Chapter 22

1. Chapter 22 The Lymphatic System and Immunity

2. The Lymphatic System • A system consisting of lymphatic vessels through which a clear fluid (lymph) passes • The major functions of the lymphatic system include: • Draining interstitial fluid • Transporting dietary lipids absorbed by the gastrointestinal tract to the blood • Facilitating the immune responses

3. The Lymphatic System • Components of the lymphatic system include: • Lymphatic capillaries • Lymphatic vessels • Lymph nodes • Lymphatic trunks • Lymphatic ducts • Primary lymphatic organs • Secondary lymphatic organs and tissues

4. Lymphatic Vessels and Fluid • Lymph is a clear to milky fluid in the extracellular fluid compartment. Extracellular fluids include: • Plasma – the liquid component of blood • Interstitial fluid – the clear fluid filtered through capillary walls when it enters the “interstitium” (space between cells, also called the intracellular space) • Lymphatic fluid – the unaltered interstitial fluid that enters the lymphatic vessels. In the GI tract, lymphatic fluids also include absorbed dietary lipids.

5. Lymphatic Vessels and Fluid • The flow of lymph fluid is always from the periphery towards the central vasculature. • It starts as interstitial fluid. • Then enters lymphatic capillaries. • It travels in lymphatic vessels to the regional lymph nodes…

6. Lymphatic Vessels and Fluid • The flow of lymph fluid continued… • Lymph ascends or descends to the thorax, either to the Left or Right Lymphatic Duct. • Lymph fluid’s final destination is the bloodstream, as it enters through the Subclavian veins.

7. Lymphatic Vessels and Fluid • Lymphatic capillaries are slightly larger than blood capillaries and have a unique one-way structure. • The ends of endothelial cells overlap and permit interstitial fluid to flow in, but not out. • Anchoring filaments pull openings wider when interstitial fluid accumulates. • There are specialized lymphatic capillaries called lacteals that take up dietary lipids in the small intestine. • Chyle is the name of this “lymph with lipids”.

8. Lymphatic Vessels and Fluid Lymphatic capillaries showing blind ends and one way flow

9. Lymphatic Vessels and Fluid • Lymphatic capillaries unite to form larger lymphatic vessels which resemble veins in structure but have thinner walls and more valves. • Lymphatic vessels pass through lymph nodes – encapsulated organs with masses of B and T cells. • Function as lymph filters

10. Lymphatic Vessels and Fluid

11. Lymphatic Vessels and Fluid • Lymphatic fluid is moved by pressure in the interstitial space and the milking action of skeletal muscle contractions and respiratory movements. • An obstruction or malfunction of lymph flow leads to edema from fluid accumulation in interstitial spaces.

12. Lymphatic Organs • The lymphatic system is composed of a number of primary and secondary organs and tissues widely distributed throughout the body - all with the purpose of facilitating the immune response.

13. Lymphatic Organs • Primary lymph organs are the bone marrow and thymus. • Sites where stem cells divide and become immunocompetent (capable of mounting an immune response) • Secondary lymphatic organs are sites where most immune responses occur, including the spleen and lymph nodes, and lymphoid nodules(follicles) an example is the tonsils.

14. Lymphatic Organs • Thymus • The outer cortex is composed of a large number of immature T cells which migrate from their birth-place in red bone marrow . • They proliferate and begin to mature with the help of Dendritic cells (derived from monocytes) and specialized epithelial cells (help educate T cells through positive selection) – only about 2% survive. • The inner medulla is composed of more mature T cells.

15. Lymphatic Organs • There are about 600 lymph nodes scattered along lymphatic vessels (in superficial and deep groups) that serve as filtersto trap and destroy foreign objects in lymph fluid. • Important group of regional lymph nodes include: • Submandibular • Cervical • Axillary • Mediastinal • Inguinal

16. Lymphatic Organs • Lymph fluid enters the node through afferent vessels and is directed towards the central medullary sinuses. • Efferent vessels convey lymph, antibodies and activated T cells out of the node at an indentation called the hilum.

17. Lymphatic Organs • The spleenis the body’s largest mass of lymphatic tissue. • The parenchyma of the organ consists of: • White pulp - lymphatic tissue where lymphocytes and macrophages carry out immune function • Red pulp – blood-filled venous sinuses where platelets are stored and old red cells are destroyed

18. Lymphatic Organs

19. The Immune Response • Our immune response includes innate and adaptive responses:

20. Innate Immunity • The innate immune response is present at birth. It is non-specific and non-adaptive. • It includes our first line of external, physical, and chemical barriers provided by the skin and mucous membranes.

21. Innate Immunity • Our nonspecific innate immune response also includes various internal defenses such as antimicrobial substances, natural killer cells, phagocytes, inflammation, and fever.

22. Innate Immunity • Internal defenses: • Phagocytes • Wandering and fixed macrophages • Natural killer (NK) cells • Endogenous antimicrobials • Complement system • Iron-binding proteins • Interferon

23. Innate Immunity • Phagocytosis is a non-specific process wherein neutrophils and macrophages (from monocytes) migrate to an infected area. There are 5 steps: • Chemotaxis • Adherence • Ingestion • Digestion • Killing

24. Innate Immunity

25. Innate Immunity • Fever is an abnormally high body temperature due to resetting of the hypothalamic thermostat. • Non-specific response: • speeds up body reactions • increases the effects of endogenous antimicrobials • sequesters nutrients from microbes

26. Innate Immunity • Inflammation is defensive response of almost all body tissues to damage of any kind (infection, burns, cuts, etc.). • The four characteristic signs and symptoms of inflammation are redness, pain, heat, and swelling. • It is a non-specific attempt to dispose of microbes and foreign materials, dilute toxins, and prepare for healing.

27. Innate Immunity • The inflammatory response has three basic stages: • Vasodilation and increased permeability • Emigration (movement) of phagocytes from the blood into the interstitial space and then to site of damage • Tissue repair

28. Innate Immunity • Vasodilation allows more blood to flow to the damaged area which helps remove toxins and debris. • Increased permeability permits entrance of defensive proteins (antibodies and clotting factors) to site of injury • Other inflammatory mediators include histamine, kinins, prostaglandins (PGs), leukotrienes (LTs), and complement.

29. Innate Immunity • Emigration of phagocytes depends on chemotaxis • Neutrophils predominate in early stages but die off quickly. • Monocytes transform into macrophages and become more potent phagocytes than neutrophils. • Pus is a mass of dead phagocytes and damaged tissue. • Pus formation occurs in most inflammatory responses and usually continues until the infection subside.

30. Innate Immunity • The inflammatory response is depicted in this graphic: • Edema results from increased permeability of blood vessels. • Pain is a prime symptom which results from sensitization of nerve endings by the inflammatory chemicals.

32. Adaptive Immunity • Substances recognized as foreign that provoke an immune response are called antigens (Ag). • Adaptive immunity describes the ability of the body to adapt defenses against the antigens of specific bacteria, viruses, foreign tissues… even toxins (think of the snake handler who becomes immune to the venom of snake bites).

33. Adaptive Immunity • Two properties distinguish between adaptive immunity and innate immunity: • Specificityfor foreign molecules which act as Ag • this involves distinguishing self-molecules (normal, not antigenic) from nonself molecules • Memoryfor previously encountered Ag

34. Adaptive Immunity • Not all foreign substances are antigenic: We don’t make antibodies to glass, for example. Molecules, or parts of molecules tend to be antigenic if they are: • Foreign – not ourselves • Organic • Structurally complex (proteins are usually complex and form many of the most potent antigens) • Large (high molecular weight)

35. Adaptive Immunity • As an antigen-presenting cell engulfs and destroys a foreign invader, it isolates the antigens those cells “display”. • The APC then presents the foreign Ag to a specific T lymphocyte called a helper T cell (also known as a CD4 cell) . Processed Ag is presented

36. Adaptive Immunity • Once stimulated by antigen presentation, helper T cells become activated. • Activated helper T cells are capable of activating other lymphocytes to become T cytotoxic cells (CD8 cells) which directly kill foreign invaders and B cells (which make antibodies that kill or helps kill foreign invaders).

37. Adaptive Immunity • Activated B and T cells form the two arms of the adaptive immune response: Antibody-mediated immunity and Cell-mediated immunity. • Helper T cells aid in both types, and both types work together to form specific bodily defenses. The Innate and Adaptive Immune systems are depicted

38. Adaptive Immunity • Cell-mediated immunity involves the production of cytotoxic T cells that directly attack invading pathogens (foreign invaders with Ag harmful to us – particularly intracellular pathogens and some cancer cells). • Suppressor and memory T cells are also produced. • Antibody-mediated immunity involves the production of B cells that transform into antibody making plasma cells. • Antibodies (Ab) circulate in extracellular fluids. • B memory cells are also produced.

40. Antibodies • Antibodies (also called immunoglobulins or Igs) are produced by plasma cells through antibody-mediated immunity. • Antibodies are composed of 4 peptide chains: • Two heavy chains and two light chains • Disulfide bonds link the chains together in a Y-shaped arrangement. • The variable region (antigen-binding region) gives an antibody its specificity. • The stem is similar for each class of antibody.

41. Antibodies • Some of the ways antibodies are effective include: • Neutralizing a bacterial or viral antibody, or a toxin by covering the binding sites and causing agglutination and precipitation (making what was soluble, insoluble) • Activating the classical complement pathway • Enhancing phagocytosis - a process called opsonization

42. Antibodies • Thousands of memory cells exist after initial encounter with an antigen - this is called Immunological Memory. • With the next appearance of the same antigen, memory cells can proliferate and differentiate within hours. • This graphic shows that serum antibody titers are much higher and much faster on the second response

43. Gaining Immunocompetence • Within the framework of innate and adaptive immunity we have discussed, there are a number of designations for the ways we can become immunocompetent: • “Natural Immunity” is not gained through the tools of modern medicine, whereas ”Artificial Immunity” is. • Active Immunity refers to the body’s response to make antibody after exposure to a pathogen (antigen). • In Passive Immunity,the body simply receives antibodies that have been preformed. • Active immunity is long-term; passive is short-term.

44. Gaining Immunocompetence • Examples • Natural active – contracting hepatitis A and production of anti-hepatitis A antibodies • Natural passive - a baby receives antibodies from its mother through the placenta and breast milk. • Artificial active - a person receives a vaccine of an attenuated (changed/weakened) pathogen that stimulates the body to form an antibody. • Artificial passive – an injection of prepared antibody

45. Immunological Surveillance • A current theory purports that the formation of cancer cells is a common occurrence in all of us, and that the immune system continually recognizes and removes them. • There are a number of well-recognized tumor antigens which are displayed on certain cancerous cells. • These cells are targeted for destruction by cytotoxic T cells, macrophages and natural killer cells. • Most effective in eliminating tumor cells due to cancer-causing viruses

46. The Immune System and Aging • Atrophy of the thymus gland results in decreased T-helper cell populations, and a diminished mediation of the specific-immune response. • There is a resulting decreased B-cell response and decreased number of T-cytotoxic cells. • Compromised immune function with age results in increased titers of autoantibodies and an increased incidence of cancer (both contribute to overall mortality rates.)