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Resistance of the body to infection: Inflammation. 1 Objectives 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 2 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 3 Phagocytosis by macrophages 1. Chemotaxis 2. Adherence 3. Ingestion 4. Digestion 5. Killing 1 CHEMOTAXIS Microbe Phagocyte 2 ADHERENCE 3 INGESTION Pseudopod Lysosome Plasma membrane 4 DIGESTION 5 KILLING Digestive enzymes Digested microb in phagolysosom Residual body (indigestible material) Phases of phagocytosis 4 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 5 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 6 Pain Kinins & PGs stimulate free nerve endings Local edema produces pressure and pain Release of clotting factors to localize the bacteria 7 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 attracted to 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. 8 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 9 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 10 Innate and acquired immunity Innate Immunity 11 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 12 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 13 IMMUNITY Innate Acquired -Salivary lysozomes -Tears with lysozomes -Acid in stomach -Macrophages/ -Neutrophils -Skin as a barrier -NK Cells Cell mediated Humoral Antibodies : B lymphocytes Ig G commonest IgM IgE allergy IgG A milk Ig D rare: unknown function T lymphocytes: 1. Helper T cells 2. Killer: Cytotoxic) 3. Memory 4. Suppressor NATURAL KILLER CELLS Resemble early large T cells Found in blood and lymphoid tissue Recognize and destroy virally infected cells & cancer cells 14 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 15 Innate Immunity Present at birth Involves external physical, and chemical barriers Helps humans resist diseases such as - Distemper ) ( سل الكالب - Cattle plague ) ( طاعون الماشية - Viral infections of animals (Lower animals do not get many human diseases: Polio, Mumps, Cholera, Syphilis, Measles) 16 17 18 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 19 Complement system C1-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 - 20 Natural Killer cells (NK Cells) Lymphocytes Effective 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 bursts CYTOLYSIS ii. Release of GRANYZYME which promote cell apoptosis Inflammation Phagocytosis by Macrophages and Neutrophils 21 ACQUIRED IMMUNITY (Adaptive immunity) 22 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 23 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 24 IMMUNITY innate acquired humoral Cell mediated Salivary lysozomes Tears Acid in stomach Neutrophils Skin as a barrier B lymphocytes Become plasma cells Produce antibodies T lymphocytes: 1. Helper T cells 2. Killer: Cytotoxic) 3. Memory 4. Suppressor Antibodies : Ig G commonest IgM IgE allergy IgG A milk Ig D rare: unknown function Antigen: foreign substance: protein, which excites immune reaction 25 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 26 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 27 Clone ) ( إستنساخ وطبيا النسيلةformation 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 28 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 29 Maturation and function of B lymphocytes B lymphocyts are activated by HELPER T & B cells Formation of plasma cells: manufacture ANTIBODIES against specific antigen Antibodies Ig G- commonest IgM IgE - allergy IgA - milk Ig D rare: unknown function Antigen-Antibody reactions 1. 2. 3. 4. 5. 6. Agglutination ) ( متراصة Enhance phagocytosis Neutralizes antigen Demobilizes bacteria Activation of complement system Precipitation of soluble antigens 30 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 IgG IgM Few weeks later same antigen dose is repeated: much bigger antibody response: Secondary response- IgG ) 31 Common vaccinations: Bacterial DPT Typhoid Cholera Viral Polio Measles Influenza 32 33 34 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 35 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 36 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) 37 Process of antigen presentation: Exogenous antigens: outside cells (bacteria, toxins, pollens, viruses) 1. Ingestion and digestion of antigen to form peptide fragments 4. Peptide s and MHC II then fuse To form a complex 5. Complex inserted in to plasma membrane 2. Synthesis of MHC II molecule in the ER and their packaging 3. Peptide fragments + MHC II mols Vesicles fuse 6.APC then migrates to lymphoid tissue To meet lymphocytes through receptors 38 Key: 1 Phagocytosis or endocytosis of antigen Exogenous antigen 5 Vesicles containing antigen peptide fragments and MHC-II molecules fuse 6 Antigen peptide fragments bind to MHC-II molecules Antigen peptide fragments MHC-II self-antigen Phagosome or endosome Antigenpresenting cell (APC) 2 Digestion of antigen into peptide fragments 4 Packaging of MHC-II molecules into a vesicle 7 Vesicle undergoes exocytosis and antigen–MHC-II complexes are inserted into plasma membrane Endoplasmic reticulum 3 Synthesis of MHC-II molecules APCs present exogenous antigens in association with MHC-II molecules 39 Endogenous antigens : INSIDE body cells (toxins, viral proteins, abnormal proteins by cancer cells) Digestion of these proteins Peptide s and MHC I then fuse To form a complex Complex inserted in to plasma membrane Formation of MHC I Peptide fragments + MHC I mols Vesicles fuse APC then migrates to lymphoid tissue To meet lymphocytes through receptors 40 Endogenous Antigens 41 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 42 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. 43 44 45 46 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 Infectious disease may induce formation of a substance which is Rheumatic heartdisease; glomerulonephritis Supressor cell dysfunction the negative feed back control is not new antigen which is now new to immune mechanisms of the host. similar to one of the host tissues. This then excites a reaction. Egs. there. 47 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. 48 49 Some autoimmune diseases Hashimoto’s Thyroiditis (Hypothyroid disease) Graves Disease (Hyperthryroidism) Myasthenia Gravis Multiple Sclerosis Atrophic gastritis 50 51