THE IMMUNE SYSTEM Dinithi Peiris Department of Zoology The Lymphatic System A system of vessels, cells and organs Vessels originate blindly and the structure is similar to that of a vein with valves The vessels transport a fluid called lymph that is similar in composition to extra cellular fluid Lymphatic system also consist of number of organs and cells that are collectively referred to as white blood cells Lymphatic System: Components Lymph Protein-containing fluid transported by lymphatic vessels Organs Lymphatic vessels: Transport the lymph at a low pressure. Structurally and functionally similar to a vein. Lymphatic vessels eventually joins with the venous system Primary lymphoid organs: Organs involved in development of cells of the lymphatic system eg: bone marrow, thymus Secondary lymphoid organs: Organs involved in housing cells of the lymphatic system and immune response eg: lymph nodes, spleen Cells Granulocytes: neutrophils, eosinophils, basophils, and mast cells Agranulocytes: monocytes, macrophages, B and T lymphocytes, and natural killer cells 1
Lymphatic System: Components Lymph The fluid, lymph (=clear spring water), is what seeps out of the blood at the peripheral capillaries. Composition is similar to plasma without the proteins Has bacteria, virus, cell debris Lipid content is high Lymphocytes content is high Lymphatic vessels Transport the lymph from tissue back to the bloodstream Starts usually along the side of a vein Similar to a vein in structure and function (low pressure system, use SK muscle and respiratory pump to help flow, valves are present to prevent backflow) Lymphatic vessels eventually joins with the venous system through the left and right subclavian veins Lymphatic System: Components Organs Primary lymphoid organs: Organs involved in development of cells of the lymphatic system eg: bone marrow, thymus Secondary lymphoid organs: Organs involved in housing cells of the lymphatic system and immune response eg: lymph nodes, spleen Lymphatic System: Components Cells Granulocytes: Neutrophils Eosinophils Basophils Mast cells Agranulocytes: large nuclei and small amount of cytoplasm Function in identification and inactivation/ destruction of pathogens Monocytes Macrophages B lymphocytes T lymphocytes (Thelper and Tcytotoxic) Natural killer cells 2
Cells of the Immune system: Granulocytes Neutrophil Eosinophil Neutrophils: granules stain at neutral ph, 3-5 lobed nucleus, receptors for antibody & complement, migrate to site of tissue damage/infection, major phagocyte, many hydrolytic enzymes digestion O 2 -dependent & O 2 -independent paths Eosinophils: granules stain with acidic dyes, two-lobed nucleus, connected by thin strand, migrate to tissues to defend against protozoa and helminths, release cationic proteins and oxygen metabolites that damage parasite s membrane Granulocytes continued Basophil Mast cell Basophils: granules stain with basic dyes, two-lobed nucleus, non-phagocytic, secrete vasoactive agents (histamine, serotonin, prostaglandin), affinity for IgE coats surface of the cell triggers cell to secrete vasoactive agents eg: hay fever, asthma, eczema Mast cells:reside in connective tissue, contains granules of histamine and many other pharmacological agents, contribute to inflammatory response, allergies and hypersensitivities Cells of the Immune system: Agranulocytes Mononuclear cells: Monocytes circulate in blood for few days and then enters into tissue and terminally differentiate into macrophages Macrophages larger, more organelles, receptors for antibody and complement, two populations fixed and wandering Lymphocytes Three cell populations: B cells, T cells, natural killer B mature in bone marrow, to lymphoid organs T mature in thymus, to blood, lymphoid organs NK circulate, destroy infected cells, cancer cells Monocytes Macrophages Lymphocyte Natural killer cell 3
Functions of the Lymphatic System Maintenance of blood volume in cardiovascular system (return of lost fluid from the capillaries) Transport of fats and fat soluble material from digestive system Filtration of foreign material to defend against infection (through the lymph nodes and spleen) Defending the body from various pathogens and parasites Organization of the defense mechanism First Line of Defense: Non specific Physical and chemical barriers Second Line of Defense: Non specific Phgocytosis Interferons Complement system Inflammation Natural killer cells Fever Third Line of Defense: Specific Cell mediated defense Humoral defenses Physical and chemical barriers Skin: Acts as an physical and chemical barrier Keratinized and therefore a dry and dead layer, inhospitable to microorganisms Constant replacement resulting in the removal of many adhering microorganisms ph = 5-6 due to fatty acids present in secretions of the sebaceous glands. Too acidic for many microorganisms Other barrier systems: Secretions containing lysozyme, antibodies -tears, saliva Secretions to trap microorganisms - earwax, mucus Acidic environments - digestive acids in stomach, vagina Elimination mechanisms - vomiting, urination, defecation Resident bacteria (normal flora) secrete antibodies 4
Engulfing any foreign body by neutrophils, monocytes, macrophages, eosinophils. Phagocytosis ( cell eating ) Pinocytosis - macromolecules internalized via nonspecific membrane envagination (sipping) Receptor-mediated endocytosis - macromolecules selectively internalized via specific receptors Engulfment of foreign body (phagosome) Merging with lysosome (phagolysosome) Digestion of the foreign body (digestive vacuole) Absorption of nutrients Elimination of unnecessary material Eukaryotic Cells, Bacteria, and Viruses 5
Interferon Family of glycoproteins secreted by viral infected cells that induces virus resistance in neighboring cells (a) (c) (b) (d) The Complement (C ) System The Complement system consists of a complex series of fifteen proteins, many of which are proteineases It is a primitive form of defense against infection, being conserved throughout evolution It performs three vital functions: cell activation cytolysis opsonization Is one of the first systems activated in the response to infection. The Complement system can be considered as a cascade of interacting proteins, acting in a defined manner, resulting in the initiation of important innate biological effects Overview of the classical pathway 6
Overview of the alternate pathway Biological Functions of Complement C5b6789 C3b ic3b C4B Anaphylatoxins: C3a, C4a, C5a Chemotaxins: C3a, C5a, C5b67 C3b Inflammatory response Process: tissue damage leads to release of histamine by basophils/mast cells, blood vessels dilate, complement marks bacteria, phagocytic cells arrive and remove invading microorganisms Signs: redness, warmth, swelling, pain. 7
Other Non Specific Chemical Defenses Fibronectin A glycoprotein that binds bacteria to block attachment and enhance removal β-lysin A cationic polypeptide secreted by platelets that disrupts cell membrane of Gram-positive bacteria Tumor necrosis factor alpha (TNF-α) - Secreted by phagocytes & some T cells in response to LPS, M. tuberculosis, etc. that activates macrophages involved in inflammatory response and promotes fever Interleukins IL-1 and IL-6 generated as a result of inflammatory response promotes fever which helps in fighting infections as Pathogens do not fair well under high temperature Immune responses are accelerated by high temperature Natural Killer Cells Natural killer cells are large granular lymphocytes NK cells recirculate via the blood and can reach virtually any location NK cells are present in low number in lymph nodes, spleen, blood, and peritoneum NK Cell Functions Innate Immune Functions Early resistance to viruses and bacteria by production of IFN-γ and lysis of virus infected cells Induction of inflammation NK cells are involved in the induction of inflammatory responses in some organs Surveillance and resistance to cancer NK cells have a role in surveillance and resistance to at least some types of cancer 8
Mechanisms of NK Cell Action Secretion of Perforin and Granzymes Perforin has considerable sequence homology with complement component C9 It self assembles to form pores in the target cell membrane and destroy its semi permeable nature Granzymes (A and B) are enzymes that induce apoptosis (cell death) of the target cells Non Specific Defense Mechanisms All the immune mechanisms considered thus far are termed as NON SPECIFIC DEFENSE MECHANISMS The characteristic features of non specific defenses are It is not directed against a specific target It has no memory and therefore each disease event will be considered as a new event Many pathogens can evade this defensive barrier Third Line of Defense Specific Defense Mechanisms Properties of specific immune response: Restricted to vertebrates primarily Lag phase to response Antigen-specific Results in the induction of memory cells Highly variable Specific Immune response: Humoral and cell mediated B cells: humoral or antibody-mediated immunity T cells: cell-mediated immunity, action by cells Helper T cells: stimulate other immune cells Cytotoxic T cells: kill abnormal and foreign cells in a specific manner (specific type of cancer cells) 9
Antibodies B cells produce molecules called Antibodies (globulins) Initially known as γ-globulins and now they are called Immunoglobulins (Igs) Expressed as secreted and B- cell membrane-bound forms Has three major functions Opsonization Neutralization Complement activation Cell Mediated Immunity - T Lymphocytes Helper T cells: Secrete cytokines that regulate functions of both cytotoxic T lymphocytes and B lymphocytes Cytotoxic T lymphocytes: Destroy virally infected cells or cancer cells by secretion two chemical mediators GRANZYME and PERFORINb What makes us sick? enemies in the environment in the form of microbes and chemicals are constantly attacking our bodies, disrupting homeostasis sometimes immune system homeostasis is disrupted on its own it may over-react to antigens such as with allergies it may under-react as with human immunodeficiency virus infection (HIV) it may react to self proteins as with autoimmune disease 10
Over-reaction to antigens the immune system reacts to antigens (allergens) that don t cause a reaction in most people like pollen Pollen grains Mast cell Dennis Kunkel Microscopy, Inc., www.denniskunkel.com a type of antibody called IgE binds to the allergen causing mast cells to produce chemicals called histamines. Common symptoms include: runny nose and itchy, watery eyes, with repeated exposure resulting in a more rapid onset of symptoms treatments antihistamines are given to counteract the histamines shots containing low doses of an allergen can help a person to become desensitized to that specific antigen Reaction to Self Occurs when the immune system sees self antigens as nonself may be due to genetic factors, infectious agents, gender, and age the autoimmune response results in tissue damage Some damage occurs in only one or a few organs, in other cases it may be body-wide (systemic) ~ 3.5 % of people have autoimmune diseases On average, women are 2.7 times more likely to develop these diseases than men most have no known cause or cure - treatment is aimed at controlling symptoms Why does the immune system attack the body that it s supposed to protect? failure to recognize some cells as self in rheumatic fever, the streptococcus antigen is very similar to a protein in heart tissue, so the body mistakenly identifies heart tissues as foreign cells seen as foreign are attacked and destroyed may be only a few select cells or organs (organ-specific) e.g., multiple sclerosis, juvenile diabetes, rheumatic fever may be systemic - e.g., systemic lupus erythematosus, rheumatoid arthritis 11
Examples of autoimmune diseases Organ-specific Multiple Sclerosis Juvenile Diabetes Systemic Systemic Lupus Erythematosus Rheumatoid arthritis Under-reaction to antigen Immunodeficiencies occur when some part of the immune system is defective or missing T cells, B cells, phagocytes, or complement these deficiencies are grouped as: primary: inherited or congenital severe combined immunodeficiency (SCID) secondary: acquired HIV infection David Vetter 1972-1984, the original bubble boy 12