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BIO 104
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Chapter 16Innate Immunity: Nonspecific Defenses of the HostA Neutrophil (Blue) Phagocytizing Aspergillus Spores (Red)Big Picture: Immunity •White blood cell (W B C) counts measure leukocytes in the blood•High W B C counts may indicate bacterial infections, autoimmune diseases, or side effects of medications•Low W B C counts may indicate viral infections, pneumonia, autoimmune diseases, or cancers
The Concept of Immunity (1 of 3)Learning Objectives16-1Differentiate between innate and adaptive immunity.16-2Define Toll-like receptors.•Immunity: ability to ward off disease•Susceptibility:lack of resistance to a disease•Innate immunity: defenses against any pathogen; rapid, present at birth•Adaptive immunity: immunity or resistance to a specific pathogen; slower to respond, has memory component•Toll-like receptors (T L Rs) on host cells attach to pathogen-associated molecular patterns (P A M Ps)•T L Rs bound to P A M Ps induce the release of cytokinesfrom the host cell that regulate the intensity and duration of immune responsesCheck Your Understanding-116-1Which defense system, innate or adaptive immunity, prevents entry of microbes into the body?16-2What relationship do T L Rs have to pathogen-associated molecular patterns?
16-3Describe the role of the skin and mucous membranes in innate immunity.16-4Differentiate physical from chemical factors, and list five examples of each.16-5Describe the role of normal microbiota in innate immunity.Physical Factors•Skin–Dermis:inner portion made of connective tissue–Epidermis:outer portion made of tightly packed epithelial cells containing keratin,a protective protein•Shedding and dryness of skin inhibits microbial growth•Mucous membranes–Epithelial layer that lines the gastrointestinal, respiratory, and genitourinary tracts–Mucus: viscous glycoproteins that trap microbes and prevent tracts from drying out–Lacrimal apparatus: drains tears; washes eye•Ciliary escalator transports microbes trapped in mucus away from the lungs•Earwax prevents microbes from entering the ear•Urinecleans the urethra via flow•Vaginal secretions move microorganisms out of the vaginal tract•Peristalsis, defecation, vomiting, diarrheaChemical Factors•Sebumforms a protective film and lowers the p H (3-5) of skin•Lysozymein perspiration, tears, saliva, and urine destroys bacterial cell walls•Low p H (1.2-3.0) of gastric juice destroys most bacteria and toxins
•Low p H (3-5) of vaginal secretions inhibits microbesNormal Microbiota and Innate Immunity:•Normal microbiota compete with pathogens via microbial antagonism (competitive exclusion)–Competitive advantage for space and nutrients–Produce substances harmful to pathogens–Alter conditions that affect pathogen survival•Commensalism:one organism benefits while the other (host) is unharmed•Probiotics:live microbial cultures administered to exert a beneficial effectCheck Your Understanding-216-3Identify one physical factor and one chemical factor that prevent microbes from entering the body through skin and mucous membranes.16-4Identify one physical factor and one chemical factor that prevent microbes from entering or colonizing the body through the eyes, digestive tract, and respiratory tract.16-5Distinguish microbial antagonism from commensalism.16-6Classify leukocytes, and describe the roles of granulocytes and monocytes.16-7Describe the eight different types of W B Cs, and name a functionfor each type.16-8Differentiate between the lymphatic and blood circulatory systemsFormed Elements in Blood•Cells and cell fragments suspended in plasma–Erythrocytes (red blood cells)–Leukocytes (white blood cells)
–Platelets•Created in red bone marrow stem cells via hematopoiesis•Granulocytesare leukocytes with granules in their cytoplasm that arevisible with a light microscope–Neutrophils: phagocytic; work in early stages of infection–Basophils: release histamine; work in allergic responses–Eosinophils:phagocytic; toxic against parasites and helminthsTable 16-1 Leukocytes (White Blood Cells) •Agranulocytesare leukocytes with granules in their cytoplasm that are not visible with a light microscope–Monocytes: mature into macrophagesin tissues where they are phagocytic–Dendritic cells: found in the skin, mucous membranes, and thymus; phagocytic–Lymphocytes:T cells, B cells, and N K cells; play a role in adaptive immunityThe Lymphatic System 16-8Differentiate between the lymphatic and blood circulatory systems.
•Lymph, lymphatic vessels, lymphoid tissue, and red bone marrow•Contains lymphocytes and phagocytic cells•Lymph carries microbes to lymph nodes where lymphocytes and macrophages destroy the pathogenCheck Your Understanding-316-6Compare the structures and functions of monocytes and neutrophils.16-7Define differential white blood cell count.16-8What is the function of lymph nodes?Phagocytes 16-9Define phagocyteand phagocytosis.16-10Describe the process of phagocytosis, and include the stages of adherence and ingestion.•Phago:from the Greek, meaning eat•Cyte:from the Greek, meaning cell•Fixed macrophages are residents in tissues and organs•Free (wandering) macrophages roam tissues and gather at sites of infectionThe Concept of Immunity:•Toll-like receptors (TLRs)on host cells attach topathogen-associated molecular patterns (PAMPs)•TLRs bound to PAMPs induce the release of cytokinesfrom the host cell that regulate the intensity and duration of immune responses•TLR1=Bacterial lipoprotein and•peptidoglycans•TLR2=Bacterial peptidoglycans•TLR3=Double stranded RNA
•TLR4=Lipopolysaccharides•TLR5=Bacterial flagella•TLR8=Single stranded RNAThe Mechanism of Phagocytosis:•Chemotaxis–Chemical signals attract phagocytes to microorganisms•Adherence–Attachment of a phagocyte to the surface of the microorganism•Ingestion–Opsonization:microorganism is coated with serum proteins, making ingestion easier•Digestion–Microorganism is digested inside a phagolysosomeCheck Your Understanding16-9What do fixed and wandering macrophages do?16-10What is the role of T L Rs in phagocytosis?Inflammation16-11List the stages of inflammation.16-12Describe the roles of vasodilation, kinins, prostaglandins, and leukotrienes in inflammation.16-13Describe phagocyte migration.•Signs and symptoms: pain, redness, immobility, swelling (edema), heat•Destroys injurious agent or limits its effects on the body•Repairs and replaces tissue damaged by the injurious agent
•Inflammation activates acute-phase proteins by the liver that cause vasodilationandincreased permeabilityof blood vessels•Histamine•Kinins•Prostaglandins•Leukotrienes•CytokinesTable 16-2 Summary of Vasoactive Mediators of InflammationVasoactive MediatorSourceEffectHistamineMast cells, basophils, and plateletsVasodilation and increased permeability of blood vesselsKininsBlood plasmaChemotaxis by attracting neutrophilsProstaglandinsDamaged cellsIntensify the effects of histamine and kinins and helpphagocytes movethrough capillarywallsLeukotrienesMast cells and basophilsIncrease permeability of blood vessels and help attachphagocytes to pathogensComplement Blood plasmaStimulates release of
histamine, attracts phagocytes, and promotes phagocytosisCytokinesFixed macrophagesVasodilation and increased permeability of blood vesselsPhagocyte Migration and Phagocytosis•Margination is the sticking of phagocytes to blood vessels in response to cytokines at the site of inflammation•Phagocytes squeeze between endothelial cells of blood vessels via diapedesisTissue Repair•Cannot be completed until all harmful substances are removed or neutralized•Stroma is the supporting connective tissue that is repaired•Parenchyma is the functioning part of the tissue that is repairedCheck Your Understanding16-11What purposes does inflammation serve?16-12What causes the redness, swelling, and pain associated with inflammation?16-13What is margination?Fever:•Abnormally high body temperature•Hypothalamus is normally set at 37 C
•Cytokines cause the hypothalamus to release prostaglandins that resetthe hypothalamus to a higher temperature•The body maintains the higher temperature until the cytokines are eliminated•As body temperature falls (crisis), vasodilation and sweating occurs•Abnormally high body temperature•Hypothalamus is normally set at 37°C•Cytokines cause the hypothalamus to release prostaglandins that resetthe hypothalamus to a higher temperature. Example: Macrophages digest Gram-negative bacteria, E. coli. When digested, E. coli releases LPS which triggered the release of interleukin 1 by macrophages. Interleukin 1 goes to the brain triggering the release of prostaglandins by the hypothalamus. Temperature goes up! •Body constricts the blood vessels, and shiveringoccurs (which raises temperature)•As body temperature falls (crisis), vasodilation and sweating occursThe Complement System•Serum proteins produced by the liver that enhances the immune system in destroying microbes–Act in a cascade in a process called complement activation•Proteins are designated with uppercase C and numbered in order of discovery–Activated fragments are indicated with lowercase aand bThe Classical Pathway•Antibodies bind to antigens, activating C1•C1 splits and activates C2 and C4•C2a and C4b combine and activate C3–C3a functions in inflammation
–C3b functions in cytolysis and opsonizationThe Alternative Pathway•C3 present in the blood combines with factors B, D, and P on microbe surface•C3 splits into C3a and C3b, functioning the same as in the classical pathwayThe Lectin Pathway•Macrophages ingest pathogens, releasing cytokines that stimulate lectinproduction in the liver•Mannose-binding lectin (MBL)binds to mannose, activating C2 and C4•C2a and C4b activate C3, which functions the same as in the classical and alternative pathwaysOutcomes of Complement Activation•Cytolysis–Activated complement proteins create a membrane attack complex (M A C)•Opsonization–Promotes attachment of a phagocyte to a microbe•Inflammation–Activated complement proteins bind to mast cells, releasing histamine•Regulation of complement–Regulatory proteins readily break down complement proteins, minimizing host cell destruction•Complement and disease–Lack of complement proteins causes susceptibility to infections•Evading the complement system
–Capsules prevent complement activationInterferons•Cytokines produced by cells; have antiviral activity•IFN-a and IFN – B : produced by cells in response to viral•infections; cause neighboring cells to produce antiviral proteins (A VPs)that inhibit viral replication•IFN – Y causes neutrophils and macrophages to kill bacteriaIron-Binding Proteins•Transferrin:found in blood and tissue fluids•Lactoferrin:found in milk, saliva, and mucus•Ferritin:found in the liver, spleen, and red bone marrow•Hemoglobin:located in red blood cells•Bacteria produce siderophoresto compete with iron-binding proteinsAntimicrobial Peptides•Short peptides produced in response to protein and sugar molecules onmicrobes–Inhibit cell wall synthesis–Form pores in the plasma membrane•Broad spectrum of activityOther Factors•Genetic resistance–Confers a selective survival advantage–E.g., sickle cell trait and Plasmodium falciparum•Age–Very young and elderly are more susceptible to disease
•Observing healthy protocols.Chapter 17 :Adaptive Immunity: Specific Defenses of the HostLymphocyte (Red) Attaches to Cancer Cell (Blue).The Adaptive Immune System :•Adaptive immunity: defenses that target a specific pathogen–Acquired through infection or vaccination–Primary response: first time the immune system combats a particular foreign substance–Secondary response: later interactions with the same foreign substance; faster and more effective due to “memory”Dual Nature of the Adaptive Immune System:•Humoral immunity–Produces antibodiesthat combat foreign molecules known as antigens▪B cells are lymphocytes that are created and mature in red bone marrow Recognize antigens and make antibodies▪Named for bursa of Fabricius in birds•Cellular immunity (cell-mediated immunity) –Produces T lymphocytes▪Recognize antigenic peptides processed by phagocytic cells▪Mature in the thymus–T cell receptors (TCRs) on the T cell surface contact antigens, causing the T cells to secrete cytokines instead of antibodies•Cellular immunity attacks antigens that have already entered cells
–Viruses; some intracellular bacteria such as M. leprae and L. monocytogenes•Humoral immunity fights invaders and threats outside cells–Extracellular bacteria and toxins–Viruses before they enter a host cellCytokines: Chemical Messengers of Immune Cells:•Cytokinesare chemical messengers produced in response to a stimulus–Interleukins (ILs): cytokines between leukocytes–Chemokines:induce migration of leukocytes–Interferons (IFNs): interfere with viral infections of host cells–Tumor necrosis factor alpha(TNF – a ): involves in the inflammation of autoimmune diseases–Hematopoietic cytokines: control stem cells that develop into red and white blood cells–Overproduction of cytokines leads to a cytokine storm–Cytokines and Their RolesCytokineSourceTarget Cell(s)EffectI L-4T sub H 2Naïve T sub H B cellsProliferate T sub H 2 cells; Classwitching to I g EI L-12Dendritic cells, macrophages, neutrophilsNaïve T sub H N K cellsStimulates growth and functionof T sub H 1 cells; Stimulates I N gamma and T N F alpha I L-17T sub H 17NeutrophilsInflammationI L-22T sub H 17Epithelial cellsStimulates epithelial cells to
make antimicrobial proteinsGamma interferon I FN gammaT sub H 1C T L, macrophagesPromote phagocytosis; activatemacrophages and humoral responseChemokinesVaries; macrophages and epithelial cellsNeutrophilsChemotaxisT N F-alpha T N F alphaMacrophages, T sub H, N K cellsTumor cellsInflammationG M-C S FMacrophages, T cells, N K cellsMyeloid stem cellsIncrease macrophages and granulocytesAntigens•Antigens:substances that cause the production of antibodies–Usually components of invading microbes or foreign substances–Antibodies interact with epitopes, or antigenic determinants, on the antigen•Haptens:antigens too small to provoke immune responses; attach to carrier moleculesSARS-CoV-19 Antigens:1.Spike protein - 52.Membrane protein - 23.Nucleoprotein - 3Humoral Immunity: Antibodies:•Globular proteins called immunoglobulins (Ig)•Valenceis the number of antigen-binding sites on an antibody–Bivalent antibodies have two binding sites•Four protein chains form a Y-shape
–Two identical light chains and two identical heavy chains joined by disulfide links•Variable (v) regions are at the ends of the arms; bind epitopes•Constant (F c) region is the stem, which is identical for a particular Ig classFive classes of I g (IgG, IgM, IgA, IgD, IgE)IgG•Monomer•80% of serum antibodies•In the blood, lymph, and intestine•Cross the placenta and protect the fetus; trigger complement; enhancephagocytosis; neutralize toxins and virusesIgM•Pentamer made of five monomers held with a J chain•6% of serum antibodies•Remain in blood vessels•Cause clumping of cells and viruses•First response to an infection; short-livedIgA•Monomer in serum; dimer in secretions•13% of serum antibodies•Common in mucous membranes, saliva, tears, and breast milk•Prevent microbial attachment to mucous membranesIgD•Monomer•0.02% of serum antibodies
•Structure similar to IgG•In blood, in lymph, and on B cells•No well-defined function; assists in the immune response on B cellsIgE•Monomer•0.002% of serum antibodies•On mast cells, on basophils, and in blood•Cause the release of histamines when bound to antigen; lysis of parasitic wormsActivation and Clonal Expansion of Antibody-Producing Cells :•Major histocompatibility complex (MHC) genes encode molecules on the cell surfaceClass IMHC are on the membrane of nucleatedanimal cells•Identify “self”Class II MHC are on the surface of antigen-presentingcells (APCs), including B cells•Inactive B cells contain surface I g that bind to antigen•B cell internalizes and processes antigen•Antigen fragments are displayed on MHC class II molecules•T helper cell (TH) contacts the displayed antigenfragment andreleases cytokines that activate B cells•B cell undergoes proliferation (clonal expansion)•Clonal selection differentiates activated B cells into: -Antibody-producing plasma cells -Memory cells•Clonal deletion eliminates harmful B cells
•T-dependent antigen : Antigen that requires a ( TH ) cell to produceantibodies•T-independent antigens:-Stimulate the B cell without the help of T cells-Provoke a weak immune response, usually producing IgM-No memory cells generatedResults of the Antigen-Antibody Interaction :•An antigen-antibody complex forms when antibodies bind to antigens–Strength of the bond is the affinity–Protects the host by tagging foreign molecules or cells for destruction▪Agglutination▪Opsonization▪Antibody-dependent cell-mediated cytotoxicity▪Neutralization▪Activation of the complement systemCellular Immunity Response Process:T cells combat intracellular pathogens–Mature in the thymus–Thymic selection eliminates immature T cells–Migrate from the thymus to lymphoid tissues–Attach to antigens via T-cell receptors (TCRs)Pathogens entering the gastrointestinal tract pass through microfold cells (M cells) located over Peyer’s patches–Transfer antigens to lymphocytes and antigen-presenting cells (APCs)
Antigen-Presenting Cells (APCs)•Dendritic cells (DCs)–Engulf and degrade microbes and display them toT cells–Found in the skin, genital tract, lymph nodes, spleen, thymus, and blood•Macrophages–Activated by cytokines or the ingestion of antigenic material–Migrate to the lymph tissue, presenting antigen to T cellsClasses of T Cells•Clusters of differentiation (CD)-CD4+ :T helper cells (TH)Cytokine signaling with B cells; interact directly with antigensBind M H C class II molecules on B cells and APCs -CD8+ :Cytoxic T lymphocytes (CTL)Bind M H C classI moleculesT Helper Cells (CD4 + T Cells) :TCR on the TH cell recognize and bind to the antigen fragment and MHC class 1l on APC • APC or TH secretes a costimulatory molecule, activating the TH cell• TH cells produce cytokines and differentiate into:-TH1 cells -TH2 cells
-TH17 cells-Memory cellsTH17 cells produce IL-17 and contribute to inflammation • TH1 cells produce IFN-y , which activates macrophages. enhances complement, and stimulates antibody production that promotes phagocytosis • TH2 cells release IL-4 cytokine and activate B cells to produce IgE; activate eosinophilsT Regulatory Cells•T regulatory cells (Treg) •Subset of CD4+cells; carry an additional CD25 molecule•Protect fetus•Suppress T cells against self and helps the normal microbiota to be tolerated by the immune system.•How? Reducing inflammation by releasing Interleukin-10 and inhibiting activation of TH(helper) cells, etc.Cytotoxic T Lymphocytes (CD8+ T Cells)•Precursor T cytotoxic cells (CTLp) are activated to become cytotoxic T lymphocytes (CTLs)-Activated into cytotoxic T lymphocyte (CTL) with the help of TH cell and costimulatory signalsCTLs recognize and kill self-cells altered by infect-Self-cells carry endogenous antigens on a spresented with MHC class I moleculesCTL releases perforinand granzymesthat induce apoptosisin the infected cell•Apoptosis–Programmed cell death–Prevents the spread of infectious viruses into other cells
–Cells cut their genome into fragments, causing the membranes to bulge outward via blebbingNonspecific Cells and Extracellular Killing by the Adaptive Immune System •Natural killer (NK) cells•Granular leukocytes destroy cells that don't express MHC class I self-antigens•Kill virus-infected and tumor cells and attack parasites•Not always stimulated by an antigen•Form pores in the target cell, leading to lysis or apoptosisPrincipal Cells That Function in Cell-Mediated ImmunityCellFunctionT Helper T sub H 1 CellActivates cells related to cell mediated immunity: macrophages, CTLs, and natural killer cellsT Helper T sub H 2 CellStimulates production of eosinophils, IgM, and IgET Helper T sub H 17 CellRecruits neutrophils; stimulates production of antimicrobial proteinsCytotoxic T Lymphocyte (CTL)Destroys target cells on contact by inducing apoptosisT Regulatory T sub reg CellRegulates immune response and helps maintain self-toleranceActivated MacrophageEnhanced phagocytic activity; attacks cancer cellsNatural Killer (N K) CellAttacks and destroys target cells; participates in antibody-dependent cell-mediated cytotoxicityAntibody-Dependent Cell-Mediated Cytotoxicity•Protozoans and helminths are too large to be phagocytized
–Protozoan or helminth target cell is coated with antibodies–Immune system cells attach to the F c regions of antibodies–Target cell is lysed by chemicals secreted by the immune system cellImmunological Memory •Secondary (memory or anamnestic) responseoccurs after the second exposure to an antigen–Class switching, where initial I g M response shifts to I g G, I g E, or I g A, occurs–More rapid, lasts many days, greater in magnitude–Memory cells produced in response to the initial exposure are activated by the secondary exposure•Antibody titer is the relative amount of antibody in the serum–Reflects intensity of the humoral responseTypes of Adaptive Immunity •Naturally acquired active immunity–Resulting from infection–Antigens enter the body naturally; body induces antibodies and specialized lymphocytes.•Naturally acquired passive immunity–Transplacental or via colostrum–Antibodies pass from mother to fetus via placenta or to infant viathe mother milk.•Artificially acquired active immunity–Injection of vaccination (immunization)–Antigens are introduced in vaccines; body produce antibodies and specialized lymphocytes.•Artificially acquired passive immunity–Injection of antibodies–Performed antibodies in immune serum are introduced by injection.
CHAPTER:The human body is a host symbiont or holobiont which actsas an ecosystem under selection to minimize conflict between individual members.Who are you? An adult human being has ten times as many microbial cells as mammalian cells. Microbes in the body have 200 times more genes than the human genome.New Names for Bacterial Phyla in this ChapterFirmicutes = BacillotaActinobacteria = ActinomycetotaProteobacteria = Pseudomonadota
Bacteroidetes = BacteroidotaFusobacteria = FusobacteriodotaThe MicrobiomeThere is growing recognition, however, that resident microbial communities influence human nutrition, development and disease. For example, dysbiosis (microbial imbalance) of the microbiome has been implicated in many phenomena, including obesity, inflammatory bowel diseases, dermatitis and atopic diseases, bacterial vaginosis and pre-term birth. •When did it start?-A team collected placental tissue from 320 mothers immediately after they gave birth and documented diverse microbes, including E. coli, Bacteroides, Prevotella tannerae,and Neisseria lactamica,among others. -In terms of species composition, the placental microbiome more closely resembles the mother’s oral microbial community than any other site on the body. But when scientists looked at the metabolic pathways of the bacteria, “interestingly, they’re far overrepresented for metabolism of cofactors and vitamins relative to other body site microbiomes,” such as the gut or the mouth. The placental microbiome likelyrepresents a baby’s first meeting with the microbial world. The birthing process, then, would be the second stop on a tour of the maternal microbiome. Once on the outside, a baby’s first embrace with his mother is really a group hug with her skin microbiome. And then there’s breastmilk, which for many decades was also considered sterile, but which is in fact a creamy bacterial soup.Vaginally= Lactobacillus, Prevotella, more Bifidobacterium, Bacteroides, increase in Bacteroidota and BacillotaC section = Actinomycetota, Pseudomonadota and Bacillota, More Staphylococcus, Clostridium, Propionibacterium, Corynebacterium, less Bifidobacterium, Bacteroides
Microbes are normally found in and on the human bodyThe following sites are “hotspots” for microbial life ( nasal , oral , skin , gastrointestinal , urogenital )Some microbes are native, normally found in the bodySome microbes are introduced, suddenly arriving at a new residence in the bodyNose:The interior lining of the nose contains mucous secretingglands. A wide variety of microbes are normally foundthere. Here’s a few:The interior lining of the nose contains mucous secretingglands. A wide variety of microbes are normally foundthere. Here’s a few:•Staphylococcus aureusbacteria is fine when kept under controlby a protease found in S. epidermidis, but if left to grow out ofcontrol, S. aureuscan become pathogenic and cause infection.•Aspergillusfungal spores are often inhaled through the nose. Ifthe immune system fails to clear these, mold can grow in thelungs•Corynebacterium accolens bacteria is rarely a pathogen, but if itenters the bloodstream due to a torn blood vessel, it can causeserious infectionsNasopharynx•Neisseria meningitidis – indigenous but can causemeningitis or septicemia. •Streptococcus pneumoniae – meningitis, otitis, sinusitis.•Haemophilus influenzae – meningitis, otitis, sinusitis.•Staphylococcus aureus –•Streptococcus pyogenes –
•Moraxella-Microbiome of different skin locationsSkin Dysbiosis•Propionibacterium acnesbacteria colonize healthy pores, but if pores become clogged, it grows out of control•Staphylococcus epidermidisbacteria normally colonizes on the skin. But when P. acnesclogs pores, S. epidermidis also grows out of control in the infected pores•Staphylococcus aureusbacteria can also infect clogged pores likeStaph epidermidis. Even worse, many antibiotic resistant strains of Staph aureus make it difficult to treat the infection.•Trichophyton and Microsporumfungi feast on keratin in the skin and cause ringworm fungal infectionsOral Cavity Dysbiosis:The oral cavity has a wide variety of microbes normally found there. Here’s a few:S. mutans Responsible for dental caries Porphyromonas ginvivalis Responsible for gingivitisPrevotella sp. bacteria have natural antibiotic resistance genes. They can attach to epithelial cells or other bacteria
and cause larger infections in inflamed areas (Periodontitis).Candida albicans fungus can cause oral infection known as thrushWhat’s Happening in the Human Gut? The highest numbers of microbes!Major barriers for microbes entering the gut:•low pH•Saliva and Bile•Immune system•Finding a place to attach to intestinal wall•Surviving a widely varied diet•Small intestine (Duodenum, Jejunum, Ileum) – 90% of the digestion andabsorbs of nutrients and food the other 10% in stomach and large intestine.•Large intestine (Cecum, Colons, Rectum, Anus) – absorbs water from the remaining indigestible food and move out the useless material from the body. Absorbs vitamins K and B made by bacteria. These commensal bacteria breakdown the undigested polysaccharides or fibers in diet into short-chain fatty acids (SCFA). The bacteria also produce gas (flatus), which is a mixture of nitrogen and carbon dioxide,with small amounts of the gases hydrogen, methane, and hydrogen sulphide. These result from the bacterial fermentation of undigested polysaccharides. Bacteroides thetaiotaomicronbacteria ferments simple carbohydrates in the gut, releasing hydrogen and CO2. Methanobrevibacter smithii archeabacteria consumes hydrogen gas from Bacteroidesand produces methane, which is lost from gut as “gas”Helicobacter pyloribacteria has a helical shape and colonizes the stomach and upper G.I. tract. It is known to be a major cause of stomach ulcers, although many with H.pylori do not get ulcers.Small intestine predominantly = Pseudomonadota (E. coli), Bacillota (Lactobacillus)Large intestine = Bacillota (Clostridium), Bacteroidota (Bacteroides)
Enterocytes- endothelial cells of small intestine Colonocytes-endothelial cells of the large intestineGoblet cells – epithelial cells make mucus to protect membranePeyer’s patches in small intestine to protect intestines against pathogensMucus layer- provides coverage and antimicrobial activity. Bacteria feed onit.Crohn's disease – significant reduction in the numbers ofBacillota (F. prausnitzii), lack of fiber, mucous layerreduced.Effects of Probiotics on Type 2 DiabetesAbnormalities of the T2 Diabetes microbiome showed a decrease inAkkermansia muciniphila and microbes involved in the fermentation ofdietary fiber to short-chain-fatty acids (SCFAs), especially butyrate.Compared to placebo all these tests were lower for WBF-011:Total glucose = Total AUCIncremental AUC (glucose) = Glycemic Index (GI)Long term Glucose control = Hemoglobin A1C**The A1C test—also known as the hemoglobin A1C or HbA1c test—is asimple blood test that measures your average blood sugar levels overthe past 3 months.. It's one of the commonly used tests to diagnoseprediabetes and diabetes, and is also the main test to help you andyour health care team manage your diabetes.
Figure 4. Distribution of highLactobacillusconcentrations. Thenumber of individuals having a high Lactobacillus concentration was 1out of 20, 8 out of 20, and 0 out of 9 for the lean, obese, and anorexicgroups, respectively.doi:10.1371/journal.pone.0007125.g004LeanObesityAnorexiaFigure 3. TheBacteroidetesquantification. Boxand whisker:10–90percentiles. Outliersare plotted asablackbubble, means are plotted asa plus, and medians are the black lines in the boxes. P value , 0.05 isrepresented as * and P value , 0.01 is represented as ** on the graph.doi:10.1371/journal.pone.0007125.g003
-Heart Disease-Three chemicals of the dietary lipid phosphatidylcholine (PC) such ascholine, trimethylamine N-oxide (TMAO), and betaine indicate a highrisk for CVD .-Intestinal microbes are needed to form TMAO from PC.PRODUCTION OF SEROTONIN•Summary•The gastrointestinal (GI) tract contains much of the body’s serotonin(5-hydroxytryptamine, 5-HT), but mechanisms controlling themetabolism of gut-derived 5-HT remain unclear. Here, we demonstratethat the microbiota plays a critical role in regulating host 5-HT.Indigenous spore-forming bacteria (Sp) from the mouse and humanmicrobiota promote 5-HT biosynthesis from colonic enterochromaffincells (ECs), which supply 5-HT to the mucosa, lumen, and circulatingplatelets. Importantly, microbiota-dependent effects on gut 5-HTsignificantly impact host physiology, modulating GI motility andplatelet function. We identify select fecal metabolites that areincreased by Sp and that elevate 5-HT in chromaffin cell cultures,suggesting direct metabolic signaling of gut microbes to ECs.Furthermore, elevating luminal concentrations of particular microbialmetabolites increases colonic and blood 5-HT in germ-free mice.Altogether, these findings demonstrate that Sp are importantmodulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-relatedbiological processes.
Indigenous bacteria produce metabolites that signal to colonicenterochromaffin cells (ECs)-ECs increase Tph1 expression & 5-HT biosynthesis-Increased 5-HT is secreted luminally & basolaterally-Increased 5-HT uptake by circulating platelets & activationafter stimulation-Increased stimulation of myenteric neurons & gut motility.Serotonin deficiency leads to increases in:• irritability • aggression • pain • depression • suicide • alcohol and drug use• eating and bingeing • sexual activity• obsessive compulsive disorder • chronic pain • seizures • hypoglycemia •insomnia • disruption of circadian rhythmsPerturbations in Gut Microbiota Composition in PsychiatricDisorders: A Review and Meta-analysis•Bipolar disorder patients showed significant decrease in bacterialdiversity•Depleted levels of Faecalibacteriumand Coprococcusand enrichedlevels of Eggerthellafor depression, bipolar disorder, psychosis,anxiety, and schizophrenia.•Reduction of anti-inflammatory butyrate-producing bacteria.•Increase in pro-inflammatory bacteria.Schizophrenia=-Increase of Bacillota-Decrease of BacteroidotaNormal Microbiota and Cancer Treatment. Science, Nov. 2015:•Commensal microbiota promotes antitumor immunity and enhancesactivity of anticancer chemotherapy
•Melanoma growth in mice having different microbiota showed differentantitumor activity•16S ribosomal RNA sequencing identified Bifidobacteriumbacteriaassociated with the antitumor effects.•Oral administration of Bifidobacteriumenhanced antitumor activity.•When combined with medication nearly abolished tumor growth.•CD8 T cells were increased by Bifidobacterium.•When you transfer fecal suspensions of Bifidobacteriumto sensitivemice, tumor growth was delayed. •They found an increase in dendritic cells.•Bifidobacteriumtriggered the production of interferon, chemokines,cytokines to enhance the immune system. A distinct Fusobacterium nucleatum clade dominates thecolorectal cancer (CRC) niche●F.nucleatumisnormalfloraoftheoralcavity●Genomic analyses have revealed an enrichment of these bacteria inhuman CRC relative to non-cancerous colorectal tissues.●F.nucleatumC2isenrichedinhumantumors●Howdoesitgettothelargeintestine?●Maybedentalprocedures●Maybe blood infections●F. nucleatumC2 treated mice showed more tumorsMice are given dextran sodium sulfate and streptomycin to inducecolitis (inflammation) and disturb the native microbiome. High Blood Pressure•An increase in Bacillota•A decrease in Actinomycetota•A decrease in Bacteroidota = Bacteroides, Bifidobacterium
•HBP less diverse bacteria•Increase in lactate producing bacteria•Decrease in butyrate and acetate producing bacteriaWhat’s Happening in the Urogenital Tract?Urinary system almost sterile due to urea and otherchemicalsUrine often flushes out microbes that find their way inIntroducing a catheter into the urethra can introducemicrobes directly into the bladder, where a biofilm cangrow and cause bladder infectionThe vagina has a low pH due to Lactobacillussecretinglactic acid and hydrogen peroxide. Let’s explore themicrobiome of this region further.Lactobacillus normally maintain low pH while other speciesare kept in small numbers in the vaginaIf Lactobacillusdecreases from antibiotics…-Candida albicans can take over and cause a yeast infection-Gardnerella vaginaliscan grow too much and causebacterial vaginosis.Vaginal microbiome transplantation in women with intractable bacterialvaginosis (BV)-The infection is accompanied by white or gray fluid discharge, vaginal discoloration, pain, itching and burning sensations, as well as bad odor.The presence of BV also increases the risk of developing additional sexually transmitted diseases and premature birth. BV is usually treated with antibiotics, but in cases of recurrent infections, the treatment option is limited.-The researchers transplanted bacteria from healthy donors' vagina fluid and found that four of them had full long-term remission of the infection until the end of follow-up at 5-21 months after vaginal microbiome transplantation (VMT).-These women showed enrichment of their vaginal microbiome with lactobacillusbacteria,
which is associated with healthy vaginal microbiome in a previous study.-The fifth patient presented with incomplete remission in clinical and laboratory features. However, no adverse effects were observed in any of the five women."We hope the new treatment will be a step closer to providing an affordable solution for millions of women around the world", the researchers concluded.Fecal Transplant for Clostridium difficileinfectionsClostridium difficile is an anaerobic, Gram-positive bacterium that is the major cause of antibiotic-associated diarrhea and a significant healthcare-associated pathogen. C. difficile challenges hospital infection control measures by exploiting an infection cycle involving the excretion of highly transmissible and resistant spores that act as an environmental transmission reservoir.Antibiotic treatment of hospitalized patients is the major risk factor for C. difficile colonization and disease that are characterized by a toxin-mediated neutrophil response and a spectrum of outcomes from asymptomatic carriage, severe diarrhea, fulminant pseudomembranous colitis, toxic megacolon and occasionally death.First line treatments for C. difficile disease are vancomycin or metronidazole, although in 20–35% of these cases a recurrent disease (relapse or re-infection) follows cessation of antibiotic therapy.CH 19: Disorders Associated with the Immune SystemHypersensitivity•Antigenic response beyond normal•Occurs when sensitized by previous exposure to an antigen (allergen)•Four types of hypersensitivity: anaphylactic, cytotoxic, immune complex, delayed cell-mediated
–Study of hypersensitivity reactions is called immunopathology.•Hygiene hypothesissuggests that limiting exposure to pathogens may lower immune tolerance and the ability to cope with harmless antigens.Types of HypersensitivityType 1 (Anaphylactic) Reactions•Occurs minutes after a person sensitized to an antigen is reexposed to that antigen•Antigens combine with IgE antibodies•IgE attaches to mast cells and basophils–Mast cells and basophils undergo degranulation,which releases mediators. ▪Histamine: increases the permeability of blood capillaries▪Leukotrienes: cause prolonged contraction of smooth muscles▪Prostaglandins:affect smooth muscle and increase mucus secretion▪Systemic anaphylaxis(anaphylactic shock)
-Results when an individual sensitized to an antigen is exposed to it again-May result in circulatory collapse and death-Treated with epinephrine▪Localized anaphylaxis-Usually associated with ingested or inhaled antigens-Symptoms depend on the route of entry-Hives, hay fever, and asthmaPreventing Anaphylactic Reactions•Antigens are inoculated beneath the epidermis to test for a rapid inflammatory reaction (wheal)•Desensitization:increasing dosages of antigen injected beneath the skin–Produces IgG, which act as blocking antibodies to intercept and neutralize antigensType 2 (Cytotoxic) Reactions•Activation of complement by the combination of IgG or IgM antibodies with an antigenic cell–Causes cell lysis or damage by macrophages•ABO blood group system–Antibodies form against certain carbohydrate antigens on R B Cs▪A antigens, B antigens, or both▪Type O RBCs have no antigens
•Rh blood group system•Rh factor antigen (RH+) found on R B C s of 85% of the population•RH+ blood given to an RH- recipient will stimulate anti-Rh antibodies in the recipient•Hemolytic disease of the newborn (HDNB)-mother with an RH+ fetus causes the mother to produce anti-R h antibodies-second RH+ fetus will receive anti-Rh antibodies,damagingfetal RBCs•Drug-induced cytotoxic reactions–Thrombocytopenic purpura-Platelets combine with drugs, forming a complex that is antigenic.-Antibody and complement destroy platelets.–Agranulocytosis-Drug-induced immune destruction of granulocytes–Hemolytic anemia-Drug-induced immune destruction of RBCsType 3 (Immune Complex) Reactions :•Antibodies form against soluble antigens in the serum.
•Form immune complexes that lodge in the basement membranes beneath the cells–Activate complement, causing inflammation•Arthus reaction–Rare side-effect of toxoid-containing vaccines–Occurs in glomeruli and other vessel walls due to complement activation in a patient with already circulating IgG to an injected antigen•Serum sickness can occur with swelling and inflammation due to injection of foreign serum.Immune Complex-Mediated Hypersensitivity:Immune complexes are deposited in wall of blood vessel.Presence of immune complexes activates complement and attracts inflammatory cells such as neutrophils.Enzymes released from neutrophils cause damage to endothelial cells of basement membraneType 4 (Delayed Cell-Mediated) Reactions•Cell-mediated immune responses caused by T cells–Delayed hypersensitivity•Antigens are phagocytized and presented to receptors on T cells, causing sensitization.•Reexposure to antigen causes memory cells to release destructive cytokines.•Allergic contact dermatitis-Haptens combine with proteins in the skin, producing an immune response.-Allergic response to poison ivy, cosmetics, metals, and latexAutoimmune Diseases •Immune system responds to self antigens, causing damage to the organs.•Autoimmunity is loss of self-tolerance.–Ability to discriminate self from nonself•Cytotoxic, immune complex, or cell-mediated
Cytotoxic Autoimmune Reactions•Multiple sclerosis–Autoantibodies, T cells, and macrophages attack myelin sheath of nerves–Compromises nerve impulse transduction–Symptoms range from fatigue and weakness to severe paralysis.–May involve genetic susceptibility and/or infective agent(s). Epstein-Barr Virus, HHV-4, was reported to be present in all cases.Immune Complex Autoimmune Reactions •Antibodies react with cell-surface antigens–Graves’ disease▪Abnormal antibodies in the thyroid produce excessive amounts of hormones.–Myasthenia gravis▪Antibodies coat acetylcholine receptors; muscles fail to receive nerve signals•Immune complexes of antibodies and complement deposit in tissues–Systemic lupus erythematosus▪Immune complexes form in the kidney glomeruli.–Rheumatoid arthritis▪Immune complexes form in the joints.Cell-Mediated Autoimmune Reactions•Mediated by T cells that attack tissues–Insulin-dependent diabetes mellitus▪T cell destruction of insulin-secreting cells–Psoriasis andpsoriatic arthritis▪Autoimmune disorders of the skinSelected Autoimmune Disorders
The Immune System and Cancer•Cancer cells are removed by immune surveillance.•Cancer cells have tumor-associated antigens that mark them as nonself.•CTL`s (activated Tc cells ) and macrophages lyse cancer cells.•Limitations-No antigenic epitope for the immune system to target-Tumor cells reproduce too rapidly.-Tumor becomes vascularized and invisible to the immune system.Immunotherapy for Cancer :•Endotoxins from bacteria (Coley’s toxins) stimulate TNF that interferes with the blood supply of cancers.•Vaccines used for prophylaxis–Cervical, anal, and throat cancer (HPV), liver cancer (hepatitis B)•Monoclonal antibodies-Herceptin for breast cancer-Immunotoxincombines a Mab with a toxic agent.-Targets and kills a tumor without damage to healthy cellsImmunodeficiencies
•Absence of a sufficient immune response•Congenital immunodeficiencies: due to defective or missing genes•Acquired immunodeficiencies: develop during an individual’s life–Due to drugs, cancers, and infectionsAcquired Immunodeficiency Syndrome (AIDS)•1981: in the United States, a cluster of cases of Pneumocystis pneumonia, Kaposi’s sarcoma, and loss of immune function are discovered in young homosexual men•1983: the discovery of a virus causing the loss of immune function (HIV)–Selectively infects T helper cellsThe Origin of AIDS•HIV crossed over into the human population in west and central Africa from chimpanzees (around 1908, from bushmeat)•Spread throughout Africa as a result of urbanization and increased sexual promiscuity•Earliest known HIV sample comes from Kinshasa, DRC, in 1920•Norwegian sailor who died in 1974 is one of the earliest known cases inWestern world–A 1969 sample from a patient in Missouri confirmed HIV infection
The Structure of HIV•Genus Lentivirus•Retrovirus•Two identical + stranded RNA genome molecules, reverse transcriptaseenzyme, phospholipid envelope•gp120 glycoprotein spikesThe Infectiveness and Pathogenicity of HIV•Spread by dendritic cells and carried to the lymphoid organs; contacts activated T cells•gp120 combines with CD4+ receptor and CCR5 or CXCR 4 coreceptors.•C D 4 molecules are carried on T helper cells, macrophages, and dendritic cells.•Virus fuses and enters into the cell.•Inside the cell, viral RNA is transcribed into DNA using reverse transcriptase.•DNA is integrated into the host’s chromosomal DNA.•Active infection: new viruses bud from the host cell•Latent infection: DNA is hidden in the chromosome as a provirus•Some become memory T cells that serve as the reservoir for HIV•Virus undergoes rapid antigenic changes and a high rate of mutation.HIV Structure and Attachment to Receptors on Target T CellAttachment: The gp120 spike attaches to a receptor and toa CCR5 or CXCR4 coreceptor on the cell. The gp41 participates in fusion of the HiV with the cell.Fusion. The virus envelope merges with the cell membrane.Entry. Following fusion with the cell, an entry pore is created. After entry, the viral envelope remains behind andthe HIV uncoats, releasing the RNA core for directing synthesis of the new viruses.
Latent and Active HIV Infection in CD4 super plus CD4+ T cellsLatent infection: Viral DNA is integrated into cellular DNA as a provirus that can later be activated to produce infective virusesActive infection: The provirus is activated, allowing it to control the synthesis of new viruses’ Final assembly takes place at the cell membrane, taking up the viral envelope proteins as the virus buds from the cell.Latent and Active HIV Infection in Macrophageslatently infected macrophage. HIV can persist either as a provirus or as a complete virion in vacuolesActivated macrophage. New viruses are produced from provirus. Completed virions are either released or persist inthe macrophage within vacuoles.Subtypes of HIV•HIV - 1–Related to viruses that infect chimpanzees and gorillas–99% of cases–Group Meter (majority) accounts for 90%•HIV - 2–Not often encountered outside of West Africa–Less pathogenic than HIV - 1–Longer asymptomatic period with lower viral load and mortality rate than HIV – 1The Stages of HIV Infection•Phase 1:asymptomatic or lymphadenopathy•Phase 2: CD4+ T cells decline steadily; only a few infected cells releasethe virus; few serious disease symptoms (persistent infections, fever, and oral leukoplakia).
•Phase 3:AID S develops; the CD4+ is count below 200 cells (indicator conditionsThe Infectiveness and Pathogenicity of HIV Infection•Initial strong and effective immune response–CTLs suppress viral numbers.•Once HIV establishes a pool of latently infected CD4+ T cells, it is impossible to clear the infection.-Challenge to make a vaccine•Variations in Response to HIV Exposure•Impact of age on survival with HIV infection–Older adults and young children do not a have fully developed immune system, making them more susceptible•Exposed, but not infected population–CCR5 mutation•Long-term survivors–Low viral load–Effective CTLsSome Diseases Commonly Associated with AIDSDiagnostic Methods
•Seroconversionis the period of time between infection and the appearance of antibodies.–Takes up to 3 months•HIV antibodies detected by ELISA•Viruses detected by Western blotting or APTIMA (RNA testing)•Plasma viral load (PVL) is determined by PCR or nucleic acid hybridization.HIV Transmission•HIV survives 6 hours outside a cell.•HIV can survive more than 1.5 days inside a cell.•Routes of transmission: sexual contact, breast milk, transplacental infection of a fetus, blood-contaminated needles, organ transplants, artificial insemination, and blood transfusion–Anal-receptive intercourse is the most dangerous form of sexual contact.AIDS Worldwide•36 million infected worldwide–70% in Africa•Heterosexual transmission is the most common mode of HIV transmission.•1/3 of cases in Eastern Europe and Central and Southeast Asia are frominjected drugs.Distribution of HIV Infection and AIDS in Regions of the World
Preventing and Treating AIDS•Biomedical interventions–Use of condoms, health services / HIV testing, needle programs•Behavioral intervention–Sex education, safe infant feeding programs, counseling•Structural interventions–Making changes in social, economic, political, and environmental factors to reduce vulnerability to HIV.•Now considered a treatable chronic disease in the developed world•Highly active antiretroviral therapy (HAART)–Use combinations of drugs to minimize survival of resistant strains•Fusion/cell entry inhibitors–Targets the gp41 region of the viral envelope that prevents fusionof the virus with the cell–Enfuvirtide and maraviroc•Reverse transcriptase inhibitors–Nucleoside reverse transcriptase inhibitors (NRTIs)
•Tenofovir and emtricitabrine–Non-nucleoside reverse transcriptase inhibitors (NRTIs)•Efavirenz•Integrase inhibitors–Inhibit HIV integrase that integrates cDNA into the host chromosome•Raltegravir, dolutegravir, elvitegravir•Protease inhibitors–Inhibit proteases that cleave viral precursor proteins into structural and functional proteins•Atazanavir, indinavir, and saquinavir•Maturation inhibitors•Tetherins–Tether viruses to the cells, preventing their release and spreadThe Challenges of Developing HIV Vaccines•No model of natural immunity to mimic•Lack of a research animal•Lack of understanding of the mechanisms of retroviruses•High mutation rate, leading to resistant strains•An ideal vaccine would:–induce immunity before reservoirs of latent viruses are established.–stimulate production of CTLs.–be affordable.Drugs That Inhibit HIV Life Cycle* Fusion/entry inhibitors Enfuvirtide Maraviroc* Reverse transcriptase inhibitors Tenofovir Emtricitabine
* Integrase inhibitorsRaltegravir* Protease inhibitors Atazanavir Indinavir Saquinavir