Resistance of the body to infection: Inflammation.

1. Resistance of the body to infection: Inflammation.

2. Define Monocyte –Macrophage Cell System and describe how monocytes are converted into macrophages. List the body tissues where this system is active. Describe the functions of macrophages Define Inflammation Describe the stages of inflammation Recommended reading: Tortora & Derrickson. . Principles of Anatomy and Physiology.12th edn. 2009 Objectives

3. The MPS (Mononucleur phagocytic system) (RE System) • Monocytes leave circulation to enter tissue • Enlarge in size as they move towards site of inflammation/infection (WANDERING MACROPHAGES) • Some collect at specific sites in body tissues (FIXED MACROPHAGES) Secrete Interleukins which stimulate bone marrow NO macrophages in the CNS: job done by MICROGLIA

4. 1 CHEMOTAXIS Microbe Phagocyte 3 INGESTION 2 ADHERENCE Pseudopod 4 DIGESTION Lysosome Digested microbe in phagolysosome Plasma membrane Residual body (indigestible material) 5 KILLING Digestive enzymes Phases of phagocytosis • Phagocytosis by macrophages • 1. Chemotaxis • 2. Adherence • 3. Ingestion • 4. Digestion • 5. Killing

5. Inflammation: nonspecific response of the body to tissue damage. Caused by • bacterial infection, trauma, chemicals, heat, hypoxia Cardinal signs • 1. Redness • 2. Pain • 3. Heat • 4. Swelling

6. Redness; Swelling; Heat • vasodilatation • increased capillary permeability to allow leakage of fluid into interstitial spaces along withy WBCs • (Emigration of WBCs) As result of release of Histamine from mast cells, basophils Kinins (bradykinin) peptides : chemotaxis Prostaglandin E from damaged tissues Leukotriens from basophils and mast cells - increase adherence of phagocytes - increase permeability - act as chemotactic agents

7. PainKinins & PGs stimulate free nerve endings Local edema produces pressure and pain Release of clotting factorsto localize the bacteria

8. Response of WBcs during inflammation: • 1st line of defence: Locally present macrophages reach the site of injury within a few minutes and start phagocytosis. • 2nd line of defence i. neutrophils are attractedto the inflamed area by CHEMOTAXIS. ii. increase capillary permeability iii. neutrophils stick to capillary walls at the site of inflammation (Margination) iv. stored neutrophils are brought into circulation • All this takes a few hours . The neutrophils which are now plenty at site of injury start their phagocytic action.

9. 3rd line of defence More macrophages are recruited to come to the inflamed area. Takes about 8 hours before the newly formed monocytes and granulocytes come into the area. • 4th line of defence Formation of these cells by bone marrow : stimulation by Interleukins, Tumour Necrosis Factor, GM and M Colony Stimulating Factors secreted by activated macrophages. Takes 3-4 days • Macrophages also initiate immune process such as activation of T and B lymphocytes • Collection of all these cells with the necrotic tissue forms PUS • Throbbing pulsating pain: presence of PUS

10. Recap: • Monocyte –Macrophage Cell System: The Wandering & the Fixed macrophages. • Body tissues where this system is active. • Phagocytosis by macrophages • Inflammation • Stages of inflammation • Pus formation

11. Innate and acquired immunity Innate Immunity

12. Objectives: • Define and classify Immunity into the two types:- innate and acquired. • Describe the process of innate immunity • Define the term antigen • Describe the two types of acquired immunity: cell mediated and humoral. • Understand that two types of lymphocytes, T and B, are responsible for acquired immunity • Appreciate that B lymphocytes produce antibodies • List the types of antibodies. • Describe the principal of vaccination • List commonly used vaccinations • Define allergy and describe the role of IgE in allergy • List common allergic conditions

13. Immunity is the body’s ability to resist organisms and toxins which may cause damage • INNATE : external physical, and chemical barriers present in the body at birth • ADAPTIVE /ACQUIRED: immunity is the ability to defend against specific bacteria, toxins, viruses, toxins – substances called ANTIGENs

14. Antibodies : B lymphocytes Ig G commonest IgM IgE allergy IgG A milk Ig D rare: unknown function IMMUNITY Humoral Acquired Innate Cell mediated -Salivary lysozomes -Tears with lysozomes -Acid in stomach -Macrophages/ -Neutrophils -Skin as a barrier -NK Cells • Tlymphocytes: • Helper T cells • Killer: Cytotoxic) • Memory • Suppressor NATURAL KILLER CELLS Resemble early large T cells Found in blood and lymphoid tissue Recognize and destroy virally infected cells & cancer cells

15. ANTIGENS are proteins/ polysaccharides which excite immune mechanisms. • Haptens small molecules which must combine with proteins to excite antigenicity • Characteristics of antigens: i. Immunogenicity: provoke formation of specific antibodies ii. Reactivity The antigen reacts with the antibody it generates

16. Innate Immunity • Present at birth • Involves external physical, and chemical barriers • Helps humans resist diseases such as - Distemper ( سل الكلاب ) - Cattle plague ( طاعون الماشية ) - Viral infections of animals (Lower animals do not get many human diseases: Polio, Mumps, Cholera, Syphilis, Measles)

19. Interferons: (α, β, γ) : proteins produced by viral infected - lymphocytes - macrophages - fibroblasts Mechanism of action: -enter non-infected cells -induce production of anti-viral proteins - stop viral multiplication CANNOT STOP VIRUSES FROM ENTERING CELLS

20. Complement systemC1-C9: - proteins which are normally lying inactive in blood • Action: when activated by antibodies- increase phagocytosis, promote inflammation • Iron binding proteins Action: deprive bacteria of iron by binding to it • Antimicrobial proteins • i. Defensins & Cathelicidins by Neutrophils and macrophages, epitheila: • ii. Dermicidin by sweat glands • iii. Thrombocidin by platelets

21. Natural Killer cells (NK Cells) LymphocytesEffective against tumour cells, viral infected cells, any cells which have abnormal proteins Action by: i. Release of proteins called PERFORINS_ dig holes in to the cell membrane- cell gets flooded with H2O) from ECF and cell burstsCYTOLYSIS ii. Release of GRANYZYME which promote cell apoptosis • Inflammation • Phagocytosisby Macrophages and Neutrophils

22. ACQUIRED IMMUNITY (Adaptive immunity)

23. Objectives: Innate and acquired immunity 2 & 3 • Define Acquired immunity as CELL MEDIATED & HUMORAL • Describe the role of the thymus in processing of T lymphocytes • List the 4 types of T lymphocytes involved, • appreciate that AIDS is a disease caused by ineffective • T lymphocyte functions . • Recognition of self • Recognize that transplanted organs are likely to be destroyed by cell mediated immune mechanisms. • Define auto-immune disease • Name important autoimmune disorders. • Appreciate that stress and aging affect immune mechanisms adversely

24. Acquired (Adaptive) immunity is the ability to defend against specific bacteria, toxins, viruses, toxins – substances called ANTIGENs i. Cell mediated immunity: -by activated T Lymphocytes in the lymph nodes: -active in tissues ii. Humoral -by activated B lymphocytes which develop circulating antibodies. -active in blood

25. IMMUNITY humoral acquired innate Antibodies : Ig G commonest IgM IgE allergy IgG A milk Ig D rare: unknown function B lymphocytes Become plasma cells Produce antibodies Cell mediated Salivary lysozomes Tears Acid in stomach Neutrophils Skin as a barrier • T lymphocytes: • Helper T cells • Killer: Cytotoxic) • Memory • Suppressor Antigen: foreign substance: protein, which excites immune reaction

26. The activation of Lymphocytes Origin of lymphocytes: Pluripotent stem cells in the embryo Bone marrow Develop in marrow: as - B lymphos & Pre T lymphos mature in the Thymus- T lymphos. Reach Immunocompetence by developing antigen receptors on their surface

27. Activation of lymphocytes so that they develop IMMUNOCOMPETENCE • T lymphocytes migrate to thymus before birth, and continue until a few months post birth and B lymphocytes s go to the bone marrow (& liver ?) • Rapid division • Specific reactivity to antigens and development of antigen receptors • Non-reactive to “self” • T cells released from Thymus go to different lymphoid tissues as Helper T cells (CD4 cells) and Cytotoxic T cells ( CD8 cells) • B lymphocytes: develop antibodies against the antigens and become PLASMA cells • The Helper T cells, Cytotoxic T cells and B cells are EFFECTOR cells: die after taking part in immune activity

28. Clone ( إستنساخ وطبيا النسيلة ) formation by lymphocytes • Both B and T cells are involved • Exposure to a particular antigen excites “cloning” of that type of cell or make IDENTICAL cells by CLONAL SELECTION (proliferation & differentiation) • Any time this antigen re-enters the body, these clones are formed to destroy it • Role of MEMORY cells, both T and B • Are not associated with the initial response to antigen • They “REMEMBER” when an antigen enters body again, and act by initiating formation of more clones of that type of lymphocyte • They do not die: they have a long life. • Types of Memory cells: Helper, Killer, B

29. T lymphocytes i. Helper T cells ii. Cytotoxic T cells iii. Memory T cells iv. Suppressor T cells I & ii = Regulatory T cells?) B lymphocytes

30. Maturation and function of B lymphocytes • B lymphocyts are activated by HELPER T & B cells • Formation of plasma cells: manufacture ANTIBODIESagainst specific antigen • Antigen-Antibody reactions • Agglutination ( متراصة ) • Enhance phagocytosis • Neutralizes antigen • Demobilizes bacteria • Activation of complement system • Precipitation of soluble antigens Antibodies Ig G- commonest IgM IgE - allergy IgA - milk Ig D rare: unknown function

31. Physiological principles of immunization • Small dose of non virulent antigen (bacteria/virus) is given • Antibodies are formed against this (type IgM). This is the PRIMAY response • Few weeks later same antigen dose is repeated: much bigger antibody response: Secondary response- IgG ) IgG IgM

32. Common vaccinations: Bacterial • DPT • Typhoid • Cholera Viral • Polio • Measles • Influenza

35. Use of immunity for protection 1. Active immunity: vaccinations 2. Passive immunity a. Mother to fetus : IgG antibodies via placenta Ig A in milk b. Injection of Immunoglobulins

36. Aging & Immunity - Old people get infections/cancers more easily - Response to vaccines is decreased - They produce more auto-antibodies to own tissues - T cells respond less to antigens • Stress and Immunity -Decreases in stress: effect of main stress hormone: corticosteroids

37. MHCs Major Histocompatibility Complexes (MHCs) Human Leucocyte Antigen (HLA) MHC I : present on all body cells (NOT RBC) MHC II : on Antigen presenting cells (Macrophages, Dendritic cells, B cells)

38. 1. Ingestion and digestion of antigen to form peptide fragments 2. Synthesis of MHC II molecule in the ER and their packaging Process of antigen presentation: Exogenous antigens: outside cells (bacteria, toxins, pollens, viruses) 3. Peptide fragments + MHC II mols Vesicles fuse 4. Peptide s and MHC II then fuse To form a complex 5. Complex inserted in to plasma membrane 6.APC then migrates to lymphoid tissue To meet lymphocytes through receptors

39. Key: Key: Key: Key: Key: Key: Key: Antigen peptide fragments Antigen peptide fragments Antigen peptide fragments Antigen peptide fragments Antigen peptide fragments Antigen peptide fragments Antigen peptide fragments 5 5 5 Vesicles containing antigen peptide fragments and MHC-II molecules fuse Vesicles containing antigen peptide fragments and MHC-II molecules fuse Vesicles containing antigen peptide fragments and MHC-II molecules fuse 1 1 1 1 1 1 1 Phagocytosis or endocytosis of antigen Phagocytosis or endocytosis of antigen Phagocytosis or endocytosis of antigen Phagocytosis or endocytosis of antigen Phagocytosis or endocytosis of antigen Phagocytosis or endocytosis of antigen Phagocytosis or endocytosis of antigen 6 6 Antigen peptide fragments bind to MHC-II molecules Antigen peptide fragments bind to MHC-II molecules Exogenous antigen Exogenous antigen Exogenous antigen Exogenous antigen Exogenous antigen Exogenous antigen Exogenous antigen MHC-II self-antigen MHC-II self-antigen MHC-II self-antigen MHC-II self-antigen MHC-II self-antigen MHC-II self-antigen MHC-II self-antigen Phagosome or endosome Phagosome or endosome Phagosome or endosome Phagosome or endosome Phagosome or endosome Phagosome or endosome 7 Vesicle undergoes exocytosis and antigen–MHC-II complexes are inserted into plasma membrane 2 2 2 2 2 2 Digestion of antigen into peptide fragments Digestion of antigen into peptide fragments Digestion of antigen into peptide fragments Digestion of antigen into peptide fragments Digestion of antigen into peptide fragments Digestion of antigen into peptide fragments 4 4 4 4 Packaging of MHC-II molecules into a vesicle Packaging of MHC-II molecules into a vesicle Packaging of MHC-II molecules into a vesicle Packaging of MHC-II molecules into a vesicle Antigen- presenting cell (APC) Antigen- presenting cell (APC) Antigen- presenting cell (APC) Antigen- presenting cell (APC) Antigen- presenting cell (APC) Antigen- presenting cell (APC) Antigen- presenting cell (APC) Endoplasmic reticulum Endoplasmic reticulum Endoplasmic reticulum Endoplasmic reticulum Endoplasmic reticulum 3 3 3 3 3 Synthesis of MHC-II molecules Synthesis of MHC-II molecules Synthesis of MHC-II molecules Synthesis of MHC-II molecules Synthesis of MHC-II molecules APCs present exogenous antigens in association with MHC-II molecules APCs present exogenous antigens in association with MHC-II molecules APCs present exogenous antigens in association with MHC-II molecules APCs present exogenous antigens in association with MHC-II molecules APCs present exogenous antigens in association with MHC-II molecules APCs present exogenous antigens in association with MHC-II molecules APCs present exogenous antigens in association with MHC-II molecules

40. Digestion of these proteins Formation of MHC I Endogenous antigens : INSIDE body cells (toxins, viral proteins, abnormal proteins by cancer cells) Peptide s and MHC I then fuse To form a complex Peptide fragments + MHC I mols Vesicles fuse APC then migrates to lymphoid tissue To meet lymphocytes through receptors Complex inserted in to plasma membrane

41. Endogenous Antigens

42. Recognition of SELF T cells must know own MHC s :SELF RECOGINITION T cells must NOT react to own peptide fragments : TOLERANCE • Positive selection • Immature T cells (before activation) form receptors that react with self MHCs & form a self antigen-MHC binding & recognize the MHC • T cells that don’t form and recognize this complex under go cell death • Negative selection • i. Deletion: self reactive T cells undergo natural cell death (apoptosis) ii. Anergy : Unresponsive to antigen stimulation • Tolerance to SELF (own tissue) develops during embryonic life

43. Abnormal immune reactions: • Basically categorized as HYPERSENSITIVITY: • Allergy: Harmful effects of hypersensitivity to environmental (exogenous) antigen • Autoimmune disease: when the body defence mechanisms act against the self. • When immune mechanisms of one individual produces reactions in another person, it is know as ALLO IMMUNITY.

47. AUTOIMMUNE disorders • Non recognition of SELF causes this reaction. • . • Sequestered antigens: tissue not drained by body lymphatics, have never been exposed to body immune mechanisms. Eg. Cornea of the eye. That is why anybodies cornea can be grafted on to anyone else’s eye. But if accidentally such tissue enters the body, it will excite a severe immune response. • Neo(new) antigens a chemical binds to a body tissue, forms a new antigen which is now new to immune mechanisms of the host. • Infectious disease may induce formation of a substance which is similar to one of the host tissues. This then excites a reaction. Egs. Rheumatic heartdisease; glomerulonephritis • Supressor cell dysfunction the negative feed back control is not there.

48. ALLOIMMUNITY: Immune system of one individual reacts against antigens of another individual: classically mismatched blood transfusion reactions, and Hemolytic disease of the new born (Rh factor deficiency) • CONGENITAL immune deficiency: Agammaglobulinemia • HIV as a immune disorder. This is an ACQUIRED immune deficiency syndrome • HIV is a RETRO virus. It carries a RNA which enters the host cell by combining with a cell surface receptor and then converts into a DNA. Once inside it may increase in number. • CD4 lies on surface of Helper T cells. HIV attaches to it, enters Helper T cells, and then destroys them.

50. Some autoimmune diseases • Hashimoto’s Thyroiditis (Hypothyroid disease) • Graves Disease (Hyperthryroidism) • Myasthenia Gravis • Multiple Sclerosis • Atrophic gastritis