1 st Year Physical Therapy Pathophysiology Stephanie Quaile Topic 5 Lymphatic System

1. 1st Year Physical Therapy Pathophysiology Stephanie Quaile Topic 5 Lymphatic System November 24th 2013

2. Learning Outcomes • Define the role of T lymphocytes, B lymphocytes and Natural Killer cells in immunity. • Describe the function of Innate and Adaptive immunity. • Identify the causes of altered immunity. • Identify and explain the pathophysiology of HIV and SLE.

3. Immune Cell Origin • Bone marrow contains pluripotent hematopoietic stem (PHS) cells. • PHS cells produce 2 precursor cell types: Lymphoid progenitor cells Myeloid progenitor cells

4. Lymphoid Progenitor cells • T lymphocytes • B lymphocytes • Natural killer cells

5. T Lymphocytes • Mature and fully differentiate in the Thymus. • Contact with antigens causes differentiation into: Cytotoxic T lymphocyte- direct destruction of antigen carrying cells. Helper T lymphocyte- enhance antibody and cell-mediated responses of the immune system. Activate other cells needed for immune response. Suppressor T lymphocytes- inhibit antibody and cell-mediated responses. • Contain T cell receptors, which bind antigens to cells.

6. B Lymphocytes • Develop in bone marrow. • Migrate to peripheral lymphoid tissue where they become activated after contact with an antigen. Example of peripheral lymph tissue? • Binding of B cell and antigen causes differentiation of B lymphocyte into antibody-secreting- plasma cells. • Recognise specific antigens due to B-cell receptors= specificity of immune response.

7. B Lymphocytes cont'd • Antibodies are released from plasma cell membranes = Immunoglobulin (Ig) • IgA, IgG, IgM, IgD, IgE. • Designed to detect and bind to specific antigens.

8. Natural Killer cells • Large granular lymphocytes. • Non antigen specific. • Circulate until they contact cells they recognise as a threat, which they attack and kill.

9. Myeloid Progenitor cells • Produce granulocytes and monocytes. • Granulocytes- neutrophils, eosinophils, basophils. • Monocytes- differentiate into macrophages when contact antigens and enter tissue. During phagocytosis, macrophages display antigen markers on cell surface which are recognised by receptors of T and B lymphocytes.

10. Immune Processes • Innate immunity. • Adaptive immunity: Antibody-mediated immunity, Cell-mediated immunity.

11. Recap Innate Immunity • Rapid response to organisms that pose a threat of infection. • Prevention of microbe colonization. • Prevention of microbe entry. • Prevention of microbe spread.

12. Innate Immunity • Inflammatory response follows detection of microbe. • Phagocytosis and release of chemical mediators. • Dendritic cells, located in tissues, are antigen- presenting cells. • Dendritic cells, help recognise nonself cells and present them to lymphocytes.

13. Adaptive Immunity • B and T lymphocytes, dendritic cells involved. • Stimulated by phagocytosis and activation of antigen- presenting cells. Key Features • Specificity- response to distinct antigen. • Diversity- recognises wide variety of antigens. • Memory- rapid response to to previously recognised antigens. • Self and nonself recognition.

14. Antigens • Antibody generators. • Entire or parts of microbes, act as antigens. • Chemical components of bacteria e.g flagella, cell walls, toxins are antigenic. • Non microbial examples – pollen, egg white, incompatible blood cells. • Epitopes – the small parts of an antigen which trigger an immune reaction.

15. Antigens • Antigens are usually proteins. • Nucleic acid, glycoproteins, polysaccharides can also act as antigens. • The immune system can recognise at least a billion epitopes before they even enter the body.

16. Active Immunity • Development of antibodies in response to an antigen. • Achieved through having a disease or by vaccination against a specific disease. Passive Immunity • Transfer from host to recipient. • Achieved via mother to baby through placenta and breastmilk. • Achieved by injection of antibodies.

17. Ch 22 pg 914. Read cell and antibody mediated immunity summary.

18. Cell-mediated Immunity • Recognition and destruction of cells carrying nonself antigens. • Cytotoxic T lymphocytes detect pathogens inside cells where they cannot be recognised by antibodies. • Cytotoxic T lymphocytes recognise cells with a virus displayed on their surface. • The entire cell is killed to prevent spread of disease.

19. Cell-mediated immunity • Major Histocompatibility complex- self antigens. • Trap antigen in cell and transport it to cell membrane. • MHC's are cell surface markers on infected cells and APC's. • Helps T lymphocytes detect antigens which are then bound to receptors. • Help to decipher body's self antigens from foreign non self antigens. • Cause rejection of transplanted tissue.

20. Major Histocompatibility Complex • Unique to individuals unless they have an identical twin. • MHC class 1- found on nucleated cells. • MHC class 2- found on antigen-presenting cells.

22. Play video of Cell Mediated Immunity Q1) What happens immediately after a pathogen is digested by macrophage? Q2) What effect on Helper T cell when it binds to macrophage? Q3)What kills the pathogen?

23. Antibody-mediated Immunity • Antibodies are immunoglobulins that react with an antigen in a specific way. • Constant region- the base of the Y and most stable. • Variable regions (2)- allow binding to specific antigens.

24. Antibodies • IgG can enter body tissue from fluid- passive immunity in fetus. • IgA provides passive immunity to baby from breastmilk. • IgM is initial antibody produced in response to an antigen. First to be produced by a new born. • IgD is involved in binding the antigen and differentiation of B lymphocytes to plasma cells.

25. Antibody-mediated Immunity • Each B lymphocyte carries a single, specific receptor which recognises an antigen= B cell receptor(BCR). • BCR + antigen = differentiation of B lymphocyte into effector cell. • Effector cells = plasma cells that secrete antibodies.

27. Antibody-mediated Immunity • BCR + antigen binding + helper T cell = clonal expansion. • Clonal expansion- clones of the B lymphocyte bound to the antigen, differentiate into plasma cells which secrete antibodies to destroy the specific antigen.

28. Antibody-mediated Immunity • Memory cells= effector cells which remain after death of antigen. • Memory cells respond quickly next time an antigen invades. • Immunological Memory through Vaccinations. -Weakend or dead microbe, activates appropriate T and B cells. Memory cells remain to respond quickly if needed in future.

29. Play video- Clonal Expansion

31. Antibody-mediated Immunity How Antibodies protect cells • Neutralization- antibody binds to antigen, preventing the cell becoming infected. • Opsonization- promotion of phagocytosis as the phagocyte recognises the constant region of the antibody which is bound to the antigen. • Activation of complement, further enhances the effect of the antibody. Pg 903- Describe the Complement System.

32. Play clip of antibody mediated immunity Q1) What activated the B-cell? Q2)Role of APC's? Q3)Role of Helper T cell? Q4)Role of a memory cell? Q5)What is responsible for producing antibodies?

33. Altered Immunity • Failure of host defense mechanisms. • Hypersensitivity- inappropriate excessive immune response. • Autoimmunity- inappropriate response to “self”. • Alloimmunity- response to tissue antigens from other individuals of the same species.

34. Host Defense Failure • Impaired ability to mount an immune response. • The pathogen grows without alerting the immune system. • Antigenic variation- pathogens with multiple variations of antigens are difficult for B and T lymphocytes to detect. Memory immunity is ineffective. • Genetic mutation of the pathogen makes the antigen slightly different and difficult to detect.

35. Host Defense Failure • Latency- a period of inactivity by a pathogen, when it avoids detection. • Pathogens may use immune system cells as hosts, which gives them protection. • Immunodeficiency- due to genetic mutation, deficient phagocyte numbers, altered T lymphocyte signalling.

36. Hypersensitivity • Excessive immune responses to allergens. • Allergens are antigens which are deemed to be harmless e.g.dust, pollen, food. • Symptoms result from tissue damage and can be local or systemic. • 4 types of Hypersensitivity.

37. Type 1: Immediate Hypersensitivity Reaction • Exposure to allergens,usually inhaled in low doses, causes production of IgE. • Allergens activate dendritic cells, which travel to lymph nodes and present allergens to naive T lymphocytes. • Chemical signals can cause B lymphocytes to produce antibodies against IgE. • IgE produced by plasma cells in inflamed tissue, binds to mast cells and basophils.

38. Immediate Hypersensitivity Reaction • IgE binds to passing allergens, causing mast cells and basophils to release chemicals which damages the tissue cells. • This damage causes the symptoms of an allergy. • Most allergies are genetic and passed from generation to generation. • Anaphylaxis- very serious response to Immediate Hypersensitivity Reaction. Causing vasodilation and edema, leading to hypotension.

39. Immediate Hypersensitivity Asthma • Stage 1: Lasts approx. 1 hour. Mast cell degranulation and release of chemical mediators- vasodilation and smooth muscle contraction. • Stage 2 : Lasts 2 to 8 hours. Lipid mediators released from degranulated cell membranes. Leukocyte and eosinophil recruitment causes inflammatory reaction.

40. Asthma Symptoms • Wheezing. • Breathlessness. • Chest tightness. • Excessive sputum production. • Coughing. • Hyperventilation leads to acidosis due to ineffective expiration.

41. Type 2: Antibody Mediated Reaction • Mistaken Identity. • Harmless cells are targeted and killed- often involves blood cells. • Seen in drug reactions, blood transfusion reactions, Grave's disease, hemolytic disease of newborns. • Antibody binds to antigen of cell, causing lysis and cell death.

42. Antibody Mediated Reactions • Cell destruction then leads to disease associated with cell loss e.g. Anemia, thrombocytopenia, leukopenia. • Treatment involves removing the antigen causing the reaction.

43. Type 3: Immune Complex Mediated Reaction • Cell and tissue damage resulting from complement activation- stimulated by insoluble antigen-antibody complexes. • Complement is a key source of chemical mediators in plasma. • Causes altered blood flow, vascular permeability, inflammation- damaging blood vessels and organs. • Systemic Lupus Erythematosus(SLE), Rheumatoid arthritis.

44. Type 4: Cell Mediated Hypersensitivity Reaction • Caused by T lymphocyte reactions. Direct Cell-mediated Toxicity • Cytotoxic T lymphocytes attack all infected cells with a recognised antigen, whether the antigen is harmful or not. • Can be more harmful than the effect of the pathogen. • E.G. Some forms of hepatitis, the liver is damged by the cell-mediated toxicity.

45. Cell-mediated Hypersensitivity Reaction Delayed Hypersensitivity Reactions • Caused by antigen specific T lymphocytes. • Small antigens pass to skin cells and react with “self” proteins, forming Major Histocompatibilty Complex, which stimulate T lymphocytes. • Sensitisation- once antigens cross to skin, they are transported to lymph nodes and activate helper T cells. Memory cells are produced and remain in the skin.

46. Cell-mediated Hypersensitivity Reaction Elicitation phase- memory cells are activated by repeat exposure to the antigen. Macrophages and additional T cells are attracted. Blood vessel permeability leads to swelling.

47. Alloimmunity • Immune response stimulated by the presence of cells from another individual of the same species. • Graft rejection- if MHC molecules do not match. • APC's from the donor travel in lymph system and activate host T lymphocytes, which travel back to the graft area and destroy donor antigens. • Grafts from a different area of the same person and from identical twins are fully accepted.

48. Autoimmunity • When the body fails to rrecognise “self” from “nonself”. • Specific recognition of self antigens. • Overzealous reaction to chronic infection. • Can be directed at specific organs e.g. Grave's disease or can have a systemic effect e.g. SLE.

49. Autoimmunity causes • Inadequate elimination of self reactive lymphocytes in central lymph tissue. • Infection over-riding the non responsive nature of immature T lymphocytes. • Close resemblance between foreign and self antigens. • Inappropriate activation of T cell receptors. • Usually genetic and passed through generations.

50. Systemic Lupus Erythematosus • SLE is an Immune-Complex mediated reaction. • Autoantibodies are targeted against self-antigenic components of the cell membrane, cytoplasm and nucleus. • Binding of antigen and antibody stimulates activation of the complement system and accumulation of immune complexes. • As the antigens are present in ALL cells, SLE can damage a wide range of tissue and organs.