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Transcript
Study of the Immune System Now that we know all about microbes….. What provokes us to fight against microbes? How do we know that they are foreign? What initiates the response? Introduction to Antigens Antigen (Ag) most antigenic Any substance that stimulates an immune response Requirements for antigenicity foreignness (recognition of nonself) large size complexity Characteristics of Antigens Epitope antigenic determinant small molecular group that is recognized by: Antibodies B cells T cells Defense Mechanisms of the Host Immune system first line of defense any barrier that blocks invasion at the portal of entry nonspecific second line of defense relies on a multilevel network of physical barriers, immunologically active cells, and a variety of chemicals 3 main lines of defense: protective cells and fluids inflammation and phagocytosis nonspecific third line of defense acquired with exposure to foreign substance Stronger immune response produces protective antibodies and creates memory cells specific Physical or Anatomical Barriers: First Line of Defense • Skin and mucous membranes: outermost layer of skin few pathogens can penetrate if intact flushing effect of sweat glands mucous coat impedes attachment and entry of bacteria blinking and tear production stomach acid nasal hair traps larger particles Vaginal secretions Structure and Function of the Organs of Defense and Immunity Immunology study of the body’s second and third lines of defense Functions of a healthy functioning immune system: 1. Constant surveillance of the body 2. Recognition of foreign material 3. Destruction of entities deemed to be foreign Blood Plasma Serum - fluid portion complement proteins and antibodies Three types of formed elements Erythrocytes Platelets Leukocytes Divided into granulocytes and agranulocytes White Blood Cells Leukocytes Housekeeping and defense Scavenge dead or worn-out cells Disease organisms Squeeze out of blood vessels and enter tissues Develop from stem cells in bone marrow Granulocytes Agranulocytes Neutrophils Eosinophils Basophils Monocytes Macrophages Lymphocytes B-cells T-cells Neutrophils Eosinophils 1-3% orange granules and bilobed nucleus destroy eukaryotic pathogens Basophils, mast cells 55-90% lobed nuclei with lavender granules phagocytes 0.5% constricted nuclei, dark blue granules release potent chemical mediators Lymphocytes 20-35% large nucleus involved in specific immune responses Monocytes, macrophages B (humoral immunity) T cells (cell-mediated immunity) 3-7% large nucleus Phagocytic Dendritic cells Activate lymphocytes Produce cytokines White Blood Cells Innate Immunity “Second” line of defense Second Line of Defense cells and mechanisms that defend the host from infection by other organisms genetically-encoded to recognize: common pathogenic features foreign substances does not confer long-lasting or protective immunity to the host provide immediate defense against infection Actions of the Second Line of Defense • • • • • Recognition Inflammation Phagocytosis Interferon Complement 1. Recognition Toll-like receptors (TLRs) protein receptors within cell membrane of macrophages recognize structurally conserved molecules derived from microbes Detect foreign molecules and signal the macrophage to produce chemicals cytokines stimulate an inflammatory response (nonspecific) promote the activity of B and T cells (specific) 2. Functions of inflammation 1. 2. 3. Mobilize and attract immune cells to site Set mechanisms to repair tissue damage Destroy microbes and block further invasion 2. Inflammatory Response Classic signs and symptoms characterized by: Redness increased circulation and vasodilation in injured tissue Warmth heat given off by the increased blood flow Swelling increased fluid escaping into the tissue as blood vessels dilate WBC’s, microbes, debris and fluid collect to form pus helps prevent spread of infection Pain edema stimulation of nerve endings Possible loss of function Fever Initiated by circulating pyrogens cytokines produced by some leukocytes reset the hypothalamus to increase body temperature signals muscles to increase heat production and vasoconstrict Benefits of fever: inhibits multiplication of temperature-sensitive microorganisms impedes nutrition of bacteria increases metabolism and stimulates immune reactions 3. Phagocytosis nonspecific defense mechanism clear microbes from infected tissues capture and digestion of foreign particles Phagocytes 3 main types of phagocytes: Neutrophils 1. • • general-purpose react early to bacteria and other foreign materials, and to damaged tissue Eosinophils 2. • attracted to sites of parasitic infections and antigen-antibody reactions Macrophages 3. • • derived from monocytes scavenge and process foreign substances to prepare them for reactions with B and T lymphocytes 4. Interferon Type of cytokine Produced in response to viruses, RNA, immune products, and various antigens Bind to cell surfaces and induce expression of antiviral proteins Inhibit expression of cancer genes 5. Complement (C) Consists of 26 blood proteins proteins are activated work in concert to destroy bacteria and viruses Adaptive Immunity “Third” line of defense Adaptive Line of Defense acquired immunity stronger immune response as well as immunological memory Production of specific antibodies dual system of B and T lymphocytes in response to an encounter with a foreign molecule allows for the generation of responses that are tailored to specific pathogens or pathogeninfected cells Specific Immunity – Adaptive Line of Defense Two features that characterize specific immunity: specificity antibodies produced function only against the antigen that they were produced in response to memory lymphocytes are programmed to “recall” their first encounter with an antigen respond rapidly to subsequent encounters Classifying Immunities Active immunity Passive immunity preformed antibodies are donated to an individual does not create memory, acts immediately, and is short term Natural immunity person is challenged with antigen that stimulates production of antibodies creates memory, takes time and is lasting acquired as part of normal life experiences Artificial immunity acquired through a medical procedure such as a vaccine Combinations of acquired immunity Natural active immunity Natural passive immunity acquired by a child through placenta and breast milk Artificial active immunity acquired upon infection and recovery acquired through inoculation with a selected Ag Artificial passive immunity administration of immune serum or globulin Development of the Immune Response System Cell receptors or markers confer specificity and identity of a cell Major functions of receptors are: 1. perceive and attach to nonself or foreign molecules 2. promote the recognition of self molecules 3. receive and transmit chemical messages among other cells of the system 4. aid in cellular development Acquired Immunity Generates Two Responses to Most Pathogens B lymphocytes (B cells) involved in producing antibodies against epitopes Humoral immune response T lymphocytes (T cells) provide resistance through lysis of infected or abnormal cells Cell-mediated immune response Lymphocyte Receptors Lymphocyte’s role in surveillance and recognition is a function of their receptors B-cell receptors bind free antigens T-cell receptors bind processed antigens Antibody Structure and Functions Immunoglobulins Large Y-shaped protein Contains 2 identical fragments (Fab) with ends that bind to specific antigen Fc binds to various cells and molecules of the immune system Classes of Antibodies IgD important in B cell activation IgM released by plasma cells during the primary immune response IgG crosses the placenta and confers passive immunity IgA helps prevent attachment of pathogens to epithelial cell surfaces IgE causing histamine release when activated B-cell Activation and Antibody Production Antibodies in Serum (Antiserum) The 1st introduction of an Ag to the immune system produces a primary response gradual increase in Ab titer The 2nd contact with the same Ag produces a secondary, or anamnestic, response due to memory cells produced during the initial response T Cells & Cell Mediated Immunity Cell mediated immunity requires the direct involvement of T lymphocytes T cells act directly against Ag and foreign cells when presented in association with an MHC carrier T cells secrete cytokines that act on other cells Sensitized T cells proliferate into long-lasting memory T cells Antibody-Antigen Interactions Opsonization Agglutination process of coating microorganisms or other particles with specific antibodies more readily recognized by phagocytes Ab aggregation cross-linking cells or particles into large clumps Neutralization Abs fill the surface receptors on a virus or the active site on a microbial enzyme prevent it from attaching Antitoxins special type of Ab that neutralize a bacterial exotoxin Immunization Passive immunization patient is given preformed antibodies form of immunotherapy Active immunization patient is vaccinated with a microbe or its antigens providing a form of advance protection Vaccines Type of active immunity Provide an antigenic stimulus that does not cause disease Most vaccine preparations are based on one of the following antigen preparations: 1. 2. 3. 4. Killed whole cells or inactivated viruses Live, attenuated cells or viruses Antigenic molecules derived from bacterial cells or viruses Genetically engineered microbes or microbial antigens Disorders in Immunity Immunopathology Allergy, hypersensitivity Autoimmunity abnormal responses to self Ag Immunodeficiency misdirected expression of immune responses to an allergen (antigen) deficiency or loss of immunity Four types….. Type Systems involved Examples IgE Mast cells Hay fever Asthma I Immediate Hypersensitivity II Antibody Mediated IgG Ab IgM Ab Blood group incompatability III Immune Complex Mediated IgG Ab-mediated inflammation Arthritis Serum sickness IV T-cell Mediated Delayed hypersensitivity Cytotoxic rxns Injection rxns Contact dermatitis Graft rxns 1. Type I Hypersensitivity Two levels of severity: Atopy any chronic local allergy Ex: hay fever or asthma Anaphylaxis a systemic, often explosive reaction that involves airway obstruction and circulatory collapse Contact With Allergens Generalized predisposition to allergies is familial not to a specific allergy Allergy can be affected by age, infection, and geographic area Atopic allergies may be lifelong or may be “outgrown” may also develop later in life Mechanism of Type I Allergy Develop in stages: Sensitizing dose on first contact with allergen specific B cells form IgE which attach to mast cells and basophils generally no signs or symptoms Provocative dose subsequent exposure with the same allergen binds to the IgE-mast cell complex Chemical Mediators and Allergic Symptoms General targets include: skin, upper respiratory tract, GI tract, and conjunctiva Responses rashes, itching, redness, rhinitis, sneezing, diarrhea, shedding tears Systemic targets smooth muscles, mucous glands, and nervous tissue Responses vascular dilation and constriction resulting in change in blood pressure and respiration Specific Diseases Atopic disease hay fever, rhinitis; seasonal, inhaled plant pollen or mold asthma Food allergy intestinal portal can affect skin and respiratory tract vomiting, diarrhea, abdominal pain possibly severe eczema, hives, rhinitis, asthma, occasionally anaphylaxis Drug allergy common side effect of treatment reaction from mild atopy to fatal anaphylaxis Sudden respiratory and circulatory disruption that can be fatal in a few minutes Bee stings, antibiotics or serum injection Treatment and Prevention General methods include: 1. Avoiding allergen 2. Use drugs • block the action of the lymphocytes, mast cells • antihistamines Desensitization therapy 3. • injected allergens 2. Type II Hypersensitivity Involve antibodies and complement leading to lysis of foreign cells Transfusion reactions ABO blood groups Rh factor hemolytic disease of the newborn Human ABO Antigens and Blood Types Genetically determined RBC glycoproteins inherited as 2 alleles of A, B, or O 4 blood types: A, B, AB, or O type O persons lack both A and B antigens Tissues other than RBCs also carry A and B antigens Antibodies Against A and B Antigens Serum contains pre-formed antibodies that react with blood of another antigenic type-agglutination Type A Type B contains Abs that react against A antigens Type O contains Abs that react against B antigens contains Abs that react against A and B antigens Type AB contains no Abs that react against A or B antigens Rh Factor Rhesus factor RBC antigen Either there or not type results from combination of 2 alleles RhRh+ Inheriting one dominant gene results in the production of the Rh antigen Rh Factor and Hemolytic Disease of the Newborn Hemolytic Disease of the Newborn (HDN) - Rh mother forms antibodies to her Rh+ fetus requires subsequent exposure to the antigen to be hemolytic Prevention use of passive immunization with antibodies against the Rh antigen prevents sensitization of mother 3. Type III Hypersensitivity Large quantity of foreign Ag stimulates Ab produce small, soluble Ag-Ab complexes Immune complexes become trapped in tissues and incite a damaging inflammatory response arthus reaction local reaction to series of injected Ag to same body site serum sickness systemic disease resulting from repeated injections of foreign proteins 4. Type IV Hypersensitivity T cell-mediated Delayed response to Ag involving activation of and damage by T cells Delayed allergic response skin response to allergens tuberculin skin test, contact dermititis from plants, metals, cosmetics Graft rejection reaction of cytotoxic T cells directed against foreign cells of a grafted tissue MHC markers of donor tissue (graft) are different host may reject graft; graft may reject host Immunodeficiency Diseases Components of the immune response system are absent B and T cells, phagocytes, and complement 2 general categories: primary immunodeficiency Congenital usually genetic errors T-cell or B-cell defect severe combined immunodeficiency (SCID) secondary diseases acquired after birth caused by natural or artificial agents Chemotherapy AIDS Evasion of the Immune System by Pathogenic Microorganisms Why develop a strategy for evasion? Pathogen evolution Microorganism capable of causing disease Must subvert host immune system Successful pathogens = effective evasion Defenses against human host responses Antiphagocytic factors Host cell invasion Glycocalyx / Capsules (Encapsulation) Grow intracellularly Neighbor cell transfer Syncytium Latency Genetic changes Antigenic shift Antigenic drift Antiphagocytic Factors The Bacterial Surface Coating Glycocalyx Coating of molecules external to the cell wall Functions: attachment inhibits killing by WBCs Talaro, 2008 Capsules Formation correlates with pathogenicity Encapsulated cells protect against WBCs Chemicals similar to those in human body Negative charges on capsule and phagocyte surface Slippery Pseudopodia cannot grip them Bauman, 2011 “Some Killers Have Pretty Nice Capsules” S. pneumoniae K. pneumoniae H. influenzae P. aeruginosa N. meningitidis C. neoformans http://medicineworld.org/stories/lead/2-2009/how-a-deadly-fungus-evades-the-human-immune-system.html Streptococcus pyogenes GAS Most serious streptococcal pathogen Many surface antigens that enable virulence and evasion Talaro, 2008 S. pyogenes…. “There’s an app for that” Capsule made of hyaluronic acid (HA) M-protein Chemically masked from HA in human tissues C-carbohydrates Protect bacterium from being dissolved by lysozyme C5a protease Catalyzes cleavage of C5a protein (hinders C-associated aspects & neutrophil response) Makes surface projections that resist phagocytosis Host Cell Invasion Survive inside phagocytes after ingestion Ingested by alveolar phagocytes Prevent fusion with lysosomes Multiply intracellularly After cell death, attract more phagocytes and continue cycle Mycobacterium Bauman, 2011 Neighboring cell transfer Can escape out of phagosomes Transfer to neighbor cells w/o leaving host cell Not exposed to Ab Listeria monocytogenes Pommerville, 2007 Syncytium Induces cells to fuse Multinucleate giant cell Allows pathogen to move from cell to cell HIV RSV Paramyxoviruses Talaro, 2008 Latency Pathogen remains inactive for period of time Reactivate at later date Herpes Bauman, 2011 Genetic Changes Viruses Glycoprotein spikes Adherence Recognized by host immune system Influenza A & B Contains two types of spikes Hemagglutin (HA) Neuraminidase (NA) Pommerville, 2007 Genetic changes of viruses Antigenic drift Mutation in spikes Change their aa composition Small changes Single strain Antigenic shift Shift of gene strand with one from another host Human, pig, birds, etc. Abrupt, major change Reorganization of strains H1N1 Bauman, 2011