Adaptive Immunity Update Presentation PDF

ADAPTIVE IMMUNITY: SPECIFIC DEFENSES OF THE HOST BIOL 230 DR. JE NNIF ER LAING Anatomical/physical Physiological barriers Specific Response barriers  THE 3RD LINE OF DEFENSE: ACQUIRED IMMUNITY Edward Jenner gave the first vaccination agains...

ADAPTIVE IMMUNITY: SPECIFIC DEFENSES OF THE HOST BIOL 230 DR. JE NNIF ER LAING Anatomical/physical Physiological barriers Specific Response barriers  THE 3RD LINE OF DEFENSE: ACQUIRED IMMUNITY Edward Jenner gave the first vaccination against small pox using cowpox in 1798 Jenner observations of milk maids Cow pox Vaccination of 8- year old  In the 1890s, the German The Iditarod sled dog race is run along the physician Emil von Behring same route used to deliver diptheria anti- discovered that serum from toxin from Nenana to Nome in 1925 animals infected with diptheria could neutralize the toxic poisons that the bacterium releases into the body The plasma component of animals suffering from a disease could be used to protect uninfected animals from infection Something in the plasma neutralized the toxins Corynebacterium This was called antisera or diphtheriae : Gram antitoxin positive, non-spore forming, bacilli  THE 3RD LINE OF DEFENSE: ADAPTIVE IMMUNITY Adaptive immunity: Can discriminate between self and nonself Has tremendous diversity (estimates suggest that it can recognize up to 10 trillion different substances) Has specificity Has memory Acquired or Adaptive Immunity has two arms of defense: Humoral Immunity (mediated by B-cells) Cellular Immunity (mediated by T-cells)  ANTIGENS Memory is acquired through microbe specific antigens Antigens are usually: high molecular weight >10,000 daltons chemically complex (proteins, polysaccharides etc) can be self or foreign and elicits an immune response Antigens are usually components of microbes, like cell walls, capsule proteins, flagella, fimbriae, products like toxins, viral components like envelopes, and capsid proteins Non microbial compounds like pollen, certain blood cell surface markers, proteins from other people and species, and transplanted organs  SOURCES OF ANTIGENS Exogenous Extracellular bacteria and their components Secreted toxins/ products Endogenous Intracellular bacteria, fungi or protozoa Viruses Autoantigens Antigens against normal cellular molecules Usually eliminated (you tolerate your own products) If not eliminated, can cause autoimmune diseases  EPITOPES Antigens have antigenic determinant sites (epitopes) Epitopes are sites ON the antigen Site that a specific antibody or T-cell binds to The valence is the number of antibodies that can combine with an antigen at one time Multivalent antigens produce stronger immune responses than monovalent antigens. Why?  HAPTENS Small organic compounds that are not antigenic by themselves Combine with a carrier molecule Once bound, they can trigger lymphocytes Either the hapten or the carrier can elicit the response (but only once they are bound together) Penicillin Urushiol  DISTINGUISHING BETWEEN SELF AND NON SELF Invading pathogens must be cleared by the immune system without harming host tissues MHC/HLA is the way this is done Class I MHC identifies “self” on all nucleated cells Plasma membrane Stimulates an immune response when cytoplasm MHCI on cells does not match Heterodimer protein: Why must you “tissue type” before Alpha chain (3 parts) transplanting a kidney/liver/heart etc? and a beta chain Why can you donate blood without “tissue typing”  MHC II Produced only on specific types of WBC Provides a means of communication between T- cells and macrophages, dendritic cells and B-cells Plasma membrane Heterodimer cytoplasm Has 2 distinct proteins: alpha and beta  ENDOGENOUS ANTIGEN PROCESSING Class I can bind antigens in the cytoplasm Foreign peptides in the cytoplasm arise from viruses, intracellular pathogens or cancer Endogenous antigen presentation Proteasome processing TAP (Transporter associated with Antigen Processing) In ER, antigen binds MHCI and is secreted to the surface EXOGENOUS ANTIGEN PROCESSING Class II MHC is used for exogenous antigen processing Antigen presenting cells (dendritic cells or macrophages)take up pathogen/antigen by phagocytosis Pathogen/antigens are digested in the phagolysosome Combined with MHC II and secreted to the cell surface  T-CELL BIOLOGY T- and B-cells are activated as part of the adaptive immune response Lymphocyte progenitors in the bone marrow migrate to the thymus where precursor T-cells differentiated into subtypes and then migrate to secondary lymphoid tissue (spleen and lymph nodes) T-cells respond to antigens presented in MHC molecules by binding with a T-cell receptor (TCR) TCRs can only bind one antigen T- CELL DEVELOPMENT Positive selection- relative binding strength to MHC If they can bind MHC they move to the next phase Negative selection- elimination of T-cells that recognize self- antigens Surviving cells mature into either CD4+ OR CD8+ cells  THE TCR Each T-cell expresses 500,000 of their TCRs on the surface The TCR will bind to the MHC and to the antigen The TCR is generated by random combination of DNA segments (TCR genes) to create a novel TCR protein Most humans have a repertoire of 2.5x10 7 different TCRs  T-CELL ACTIVATION All naïve T-cells must be activated by 2 signals Signal 1: antigen fragment presented on an MHC molecule of an APC binds the appropriate TCR CD4+ (TH) cell is activated by class II MHC CD8+ (CTL) cell is activated by class I MHC If the T-cell is only stimulated by signal 1 it becomes angergic Signal 2: co-stimulatory signal binding of B7 (on the the APC) to CD 28 receptor on T-cell Activated T-cells secrete cytokines which drives proliferation (clonal expansion) and differentiation  T- HELPER CELLS (CD4) T-Helper cells differentiate into six functional phenotypes TH1- promote cytotoxic T-cell (CD8) activation, macrophages and inflammation TH2- stimulate antibody responses (B-cells), anti- inflammatory responses, defends against helminths and allergic responses TH17- autoimmune disease, host/graft rejection Treg- maintenance of self-tolerance, feto-maternal tolerance and suppression of immune functions and allergies.  CYTOTOXIC T-CELLS (CD8) Activated by endogenous antigen presentation and MHC I TH1 cells produce cytokines that can drive clonal expansion of Tc cells Destroy host cells that have been infected by intracellular pathogens and trigger alterations in MHC I CTL kill using perforins or by triggering apoptosis Cytotoxic T-cells Naïve T-Cell  MEMORY Adaptive immune responses have a memory component After the initial response, the generation of memory allows the adaptive immune response to respond quicker and more robustly when re-exposure to the antigen occurs  B-CELL BIOLOGY Lymphocyte progenitors in the bone marrow migrate to different parts of the bone marrow where precursor B-cells differentiated into subtypes and then migrate to secondary lymphoid tissue (spleen and lymph nodes) Activated an antigen being bound to a B-cell receptor (BCR) BCR is a transmembrane immunoglobulin and co-receptors  BCR The BCR is made through gene recombination just as the TCR was There are two loci: one for the heavy chain and one for the light chain The variable region is made by recombination There are also 2 constant regions that code for the type of abs that is being produced B cell receptor ANTIBODIES Antibodies are proteins- also called immunoglobulin (Ig) Each antibody has 2 heavy chains and 2 light chains Each antibody has 2 binding sites for the epitope of an antigen  B-CELL ACTIVATION Antigen presented along with MHC must bind to a specific BCR A single B-cell can carry as many as 50,000 BCRs on its surface At any given time you have a receptor for almost 10 trillion different antigens Once these naïve B-cells bind an antigen with the specific BCR, they are activated B-cells differentiated into plasma cells which produce antibodies (secreted)  B-CELL ACTIVATION T-dependent antigen triggering Signal 1: TH2 cells present antigen to the B-cell (via MHC and BCR) Where did the TH2 receive the antigen from? Signal 2: TH2 cells also secretes cytokines that trigger proliferation of B-cells and differentiation into plasma cells T-independent antigen triggering Antigen binds to BCR and triggers antibody production This type of activation does not allow memory cells to form  ANTIBODY FUNCTIONS 1. Agglutination- act as agglutinins to cause clumping or aggregation of antigens. microbes are more susceptible to macrophages when they are agglutinated 2. Opsonization- coat antigens/microbes to enhance ingestion and lysis by phagocytes/ initiate complement- makes them more “recognizable” as foreign 3. Neutralization- mostly for antitoxin functions- inactivate a toxin by binding them up and preventing them from binding to their target, also prevents viruses from attaching to cells 4. Activation of complement system- the Fc region of antibodies is the signal for complement (which type of complement is initiated by opsonization?)  ANTIBODIES (CONT) 1. IgG- most common (80% of serum antibodies) because it is involved in the memory component- crosses placenta (protects fetus), involved in agglutination, neutralizes toxins and viruses, and enhances phagocytosis 2. IgM- First antibody made in response to infection, involved in agglutination, does NOT cross placenta 3. IgA- Mucosal surface Ig, found primarily in secretions- tears, saliva, spinal fluid, breast milk, nasal exudates 4. IgD- Involved in initiation of response to immune memory (less than 1% of total serum antibodies) 5. IgE- Involved in allergic reaction and anaphylaxis, also anti-helminth antibody (lowest abundance Ig in the blood) CLASSIFYING IMMUNITIES  SUPERANTIGENS Superantigens (SAgs)are released by certain types of bacteria and viruses Superantigens activate a huge number of T-cells and overwhelm the immune system Instead of a specific response to an epitope This causes a tremendous release of inflammatory cytokines called a cytokine storm The cytokine storm can cause tissue damage, shock, fluid loss and organ failure http://highered.mcgraw- hill.com/sites/0072556781/student_view0/chapter32/animation_quiz_4.html  HYPERSENSITIVITY Hypersensivity is an abnormal immune response to an antigen- this is also known as an allergy There are two kinds of hypersensitive reactions: 1. Immediate 2. Delayed  TYPE I: SYSTEMIC ANAPHYLAXIS Histamine, prostaglandins and leukotrienes released from mast cells and basophiles Promotes vessels dilation and increased permeability Histamine receptors can cause bronchospasams, tachycardia or bradycardia, headache, lightheadedness, and hypotension Can be life threatening depending on the severity of the allergic reaction  TYPE I: LOCALIZED ALLERGIC REACTIONS [ATOPY] Cutaneous Urticaria [hives] Allergic rhinitis [hay fever] Some food allergies Atopic dermatitis [allergic eczema] Some forms of asthma BLOOD TYPING  TYPE 2: ERYTHROBLASTOSIS FETALIS [HEMOLYTIC DISEASE OF NEWBORNS] Maternal abs lyse fetal RBC Anemia, hypoalbuminemia, high-output heart failure or fetal death Anemia stimulates fetal bone marrow to produce and release immature RBCs into fetal peripheral circulation Hemolysis results in elevated indirect bilirubin levels in neonates  TYPE 3: SYSTEMIC LUPUS ERYTHEMATOUS [SLE] Autoimmune disease Antibodies vary, but a larger percentage have autoantibodies generated against neutrophils Inflammatory responses drive symptoms Flare-ups followed by periods of improvement (relapsing remitting) Systemic involvement including renal, constitutional, musculoskeletal, vascular, dermatological and GI Manifests as muscle pain, fatigue, joint pain, rash with other symptoms as determined by systemic invovlment  TYPE 4: CONTACT DERMATITIS Skin allergy resulting from contact with a substance that elicits an immune response Common triggers include soaps, detergents, synthetic fibers, metal jewelry (commonly nickel),diapers [diaper rash] and poison ivy [urushiol oil] Rash presents where the skin was exposed to the allergen  CLINICAL USE OF TYPE 4: MANTOUX/PPD Most common TB test in US Purified protein derivative (PPB) is injected subcutaneously Induration is measured (not erythema) to determine possibility to TB infection/exposure 48- 72 hours later  VACCINATION Vaccination takes advantage of the adaptive immune response to protect against a disease Artificial Active Immunity  SOURCES OF ANTIGEN Attenuated vaccines Inactivated vaccines Toxoid vaccines Subunit or conjugate vaccines Recombinant gene vaccines Combination vaccines