1. Chapter 22: Lymphatic System and Immunity
BIOL 2402

2. Introduction
The ability of the body to protect itself from damage or disease is called resistance. Two main types of resistance are:
Nonspecific resistance (innate defenses): provide defense mechanism against a range of pathogens in a general way.
Specific resistance (immunity): provides defense mechanism against a specific pathogen by specialized lymphocytes.

3. Functions of the Lymphatic System
Fluid balance
Excess interstitial fluid enters lymphatic capillaries and becomes lymph. Finally drained into the circulatory system.
Fat Absorption
Lymphatic system helps to absorb fat and other substances from the digestive system with the help of specialized vessels called lacteals.
Defense
Lymphocytes residing in the lymphatic tissues of the body, protect the body against microorganisms and foreign substances.

4. Lymphatic Structures Lymphatic System consists of:
Lymph: fluid similar to plasma but does not have plasma proteins.
Lymphatic vessels (lymphatics): Carry lymph from peripheral tissues to the venous system
Lymphoid tissues and lymphoid organs.
Lymphocytes, phagocytes, and other immune system cells.

5. Components of the Lymphatic System
Lymph: fluid drained from interstitial spaces in all tissues of the body. Composition equivalent to the interstitial fluid.
Returns to circulatory system via Lymphatic vessels; essential for fluid balance.
Lymph  Lymphatic Capillaries  Lymphatic vessels  Lymph nodes  lymphatic trunk  Lymphatic duct  Drain into large veins of the body.

6. Lymphatic Capillaries
Lymph capillaries: Very similar to blood capillaries in structure with 2 modifications.
Lymphatic capillaries have endothelial cells which are loosely attached and are therefore more permeable.
Lymphatic capillaries have one way valves to prevent back flow of lymph into interstitial space.

7. Lymphatic Vessels
Lymph capillaries merge to form lymphatic vessels which have valves and are similar in structure to veins.
They have all three layers and one way valves.
Lymph moves through the vessels with the help of milking action carried out by the skeletal muscles and pressure changes created by the respiration.
Lymph nodes: bean-shaped clusters of B and T cells found at intervals along the length of the vessels; lymph flows through the nodes.
Function to filter lymph.

8. Lymph Lymphatic vessels/ Trunks
As lymphatic vessels exit from lymph nodes, they merge and form lymph trunks
Each lymphatic trunk drains fluid from a certain area of the body.
e.g. jugular trunks drain from the head and neck, subclavian trunks drain from the upper arms and superficial thoracic wall.

9. Lymph Ducts Lymphatic trunks drain into two lymphatic ducts
Thoracic duct: Main collecting duct of the lymphatic system.
Receives lymph from the left side of the head, neck, and chest, the left upper extremity, and the entire body below the ribs.
Drains lymph into venous blood at junction of the left subclavian vein and internal jugular vein.
Right lymphatic duct: drains right side head, arm and chest. Empties into venous system at junction of right subclavian vein and right jugular vein.

10. Lymphocytes
Make up 20–30% of circulating leukocytes Most are stored, not circulating Types of Lymphocytes T cells: Thymus-dependent B cells: Bone marrow–derived NK cells: Natural killer cells

11. Lymphocytes (contd) – T cells
T Cells : Make up 80% of circulating lymphocytes. Formation: Stem cells in the red bone marrow ---> divide and differentiate into blood cells-->lymphocyte stem cells exit bone marrow --> migrate to thymus gland --> mature and differentiate in thymus --> form T-cells. Main Types of T Cells
Cytotoxic T (TC) cells: Attack cells infected by viruses. Produce cell-mediated immunity
Memory T cells TM: Formed in response to foreign substance. Remain in body to give “immunity”
Helper T (TH) cells: Stimulate function of T cells and B cells

12. Lymphocytes (contd) – B cells
- Make up 10–15% of circulating lymphocytes
- Differentiate (change) into plasma cells which produce and secrete antibodies (immunoglobulin proteins).
- Formation: Stem cells in the red bone marrow ---> divide and differentiate into blood cells --> some lymphocyte cells remain in bone marrow --> mature and differentiate in bone marrow --> form B-cells.

13. Lymphocytes (contd) – Natural Killer (NK) cells
- Also called large granular lymphocytes
- Make up 5–10% of circulating lymphocytes
- Responsible for immunological surveillance
- Attack foreign cells, virus-infected cells, and cancer cells

14. Types of Lymphocytes

15. Lymphatic tissues and Organs
Classified into two groups
Primary Lymphatic organs:
where the lymphocytes originate and mature to become immunocompetent.
e.g. red bone marrow and thymus gland.
Secondary Lymphatic organs:
are the sites where the mature lymphocytes reside and carry out immune response.
e.g. spleen, lymph nodes and nodules

16. Lymphatic Nodules
are aggregates of lymphatic tissue not surrounded by a capsule. Examples include
Mucosa associated lymphatic tissue (MALT): scattered throughout the lamina propria of mucous membranes lining the GI tract, respiratory airways, urinary tract, and reproductive tract.
Peyers patches: aggregates of lymphatic tissue in appendix and small intestines for protection
Tonsils: large groups of nodules in the mucosa of the pharynx. Provide protection against bacteria entering the body through the mouth or nasal cavities.
Pharyngeal tonsil (adenoids)
Palatine tonsils on each side wall
Lingual tonsil in the back of the tongue

17. Lymphatic nodules (tonsils)

18. Lymph Nodes
Bean-shaped or oval structures located along lymphatic vessels.
Superficial (near skin) and deep. Concentrated near mammary glands, axilla, groin
Function to filter lymph
A dense connective tissue capsule surround each lymph node. Capsule extends in the lymph node as trabeculae.
Outer part of the node is called cortex which is made up of lymphatic nodules containing lymphocytes and macrophages.
Inner medulla is made up of irregular strands of lymphatic tissue called medullary cords.
Lymph enters the nodes via the afferent lymphatic vessel and leaves via the efferent lymphatic vessel.

19. Lymph node structure

20. Metastasis Through Lymphatic System
Characteristic of malignant tumors
Spread of disease from one organ to another
cancer cells travel via blood or lymphatic system
cells establish new tumors where lodge
Secondary tumor sites can be predicted by direction of lymphatic flow from primary site

21. Relationship of Circulatory and Lymphatic Systems

22. Thymus Gland Large organ in infants but atrophied as adult.
2 lobed organ located in mediastinum

23. Thymus Gland (contd) Surrounded by a connective tissue capsule
Trabeculae extend from capsule and divide it into lobules
Each lobule has cortex and medulla
Cortex (numerous lymphocytes) and medulla (fewer lymphocytes)
Site of maturation of T cells: many T cells produced here.

24. Spleen
Left superior side of abdomen; can be ruptured in traumatic abdominal injuries resulting in bleeding, shock, death
Functions
Destroys defective RBCs
Detects and responds to foreign substances
Limited reservoir for blood
The spleen is often damaged in abdominal trauma. A splenectomy may be required to prevent excessive bleeding.

25. Spleen (structure)
Outer Layer of connective tissue called Capsule. Extensions of the capsule called trabeculae divide the spleen into smaller compartments.
Each compartment is filled with white and red pulp.
- White pulp is lymphatic tissue while red pulp is sire for destruction of old RBCs
The depression on the Spleen where the splenic blood vessels enter and leave is called hilum.

26. REVIEW!!!!
Now that we have completed the study of the organization of the lymphatic system, attempt the following questions:
What is the function of the lymphatic vessels?
What structure prevents the backflow of lymph in the lymphatic vessels?
Name the two large lymphatic ducts and the parts of the body they drain lymph from?
Explain lymphedema?
Identify the three main classes of lymphocytes?

27. REVIEW !! (contd)
Which cells are responsible for antibody mediated immunity?
Define tonsils, and name the three main ones?
Where is the thymus gland located?
What is the function of spleen?
Describe red pulp and white pulp found in the spleen?
If you are comfortable with this material move on to the second part of the lecture outline.

28. Resistance
Is defined as the ability to resist damage from foreign substances such as microorganisms and harmful chemicals.
Susceptibility: lack of resistance.
Categories
Innate or nonspecific resistance
Adaptive or specific immunity.

29. Innate (nonspecific) defense mechanisms
Prevent entry, limit the spread of microorganisms or other environmental hazards. There are seven major categories of innate defenses Physical barriers 2. Phagocytes 3. Immunological surveillance 4. Interferons 5. Complement 6. Inflammatory response 7. Fever

30. 1. Physical barrier
Prevent entry of microbes in the body. Provided by the skin and mucous membrane.
Intact skin - physical barrier to entrance of microbes.
Mucous membrane that lines the digestive respiratory and urogenital tract secrete a viscous mucus - prevents entry of potentially harmful microbes.
In addition many of the secretions like saliva, tears etc. also contain proteins like lysozyme which digest cell wall of microbes and destroy it.

31. 1. Physical barrier (contd)

32. 2. Phagocytes Perform phagocytosis.
Cells involved in this process include:
Neutrophils: % of all WBCs. They leave blood and migrate to the infected area, attracted to the chemicals released by the damaged cells and phagocytose bacteria
Monocytes:- 5% of WBC. They leave the blood, migrate into tissues and develop into macrophages. Some macrophages are wandering (moving around the body) and others are fixed (stationary). They extend pseudopodia and phagocytose microbes.

33. 3. Immunological surveillance
Is carried out by natural killer (NK) cells. They attack cancer cells and body cells infected with viruses. Their mechanism of action is outlined below:
Activated NK Cells identify and attach to abnormal cell (nonselective)
Golgi apparatus in NK cell forms perforin vesicles
Vesicles release proteins called perforins (exocytosis)
Perforins lyse cell by forming pores in the target cell membrane

34. 3. Immunological surveillance (contd)

35. 4. Interferons
Inteferons:- are chemicals released by virus infected cells. 
They cannot save the infected cell, but they diffuse to neighboring healthy cells, where they stimulate the production of antiviral proteins that inhibit viral replication in these cells. Thus an infected cell helps to protect uninfected cells.
There are three known types of interferons, alpha, beta, gamma. - are most effective in controlling short term infections, such as cold and influenza.

36. 5. Complement System
Plasma contains 11 special complement (C) proteins. These proteins form complement system and complement antibody action. Complement proteins work together in cascades.
Two pathways activate the complement system: Classical pathway and Alternative pathway
Effects of Complement Activation Pore formation: Destruction of target plasma membranes. Five complement proteins join to form membrane attack complex (MAC)
Enhancement of phagocytosis by opsonization. Complements working with antibodies (opsonins)
Histamine release: Increases the degree of local inflammation and blood flow

37. 6. Inflammation
Triggered by physical injury, such as a cut, or by entry of microorganisms.
Symptoms include redness, pain, heat and swelling.
White blood cells called, basophils & mast cells release histamine which triggers vasodilation.
Small blood vessels near the injury dilate, increasing the blood supply (causing redness & heat). Fluids from the dilated vessels also move into neighboring tissues, causing swelling.
Inflammatory response also involves the migration of phagocyte from the blood into the infected tissues, which eliminate the pathogens by phagocytosis.

38. Inflammation
Products of Inflammation: Necrosis: Local tissue destruction in area of injury
Pus: Mixture of debris and necrotic tissue
Abscess: Pus accumulated in an enclosed space

39. 7. Fever
Fever : is defined as a maintained body temperature above 37 0C (99 0F)
Pyrogens: Any material that causes the hypothalamus to raise body temperature.
A variety of stimuli either act as pyrogens themselves or stimulate macrophages to release pyrogens, e.g. Circulating pathogens, toxins, or antibody complexes.
Active macrophages release cytokine called endogenous pyrogens or interleukin-1 (IL-1).

40. Specific (adaptive) defense mechanisms
Responds to specific antigens
With coordinated action of T cells and B cells
Specific Defenses
T Cells: Provide cell-mediated immunity Defend against abnormal cells and pathogens inside cells
B Cells: Provide antibody-mediated immunity Defend against antigens and pathogens in body fluids

41. Specific Resistance: Immunity
Operates after the microbe has crossed the nonspecific line of defense
4 characteristic features of the immune system are:-
Specificity:- recognition of a specific pathogen or toxin and then destroying it.  Each lymphocyte is highly specific in responding to a particular pathogen or toxin.
Diversity:- Immune system on the whole has the ability to respond to millions of different kind of invaders.
Memory:- Immune system has the ability to ‘remember’ pathogens or toxins it encounters.  This property is carried out by specialized cells termed the memory cells.
Self/nonself recognition:- Immune system distinguishes the body's own molecules from foreign molecules.

42. Specific Resistance: Immunity (contd)
Types of Immune Responses:
Cell mediated immunity:  works best against intracellular antigens which invade and are present in an infected cell. e.g. viruses, parasites, fungi and cancer cells and tissue transplants.  Antigens bind to a specific T-cell receptor --> T-cell becomes activated and differentiates into Killer cell and directly attacks the infected cell causing its lysis.
Humoral or antibody mediated response: In this response antigens trigger and activate a specific B-cell --> which differentiates into plasma cells & reacts by producing antibodies --> which are released in the blood and lymph.  These antibodies then inactivate the foreign antigen by a number of possible mechanisms.  This type of immune response works against extracellular antigens circulating in body's fluid.
Often a pathogen provokes both types of immune response
Some T cells act as intermediaries between antibody-mediated and cell-mediated immunity.

44. Key Terminologies used in Immunity
Antigen: A foreign molecule capable of triggering a response form the adaptive Immunity.  
e.g. of antigens - bacteria, viruses, fungi, protozoa, pollens, & transplanted tissue.
Required characteristics to be considered an antigen
immunogenicity = ability to provoke immune response
reactivity = ability to react to cells or antibodies it caused to be formed
Epitope:- localized region on the surface of an antigen capable of initiating immune response, is called epitope.
A single antigen can have several effective epitopes.
Foreign antigens: not produced in the body.
Allergens: cause an overreaction of the Immune system.
Self antigens: molecules within the body triggering immune system. Can prove to be dangerous – autoimmune diseases.

45. Diversity of Antigen Receptors
Immune system can recognize and respond to a billion different epitopes. This recognition is done with the help of specific receptors.
Antigen receptors: site on B or T cells that can bind epitopes.
Each B or T cell has its own unique antigen receptor inserted in the cell membrane.

46. Major Histocompatibility Complex
B cells and T cells must have the ability to recognize both molecules that are antigenic (non-self) and self antigens. This recognition is done via the MHC molecules.
Major histocompatability complex (MHC) antigens: glycoproteins found on the surface of cells. Unique for each genetically different individual – serve as identity markers.
B and T-cell receptors do not elicit any response against body's own MHCs, but when the MHC is attached to a foreign antigen it initiates an immune response in the body.
Two classes of MHCs are:
Class I (MHC-1): found on surface of all cells except RBCs.
Class II (MHC-2): are produced and appear on the surface of specialized cells called antigen-presenting cells (APCs).

47. Processing of exogenous antigens
Exogenous antigens are the ones present outside body cells, e.g. bacteria, parasitic orms, bacterial toxins.
Cells that help to process and present exogenous antigens are called the antigen-presenting cells (APCs) which include macrophages, B cells, and dendritic cells.
The steps in this process are:
APCs ingest antigens by phagocytosis.
Inside the APCs, the antigen is digested into shorter pieces.
APCs synthesize MHC-II molecules.
Inside the APCs, MHC-II molecules and the antigen pieces bind to one another.
MHC-II-antigen complex is then inserted in the plasma membrane of the APC. This APC then migrates to lymphatic tissue to present the antigen to the T cells.
APC migrates to lymphatic tissue to find T cells
Display of MHCII with foreign antigen is like “Rally round the flag”, stimulates other immune system cells to respond to the antigen.

48. Processing of Exogenous Antigens

49. Processing of endogenous antigens
Endogenous antigens are synthesized within the body and include viral proteins or proteins produced by cancer cells.
Most of the cells of the body can process endogenous antigens
Fragments of endogenous antigen are associated with MHCI molecules inside the cell.
The antigen MHCI complex moves to the cell’s surface. This complex signals the lymphatic system that a cell has been infected and needs help.

50. Processing of Endogenous antigens (contd)

51. Cell-Mediated Immunity
Works best against intracellular antigens which invade and are present in an infected cell. e.g. viruses, parasites, fungi and cancer cells and tissue transplants.
In order for T cells to defend the body they must be activated, proliferate and differentiate into effector cells
Antigen Recognition: Binding of the T cell receptor with antigen on antigen presenting cell.
Costmulation: Involves costimulation by cytokines such as interleukin-1 and interleukin-2.
Activation by CD4 or CD8 cells: enlargement then mitosis of the activated T cell into many cells.These cells differentiate into effectors: helper T cells, cytotoxic T cells, and memory T cells
Only a few T cells are activated but this results in thousands of differentiated T cells.

52. Antigen Recognition
T cell receptors recognize antigen fragments associated with MHC molecules on the surface of a body cell.
CD Markers are cluster of proteins on T cell membranes that play an important role in antigen recognition. Two important CD markers are:
CD8 Markers: Found on cytotoxic T cells and suppressor T cells. Respond to antigens on Class I MHC proteins.
CD4 Markers: Found on helper T cells. Respond to antigens on Class II MHC proteins

53. Costimulation
Proliferation of T cells requires costimulation, by cytokines such as interleukin-1 (IL-1) and interleukin-2 (IL-2), or by pairs of plasma membrane molecules, one on the surface of the T cell and a second on the surface of an APC.

54. Activation of CD8 cells
Activated by exposure to antigens on MHC protein.
Results in the production of two types of T cells: TC and Memory T cells
Cytotoxic T cells Seek out and immediately destroy target cells by using several different mechanisms.
Memory TC Cells: Stay in circulation and Immediately form cytotoxic T cells if same antige n appears again.

55. Activation of CD4 cells
Upon activation, undergo a series of divisions and differentiate into:
Active helper T cells (TH cells): Secrete cytokines that stimulate both cell-mediated and antibody-mediated immunity.
Memory helper (TH) cells: Remain in reserve

58. Antibody Mediated Immunity
B Cells
Responsible for antibody-mediated immunity
Attack antigens by producing specific antibodies
Millions of populations, each with different antibody molecules
This type of immune response works against extra cellular antigens circulating in body's fluid.

59. Sensitization
Corresponding antigens in interstitial fluids bind to B cell receptors
B cell prepares for activation, preparation process is sensitization. During sensitization, antigens are:
Taken into the B cell
Processed
Reappear on surface, bound to Class II MHC protein
B Cell Activation
Helper T cell binds to MHC complex
Secretes cytokines that promote B cell activation and division
B Cell Differentiation Activated B cell divides into: Plasma cells: Synthesize and secrete antibodies into interstitial fluid
Memory B cells: Like memory T cells, remain in reserve to respond to next infection.

61. Antibodies
Antibodies constitute a class of proteins called Immunoglobulins (Igs ).
Antibody can be either T- or Y-shaped.
Four polypeptide chains: two heavy and two light. Each light is held to a heavy by a disulfide bond.
Each chain has two regions; a constant region (C) which is the same within a class of antibody and a variable region (V) which varies from one antibody to the other.
V region from each chain has the antigen binding site to recognize and specifically attach to a particular antigen.

62. Antibodies (contd)
Based on chemistry and structure, antibodies are grouped into five principal classes each with specific biological roles (IgG, IgA, IgM, IgD, and IgE).

63. Antibody Action
Antigen–Antibody Complexes can destroy the antigen in one of the following ways:
Neutralization of antigen binding sites: antibodies bind to specific sites on bacteria and viruses which prevents them from attaching to a body cell.
Precipitation and agglutination - antibodies link large number of antigens togetehr, resulting in the formation of immune complex which becomes too large and therefore precipitates.
Activation of complement
Attraction of phagocytes
Opsonization: coating of an antigen by antibodies is called opsonization, which increases phagocyte efficiency
Stimulation of inflammation by stimulating basophils and mast cells.
Prevention of bacterial and viral adhesion.

64. Primary and Secondary Immune Response
Primary immune response
First exposure to antigen response is steady, slow
resulting in proliferation of lymphocytes to form clones of plasma cells and memory cells.
Secondary immune response with second exposure to the same antigen
Memory cells proliferate and differentiate into plasma cells
Faster and stronger than the primary immune response.

66. Types of Adaptive Immunity
Active immunity: is when the body's immune system is stimulated to make antibodies and other immune cells (killer cells).
This immunity takes time to work, it generates memory cells which protect against future encounters with the same antigen.
Active immunity can be naturally acquired or artificially.
Naturally acquired active immunity: is seen when the individual is exposed to the antigen in a natural manner.
Body responds to this antigen by activating B and/or T cells, and memory cells are made.
e.g. being exposed to chicken pox virus through a friend.
Artificially acquired active immunity: is when a weak or killed antigen is injected into the individual.
Individual responds by activating a specific B and/or T cell, and antigen is inactivated. In this process memory cells are also made for future encounters.
This type of immunity forms the basis for vaccination.

67. Types of Adaptive Immunity (contd)
Passive immunity: is when prepared antibodies are received by an individual.
This immunity provides immediate protection but lasts for a short term, since antibodies are proteins and undergo breakdown.
Body's immune system is not involved in this immunity and hence no memory cells are produced.
Naturally acquired passive immunity: e.g. when IgG naturally crosses the placenta from mother's blood to fetus blood or when IgA is fed to the new born through the breast milk. These antibodies work for a short period of time.
Artificially acquired passive immunity: is when an individual is given shots of prepared antibodies or serum to treat or prevent infections. Shots of gamma globulins are often given to hospital patients and travelers for temporary protection against hepatitis.

68. Types of adaptive Immunity (contd)

69. Immune System Disorders: AIDS
HIV is a form of retrovirus with a protein coat wrapped by an envelope of glycoproteins.
Host cell for HIV are the helper T cells.
New HIV DNA is produced in the T cell along with new protein coats and then released.
The T cells are ultimately destroyed.
Progression to Acquired Immunodeficiency Syndrome (AIDS) occurs because of reduced numbers of T cells and resulting immunodeficiency. AIDS lowers the body’s immunity by decreasing the number of helper T cells.
Although HIV has been isolated from several body fluids, the only documented transmissions are by way of blood, semen, vaginal secretions, and breast milk from an infected nursing mother.
Treatment of HIV infection with reverse transcriptase inhibitors and protease inhibitors has shown to delay the progression of HIV infection to AIDS.

70. Hypersensitivity Reactions: Allergies
Inappropriate or excessive immune responses to antigens Allergens
Allergens: antigens that induce an allergic reaction in some people but are tolerated by most people.
Allergic (hypersensitive) people respond to allergens.

71. Diseases of the Immune System:
autoimmune diseases: Immune system initiates immune response against body’s own cells
Rheumatoid arthritis leads to damage and painful inflammation of the cartilage and bone of joints.
In insulin-dependent diabetes mellitus, the insulin-producing beta cells of the pancreas are the targets of autoimmune cell-mediated responses.
Multiple sclerosis (MS) is the most common chronic neurological disease.

72. Age Related Changes
Immune System Diminishes with Age Increasing vulnerability to infections and cancer
Four Effects of Aging
Thymic hormone production is greatly reduced
T cells become less responsive to antigens
Fewer T cells reduces responsiveness of B cells
Immune surveillance against tumor cells declines

73. REVIEW!!
Now that you have reviewed the Specific defenses of the human body, try to answer the following questions: Describe antigen presentation.
What is the major histocompatibility (MHC) complex?
Where are the class I and Class MHC molecules found?
Describe CD markers.
Define the function of cytokines secreted by helper T cells in the activation of B cells?
Describe the structure of antibody? Which part plays an important role in antigen recognition?
Highlight the differences between primary and secondary immune response.
Define allergy and allergens.
What is anaphylaxis?
Define autoimmune diseases and immunodeficiency diseases.