. Although IFNs do not prevent viruses from attaching to and penetrating host cells, they do stop replication. Viruses can cause disease only if they can replicate within body cells.
IFNs are an important defense against infection by many different viruses. The three types of interferons:
A group of normally inactive proteins in blood plasma and on the plasma membranes makes up the complement system.
When activated, these proteins “complement” or enhance certain immune reactions. The complement system causes cytolysis (bursting) of microbes, promotes phagocytosis, and contributes to inflammation
Iron-binding proteins inhibit the growth of certain bacteria by reducing the amount of available iron.
- transferrin (found in blood and tissue fluids)
- lactoferrin (found in milk, saliva, and mucus)
- ferritin (found in the liver, spleen, and red bone marrow)
- hemoglobin (found in red blood cells)
Antimicrobial proteins (AMPs) are short peptides that have a broad spectrum of antimicrobial activity.
Examples of AMPs:
- dermicidin (der-ma-SI¯-din) (produced by sweat glands)
- defensins and cathelicidins (cath-el-i-SI¯-dins) (produced by neutrophils, macrophages, and epithelia)
- thrombocidin (throm-bo¯-SI¯-din) (produced by platelets)
Besides killing a wide range of microbes, AMPs can attract dendritic cells and mast cells, which participate in immune responses. Interestingly enough, microbes exposed to AMPs do not appear to develop resistance, as often happens with antibiotics.
Natural Killer Cells and Phagocytes
When microbes penetrate the skin and mucous membranes or bypass the antimicrobial substances in blood, the next nonspecific defense consists of natural killer cells and phagocytes.
About 5–10% of lymphocytes in the blood are natural killer (NK) cells. They are also present in the spleen, lymph nodes, and red bone marrow.
NK cells lack the membrane molecules that identify B and T cells, but they have the ability to kill a wide variety of infected body cells and certain tumor cells. NK cells attack any body cells that display abnormal or unusual plasma membrane proteins.
The binding of NK cells to a target cell, such as an infected human cell, causes the release of granules containing toxic substances from NK cells. Some granules contain a protein called perforin (PER-for-in) that inserts into the plasma membrane of the target cell and creates channels (perforations) in the membrane.
As a result, extracellular fluid flows into the target cell and the cell bursts, a process called cytolysis (sı¯-TOL-i-sis; cyto- cell; -lysis loosening).
Other granules of NK cells release granzymes (GRAN-zı¯ms), which are protein-digesting enzymes that induce the target cell to undergo apoptosis, or self-destruction.
This type of attack kills infected cells, but not the microbes inside the cells; the released microbes, which may or may not be intact, can be destroyed by phagocytes.
Phagocytes (FAG-o¯-sı¯ts; phago- eat; -cytes cells) are specialized cells that perform phagocytosis (fag-o¯-sı¯-TO¯ -sis; -osis process), the ingestion of microbes or other particles such as cellular debris.
The two major types of phagocytes are:
- macrophages (MAK-ro¯-fa¯-jez).
When an infection occurs, neutrophils and monocytes migrate to the infected area. During this migration, the monocytes enlarge and develop into actively phagocytic macrophages called wandering macrophages.
Other macrophages, called fixed macrophages, stand guard in specific tissues. Among the fixed macrophages are:
- histiocytes (HIS-te¯-o¯-sı¯ts) (connective tissue macrophages)
- stellate reticuloendothelial cells or Kupffer cells (KOOP-fer) in the liver
- alveolar macrophages in the lungs
- microglia in the nervous system
- and tissue macrophages in the spleen, lymph nodes, and red bone marrow.
In addition to being an innate defense mechanism, phagocytosis plays a vital role in adaptive immunity.
Phagocytosis occurs in five phases:
- and killing:
Phagocytosis begins with chemotaxis (ke¯-mo¯- TAK-sis), a chemically stimulated movement of phagocytes to a site of damage.
Chemicals that attract phagocytes might come from invading microbes, white blood cells, damaged tissue cells, or activated complement proteins
Attachment of the phagocyte to the microbe or other foreign material is termed adherence.
The binding of complement proteins to the invading pathogen enhances adherence.
The plasma membrane of the phagocyte extends projections, called pseudopods (SOO-do¯ -pods), that engulf the microbe in a process called ingestion. When the pseudopods meet, they fuse, surrounding the microorganism with a sac called a phagosome (FAG-o¯-so¯m)
The phagosome enters the cytoplasm and merges with lysosomes to form a single, larger structure called a phagolysosome (fag-o¯-LI¯ -so¯-so¯m).
The lysosome contributes lysozyme, which breaks down microbial cell walls, and other digestive enzymes that degrade carbohydrates, proteins, lipids, and nucleic acids. The phagocyte also forms lethal oxidants in a process called an oxidative burst
The chemical onslaught provided by lysozyme, digestive enzymes, and oxidants within a phagolysosome quickly kills many types of microbes. Any materials that cannot be degraded further remain in structures called residual bodies.
Inflammation is a nonspecific, defensive response of the body to tissue damage.
Among the conditions that may produce inflammation are:
- chemical irritations
- distortion or disturbances of cells
- and extreme temperatures
The four characteristic signs and symptoms of inflammation are:
Inflammation can also cause a loss of function in the injured area (for example, the inability to detect sensations), depending on the site and extent of the injury.
Inflammation is an attempt to dispose of:
- or foreign material
at the site of injury, to prevent their spread to other tissues, and to prepare the site for tissue repair in an attempt to restore tissue homeostasis.
Because inflammation is one of the body’s nonspecific defense mechanisms, the response of a tissue to a cut is similar to the response to damage caused by burns, radiation, or bacterial or viral invasion. In each case, the inflammatory response has three basic stages:
- (1) vasodilation and increased permeability of blood vessels
- (2) emigration (movement) of phagocytes from the blood into interstitial fluid
- (3) tissue repair.
VASODILATION AND INCREASED BLOOD VESSEL PERMEABILITY
Two immediate changes occur in the blood vessels in a region of tissue injury:
- vasodilation (increase in the diameter) of arterioles
- and increased permeability of capillaries.
Increased permeability means that substances normally retained in blood are permitted to pass from the blood vessels.
Vasodilation allows more blood to flow through the damaged area, and increased permeability permits defensive proteins such as antibodies and clotting factors to enter the injured area from the blood. The increased blood flow also helps remove microbial toxins and dead cells.
Among the substances that contribute to vasodilation, increased permeability, and other aspects of the inflammatory response are the following:
- Histamine. In response to injury, mast cells in connective tissue and basophils and platelets in blood release histamine. Neutrophils and macrophages attracted to the site of injury also stimulate the release of histamine, which causes vasodilation and increased permeability of blood vessels.
- Kinins. These polypeptides, formed in blood from inactive precursors called kininogens, induce vasodilation and increased permeability and serve as chemotactic agents for phagocytes. An example of a kinin is bradykinin.
- Prostaglandins (PGs) (pros-ta-GLAN-dins). These lipids, especially those of the E series, are released by damaged cells and intensify the effects of histamine and kinins. PGs also may stimulate the emigration of phagocytes through capillary walls.
- Leukotrienes (LTs) (loo-ko¯-TRI¯-e¯ns). Produced by basophils and mast cells, LTs cause increased permeability; they also function in adherence of phagocytes to pathogens and as chemotactic agents that attract phagocytes.
- Complement. Different components of the complement system stimulate histamine release, attract neutrophils by chemotaxis, and promote phagocytosis; some components can also destroy bacteria.
Dilation of arterioles and increased permeability of capillaries produce three of the signs and symptoms of inflammation:
- redness (erythema)
- and swelling (edema)
Heat and redness result from the large amount of blood that accumulates in the damaged area. As the local temperature rises slightly, metabolic reactions proceed more rapidly and release additional heat.
Edema results from increased permeability of blood vessels, which permits more fluid to move from blood plasma into tissue spaces.
Pain is a prime symptom of inflammation. It results from injury to neurons and from toxic chemicals released by microbes. Kinins affect some nerve endings, causing much of the pain associated with inflammation. Prostaglandins intensify and prolong the pain associated with inflammation. Pain may also be due to increased pressure from edema.
The increased permeability of capillaries allows leakage of blood-clotting factors into tissues. The clotting sequence is set into motion, and fibrinogen is ultimately converted to an insoluble, thick mesh of fibrin threads that localizes and traps invading microbes and blocks their spread.
EMIGRATION OF PHAGOCYTES
Within an hour after the inflammatory process starts, phagocytes appear on the scene. As large amounts of blood accumulate, neutrophils begin to stick to the inner surface of the endothelium (lining) of blood vessels).
Then the neutrophils begin to squeeze through the wall of the blood vessel to reach the damaged area. This process, called emigration, depends on chemotaxis. Neutrophils attempt to destroy the invading microbes by phagocytosis.
A steady stream of neutrophils is ensured by the production and release of additional cells from red bone marrow. Such an increase in white blood cells in the blood is termed leukocytosis (loo-ko¯-sı¯-TO¯ -sis). Although neutrophils predominate in the early stages of infection, they die off rapidly.
As the inflammatory response continues, monocytes follow the neutrophils into the infected area. Once in the tissue, monocytes transform into wandering macrophages that add to the phagocytic activity of the fixed macrophages already present.
True to their name, macrophages are much more potent phagocytes than neutrophils. They are large enough to engulf damaged tissue, worn-out neutrophils, and invading microbes. Eventually, macrophages also die.
Within a few days, a pocket of dead phagocytes and damaged tissue forms; this collection of dead cells and fluid is called pus. Pus formation occurs in most inflammatory responses and usually continues until the infection subsides. At times, pus reaches the surface of the body or drains into an internal cavity and is dispersed; on other occasions the pus remains even after the infection is terminated. In this case, the pus is gradually destroyed over a period of days and is absorbed.
Fever is an abnormally high body temperature that occurs because the hypothalamic thermostat is reset. It commonly occurs during infection and inflammation. Many bacterial toxins elevate body temperature, sometimes by triggering release of fever-causing cytokines such as interleukin-1 from macrophages. Elevated body temperature intensifies the effects of interferons, inhibits the growth of some microbes, and speeds up body reactions that aid repair.
- Define adaptive immunity, and describe how T cells and B cells arise
- Explain the relationship between an antigen and an antibody
- Compare the functions of cell-mediated immunity and antibody-mediated immunity
The ability of the body to defend itself against specific invading agents such as bacteria, toxins, viruses, and foreign tissues is called adaptive (specific) immunity. Substances that are recognized as foreign and provoke immune responses are called antigens (Ags) (AN-ti-jens), meaning antibody generators.
Two properties distinguish adaptive immunity from innate immunity:
- (1) specificity for particular foreign molecules (antigens), which also involves distinguishing self from nonself molecules, and
- (2) memory for most previously encountered antigens so that a second encounter prompts an even more rapid and vigorous response.
The branch of science that deals with the responses of the body when challenged by antigens is called immunology. The immune system includes the cells and tissues that carry out immune responses.
Maturation of T Cells and B Cells
Adaptive immunity involves lymphocytes called B cells and T cells.
Both develop in primary lymphatic organs (red bone marrow and the thymus) from pluripotent stem cells that originate in red bone marrow.
B cells complete their development in red bone marrow, a process that continues throughout life. T cells develop from pre-T cells that migrate from red bone marrow into the thymus, where they mature. Most T cells arise before puberty, but they continue to mature and leave the thymus throughout life.
B cells and T cells are named based on where they mature.
In birds, B cells mature in an organ called the bursa of Fabricius. Although this organ is not present in humans, the term B cell is still used, but the letter B stands for bursa equivalent, which is the red bone marrow since that is the location in humans where B cells mature. T cells are so named because they mature in the thymus gland.
Before T cells leave the thymus or B cells leave red bone marrow, they develop immunocompetence (im-u¯-no¯-KOM-petens), the ability to carry out adaptive immune responses.
This means that B cells and T cells begin to make several distinctive proteins that are inserted into their plasma membranes. Some of these proteins function as antigen receptors—molecules capable of recognizing specific antigens.
There are two major types of mature T cells that exit the thymus:
- Helper T cells
- Cytotoxic T cells.
Helper T cells are also known as CD4 T cells, which means that, in addition to antigen receptors, their plasma membranes include a protein called CD4.
Cytotoxic T cells are also referred to as CD8 T cells because their plasma membranes not only contain antigen receptors but also a protein known as CD8. These two types of T cells have very different functions.
Types of Adaptive Immunity
There are two types of adaptive immunity:
- cell-mediated immunity
- antibody-mediated immunity
Both types of adaptive immunity are triggered by antigens.
In cell-mediated immunity, cytotoxic T cells directly attack invading antigens.
In antibody-mediated immunity, B cells transform into plasma cells, which synthesize and secrete specific proteins called antibodies (Abs) or immunoglobulins (Igs) (im-u¯-no¯-GLOB-u¯-lins).
A given antibody can bind to and inactivate a specific antigen. Helper T cells aid the immune responses of both cell-mediated and antibody-mediated immunity.
Cell-mediated immunity is particularly effective against:
- intracellular pathogens, which include any viruses, bacteria, or fungi that are inside cells
- some cancer cells
- foreign tissue transplants.
Thus, cell-mediated immunity always involves cells attacking cells.
Antibody-mediated immunity works mainly against:
- extracellular pathogens, which include any
- or fungi that are in body fluids outside cells.
Since antibody mediated immunity involves antibodies that bind to antigens in body humors or fluids (such as blood and lymph), it is also referred to as humoral immunity.
In most cases, when a particular antigen initially enters the body, there is only a small group of lymphocytes with the correct antigen receptors to respond to that antigen;
This small group of cells includes a few:
- Helper T cells
- Cytotoxic T cells
- B cells
Depending on its location, a given antigen can provoke both types of adaptive immune responses. This is due to the fact that when a specific antigen invades the body, there are usually many copies of that antigen spread throughout the body’s tissues and fluids. Some copies of the antigen may be present inside body cells (which provokes a cell-mediated immune response by cytotoxic T cells), while other copies of the antigen may be present in extracellular fluid (which provokes an antibody-mediated immune response by B cells).
Thus, cell-mediated and antibody-mediated immune responses often work together to get rid of the large number of copies of a particular antigen from the body.
Clonal Selection: The Principle
When a specific antigen is present in the body, there are usually many copies of that antigen located throughout the body’s tissues and fluids. The numerous copies of the antigen initially outnumber the small group of helper T cells, cytotoxic T cells, and B cells with the correct antigen receptors to respond to that antigen. Therefore, once each of these lymphocytes encounters a copy of the antigen and receives stimulatory cues, it subsequently undergoes clonal selection.
Clonal selection is the process by which a lymphocyte proliferates (divides) and differentiates (forms more highly specialized cells) in response to a specific antigen. The result of clonal selection is the formation of a population of identical cells, called a clone, that can recognize the same specific antigen as the original lymphocyte.
Before the first exposure to a given antigen, only a few lymphocytes are able to recognize it, but once clonal selection occurs, there are thousands of lymphocytes that can respond to that antigen. Clonal selection of lymphocytes occurs in the secondary lymphatic organs and tissues. The swollen tonsils or lymph nodes in your neck you experienced the last time you were sick were probably caused by clonal selection of lymphocytes participating in an immune response.
A lymphocyte that undergoes clonal selection gives rise to two major types of cells in the clone:
- Effector cells
- Memory cells
The thousands of effector cells of a lymphocyte clone carry out immune responses that ultimately result in the destruction or inactivation of the antigen.
Effector cells include:
- active helper T cells, which are part of a helper T cell clone
- active cytotoxic T cells, which are part of a cytotoxic T cell clone
- and plasma cells, which are part of a B cell clone.
Most effector cells eventually die after the immune response has been completed.
Memory cells do not actively participate in the initial immune response to the antigen. However, if the same antigen enters the body again in the future, the thousands of memory cells of a lymphocyte clone are available to initiate a far swifter reaction than occurred during the first invasion.
The memory cells respond to the antigen by proliferating and differentiating into:
- more effector cells
- more memory cells
Consequently, the second response to the antigen is usually so fast and so vigorous that the antigen is destroyed before any signs or symptoms of disease can occur.
Memory cells include:
- memory helper T cells, which are part of a helper T cell clone
- memory cytotoxic T cells, which are part of a cytotoxic T cell clone
- and memory B cells, which are part of a B cell clone.
Most memory cells do not die at the end of an immune response. Instead, they have long life spans (often lasting for decades).
Antigens and Antigen Receptors
Antigens have two important characteristics:
Immunogenicity (im-u¯-no¯-je-NIS-i-te¯; -genic producing)
is the ability to provoke an immune response by stimulating the production of specific antibodies, the proliferation of specific T cells, or both. The term antigen derives from its function as an antibody generator.
is the ability of the antigen to react specifically with the antibodies or cells it provoked. Strictly speaking, immunologists define antigens as substances that have reactivity.
Substances with both immunogenicity and reactivity are considered complete antigens. Commonly, however, the term antigen implies both immunogenicity and reactivity, and we use the word in this way.
Entire microbes or parts of microbes may act as antigens. Chemical components of bacterial structures such as flagella, capsules, and cell walls are antigenic, as are bacterial toxins. Nonmicrobial examples of antigens include chemical components of pollen, egg white, incompatible blood cells, and transplanted tissues and organs. The huge variety of antigens in the environment provides myriad opportunities for provoking immune responses.
Typically, just certain small parts of a large antigen molecule act as the triggers for immune responses. These small parts are called epitopes (EP-i-to¯ ps), or antigenic determinants. Most antigens have many epitopes, each of which induces production of a specific antibody or activates a specific T cell.
Antigens that get past the innate defenses generally follow one of three routes into lymphatic tissue:
- (1) Most antigens that enter the bloodstream (for example, through an injured blood vessel) are trapped as they flow through the spleen.
- (2) Antigens that penetrate the skin enter lymphatic vessels and lodge in lymph nodes.
- (3) Antigens that penetrate mucous membranes are entrapped by
mucosa-associated lymphatic tissue (MALT).
Chemical Nature of Antigens
Antigens are large, complex molecules. Most often, they are proteins.
However, nucleic acids, lipoproteins, glycoproteins, and certain large polysaccharides may also act as antigens.
Complete antigens usually have large molecular weights of 10,000 daltons or more, but large molecules that have simple, repeating subunits—for example, cellulose and most plastics—are not usually antigenic. This is why plastic materials can be used in artificial heart valves or joints.
A smaller substance that has reactivity but lacks immunogenicity is called a hapten (HAP-ten to grasp). A hapten can stimulate an immune response only if it is attached to a larger carrier molecule. An example is the small lipid toxin in poison ivy, which triggers an immune response after combining with a body protein.
Likewise, some drugs, such as penicillin, may combine with proteins in the body to form immunogenic complexes. Such hapten stimulated immune responses are responsible for some allergic reactions to drugs and other substances in the environment.
As a rule, antigens are foreign substances; they are not usually part of body tissues. However, sometimes the immune system fails to distinguish “friend” (self ) from “foe” (nonself ). The result is an autoimmune disorder in which self-molecules or cells are attacked as though they were foreign.
Diversity of Antigen Receptors
An amazing feature of the human immune system is its ability to recognize and bind to at least a billion (109) different epitopes. Before a particular antigen ever enters the body, T cells and B cells that can recognize and respond to that intruder are ready and waiting.
Cells of the immune system can even recognize artificially made molecules that do not exist in nature. The basis for the ability to recognize so many epitopes is an equally large diversity of antigen receptors.
Given that human cells contain only about 35,000 genes, how could a billion or more different antigen receptors possibly be generated?
The answer to this puzzle turned out to be simple in concept.
The diversity of antigen receptors in both B cells and T cells is the result of shuffling and rearranging a few hundred versions of several small gene segments. This process is called genetic recombination. The gene segments are put together in different combinations as the lymphocytes are developing from stem cells in red bone marrow and the thymus. The situation is similar to shuffling a deck of 52 cards and then dealing out three cards. If you did this over and over, you could generate many more than 52 different sets of three cards.
Because of genetic recombination, each B cell or T cell has a unique set of gene segments that codes for its unique antigen receptor. After transcription and translation, the receptor molecules are inserted into the plasma membrane.
Major Histocompatibility Complex Antigens
Located in the plasma membrane of body cells are “self-antigens,” the major histocompatibility complex (MHC) antigens.
These transmembrane glycoproteins are also called human leukocyte antigens (HLA) because they were first identified on white blood cells. Unless you have an identical twin, your MHC antigens are unique. Thousands to several hundred thousand MHC molecules mark the surface of each of your body cells except red blood cells.
Although MHC antigens are the reason that tissues may be rejected when they are transplanted from one person to another, their normal function is:
“to help T cells recognize that an antigen is foreign, not self”
Such recognition is an important first step in any adaptive immune response.
The two types of major histocompatibility complex antigens are:
- Class I
- Class II
Class I MHC (MHC-I) molecules are built into the plasma membranes of all body cells except red blood cells.
Class II MHC (MHC-II) molecules appear on the surface of antigen–presenting cells
Pathways of Antigen Processing
For an immune response to occur, B cells and T cells must recognize that a foreign antigen is present.
B cells can recognize and bind to antigens in lymph, interstitial fluid, or blood plasma. T cells only recognize fragments of antigenic proteins that are processed and presented in a certain way.
In antigen processing:
- Antigenic proteins are broken down into peptide fragments
- Then they associate with MHC molecules
- Next the antigen–MHC complex is inserted into the plasma membrane of a body cell
The insertion of the complex into the plasma membrane is called antigen presentation.
When a peptide fragment comes from a self-protein, T cells ignore the antigen–MHC complex. However, if the peptide fragment comes from a foreign protein, T cells recognize the antigen–MHC complex as an intruder, and an immune response takes place.
Antigen processing and presentation occurs in two ways, depending on whether the antigen is located outside or inside body cells.
Processing of Exogenous Antigens
Foreign antigens that are present in fluids outside body cells are termed exogenous antigens (ex-OG-e-nus).
They include intruders such as:
- Bacteria and bacterial toxins
- Parasitic worms
- Inhaled pollen and dust
- and viruses that have not yet infected a body cell.
A special class of cells called antigen-presenting cells (APCs) process and present exogenous antigens. APCs include dendritic cells, macrophages, and B cells.
They are strategically located in places where antigens are likely to penetrate the innate defenses and enter the body, such as:
- the epidermis and dermis of the skin (Langerhans cells are a type of dendritic cell)
- mucous membranes that line the respiratory, gastrointestinal, urinary, and reproductive tracts; and lymph nodes.
After processing and presenting an antigen, APCs migrate from tissues via lymphatic vessels to lymph nodes.
The steps in the processing and presenting of an exogenous antigen by an antigen-presenting cell occur as follows:
- Ingestion of the antigen. Antigen-presenting cells ingest exogenous antigens by phagocytosis or endocytosis. Ingestion could occur almost anywhere in the body that invaders, such as microbes, have penetrated the innate defenses.
- Digestion of antigen into peptide fragments. Within the phagosome or endosome, protein-digesting enzymes split large antigens into short peptide fragments.
- Synthesis of MHC-II molecules. At the same time, the APC synthesizes MHC-II molecules at the endoplasmic reticulum (ER).
- Packaging of MHC-II molecules. Once synthesized, the MHC-II molecules are packaged into vesicles.
- Fusion of vesicles. The vesicles containing antigen peptide fragments and MHC-II molecules merge and fuse.
- Binding of peptide fragments to MHC-II molecules. After fusion of the two types of vesicles, antigen peptide fragments bind to MHC-II molecules.
- Insertion of antigen–MHC-II complexes into the plasma membrane. The combined vesicle that contains antigen–MHC-II complexes undergoes exocytosis. As a result, the antigen–MHC-II complexes are inserted into the plasma membrane.
After processing an antigen, the antigen-presenting cell migrates to lymphatic tissue to present the antigen to T cells. Within lymphatic tissue, a small number of T cells that have compatibly shaped receptors recognize and bind to the antigen fragment– MHC-II complex, triggering an adaptive immune response.
The presentation of exogenous antigen together with MHC-II molecules by antigen-presenting cells informs T cells that intruders are present in the body and that combative action should begin.
Processing of Endogenous Antigens
Foreign antigens that are present inside body cells are termed endogenous antigens (en-DOJ-e-nus).
Such antigens may be:
- viral proteins produced after a virus infects the cell and takes over the cell’s metabolic machinery
- toxins produced from intracellular bacteria
- or abnormal proteins synthesized by a cancerous cell
The steps in the processing and presenting of an endogenous antigen by an infected body cell occur as follows:
- Digestion of antigen into peptide fragments. Within the infected cell, protein-digesting enzymes split the endogenous antigen into short peptide fragments
- Synthesis of MHC-I molecules. At the same time, the infected cell synthesizes MHC-I molecules at the endoplasmic reticulum (ER).
- Binding of peptide fragments to MHC-I molecules. The antigen peptide fragments enter the ER and then bind to MHC-I molecules.
- Packaging of antigen–MHC-I molecules. From the ER, antigen– MHC-I molecules are packaged into vesicles.
- Insertion of antigen–MHC-I complexes into the plasma membrane. The vesicles that contain antigen–MHC-I complexes undergo exocytosis. As a result, the antigen–MHC-I complexes are inserted into the plasma membrane.
Most cells of the body can process and present endogenous antigens. The display of an endogenous antigen bound to an MHC-I
molecule signals that a cell has been infected and needs help.
Cytokines (SI¯-to¯-kı¯ns) are small protein hormones that stimulate or inhibit many normal cell functions, such as cell growth and differentiation.
Lymphocytes and antigen-presenting cells secrete cytokines, as do fibroblasts, endothelial cells, monocytes, hepatocytes, and kidney cells. Some cytokines stimulate proliferation of progenitor blood cells in red bone marrow. Others regulate activities of cells involved in innate defenses or adaptive immune responses.
CELL-MEDIATED IMMUNITY OBJECTIVES
- Outline the steps in a cell-mediated immune response
- Distinguish between the action of natural killer cells and cytotoxic T cells
- Define immunological surveillance.
A cell-mediated immune response begins with activation of a small number of T cells by a specific antigen. Once a T cell has been activated, it undergoes clonal selection.
Recall that clonal selection is the process by which a lymphocyte proliferates (divides several times) and differentiates (forms more highly specialized cells) in response to a specific antigen. The result of clonal selection is the formation of a clone of cells that can recognize the same antigen as the original lymphocyte.
Some of the cells of a T cell clone become effector cells, while other cells of the clone become memory cells. The effector cells of a T cell clone carry out immune responses that ultimately result in elimination of the intruder.
Activation of T Cells
At any given time, most T cells are inactive.
As you learned in the last section, antigen receptors on the surface of T cells, called T-cell receptors (TCRs), recognize and bind to specific foreign antigen fragments that are presented in antigen–MHC complexes.
There are millions of different T cells; each has its own unique TCRs that can recognize a specific antigen–MHC complex. When an antigen enters the body, only a few T cells have TCRs that can recognize and bind to the antigen.
Antigen recognition also involves other surface proteins on T cells, the CD4 or CD8 proteins. These proteins interact with the MHC antigens and help maintain the TCR–MHC coupling. For this reason, they are referred to as coreceptors.
Antigen recognition by a TCR with CD4 or CD8 proteins is the first signal in activation of a T cell. A T cell becomes activated only if it binds to the foreign antigen and at the same time receives a second signal, a process known as costimulation.
Of the more than 20 known costimulators, some are cytokines, such as interleukin-2. Other costimulators include pairs of plasma membrane molecules, one on the surface of the T cell and a second on the surface of an antigen presenting cell, that enable the two cells to adhere to one another for a period of time.
The need for two signals to activate a T cell is a little like starting and driving a car:
When you insert the correct key (antigen) in the ignition (TCR) and turn it, the car starts (recognition of specific antigen), but it cannot move forward until you move the gear shift into drive (costimulation).
The need for costimulation may prevent immune responses from occurring accidentally. Different costimulators affect the activated T cell in different ways, just as shifting a car into reverse has a different effect than shifting it into drive.
Moreover, recognition (antigen binding to a receptor) without costimulation leads to a prolonged state of inactivity called anergy (AN-er-je¯) in both T cells and B cells. Anergy is rather like leaving a car in neutral gear with its engine running until it’s out of gas!
Once a T cell has received these two signals (antigen recognition and costimulation), it is activated. An activated T cell subsequently undergoes clonal selection.
Activation and Clonal Selection of Helper T Cells
Most T cells that display CD4 develop into helper T cells, also known as CD4 T cells.
Inactive (resting) helper T cells recognize exogenous antigen fragments associated with major histocompatibility complex class II (MHC-II) molecules at the surface of an APC. With the aid of the CD4 protein, the helper T cell and APC interact with each other (antigenic recognition), costimulation occurs, and the helper T cell becomes activated.
Once activated, the helper T cell undergoes clonal selection. The result is the formation of a clone of helper T cells that consists of active helper T cells and memory helper T cells. Within hours after costimulation, active helper T cells start secreting a variety of cytokines.
One very important cytokine produced by helper T cells is interleukin-2, which is needed for virtually all immune responses and is the prime trigger of T cell proliferation. IL-2 can act as a costimulator for resting helper T cells or cytotoxic T cells, and it enhances activation and proliferation of T cells, B cells, and natural killer cells. Some actions of interleukin-2 provide a good example of a beneficial positive feedback system.
As noted earlier, activation of a helper T cell stimulates it to start secreting IL-2, which then acts in an autocrine manner by binding to IL-2 receptors on the plasma membrane of the cell that secreted it. One effect is stimulation of cell division. As the helper T cells proliferate, a positive feedback effect occurs because they secrete more IL-2, which causes further cell division.
IL-2 may also act in a paracrine manner by binding to IL-2 receptors on neighboring helper T cells, cytotoxic T cells, or B cells. If any of these neighboring cells have already become bound to a copy of the same antigen, IL-2 serves as a costimulator.
The memory helper T cells of a helper T cell clone are not active cells.
However, if the same antigen enters the body again in the future, memory helper T cells can quickly proliferate and differentiate into more active helper T cells and more memory helper T cells.
Activation and Clonal Selection of Cytotoxic T Cells
Most T cells that display CD8 develop into cytotoxic T cells, also termed CD8 T cells. Cytotoxic T cells recognize foreign antigens combined with major histocompatibility complex class I (MHC-I) molecules on the surface of:
- (1) body cells infected by microbes
- (2) some tumor cells
- (3) cells of a tissue transplant
Recognition requires the TCR and CD8 protein to maintain the coupling with MHC-I. Following antigenic recognition, costimulation occurs.
In order to become activated, cytotoxic T cells require costimulation by interleukin-2 or other cytokines produced by active helper T cells that have already become bound to copies of the same antigen.
(Recall that helper T cells are activated by antigen associated with MHC-II molecules.) Thus, maximal activation of cytotoxic T cells requires presentation of antigen associated with both MHC-I and MHC-II molecules.
Once activated, the cytotoxic T cell undergoes clonal selection. The result is the formation of a clone of cytotoxic T cells that consists of active cytotoxic T cells and memory cytotoxic T cells.
Active cytotoxic T cells attack other body cells that have been infected with the antigen.
Memory cytotoxic T cells do not attack infected body cells. Instead, they can quickly proliferate and differentiate into more active cytotoxic T cells and more memory cytotoxic T cells if the same antigen enters the body at a future time.
Elimination of Invaders
Cytotoxic T cells are the soldiers that march forth to do battle with foreign invaders in cell-mediated immune responses. They leave secondary lymphatic organs and tissues and migrate to seek out and destroy infected target cells, cancer cells, and transplanted cells.
Cytotoxic T cells recognize and attach to target cells. Then, the cytotoxic T cells deliver a “lethal hit” that kills the target cells.
Cytotoxic T cells kill infected target body cells much like natural killer cells do. The major difference is that cytotoxic T cells have receptors specific for a particular microbe and thus kill only target body cells infected with one particular type of microbe; natural killer cells can destroy a wide variety of microbe-infected body cells.
Cytotoxic T cells have two principal mechanisms for killing infected target cells:
- Cytotoxic T cells, using receptors on their surfaces, recognize and bind to infected target cells that have microbial antigens displayed on their surface. The cytotoxic T cell then releases granzymes, protein-digesting enzymes that trigger apoptosis. Once the infected cell is destroyed, the released microbes are killed by phagocytes
- Alternatively, cytotoxic T cells bind to infected body cells and release two proteins from their granules: perforin and granulysin. Perforin inserts into the plasma membrane of the target cell and creates channels in the membrane. As a result, extracellular fluid flows into the target cell and cytolysis (cell bursting) occurs.
- Other granules in cytotoxic T cells release granulysin (gran-u¯-LI¯-sin), which enters through the channels and destroys the microbes by creating holes in their plasma membranes.
- Cytotoxic T cells may also destroy target cells by releasing a toxic molecule called lymphotoxin (lim-fo¯-TOK-sin), which activates enzymes in the target cell. These enzymes cause the target cell’s DNA to fragment and the cell dies.
- In addition, cytotoxic T cells secrete gamma-interferon, which attracts and activates phagocytic cells, and macrophage migration inhibition factor, which prevents migration of phagocytes from the infection site.
After detaching from a target cell, a cytotoxic T cell can seek out and destroy another target cell.
When a normal cell transforms into a cancerous cell, it often displays novel cell surface components called tumor antigens.
These molecules are rarely, if ever, displayed on the surface of normal cells. If the immune system recognizes a tumor antigen as nonself, it can destroy any cancer cells carrying that antigen.
Such immune responses, called immunological surveillance, are carried out by:
- cytotoxic T cells
- natural killer cells.
Immunological surveillance is most effective in eliminating tumor cells due to cancer-causing viruses. For this reason, transplant recipients who are taking immunosuppressive drugs to prevent transplant rejection have an increased incidence of virus-associated cancers. Their risk for other types of cancer is not increased.
ANTIBODY-MEDIATED IMMUNITY OBJECTIVES
- Describe the steps in an antibody-mediated immune response
- List the chemical characteristics and actions of antibodies
- Explain how the complement system operates
- Distinguish between a primary response and a secondary response to infection.
The body contains not only millions of different T cells but also millions of different B cells, each capable of responding to a specific antigen.
Cytotoxic T cells leave lymphatic tissues to seek out and destroy a foreign antigen, but B cells stay put. In the presence of a foreign antigen, a specific B cell in a lymph node, the spleen, or mucosa-associated lymphatic tissue becomes activated. Then it undergoes clonal selection, forming a clone of plasma cells and memory cells.
Plasma cells are the effector cells of a B cell clone;
- they secrete specific antibodies, which in turn circulate in the lymph and blood to reach the site of invasion.
Activation and Clonal Selection of B Cells
During activation of a B cell, an antigen binds to B-cell receptors (BCRs). These integral transmembrane proteins are chemically similar to the antibodies that eventually are secreted by plasma cells. Although B cells can respond to an unprocessed antigen present in lymph or interstitial fluid, their response is much more intense when they process the antigen.
Antigen processing in a B cell occurs in the following way:
- The antigen is taken into the B cell, broken down into peptide fragments and combined with MHC-II self-antigens, and moved to the B cell plasma membrane.
- Helper T cells recognize the antigen– MHC-II complex and deliver the costimulation needed for B cell proliferation and differentiation. The helper T cell produces interleukin-2 and other cytokines that function as costimulators to activate B cells.
- Once activated, a B cell undergoes clonal selection. The result is the formation of a clone of B cells that consists of plasma cells and memory B cells.
- Plasma cells secrete antibodies. A few days after exposure to an antigen, a plasma cell secretes hundreds of millions of antibodies each day for about 4 or 5 days, until the plasma cell dies. Most antibodies travel in lymph and blood to the invasion site.
- Interleukin-4 and interleukin-6, also produced by helper T cells, enhance B cell proliferation, B cell differentiation into plasma cells, and secretion of antibodies by plasma cells.
- Memory B cells do not secrete antibodies. Instead, they can quickly proliferate and differentiate into more plasma cells and more memory B cells should the same antigen reappear at a future time.
Different antigens stimulate different B cells to develop into plasma cells and their accompanying memory B cells. All of the B cells of a particular clone are capable of secreting only one type of antibody, which is identical to the antigen receptor displayed by the B cell that first responded.
Each specific antigen activates only those B cells that are predestined (by the combination of gene segments they carry) to secrete antibody specific to that antigen.
Antibodies produced by a clone of plasma cells enter the circulation and form antigen–antibody complexes with the antigen that initiated their production.
An antibody (Ab) can combine specifically with the epitope on the antigen that triggered its production. The antibody’s structure matches its antigen much as a lock accepts a specific key. In theory, plasma cells could secrete as many different antibodies as there are different B-cell receptors because the same recombined gene segments code for both the BCR and the antibodies eventually secreted by plasma cells.
Antibodies belong to a group of glycoproteins called globulins, and for this reason they are also known as immunoglobulins.
Most antibodies contain four polypeptide chains.
Two of the chains are identical to each other and are called heavy (H) chains; each consists of about 450 amino acids. Short carbohydrate chains are attached to each heavy polypeptide chain. The two other polypeptide chains, also identical to each other, are called light (L) chains, and each consists of about 220 amino acids.
A disulfide bond (S—S) holds each light chain to a heavy chain. Two disulfide bonds also link the midregion of the two heavy chains; this part of the antibody displays considerable flexibility and is called the hinge region. Because the antibody “arms” can move somewhat as the hinge region bends, an antibody can assume either a T shape or a Y shape. Beyond the hinge region, parts of the two heavy chains form the stem region.
Within each H and L chain are two distinct regions. The tips of the H and L chains, called the variable (V) regions, constitute the antigen-binding site. The variable region, which is different for each kind of antibody, is the part of the antibody that recognizes and attaches specifically to a particular antigen.
Because most antibodies have two antigen-binding sites, they are said to be bivalent. Flexibility at the hinge allows the antibody to simultaneously bind to two epitopes that are some distance apart—for example, on the surface of a microbe.
The remainder of each H and L chain, called the constant (C) region, is nearly the same in all antibodies of the same class and is responsible for the type of antigen–antibody reaction that occurs. However, the constant region of the H chain differs from one class of antibody to another, and its structure serves as a basis for distinguishing five different classes, designated:
Each class has a distinct chemical structure and a specific biological role.
Because they appear first and are relatively short-lived, IgM antibodies indicate a recent invasion. In a sick patient, the responsible pathogen may be suggested by the presence of high levels of IgM specific to a particular organism.
Resistance of the fetus and newborn baby to infection stems mainly from maternal IgG antibodies that cross the placenta before birth and IgA antibodies in breast milk after birth.
The actions of the five classes of immunoglobulins differ somewhat, but all of them act to disable antigens in some way.
Actions of antibodies include the following:
- Neutralizing antigen. The reaction of antibody with antigen blocks or neutralizes some bacterial toxins and prevents attachment of some viruses to body cells.
- Immobilizing bacteria. If antibodies form against antigens on the cilia or flagella of motile bacteria, the antigen–antibody reaction may cause the bacteria to lose their motility, which limits their spread into nearby tissues.
- Agglutinating and precipitating antigen. Because antibodies have two or more sites for binding to antigen, the antigen–antibody reaction may cross-link pathogens to one another, causing agglutination (clumping together). Phagocytic cells ingest agglutinated microbes more readily. Likewise, soluble antigens may come out of solution and form a more easily phagocytized precipitate when cross-linked by antibodies.
- Activating complement. Antigen–antibody complexes initiate the classical pathway of the complement system (discussed shortly).
- Enhancing phagocytosis. The stem region of an antibody acts as a flag that attracts phagocytes once antigens have bound to the antibody’s variable region. Antibodies enhance the activity of phagocytes by causing agglutination and precipitation, by activating complement, and by coating microbes so that they are more susceptible to phagocytosis.
Role of the Complement System in Immunity
The complement system is a defensive system made up of over 30 proteins produced by the liver and found circulating in blood plasma and within tissues throughout the body.
Collectively, the complement proteins destroy microbes by causing:
- they also prevent excessive damage to body tissues.
Most complement proteins are designated by an uppercase letter C, numbered C1 through C9, named for the order in which they were discovered.
The C1–C9 complement proteins are inactive and become activated only when split by enzymes into active fragments, which are indicated by lowercase letters a and b. For example, inactive complement protein C3 is split into the activated fragments, C3a and C3b.
The active fragments carry out the destructive actions of the C1–C9 complement proteins. Other complement proteins are referred to as factors B, D, and P (properdin).
Complement proteins act in a cascade—one reaction triggers another reaction, which in turn triggers another reaction, and so on. With each succeeding reaction, more and more product is formed so that the net effect is amplified many times.
Complement activation may begin by three different pathways, all of which activate C3. Once activated, C3 begins a cascade of reactions that brings about phagocytosis, cytolysis, and inflammation as follows):
- Inactivated C3 splits into activated C3a and C3b
- C3b binds to the surface of a microbe and receptors on phagocytes attach to the C3b. Thus C3b enhances phagocytosis by coating a microbe, a process called opsonization (op-so¯-ni-ZA¯-shun). Opsonization promotes attachment of a phagocyte to a microbe.
- C3b also initiates a series of reactions that bring about cytolysis. First, C3b splits C5. The C5b fragment then binds to C6 and C7, which attach to the plasma membrane of an invading microbe. Then C8 and several C9 molecules join the other complement proteins and together form a cylinder-shaped membrane attack complex, which inserts into the plasma membrane.
- The membrane attack complex creates channels in the plasma membrane that result in cytolysis, the bursting of the microbial cells due to the inflow of extracellular fluid through the channels.
- C3a and C5a bind to mast cells and cause them to release histamine that increases blood vessel permeability during inflammation. C5a also attracts phagocytes to the site of inflammation (chemotaxis).
C3 can be activated in three ways:
- (1) The classical pathway starts when antibodies bind to antigens (microbes). The antigen– antibody complex binds and activates C1. Eventually, C3 is activated and the C3 fragments initiate phagocytosis, cytolysis, and inflammation.
- (2) The alternative pathway does not involve antibodies. It is initiated by an interaction between lipid–carbohydrate complexes on the surface of microbes and complement protein factors B, D, and P. This interaction activates C3.
- (3) In the lectin pathway, macrophages that digest microbes release chemicals that cause the liver to produce proteins called lectins. Lectins bind to the carbohydrates on the surface of microbes, ultimately causing the activation of C3.
Once complement is activated, proteins in blood and on body cells such as blood cells break down activated C3. In this way, its destructive capabilities cease very quickly so that damage to body cells is minimized.
A hallmark of immune responses is memory for specific antigens that have triggered immune responses in the past. Immunological memory is due to the presence of long-lasting antibodies and very long-lived lymphocytes that arise during clonal selection of antigen-stimulated B cells and T cells.
Immune responses, whether cell-mediated or antibody-mediated, are much quicker and more intense after a second or subsequent exposure to an antigen than after the first exposure.
Initially, only a few cells have the correct specificity to respond, and the immune response may take several days to build to maximum intensity. Because thousands of memory cells exist after an initial encounter with an antigen, the next time the same antigen appears they can proliferate and differentiate into helper T cells, cytotoxic T cells, or plasma cells within hours.
One measure of immunological memory is antibody titer (TI¯-ter), the amount of antibody in serum. After an initial contact with an antigen, no antibodies are present for a period of several days. Then, a slow rise in the antibody titer occurs, first IgM and then IgG, followed by a gradual decline in antibody titer. This is the primary response.
Memory cells may remain for decades. Every new encounter with the same antigen results in a rapid proliferation of memory cells. After subsequent encounters, the antibody titer is far greater than during a primary response and consists mainly of IgG antibodies. This accelerated, more intense response is called the secondary response.
Antibodies produced during a secondary response have an even higher affinity for the antigen than those produced during a primary response, and thus they are more successful in disposing of it.
Primary and secondary responses occur during microbial infection. When you recover from an infection without taking antimicrobial drugs, it is usually because of the primary response. If the same microbe infects you later, the secondary response could be so swift that the microbes are destroyed before you exhibit any signs or symptoms of infection.
Immunological memory provides the basis for immunization by vaccination against certain diseases (for example, polio). When you receive the vaccine, which may contain attenuated (weakened) or killed whole microbes or portions of microbes, your B cells and T cells are activated. Should you subsequently encounter the living pathogen as an infecting microbe, your body initiates a secondary response.