W9L17 The Yin and Yang of Human Defense

Transcription

1 W9L17 The Yin and Yang f Human Defense Learning utcmes: - The cncept f a micrbime as a part f us and its implicatins fr recgnitin f self - The micrbime trade-ffs f nutritinal benefit and infectin risk - Nutrient-based cntrl f the gut micrbime - Immune-based cntrl f the gut micrbime - Can give examples f hw and why the hst system encurages gut micrbe activity, especially the cln Why- benefits t hst Hw- by prving permissive grwth envirnment (HMO in infants) - Can explain with examples, hw the hst influence n micrbial grwth in the small and large intestines in different Examples f nutrient availability (ex. amin acid, irn limitatin) Examples f antimicrbial stress (ex. bile) Examples f death rate (ex. transit time) - Can describe key factrs in cntaining micrbes within the gut - Can explain the different rles f cnserved and variable micrbial mlecules in recgnitin by the immune system with examples MAMPs are fr general recgnitin by PRRs (ex. LPS, Peptidglycan) Variable surface mlecules are fr specific recgnitin by immunglbulins - Can relate the cncept f immune balance t the relative numbers f effectr and regulatry cells - Can be a simple example f hw micrbial signals can lead t change in immune balance (ex. rle f SCFA as signals fr Treg maturatin) Micrbime: the stable micrbial cmmunity f a defined habitat - Small intestine: physic-chemically distinct frm the large intestine (divided by the ile-cecal valve) A site f cmpetitin with micrbes fr nutrients - The large intestine: has distinct cnditins- far higher micrbe cell density A site f c-peratin with micrbes - Mst ther internal rgans are sites where presence f micrbes is nt tlerated Nutritin-related chrnic diseases cnnect diet, gut micrbime and immune functins: Gut-Assciated Lymphid Tissue (GALT): present alng virtually the entire length f the intestines majr site f crss-talk between hst and micrbime - Immune functins must be mdulated at every level: Immune functins must allw beneficial micrbial activity in cln Immune functins must prevent micrbial vergrwth r escape - Micrbe grwth in ur gut is cntrlled hwever cells f ur immune system are nt the majr surce f cntrl. Diet changes ur relatinship with ur micrbime - Easily digestible carbs ex. sucrse desn t supprt clnic micrbes because it s absrbed t bld as glucse - Partially digestive carbs ex. starch supprt clnic micrbes absrbed t bld as micrbial metablites (mainly SCFA) Micrbe grwth in gut lumen micrbe grwth is cntrlled nt prevented primary cntrl being envirnmental regulatin Grwth rate: the speed f new cells being prduced per unit time Temperature ph Any stress Cncentratin f any nutrient Grwth yield: the number f new cells being prduced per vlume r mass Death rate Metablic efficiency

2 Cell density: the number f micrbes in an pen system is determined by balance f cell prductin & cell lss - The rate at which fd material mves thrugh the gut dictates the rate at which bacteria must keep grwing t maintain their ppulatin - Sphincter= the grwth cnditins and transit time in gut regins differs Underpins different cell densities - A chemstat lets us experimentally mdel effect f grwth cnditins and dilutin rate n bacteria Hence, The cell density f micrbes in ur gut is a prduct f balanced grwth rate and death rate The prductin f micrbes in ur gut is cntrlled by factrs that limit grwth rate The prductin f micrbes in ur gut is cntrlled by factrs that limit grwth rate and death rate

3 Cell numbers in the small intestine are cntrlled by nutrient availability, antimicrbials and dilutin rate: Micrbes in SI (limited xygen; high flux f nutrient substrates that depletes rapidly; lw flux fibre) have t: - Grw fast under stress and while cmpeting fr preferred substrates befre getting washed ut Stress xidative stress Shrt residence time f chyme high death rate High cncentratin f bile (anti-micrbial) Micrbes in cln (N xygen; very lw substrates remain; mst dietary fibre remains; input f waste N) can: - Grw slwly under reduced stress, while using fibre substrates by fermentative metablism Lng residence time f chyme lw death rate Lw antimicrbials bile resrbed in ileum Cell lcatin by innate and adaptive immunity: 1. Nutritinal immunity: determines ppulatin size and activity in the gut: Bdy rapidly remves preferred nutrient surces directs bacterial grwth Bdy excretes waste N t gut directs bacterial grwth Bdy rapidly remves irn (lactferrin) limits bacterial grwth bacteria encuraged 2. Other immune functins cntain bacterial activity within the gut: The intestinal mucsal surface has much lwer numbers than the lumen The lamina prpria kept sterile bacteria nt tlerated Spatial structure f interactins with micrbes within immune functins: - Gblet cells in lumen (inner mucus layer) cntrl bacterial activity by prducing glycprtein Mucsal immune functins further limit bacteria-epithelium interactin: 1. A lse, diffusive uter layermucin layer and dense adherent inner layer prvide a physical barrier 2. Antimicrbial peptides (AMPs) secretin prvides a bicide barrier 3. IgA secreted int the lumen cats surface f bacteria Immune functins can nnspecifically (AMPs) r specifically (IgA) impact micrbes Mucin (the diffusive) layer plays imprtant rles in cntainment f micrbes and spatial structure f immune respnse: Stps micrbe cells and human cells hurting each ther - Physical barrier t micrbe cells = can t get t epithelium - Diffusin barrier t macrmlecules = antimicrbials dn t diffuse t lumen Glycprtein secreted by gblet cells: - Expressin pattern f mucin genes influenced by micrbial metablites, ntably butyrate In cln, the diffuse uter layer supprts grwth f gd micrbes In cln, the dense inner layer limits micrbe prximity/ cntact with epithelium surface

4 The fundamental rle f secreted IgA t limit cntact between micrbes and epithelial cells Natural IgA/ Primitive IgA: - Desn t impair bacterial grwth in the lumen f the intestine Classical IgA - Specific antibdy prevents ptential pathgens adhering t epithelium - Neutrphils can enter mucus layer and phagcytse pathgens Bacteria: Micrbe-Assciated Mlecular Patterns (MAMPs) and antigens: same mlecule in wide range f micrbes - Surface structure: the majr structures f the cell envelp include distinctive mlecules Cell wall Pili Flagella - Plasma membrane (all cells) Peptidglycan: a cnserved cell wall mlecule in mst bacteria - Cell wall (mst bacteria) - Other membrane (gram negative bacteria) - Lipplysaccharide (LPS): attached t uter membrane Lipid A: a part f LPS that is cnserved in Gram negative bacteria O antigen: the plysaccharide part f LPS it s highly variable and is nt a MAMP

5 Healthy immune functin depends n recgnitin, interpretatin and memry: 1. Mlecules that signal what type f agent is present: - MAMPS, O-Antigens 2. Mlecules that signal if a cell/tissue is damaged r wrking hw it s suppsed t. - Micrbe, Metablites 3. Interpretatin aim t avid damage frm pathgens and damage t self - Actin: engage immune effectrs - Preparatin: stimulate cell develpment *When and where the specific receptrs fr these signals are expressed is imprtant because it impacts where and hw the respnse by apprpriate immune cells ccurs. Immune balance: Dwn regulatin f immune respnses: inability t regulate immune respnse - Allergies - Autimmunity and inflammatry bwel disrders Up-regulatin f immune respnses: - Susceptibility t infectins and cancer are utcmes f weak immune respnse r immundeficiency Immune balance the relative numbers f cells with distinct immune functins- predispses t different utcmes - The prcesses f develpment and differentiatin f precursr immune cells aim t prepare the bdy fr a balanced respnse - Interpretatin f freign cell presence (graft utcme) is strngly influenced by immune balance Micrbe recgnitin by PRRs, GPCRs and immunglbulins in the gut supprts healthy micrbe interactin: 1. Pattern Recgnitin Receptrs (PRRs) general respnse t any micrbes MAMPs 2. Immunglbins target respnse t specific micrbes Variable-surface macrmlecules 3. G prtein-cupled receptrs (CPCRs) respnd t what micrbes have been ding Cell metablites: useful as nutrient (ex. acetate, butyrate) PRRs, GPCRs and immunglbins as part f immune system: MAMPs such as peptidglycan trigger develpment f adaptive immune system prepared t respnd t diverse micrbes Infectin by pathgens can trigger expansin f specific antibdy-prducing B cells and frmatin f memry prepared fr respnse t re-infectin Metablites such as acetate can prmte the develpment f T regulatry cells prepared t balance immune respnse t nrmal antigens Micrbe signal trigger immune cell maturatin: mst bvius in requirement fr pstnatal immune develpment Present prenatally: Undevelped lymphid tissue - Pattern Recgnitin Receptrs (PRR) Only present pstnatally: Mature lymphid architecture, B cells, immunglbins, antimicrbial peptides - Ligand fr PRRs (MAMPs) - Antimicrbial peptides (defensins) - Specific receptrs (IgA)

6 Thrughut life, micrbe-derived signals can influence the balance f effectr and regulatry cells: With the recipient naïve T cell (APC): - Fd allergy: Greater Teff than Treg - Fd tlerance: Greater Treg than Teff Hence, what we eat influences micrbes, by changing the signalling inputs that determine immune balance

7 W9L20 Innate Immunity and Inflammatin Learning utcmes: - Where is the immune system? - What is meant by innate immunity? - Inflammatin, what causes it, and why we need it - What happens if there s t much inflammatin, r it persists - Hw the different cmpnents f innate immunity functin t cmbat different kinds f micrbes - Hw innate immune reactins stimulate and interact with adaptive immune respnse The Immune System: - A cllectin f cells, tissues, and mlecules that mediate resistance t infectins and eliminate tumurs - The functin: T prevent infectins T eradicate established infectins T detect and eliminate tumurs and als tlerate them Immunity: resistance t disease Infectius diseases caused by: - Bacterial infectins - Viral infectins - Fungal infectins - Parasitic infectins - Tumur immunity Lcatin f the immune system: Integrated with ther systems such as gastrintestinal, cardivascular etc. Immune cells are scattered in all parts f the bdy: - Many f them migrate - Others resident cells Mlecules f the immune system can act in an: - Autcrine - Paracrine, r - Endcrine manner (when secreted) The anatmy f the immune system Physical and chemical barriers: - Epithelial cells f skin, gut, respiratry tract - Secretins incl. sweat, wax, and tears - Mucus in the nse, trachea, gut - Urine - Prtelytic enzymes - Lw stmach ph - Nrmal gut flra The cells and mlecules f the immune system access mst rgans via: - The bld vessels - The lymphatic vessels Central sites: - Lymphid tissues r rgans: Primary lymphid rgans bne marrw, thymus - Secndary lymphid rgans: Spleen, lymph ndes, mucsal and cutaneus assciated lymphid tissues

8 Peripheral sites: - All ther tissues and systems: skin, liver, gut, CNS, etc. Innate Immune System: cmmn myelid prgenitr Neutrphil Basphil Esinphil Mncyte Speed: early; rapid Duratin: shrt-lived Repetitive: respnds the same each time Interactive: with ther cells f the innate & adaptive immune system Nn-reactive t the hst Cmpnents f innate immunity: - Epithelial barriers - Cells in circulatin and tissues Phagcytes: Neutrphils and macrphages Scavengers that ingest micrbes Excytes: Esinphils, mast cells, basphils Release active mediatrs frm granules - Mlecules: Tumur necrsis factr (TNF), interleukin-1 (IL-1) Cells Recgnise and Respnd t Patterns: - Epithelial, endthelial, resident immune cells express receptrs n their surface that allw them t sense danger - Different micrbes express different patterns - Our wn ells dn t express these patterns ne way in which the innate immune system can tell the difference between self and nn-self Tissue Resident cells: When danger is detected: - Release f histamine and inflammatry cytkines Tumur necrsis factr (TNF) and interleukin-1 (IL-1) causes inflammatin - Dilated bld vessels allw fr mre bld flw t the area and fluid t cme in Carrying innate immune cells and plasma prteins Cmplement and antibdies - Prmpts the expressin f adhesin mlecules n endthelial cells lining the bld vessels Attracts innate immune cells neutrphils mainly Perfrm phagcytsis Secrete mre inflammatry cytkines Extend web-like extracellular traps fr bacteria Mast cells: - Mast cells reside in peripheral tissues expsed t the envirnment Skin, lung, gut - Have receptrs n their surface that allw them t sense danger One f the first cells t respnd t danger - Perfrm antibacterial functins: Degranulate the cntents f their cytplasm Granules cntain histamine and ther sluble factrs Increases vascular permeability and prmtes inflammatin Cytkines: - Prteins prduced and secreted by different cell types - Mdulate inflammatry and immune reactins - Principle mediatr f cmmunicatin between cells

9 - Target cells in an: Autcrine manner: acting n the cell that prduced the cytkine Paracrine manner: acting n neighburing cells Endcrine manner: acting n distance cells r systemically Chemkines: makes cell migratin pssible: - Chem-tactic cytkines - Different cells express different chemkine receptrs Allws the cell t respnd t different chemkines Inflammatin: T much inflammatin: Septic shck Chrnic inflammatin severe diseases such as cancer and diabetes

10 W9L21 Adaptive Immunity Learning bjectives: - Sme f the cells and mlecules that make up the adaptive immune system - Hw adaptive immune respnses are generated and maintained - Sme f the hallmark features f adaptive immune respnses Lymphcytes: - B lymphcytes (r B cells) - T lymphcytes (r T cells) T as they mature in the Thymus *Thymus primary lymphid rgan Types f adaptive immunity: - In humral immunity, B-lymphcytes secrete antibdies that eliminate extracellular micrbes. - In cell-mediated immunity, different types f T-lymphcytes: Help phagcytes t destry ingested micrbes Kill infected cells 2 main types f T-cells in the periphery: - Helper T-cells (Th cells) Help ther cells f the immune respnse Different types exist with specialised functins Sme Th cells suppress r regulate the immune respnse rather than activate the immune respnse - Cyttxic T Lymphcytes (CTLs) Kill their target cells in a highly specific way Get help frm Th cells CTLs play a key rle in: Viral infectins Anti-tumur immunity Dendritic cells (DC): - Peripheral tissues cntain DC - Strategically lcated t maximise chance f 1 st encunter - DC detect micrbes

11 - DC initiate adaptive immune respnses Bridge between innate and adaptive immunity Lymph System: - Lymph cnstantly leaks ut f bld vessels in all epithelia and cnnective tissues and mst parenchymal rgans - Lymph is drained by lymphatic vessels frm the tissues t the lymph ndes - Dendritic cells pick up micrbes frm the periphery and transprt these t the lymph ndes - Lymph ndes prvide a meeting place fr T cells and DC Antigens: Substances (ften freign) that are recgnised by the immune system : antibdy generatr Lymphcytes have receptrs n their surface t respnd t specific antigens Native and activated lymphcytes - Native lymphcytes: Thse that exist befre antigen expsure Never was in cntact with their antigen The number f native lymphcyte specific fr any ne antigen is very lw DC will display antigens they have encuntered n their surface fr inspectin by naïve T-cells Once the right T-cell clne is fund, the DC will activate the lymphcyte Reasn why DC are called Antigen-presenting cells The newly activated T cell will underg clnal expansin - Activated lymphcytes: Thse that have seen their antigen and been activated Memry lymphcytes survive fr lng perids in the absence f antigen:

12 W10L22 Immunlgy in Human Disease Learning bjectives: - Link sme cmmn human diseases t the immune system - Describe sme f the ways in which targeting the immune system is helping us fight human disease Immunlgical Tlerance a system fr determining which lymphcyte clnes will be allwed t survive There are 2 types f tlerance: 1. Central - Occurs in the primary lymphid tissues Bne marrw (fr B cells) Thymus (fr T cells) 2. Peripheral - Mediated primarily by regulatry cells *A breakdwn in tlerance can lead t autimmune diseases Genetic factrs - Many autimmune diseases are linked t the inherited genes respnsible fr: 1. T cell activatin 2. Maintaining immunlgical tlerance Finding and destrying self-reactive lymphcytes Activity f regulatry cells Envirnmental Factrs - Autimmune disease is ften preceded by an infectin - Other envirnmental/ hst factrs may cntribute: Many autimmune diseases appear mre cmmnly in wmen Lcal trauma leading t an inflammatry reactin may release previusly hidden antigens that ur immune system respnds t: Expsure t sunlight trigger the develpment f the autimmune disease systemic lupus erythematsus (SLE) in which antibdies are prduced against self-antigens. It s pstulated that these nuclear antigens may be released frm cells that die as a cnsequence t the sun In ther cntexts (ex. Multiple Sclersis), a lack f Ultravilet Radiatin frm sunlight is a cntributing factr t autimmunity

13 Autimmune disease may by rgan specific r systemic Autimmune diseases invlve all aspects f the adaptive immune respnse Systemic lupus erythematsus Type 1 diabetes Multiple Sclersis T cells B cells Antibdy Pathgenic Helper T Make aut-antibdies Pathgenic cells Pathgenic Cyttxic T Pssibly pathgenic Present but rle unclear cells Pathgenic Helper T Pathgenic Present but rle unclear Cells Type 1 Insulin Dependent Diabetes Mellitus - The insulin-secreting B cells in the pancreas are targets f T cells - Activated cyttxic T cells find their way t pancreas - B cell-specific CTLs kill the B ells N insulin prduced The a and gamma cells are unaffected highlights exquisite antigen specifically

14 Multiple Sclersis (MS) MS is a multifcal demyelinating disease with prgressive neurdegeneratin caused by an autimmune respnse t self-antigens in a genetically susceptible individual. Symptms: - mtr cntrl crdinatin, balance, functining f the extremities - fatigue including heat sensitivity - ther neurlgical symptms vertig, pins and needles, neuralgia and visual disturbances - cntinence prblems incntinence and cnstipatin - neurpsychlgical symptms memry lss, depressin and cgnitive difficulties Treating MS by remving B cells and T cells: Immune Surveillance: Patients with tumurs that have been infiltrated with lymphcytes have a better prgnsis Enlarged tumur-draining lymph ndes = better prgnsis When Transplanted tumurs are rejected: immundeficient patients have a higher susceptibility t tumur grwth - transplant patients n immunsuppressive therapy - peple with acquired immundeficiencies: lder ppulatins, thse with certain infectius diseases, expsure t envirnmental carcingens (ex. UV, radiatins)

15 New cancer therapies that target the immune system - bne marrw transplantatin certain types f leukemia - re-engineered T cells Chimeric Antigen Receptr (CAR) T cells - antibdies remve the immunlgical brakes apply the immunlgical acceleratr

16 W10L23 Where des the waste cme frm and hw is it remved? Learning bjectives: - Identify the different types f waste and where they are prduced and excreted - Discuss the functin f the majr excretry rgans- the kidneys - Describe the rle f hrmnes in the regulatin f urine vlume and bld pressure Examples f types f waste and the prductin lcatin: - Undigested fd in the large intestines faeces - Excess ins and water - Bilirubin breakdwn f haemglbin - Metablism prduces wastes Breakdwn f amin acids in the frm f NH 3 (ammnia), txic liver cmbines ammnia with CO 2 t frm urea, less txic, adequate fr strage and excretin in cncentrated frm Breakdwn f creatine phsphate ( imprtant fr muscle cntractin) in the frm f creatinine breakdwn f nitrgenus bases frm RNA in the frm uric acid Excretry rgans: 1. Lungs- CO 2, water and heat 2. Skin 3. Liver (prepares waste) Bilirubin Cnverts ammnia int less txic urea 4. Digestive system 5. Kidneys Kidney functins: - Kidneys filter abut 180L fluid/filtrate frm the bld per day - 99% re-absrbed - 1% (1-2L) frms urine t be excreted - Main structures f Urinary system: kidney, ureter, urinary bladder, urethra - Micturitin reflex Excretin - Urine: Urea Pisns Uric acid Creatinine Excess water and slutes such as sdium and ptassium Drugs ex. Penicillin Hmestasis - Water level determines bld vlume - Electrlytes balance in tissue fluid and bld Sdium, ptassium, etc. - ph - Bld pressure - Regulating numbers f RBC entering the circulatin by secreting erythrpietin Nephrn- (1) tubules - Bwman s capsule - prximal cnvluted tubules (PCT) - Lp f Henle - Distal cnvluted tubules (DCT) - Cllecting ducts - Renal pelvis

17 Nephrn- (2) bld vessels - Frm Renal artery - Afferent arterile - Glmerulus - Efferent arterile (narrw) increases pressure in glmerulus - Peritubular capillaries arterial end fes dwn ascending lp f Henle venule end ges up descending lp f Henle Bwman s capsule - Mvement f filtrate frm glmerulus (high pressure) t Bwman s capsule (lw pressure) At this stage, glmerular filtrate cntains nutrients, salts, wastes and water - Bld cells and large prteins remain in glmerulus Prximal cnvluted tubules (PCT) All glucse is remved in this prcess (except fr diabetic patients) - Sdium, amin acids, vitamins, glucse (active transprt) PCT (mitchndria release ATP) peritubular capillaries - Water (passive transprt/ smsis) alng with slutes Lp f Henle (1) Descending - Walls permeable t water - Mre water reabsrbed/ smsis (Tubule with lw cncentratin f slutins Medulla Venule) - Walls mderately permeable t slutes High relative cncentratin f slutes in surrunding tissue = sme mvement f slutes int tubule by diffusin (sdium, ptassium and urea) - Filtrate becmes mre cncentrated Lp f Henle (2) Ascending - Walls nt permeable t water - Permeable t slutes such as sdium, ptassium, and chlrine mvement ut f tubule int arterile is by: Diffusin (thin sectin) Active transprt (thick sectin) - Filtrate becmes mre dilute - Cunter current Distal cnvluted tubules (DCT) Reabsrptin - f water (19%) by smsis - slutes by active transprt - Cntrlled by Aldsterne and Anti-diuretic hrmne (ADH) Hrmnes: aldsterne - Secreted by adrenal gland when lw plasma [Na + ], ex. after exercise r sweating increases Na + absrptin (frm DCT and cllecting ducts int the bld) - If high plasma [Na + ], ex. cnsuming a salty meal lw aldsterne secretin mre Na+ excreted in urine (retained in DCT and cllecting ducts) Hrmnes: anti-diuretic hrmne (ADH) - Secreted by pituitary gland when lw plasma water cncentratin Increases permeability f DCT and cllecting ducts Increases resrptin f water int bld Increases bld vlume and pressure - Increases bld pressure Negative feedback reduces ADH secretin - Alchl and caffeine interfere with ADH