:PNB 2265 (Exam II) study Guide.
:PNB 2265 (Exam II) study Guide. PNB 2265
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This 33 page Study Guide was uploaded by Dera Notetaker on Saturday February 20, 2016. The Study Guide belongs to PNB 2265 at University of Connecticut taught by Kristen Kimball in Winter 2016. Since its upload, it has received 43 views. For similar materials see Human Physiology and Anatomy (PNB 2265) in Physiology at University of Connecticut.
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Date Created: 02/20/16
PNB 2265 Next Exam Guide. (Exam 2) POWERPOINT: NONSPECIFIC DEFENSE (INNATE IMMUNITY) Non-specific (Innate Immune) vs. Specific (Adaptive Immune) Defense Mechanisms Non-specific – general; first line of defense; non specific recognition of something bad Example – skin – the physical barrier Specific – using antibodies – B cells Example: bank walls (keep bank robbers out) vs. video surveillance camera (identify specific bank robber) Role of Immune Responses Defend against infection by microbes Immune surveillance o Controlling the body; looking for things that look wrong; i.e. – looking for cancer cells Eliminate damaged cells Negative aspect – allergies, autoimmune diseases, transplant rejection Control balance via lots of signals Overview: Lymphatic System Second circulatory system – one way Originates in tissues and goes one way head back to regular circulatory system Lymph Lymphatic vessels o Capillaries are blind-ended – originates in tissues – capillary bed Lymphoid tissues/organs Primary: bone marrow & thymus Secondary: lymph nodes, spleen, Peyer’s Patches, Tonsils Functions: o Body fluid homeostasis o Immune system When blood circulates to a systemic capillary bed, it enters the capillary – purpose: exchange; are pores – permeable o Fluid can get out Under pressure, fluid leaves the capillaries and enter the interstitial spaces as blood goes through the capillary bed Driving force – hydrostatic blood pressure pushing fluid out Plasma minus the proteins fluid needs to be picked up before enter the venous system o Another force helps suck it back in to the capillary bed – osmosis – pulls fluid back in Osmotic force due to plasma proteins stuck in the blood pulling fluid back in Osmotic force doesn’t reclaim all the fluid that was filtered out The osmotic force pulling fluid back in the capillaries is smaller than the hydrostatic force pushing it out Some proportion of blood fluid stays in the interstitial fluid Empty in subclavian vein; end up back in venous circulation Immune: lymph filters through lymph nodes – located in the vessels look for what’s wrong Lymphoid Organs: Primary Bone Marrow: o Site of Production of all lymphocytes o Maturation of B lymphocytes o Site of production of all blood cells – including WBCs Thymus o Maturation of T lymphocytes Maturation: I get my specific receptors T – part of specific immune system; preprogramed to recognize that only one antigen; do that recognition via receptors; get the receptors during fetal development in the bone marrow for B cells and thymus for T cells Lymphoid Organs: Lymph Nodes Aren’t primary lymphoid organs – are secondary Fibrous capsule; partitions o ^ Reason why they’re organs Afferent and efferent lymphatic vessels o Don’t have supply of lymph o Have a supply of lymph that’s afferent; deliver to lymph nodes o Lymph filters through the node in the outer region (where there’s B cells and inner region – T cells) lymph gather into one efferent vessels and leaves lymph node and continues its journey back to the venous circulation Macrophages o Can phagocytosis – for pathogens 99% antigens removed, processed Filters Dendritic cells o Not lymphocytes o Found in many tissues o In lymph nodes Lymphatic Nodules Lymphocytes packed in connective tissue No capsule Found in CT under epithelium of respiratory, digestive, urinary tracts o I.e. - skin o Places where the external environment can come in contact with the internal environment – ports of entry – easy for pathogens to get in the body E.g.: tonsils, Peyer’s Patches o Patches are found in the intestine Piles of lymphatic tissues of lymphocytes Lymphoid Organs: Spleen Remove RBCs – damages Stores and recycle Fe May initiate immune responses Derivation of different blood cells from hemocytoblasts Myeloid stem cells o Stem cells for all blood o All cell types except lymphocytes Lymphoid stem cells Cells Mediating Immune Responses Neutrophils o Inflammation, phagocytosis Basophils o Histamine, heparin Eosinophils o Defend against parasitic worms Monocytes o Become macrophages Lymphocytes o Specific immune Lymphocytes Born in the red bone marrow All (except NK cells) participate in specific immune responses From hemocytoblasts that differentiates into lymphoid stem cells break up the differentiate into those that will migrate to the thymus to get their specific receptors – T cells then leave the thymus transported to peripheral tissues or back to bone marrow with their receptors giving them their specific immune recognition capability Other hemocytoblasts differentiate into lymphoid stem cells that will differentiate into B cells – who remain the bone marrow to acquire their receptors and mature B cells acquire the specific receptors in the bone marrow Natural killer – NK cells aren’t specific; don’t have specific receptor but do nonspecific killing NK cells may be recruited to help finish off a specific immune response Other Cells derived from white blood cells Macrophages – phagocytosis o Monocytes can become macrophages – giant phagocytes o Some are motile or fixed in tissues o Important to initiate specific immune responses Mast cells – histamine o Secrete histamine – important inflammatory mediator Plasma cell o Contains an ER, big nucleus, Golgi apparatus o Synthesis of proteins o Is an antibody factory o Are B cells that modified to pump out specific antibodies Dendritic Cells Highly motile NOT macrophages but can phagocytize Found in almost all tissues o Especially “ports of entry” where external and internal environment meet Internal environment – plasma and interstitial fluid Other Defense Mechanisms Detoxification o Usually liver o Microsomal enzyme system Stress Syndrome o Protect body in terms of the brain Non-Specific Defenses No specific recognition of identity of foreign cell/matter Some response regardless of stimulus Prevention first No matter the insult, same response Non-Specific (Innate Immune) Defenses: We will look at “First line” – physical/chemical barriers Inflammation Role of phagocytes Complement system Immunological surveillance Antimicrobial proteins (interferons) Fever “First Line” Skin and mucous membranes = physical barrier o Physical + chemical barrier o Mucous – line port of entries Variety of protective chemicals o Acidity of skin o Gastric HCl; proteolytic enzymes o Lysozyme of saliva o Sticky mucous Other factors: Ciliated mucosa of respiratory system o Trying to get rid of inhale ‘crap’ o Smoking destroys cillia ‘”Friendly” microorganisms (E. coli) o Keep out nasty microorganisms o Keep things in balance Macrophages – Kupffer cells in liver; alveolar macrophages; macrophages in subcutaneous tissue; etc. o Found in ports of entry o Anything that escapes the ciliated mucous Inflammation May be set off by: o Physical trauma Dropping something on your toe o Intense heat Causing a burn o Irritating chemicals Causing a rash or chemical burn o Infection by pathogens Inflammation “walls off” infection to prevent spread o Purpose – helps set the stage of tissue repair Response to all of these are going to be the same – same set of responses Class Diagram 4 cardinal signs of inflammation: swelling, pain, red and heat REVIEW IT! (39-50 mins) Sequence of Events to a Nonspecific Local Inflammatory Response to Bacteria: Entry of bacteria into tissue; injury to tissues causes release of chemicals to initiate the following events Vasodilation of the microcirculation in the infected area, leading to increased blood flow Large increase in protein permeability of the capillaries and venules in the infected area, with resulting diffusion of protein and filtration of fluid into the interstitial fluid Chemotaxis: movement of leukocytes from the venules into the interstitial fluid of the infected area Destruction of bacteria in the tissue either through phagocytosis or by other mechanisms Tissue repair Margination only happens where you have a signal that indicates you nee WBCs to get out of the circulatory system – inflammation Most of time – want cells in circulation Wound Local Inflammatory Events Bacteria are introduced into a wound Chemical mediator cause vasodilation and capillary permeability; chemoattractants recruit neutrophils to area Diapedesis results in neutrophils entering tissue where they engulf bacteria Capillaries return to normal as neutrophils continue to clear the infection What are the “Chemical Alarms” that mediate inflammation? Look at table Histamines o Released by mast cells o Vasodilation, increased capillary permeability Kinins (e.g., bradykinin) o Proteins o Enzymely activated o Vasodilation, capillary permeability; also chemotaxis; stimulate neutrophils (initial phagocytes); induce pain o Allow WBCs to know where to migrate to Prostaglandins (eicosanoids) o Sensitize blood vessels to effects of other mediators; pain o Pain mediators Complement Cytokines How are phagocytes mobilized? Neutrophils enter bloodstream Margination (“pavementing’) Diapedesis o Neutrophils cross capillary wall Chemotaxis Circulate to damage tissues – stick to blood vessels diapedesis chemoattractants being released from damages area will tell them where to go Phagocytosis Intracellular destruction of microbe Have to have endocytosis bring bacteria into macrophage digest by combining that vesicle with a lysosome spit out the end products Complement System Major mechanisms for destroying foreign substances o > 20 plasma proteins o activated via cascade o two pathways for activation: Classical and Alternative o activate one, activate the others in a domino effect once activated: o amplify all aspects of inflammation o directly lyse target cells via “membrane attack complex” membrane blasting protein o opsonization – to enhance phagocytosis (through chemotaxis) bind to a target and phagocytes will notice Classical Pathway Antigen-antibody complex initiates “complement fixation” C1 binds constant (Fc) region of antibody An antibody finds its specific target and tags it Antibody with its specific receptor – binding its antigen Alternative Pathway Polysaccharides on cell surfaces of certain fungi and bacteria Secrete Factors B, D, etc. Pathways converge at C3 hydrolysis Stimulate all aspects of inflammation stimulating phagocytes Complement is also nonspecific Bacteria and fungi are tagged by Factors B & D Certain bacteria and fungi jump to C3 by themselves when they interaction with these factors and bypass the initial steps to activate C3B by itself - alternative pathway 22 February 2016 How are phagocytes mobilized? Neutrophils enter bloodstream o Kill bacteria – engulfs them by phagocytosis Margination (“pavementing”) Diapedesis o Neutrophils cross capillary wall Chemotaxis Phagocytosis – intracellular destruction of microbe Complement System Another nonspecific mechanism Second set of reactions/events Involves plasma proteins Activate first one or alternative route all these events Classical vs. Alternative Pathway Classical: C1, first protein, binds with constant region of the antibody which has to be tagging an antigen Once antibodies found their antigen – get rid of antigen via complement C1 which is circulation – bind to stem region Then, activation of other protein to get to the hydrolysis into A & B C3b – as the key to everything else; inflammation enhancement, stimulation of core Alternative: Certain bacteria/fungi directly interact with C3b via these factors (B, D, P) C3 c3b Skip all those first step – C1 isn’t involved C3b functions as a opsonin which is protein that will cause phagocytosis o Tags to target Effects: C3b functions as opsonin, attracting phagocytosis Inflammation enhanced MEMBRANE ATTACK COMPLEX forms lysis of target cell Complement Function o Increase/enhance inflammation o Kill bacteria, other cells that have caused an immune response o Mechanism for elimination of “tagged” antigen (result of antibody-mediated immune response) Nonspecific immune response C3b binds with bacteria/other cells Antimicrobial Proteins: Interferons Protein family with antiviral effects o Host (not virus) specific o Interfere with viral replication, stimulate NK cells, stimulate macrophages Not targeted to different viruses Same interferons groups that do the same reactions to a bunch of different targets Toll-Like Receptors (TLRs) Many pathogens share molecular features known as “PAMPs” (pathogen-associated molecular patterns) Certain immune cells, including macrophages and dendritic cells, express TLRs that recognize and bind to PAMPs These cells now secrete inflammatory mediators o Enhance innate response o May also be involved in adaptive immune response to pathogen Immunological Surveillance Natural Killer Cells o Bind directly and non-specifically to virus-infected cells and cancer cells to kill them o Type of lymphocyte but not specific Fever Resetting of hypothalamic thermostat o Via Pyrogens – fever causing chemicals Adaptive value: o Interferes with bacterial replication – higher temp o Increased MR speeds up defensive reactions and repair Feel cold at first – because hypothalamic thermostat has been turned up – heat generating mechanisms to meet new set point – good thing POWERPOINT: SPECIFIC (ADAPTIVE/ACQUIRED) IMMUNE RESPONSES Overview Antibody-mediated o Defends against free bacteria and viruses in body fluids/blood o I.e. – flu – virus is in the fluid and affecting cells Cell-mediated o Defends against abnormal cells (i.e., cells transformed by cancer, viral infections; foreign cells) Both categories have 3 stages: Antigen encounter and recognition by lymphocyte o Recognition means binding Lymphocyte activation and clonal expansion Attack o Kill and effector mechanism to finish the job Both categories require activation of specific helper T cells Bacteria initiates the alternative pathway Classical activation of complement involves antibody tagged antigen o Help finish specific immune responses Forms of Acquired (Adaptive) Immunity Have immunity; Had an immune response & have memory – active o Long lasting Passive – haven’t had own response but got antibodies from someone else o Short term immunity o Get it from mom – placental transfer of antibodies during gustation and breast milk How do we do active immunity? GET THE DISEASE With the vaccine for chickenpox– induced active immunity memory Properties of Active Acquired Immunity Specificity o By the receptor the lymphocyte has o Recognize antigen colonial expansion and differentiation o Once have antibody attack o Going to remember ~ memory Versatility o Competent to recognize any antigen we can acquire/come in contact with o During development, before born, when T and B cells goes through the maturation, these cells are getting random genetic shuffling of specific receptors Memory o First expose to antigen memory have immune sense for next time Tolerance o As part of development, tune out cells Types of Lymphocytes T lymphocytes o Mature in thymus; originally come from bone marrow o Three types Cytotoxic T cells Helper T cells Suppressor T cells B lymphocytes o Mature in bone marrow o Give rise to antibody-secreting plasma cells Types of Lymphocytes Cytotoxic T (T c cells o Effectors of cell-mediated immunity o Attack infected/transformed cells o CD8 receptors – cell differentiated 8 Helper T (T Hcells o Regulatory function in both cell-mediated and antibody- mediated immunity o Without it, don’t get colonial expansion and don’t get a response o CD4 (T4) receptors Suppressor T cells o Aka regulatory T cells o Inhibit B and T cells o Prevent over done immune response o Preventing inappropriate immune behavior B cells o Carry out antibody-mediated (humoral) immunity Lymphocyte Receptors: How Lymphocytes “Recognize” Antigens (Ags) T Cell Receptors o Two-chained proteins, which cannot bind (“see”) antigen unless Ag is complexed to MHC “self” proteins (“processing” of Ag) o Cytotoxic T cells – CD8 receptors o Helper T cells – CD4 receptors o Need their antigen to be processed B Cell Receptors o Immunoglobulin (Ig) attached to B cell o Ig is an exact copy of antibody that cell can produce Definitions Immunocompetence (maturation) o Lymphocytes acquire ability to “recognize” their one specific Ag when they acquire receptors specific to Ag o This process is genetically determined! o Confers specificity + versatility to specific immune system o Don’t have to be exposed to antigen to get receptor o Born with the receptor B cells mature in bone marrow T cells mature in thymus Antigen (Ag) o Any foreign molecule that can trigger specific immune response o Antigenic determinants (epitopes) o Receptor recognize a chuck – epitope o One bacteria may have multiple epitopes; have 4 different lymphocytes that recognize the 4 epitopes and get a immune response o Activation of 4 different lines of lymphocytes to produce different types of antibodies o Not the whole bug – just the epitope Antibody o Specific defense protein secreted by specific B lymphocytes o “Y” shape Stem is constant with antibody and is what that bind to complement Nonspecific stem o Variable regions binds Ag – “lock and key” mechanism o Constant region involved in effector mechanisms E.g. – complement fixation Classes of Antibodies IgG o “Typical” Ab (80%) o Can cross placenta o Mediate the main response to any immune response o Provides natural passive immunity to the developing fetus by crossing the placenta IgE o Allergic responses o Give all symptoms of allergy o Inappropriate antibodies IgD o Functions unclear IgM o First to appear after Ag exposure IgA o Saliva, tears, mucus; also colostrum; breast milk o Role in protecting mucosal surfaces Histocompatibility Major Histocompatibility Complex Proteins identify “self” Unique to you – exception for identical twins MHC Class I: o On all nucleated cells – everyone has this except RBCs o Recognized by cytotoxic T cells (CD8 receptors) MHC Class II: o On macrophages, B cells and dendritic cells “Antigen Presenting Cells” (APCs) for helper T cells o Recognized by helper T cells (CD4 receptors) Antigen Processing Necessary for T cells to recognize Ag Ag must be taken into cell and complexed with MHC protein – then cell “presents” the processed Ag (with MHC protein) on surface Which MHC protein is recognized depends on type of CD marker is in T cell membrane o CD8: cytotoxic (and suppressor T cells) o CD4: helper T cells Antigen Presentation Infected cells present antigen to cytotoxic T cells APCs present antigen to helper T cells Cytokines Cell chemicals that mediate immune response Already mentioned: interferons, CSFs Interleukins: IL-1; IL-2 and more Antigen Processing and Presentation to Helper T Cells Macrophages, B cells and dendritic cells are antigen presenting cells (APCs) o Also has MHC Class II Macrophages and dendritic cells both have hole like receptors than can recognize PAMPs “Bug” is recognized nonspecifically by a macrophage Macrophages removes the antigen fragment/epitope and complexes it together with Class II HMC MHC I wont work with helper T Helper T is a lymphocyte that has the CD4 markers Three Events are Required for the Activation of Helper T Cells 1.) Presentation of Ag bound to class II MHC protein on an APC 2.) Costimulation: the binding of matching nonantigentic proteins in membrane of APC and helper T cell o Ensure only activated appropriately o A general lock and key 3.) APC secretes cytokines that act on helper T cell o IL-1 – first interleukin comes from the presenting cells o TNF-a Result of cytokines activate the T cells – now can get a clone Humoral (Antibody-Mediated) Immunity Defends against free bacteria and viruses in body fluids Specific B lymphocytes are activated to produce specific antibodies, which “tag” antigen Activated to make a clone memory cells make antibody factories to make antibodies with the help of helper T Antibody-Mediated Immune Response Ag recognized by specific B cell (selection); and processed + presented by APC to specific Helper T cell Helper T cytokines required for clonal expansion o Activates B cell o Without clone – don’t have a response Selected B cell differentiates plasma and memory cells o Plasma cells doesn’t have receptor – just pump out antibodies o Memory cells have receptors Effector Mechanisms in Antibody-Mediated Responses Antibodies tag antigen – do not directly destroy it Antibodies link tagged microbe to one or more effector (killing) mechanisms TOP figure – illustrates direct enhancement of phagocytosis by antibody BOTTOM figure – illustrates activation of the classical complement pathway Both effector mechanisms are non-specific Ab binding Ag may directly enhance phagocytosis Secondary Immune Response When challenged by some antigen, memory cells produce a rapid and amplified immune response Result of primary immune response – hopefully immune from that bug Immunocompetence – born with those receptors to recognized that antigen Immune – have the memory 24 February 2016 Cell-Mediated Immunity Defends against abnormal/transformed cells o Cells transformed by viral infection or cancer o Foreign cells o Fungi, protozoa – defended against Humoral immunity – defends against free bacteria/virus Defense is carried out by Cytotoxic T cells Specific Tccell must first recognize Ag complexed with MHCI protein o CD8 receptors o T cells respond only to antigenic determinants displayed on surfaces of body’s own cells o Infected cell processes and presents antigen to T celc Cytotoxic T cell recognized antigens on surface of virus-infected cell Any cell with a nucleus can present antigen to the cytotoxic T cell Processing and Presentation of Viral Ag to Cytotoxic T cell TC cells Ag bound MHC I proteins o Presented by any nucleated cell Infected cell has the virus in it – cell is going to process antigen sent out the alert to get immune system to respond when dying Combo of MHC I plus antigen will be recognized by the immunocompetent cytotoxic T cell preprogramed for that antigen Ag Recognition/Activation of Helper T Cells Helper T (T )Hcells recognize Ag bound to MHC II proteins o APCs – antigen presenting cell – i.e.: B cell, macrophages, dendritic cells Cant move from recognition to activation unless we have helper T cells Cell Mediated Response to Virus-Infected Cells Similar sequence for cancer cells o Oncogenes code for proteins that act as antigens Cytokines from Helper T cell required for clonal expansion Cytotoxic T cells can directly kill infected/transformed cells (Perforin) o Put a whole in the target cell Have to have binding of specific helper T receptor to the processed antigen nd Need Costimulation – 2 accelerator – activate the cell o Need matching cells of protein Helper T cells makes interleukins Activation – where you get the clone; DIVISION Not making antibodies Making memory cells Cell-Mediated Defense Response Activated T cclls “roam” tissues, and destroy other cells displaying processed antigen o Perforin o Lymphotoxin – killing chemical o Activate genes apoptosis – cell destroy mechanism o Can kill many viral cells Memory T cecls are not activated Remain available to respond to next “challenge” by same Ag Can produce immediate, amplified Secondary Immune Response o Get rid of infection after it infected a few cells Center Role of Helper T cells The cytokines released by activates specific Helper T cells are required for forming a clone of activated B or Cytotoxic T cells Without clonal expansion – immune response stops at first (recognition) stage Without helper T cells – cant get passed the recognition stage for either antibody mediated or cell mediated immunity T Hells are required for most humoral as well as cell-mediated immunity Cytokines include IL-2 and Gamma Interferon o Alpha – antiviral; slow down viral reactions nonspecifically o Using gamma in the middle of specific response Roles: o Stimulate T cell divisions and formation of memory cells o Enhance nonspecific defenses E.g. – macrophages o Stimulate NK cells o Activate B cells – humoral immunity Any type of antibody mediated immunity – is T dependent – needs Helper T What activates the memory cells is the secondary response – another viral/antigen challenge Autoimmune Disease Immune system goes after you – auto Myasthenia Gravis o Antibodies to ACh receptors paralysis Rheumatoid Arthritis o Antibodies to connective tissue of joints symptoms of systemic arthritis Allergy Hypersensitivity o Allergens o Anaphylaxis Associated with IgE HIV/AIDS Human Immunodeficiency Virus Acquired Immune Deficiency Syndrome Retrovirus destroys Helper T cells (CD4 cells) Anti-AIDS drugs include o Reverse transcriptase inhibitors o Protease inhibitors Preventing the virus from making a functional copy of itself/cant protein edit because of inhibitor OR inhibit the enzyme that allows the virus to take over your genetic machinery – can hold infection at bay AIDS – destroy helper T cells – means destroy both kinds of immunity Can an immunocompetent B cell recognize its target if you have AIDS? o Yes Can it close? NO because you need helper T Vaccine “Controversy” If a critical proportion of a community is immunized against a contagious disease, there is little opportunity for an outbreak, this protecting even those who cannot be immunized – Herd immunity o Infants o Immunocompromised patients o Pregnant women – who can pass something to the fetus even if they don’t get recognizably sick from it How many must be vaccinated to provide herd immunity? Vc = 1-1/R ,0where: o V =ccritical vaccination level o R =0basic reproduction number No one immunized – everyone get sick Some – less get sick Critical proportion immunized – pretty much protect population The higher the R t0, more people need to be vaccinated in order to achieve that vaccination level that protects all of us Critical Vaccination Level required to provide Herd Immunity depends upon several factors, including: How much “mixing” of population occurs – live all of Earth or in the same dorm How infectious/transmissible the pathogen is – deals with R 0 o Higher R iO more infectious How effective the vaccine is Cancer Immunotherapy – an introduction Targets include proteins whose normal function is to modulate normal immune responses (to be breaks) & suppress inappropriate immune responses o CTLA-4 (Cytotoxic T Lymphocyte Associated protein 4) Expressed by (mostly) T cells, including CD-4 & CD-8 Sends inhibitory signal to APCs, blocks Costimulation Made antibodies so immune system wont be suppressed and will go after the cancer cells Coinhibition – dials it down o PD-1 Expressed on several immune cells, especially T (CcL)s Works when it binds with one ligand (of two) is PD-L1, expressed by certain cell types, including T cells and APCs Interaction of PD-1 and PD-L1 acts as brake on T cell activation/proliferation PD – programmed cell death PD-1 + one if its ligand – will be the inhibitory signal to act as a break o Cancer cells expressed the PDL-1 receptor Both play roles in prevention of auto-immune disease and allowing tolerance of fetus during pregnancy Want to s PD-1 signaling Example of PD-1 signaling to weaken response to viral infection (normal “braking” function to prevent autoimmunity) Tumor cells expressing PD-L1 can escape immune response Role in Cancer Treatment Diagram shows immunosuppression as result of PD-L1 (orPD-L2) expressed by tumor cells Diagram (left) shows immunosuppression as result of PD-L1 (or PD- L2) expressed by tumor cells Blocking (right) the PD-1-PD-L1 interaction can potentiate CD-8 T cells’ attacking tumors o General break L1 is specific break so if you knock it out, you’re not knocking it out too much Make antibodies to the PD-L1 protein 29 FEBRUARY 2016 POWERPOINT: RESPIRATION External Respiration Movement of air Temperature regulation Air conditioning Air purification Gas exchange Sound production Smell & taste pH regulation – CO 2 bicarbonate – which is used as a buffer Bringing air into the body and allow it to exit – gas exchange Respiratory system is the fastest way to regulate pH Respiratory System Anatomy Two divisions: o Upper respiratory system/tract Dividing point – larynx/voice box o Lower respiratory system/tract Gross Anatomy Upper Respiratory Tract o Noses, sinuses o Pharynx Lower Respiratory Tract o Larynx – dividing point ; windpipe here o Trachea o Bronchial tree Thoracic Cavity o Lungs o Pleural membranes Functional Divisions Conducting Zone: Transports Air o Nose, nasal cavity o Pharynx o larynx o trachea o bronchi o bronchioles terminal bronchioles Respiratory Zone: Gas Exchange* o Respiratory bronchioles o Alveolar ducts o Alveoli Upper Respiratory System/Tract All part of conducting zone Entry point into respiratory tract Air entering the body must be filtered, warmed and humidified Structures of Interest: o Nose/mouth o Pharynx – shared between respiratory & digestive system o Sinuses Lower Respiratory Tract: The Larynx Voice box Dividing point Boundaries: o Arytenoid cartilage o Thyroid cartilage (vestibular ligament & vocal ligament connect) Vocal cords (folds) o Extend between thyroid and arytenoid cartilage o “Vibrate” to allow speaking Lower Respiratory Tract: Trachea Wind pipe Tracheal cartilage – structural support of lumen Smooth muscle – regulates lumen diameter (deep) Pseudostratified ciliated epithelium (deep) o Down to respiratory zone o Cilia – helps to move particles i.e. - mucous Mucous Ridges – cartilage found from trachea down to conducting zone structures Functional Divisions conducting Zone o pharynx o bronchi o terminal bronchiole Respiratory Zone o bronchioles o alveolar ducts/alveoli Thoracic Cavity o Lungs/pleura o Diaphragm Lungs Right lung – 3 lobes (3 secondary bronchi) Left lung – 2 lobes (2 secondary bronchi) o A little smaller than right lung o Has a chunk taken out of it – cardiac notch o Where the apex of the heart sits Conducting Zone: Bronchial Tree Respiratory Passages: Primary bronchi (1 branch) – divide into secondary nd Secondary bronchi (2rd branch) – divide into tertiary Tertiary bronchi (3 branch) Bronchioles (small) Terminal bronchioles (smallest) Tissues: Pseudostratified – have cilia , working like brooms Stratified Cuboidal Simple squamous (alveoli) – where gas exchange happens & goes by diffusion Cartilage (trachea) – present all the way throughout; absent at the end in the respiratory zone b/c will give barrier Smooth muscle (bronchiole) – regulation here Bronchoconstriction – parasympathetic – smooth muscle contraction o Decrease in radius o Reduces flow o Shut down air flow into the alveoli o Contract smooth muscle by decreasing levels of cAMP Bronchodilation – sympathetic – dilate smooth muscle by increasing cAMP o Increase radius increase air flow ^ Both are regulated by autonomic nerve system Do Bronchodilation/constriction – using just one mechanism – stimulate one or the other or removing one Epithelia Line Conducting Zone The inferior pharynx has stratified epithelium o barrier The nasopharynx pharynx & lower respiratory tract o Single cell layer; use cilia Pseudostratified columnar epithelium – keeps airways from getting back up/clogged o Keep resistance in airways low Cilia – remove debris “The Mucous Escalator” Mucous – traps dust/pathogens, humidify air Mucous lining our conducting zone structures Dusts particles gets trapped in mucous Cilia move mucus moves debris from the upper and lower respiratory tract towards pharynx o Cough it up and get it out of body NOT found in bronchioles/alveoli (alveolar macrophages) Hard for our immune system to access these tissues; hard to have immune response Alveolar macrophages – down to bronchial tree- don’t have pseudostratified tissues, have simple squamous for gas exchange o Without, there will be no way to clear out pathogens Respiratory Zone Respiratory bronchioles (minor) Alveolar ducts/sacs (major) Type I cells: squamous epithelium o Forming the alveoli o Single cell layer o Doing the gas exchange across the membrane of these cells Type II cells: surfactant (chemical) o Secretory cells o Produce surfactant o Small amount of gas exchange Single cell layer thick – simple squamous which make up the alveoli Gas Exchange Occurs at Membrane Fused basal lamina, large surface area Alveolar wall – Type I cells Both CO A2D O are 2ipid soluble easy diffusion across membrane No need to transporter or ion channels Specialization at respiratory membrane If we want to bring O i2to the body, it had to move from the alveoli across the respiratory membrane into blood stream CO w2ll move in the opposite direction – from blood cross the membrane into the alveoli to exhale it To optimize this region for diffusion – have endothelial cells of the capillary (tunica interna) share a membrane with the Type I alveolar cells o Fused together – less distance that gas has to travel to get across One specialization is infusion of the two membranes that we collectively call the respiratory membrane Why do we have two types? Surface tension Surface Tension Has to do with water The Type I epithelia are the site of gas exchange (<90% of alveoli) Epithelial cells must be moist to survive The Law of La Place (remember from circ) o Small alveoli collapse o Pressure = 2T/r Water creates surface tension, a force which pulls molecules together (this is bad) As the radii decreases, the wall tension (pressure) gets larger and can potentially lead to vessel collapse Too much surface tension: o Difficult to inflate lunge (especially at lower volumes) Too little surface tension: o No recoil (more difficult expiration) There must be something that regulates surface tension in the lungs! Water molecules – H bonding occurs – binding to other water molecules; forces are evenly distributed – in a beaker – so on the bottom and sides At the top there is air – no H bonding downward pull This cell is pulled away from surface but pulled into/closer to the aqueous in the water filled parts Causes cells to shrink – problem because don’t want alveoli to shrink o b/c less surface area for gas exchange all these alveoli connected to each other larger vessels have more force – more likely to burst/rupture small vessels are more likely to collapse surface tensions makes the alveoli want to collapse – easier to shrink/collapse the alveoli – don’t want this to happen Type II Cells Secrete Surfactant Surfactant lowers surface tension by breaking intermolecular forces Improves lung compliance (more elasticity) Prevents small alveoli from losing volume into larger alveoli Respiratory Distress Syndrome o Infants – born with low surfactant production; alveoli will keep collapsing; has to be quickly corrected o Adults This breaks the hydrogen bonds – get rid of downward pull forces that are working on those cells A lot of surface tension a lot of inward pull on alveoli – moving to collapse but also mean hard to inflate/expand the alveoli when bring air in Need some surface tension – not too much If get rid of all of it – losing ability to come back to resting shape Surface tension is regulated by surfactant w/o surfactant – tendency for alveoli to shrink alveoli collapse air going into larger alveoli What produces the large alveoli is the small one collapsing Surfactant prevents those alveoli from collapsing so that the volume is equally distrusted across many alveoli – a lot of surface area for gas exchange to take place Pressures Gradients In the Lungs Atmospheric pressure (Patm/Pb) o Doesn’t really fluctuate o Change when above or below sea level Alveolar Pressure (Palv) o Pressure in alveolus o Determines direction of air flow o Can be higher or lower than Patm o If less than Patm – air is going to move in into the alveoli o If higher than Patm – air is going to move out of the alveoli o Nothing going to break this rule Intrapleural Pressure o Pressure in intrapleural space o Our heart & lungs is surrounded by serous membrane o Have a visceral and partial membrane with fluid in between o This refers to the pressure in between those membranes Pressure outside and inside are equal, so no air movement occurs Anatomy Facilitates Respiration “Respiration” is a process to move air in & out of lungs Boyle’s Law o Closed system o Decrease volume, increase pressure o Increase volume, decrease pressure o There’s a relationship between pressure and volume in a closed system Air flows in response to pressure gradient Inspiration – increase thoracic volume, decrease pressure in lungs, air flows in Expiration – decrease thoracic volume, increase pressure in lungs, air flows out Want to create a low pressure environment so air can come into lungs – have to create higher volume - inspiration Send air out – decrease the size of volume and create high pressure that higher than Patm – expiration The Thoracic Cavity Regulates Pressure Pleural Sac: Serous membrane (visceral + parietal) Thorax: External intercostal muscles (inspiration) & Internal intercostal muscles (expiration) o They can expand or reduce the volume of the thoracic cavity by moving Diaphragm – important Pleural Pressure Expands Lungs There is NEGATIVE pressure in Pleural Cavity at rest Keep lungs from collapsing During inhalation – contract diaphragm – moves down & thoracic cavity got bigger – meaning it increase volume and drop in pressure – air can come in Intrapulmonary pressure – pressure in the lungs o During inhalation, starts off negative o As I contract the muscle creating a drop in pressure air move in o During exhalation, relax diaphragm – reduce the size of thoracic cavity – decrease the volume – pressure goes up which is higher than pressure outside; intrapulmonary pressure is at its highest Intrapleural pressure is always negative – keeps lungs from collapsing Pneumothorax Loss of intrapleural pressure (e.g. trauma, lung damage); collapsed lung No negative intrapleural pressure Positive intrapleural pressure Parietal membrane is attached to the thoracic wall/cage Inner layer – visceral – attached to the lung tissue itself When thoracic cavity expands lungs going to get pulled along with rib cage o This is why when you change cavity, you change the size of lung o Lung cant deflate o This create negative pressure When someone has an injury and punctures your lung Patm is going to equalize with intrapleural pressure which becomes more positive ungluing the lung from thoracic wall lungs going to collapse due to loss pressure Inspiratory Respiratory Muscles Normal Inspiration: o Diaphragm (contract) o External intercostals Forced Inspiration: o Diaphragm (contracted) o External intercostals o Pectoralis minor o Scalene o SCM Expiratory Respiratory Muscles Occurs positively at rest Forced Expiration: o Diaphragm (relaxes) o Internal intercostals o Pectoralis minor – relaxing o Abdominal muscles -tightening Types of Breathing Quiet breathing: active inhale, passive exhale Forced breathing: active inhale, active exhale COPD: o Aka chronic obstructive pulmonary disease o Bronchitis + emphysema Control of Pulmonary Ventilation Resistance in Air Passages: Should be zero in upper respiratory tracts Greatest resistance in bronchioles Smoke, stress, mucous buildup o Cause reduced flow Physiologically (Radius): Parasympathetic constriction (Gi) o Getting rid of cAMP; inhibitory Sympathetic dilation (Gs) o Increasing cAMP – which is caused by Gs – beta-adrenergic receptors Non-adrenergic/non-cholinergic (NANC) o Nitric oxide – increase in flow Airways are regulated by autonomic nervous system 2 March 2016 Lung Volumes Tidal Volume: air moved during normal breathing Inspiratory Reserve: air moved during forced exhale Expiratory Reserve: air moved out forced exhale Residual Volume: air left forced exhale Dead Spaces Anatomical Dead Spaces: Due to air being occupied by the non-respiratory parts of the respiratory system (e.g. conducting zone) Aging increase resistance (increased residual volume) Physiological Dead Spaces: Due to failure of the respiratory zones to do gas exchange Emphysema destroys alveoli RESPIRATORY II: MECHANICS Overview: Respiratory Physiology Ventilation – bulk flow; need ATP; use negative pressure breathing/ventilation Gas exchange – diffusion – no energy to transport Transport of respiratory gases in the blood o Have Hemoglobin o Adaptations to increase carrying capacity of blood Goal – to use minimal energy Thermoregulating End goal of respiratory is to get oxygen to tissues so they can use to it to be efficient at extracting energy for fuel Thoracic Cavity Thorax o Thoracic vertebrae o Ribs (+ intercostal muscles) o Sternum o Diaphragm = “floor” Pleural Sac o Double (serous) membrane o Visceral pleura o Parietal pleura o Intrapleural fluid – polar, sticky – bring membranes together Ventilation: Respiratory Mechanics Air moves in and out of lungs by bulk flow: F= ΔP/R Pressures o Atmospheric pressure (Patm) = 0 (not really 0, if so, we’ll be in space) o Alveolar pressure (Palv) – 0 – means at Patm Always equilibrate with atmospheric Open to outside Change with ventilation o Intrapleural pressure (P ) IP In that fluid Normally subatmospheric = negative compared to Patm o Transpulmonary Pressure (P ) = PTPv-P IP Should be negative If positive – lungs collapse o Chest wall (P ) CWP - PIP ATM Definitions Alveolar Pressure (Palv); aka Intrapulmonary pressure o Pressure w/ in alveoli, equalizes with P ATM Intrapleural Pressure (P )IP o Pressure in intrapleural fluid, about 4 mmHg less than P ATM (and up to ~7 mmHg less during inspiration) Transpulmonary Pressure (P TP= Palv-P IP o Pressure across lung wall o Holds lungs open o Causes air flow o Positive pressure o Inside the lungs and immediate outside the lungs o Right outside of lungs – intrapleural fluid If pressure inside thoracic cavity where the Pip is greater – atmosphere is compressing the chest Rhythmic Breathing at Rest Humans, like all mammals, are negative pressure breathers **Sequence of events** Physical Factors Influencing Pulmonary Ventilation Respiratory Passageway Resistance o Should be insignificant Diameter of bronchioles o Controlled by smooth muscle o Parasympathetic stimulation; constricts o Sympathetic stimulation; EPI: dilate bronchioles Asthma Increased smooth muscle constriction (and airway constriction) increased resistance to airflow Increase mucus Smoke, stress, exercise can exacerbate Harder to breathe Physical Factors Influencing Pulmonary Ventilation Lung compliance o A measure of distensibility o C= ΔV/ΔP How “easy” it is for lungs to stretch o How much of a pressure change is required? o Normally, only a few mmHg Factors Determining Lung Compliance Lung elasticity Alveolar surface tension o Water coating alveoli tends to collapse alveoli – surface tension forces o Surfactant prevents this Lipoprotein with detergent action to decrease surface tension Produced by type II (cuboidal) alveolar epithelial cells Changes in either elasticity or alveolar surface tension will change lung compliance Pulmonary Fibrosis Loss of elasticity o Scarring Fibrosis between alveoli o Decreased compliance o Also decreased gas exchange o Harder to expand Most causes idiopathic o Genetic predisposition Respiratory Distress Syndrome Increased surface tension of alveolar fluid In adult, many causes o Sepsis, shock, gastric aspiration, etc. o Epithelial damage inflammation loss of surfactant o Lungs become “stiff” and difficult to inflate Newborn: Prematurity o “Immature” lungs do not yet produce surfactant o Very strenuous to breathe o Lungs don’t want to expand o Baby fighting for every breath o Force breathing Emphysema – complicated pathology In emphysema, blockage is caused by collapse of lower airways (from terminal bronchioles beyond) There is decreased lung elasticity in emphysema; this leads to lungs inability to RECOIL properly for easy exhalation/expiration However, due to dilation of alveoli and loss of many alveolar walls in emphysema (recall loss of area for exchange), lungs actually increase in compliance o Collapse of small alveoli Lungs are easy to DISTEND (then empty only slowly due to the lack of elastic recoil) Less diffusion High compliance -> easy to expand alveoli Respiratory passageways are clogged Signs & Symptoms Pale conjunctivae Abnormal breath sounds Difficulty speaking Use of accessory muscles Coughing Tripod position Barrel chest What is COPD? Chronic Obstructive Pulmonary Disease Two main forms o Chronic bronchitis – long-term cough with mucus o Emphysema Symptoms o Cough with mucus o Shortness of breath (dyspnea) that gets worse with mild activity o Fatigue o Frequent respiratory infections o Wheezing Main cause: Smoking RESPIRATORY III: GAS EXCHANGE & TRANSPORT; REGULATION Basic Properties of Gases Gases diffuse within liquid (or gas) according to partial pressure gradient o Partial pressures depend on dissolved gasses in the blood Dalton’s Law of Partial Pressures o In a mixture of gases, the pressure each gas exerts is independent of the pressure the others exert o Total pressure of the mixture is the sum of the individual gas pressures P O2 – 21%; 160 mmHg P CO2– 79%; 600 mmHg Total pressure at sea level – 760 mmHg Basic Properties of Gases: Henry’s Law A gas dissolves into (and out of) liquid in proportion to its partial pressure Volume of gas dissolving is also dependent upon: o Solubility: CO 2s much more soluble in water than O ( 2n our blood) CO 2s easier to move o Temperature – keep it constant Pressure governs the movement High pressure outside in the air – it will push gas into liquid & vice versa Partial pressures of CO2and O 2n inspired air at sea level and in the body High oxygen, low P c02 Blood entering the lungs has low oxygen and high CO – g2adient that moves CO2 into lungs and O2 into blood After exchange – high O2 and low CO2 in the blood In tissue – consuming oxygen and generating CO2 – reverse gradient o Low O2 in the tissues – pulls oxygen out of the blood o High CO2 in the tissues – pushes CO2 into the systemic capillaries in the blood Alveolar-Blood Gas Exchange (“External” Respiration) Movement of gases across respiratory membrane affected by: o Partial pressure gradients o Gas solubilities (which gas is more soluble?) CO 2 o Thickness of respiratory membrane – normal = 1 micron o Surface area for exchange – normal – 140m 2 o Biconcave disk shape of RBC facilitates transport More surface area Exchange is rapid and complete (to equilibrium) Diseases such as emphysema impede gas exchange Emphysema affects: o Thickness of respiratory membrane increased o Surface area for exchange decreased o Hard to breathe in/out and hard for gas exchange Pulmonary edema also impedes gas exchange
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