Topic 13: Innate Defense System

  • Overview of Host Resistance
      * immune system
        * composed of wide variety of cells, tissues, and organs
        * recognizes foreign substances or microbes and acts to neutralize or destroy them
        * “probiotic—up to 500 species”, “prebiotic” – up to ¾ immune system reside in your gut
          * probiotic line intestine (mental health importance; dependent on nutrition)
          * said will not ask # of species
          * know difference between the two?
        * compromised by stress, health problems & unhealthy food / lifestyle
      * immunity
        * ability of host to resist a particular disease or infection
      * immunology
        * science concerned with immune responses
  • Terminology
      * Susceptibility: Lack of resistance to a disease
      * Immunity: Ability to ward off disease
      * Innate immunity: Defenses against any pathogen
        * “nonspecific immunity”
      * Adaptive immunity: Immunity, resistance to a specific pathogen
  • Types of immune responses
      * Innate (nonspecific) defense system
        * responds quickly, offers resistance to any microbe or foreign substance, lacks immunological memory, and consists of:
          * First line of defense – skin and membranes
          * Second line of defense – antimicrobial proteins, phagocytes, and other cells
            * Inhibit spread of invaders throughout the body (stop the invaders)
            * Inflammation is its hallmark and most important mechanism (cause of swelling, heat, redness)
            * Where did you hear phagocytosis?
              * WBC will “eat” them; bacterias with capsule resistant to phagocytosis
  • Immunity
      * Innate Immunity
        * First Line of Defense
          * Intact skin
          * Mucous membranes and their secretions
          * Normal Microbiota (antagonism)
            * antagonism is your normal bacteria on skin that keeps you “clean” → will be “mean/antagonize” new bacteria
        * Second Line of Defense
          * Natural Killer cells and phagocytic WBC
          * Inflammation
          * Fever
          * Antimicrobial substances
      * Adaptive Immunity (“specific”)
        * Third Line of Defense
          * Specialized lymphocytes: T and B cells (T cells are HIV’s target; B cells give antibodies)
          * Antibodies
            * received by getting sick and producing B cells or getting vaccine with B cells
  • Adaptive (specific) defense system
      * Also called acquired or induced immunity, has immunological memory, responds to a very particular foreign substance (why some substances last a shorter time than others? they don’t know yet; COVID is one that doesn’t have a long memory)
        * about 2 weeks to produce antibodies (don’t get vaccine when people are already sick, do it sooner)
      * Third line of defense
        * Takes longer to react than the innate system
        * Works in conjunction with the innate system

 Covid 19 target is B cells; donation of plasma was needed because it has B cells; B cells have lock and key neutralization of covid; acquired side = adapative; covid 19 vaccine causing autoimmune diseases?

  • Components of the Innate Immune System
      * Skin (biggest organ)
      * Mucous
        * most pathogens go through mucous membrane (eyes, nose, mouth)
        * Covid going for respiratory; cytocines? caused continous inflammation
      * Chemical
        * stomach acid
        * food poisiong indicates eating a lot of bacteria
      * bacteria can go up through urinary tract and cause UTI, if not treated the bacteria can travel upwards
      * lysozyme cuts galasidic bond?
      * smokers cough in morning because paralysis of cilia (cilia moves the fluid upwards)
  • Innate (non-specific) defense systems
      * Surface Barriers: Skin, mucous membranes, and their secretions make up the first line of defense
        * sebaceous glands → oils (sebum)

 Use preparation H for when you get burned (its a hemmeroid cream); pain is good thing because it means the nerve endings are still intact; once infection reaches bone, doctors are unable to do anything to treat other than amputation; burn victims suspectible to infections becasue skin is exposed

  • Skin
      * Largest organ (20 sqft), 10+/- pounds
      * strong mechanical barrier to microbial invasion
        * keratin produced by keratinocytes (=basal cells) in outer layer
        * resists absorption of water and most inorganic chemicals; allows absorption of many organic and a few inorganic chemicals
  • Skin infection/reaction by microbes
      * Cellulitis: inflammation due to infection
        * does not have to be an open cut
      * Warts: viral infection cause excess skin growth
      * Herpes: HSV-1&HSV-2, periodic blisters around lips or genitals
        * cold sores
      * Hives: allergic reaction – not infection
      * Tinea: skin mycosis
        * fungal skin infection
      * Shingles: varicella zoster virus (linear DNA, lipid enveloped, herpes group)
        * DNA virus, enveloped, hide when young but “come out” when older
        * younger people can get it as well
  • Skin = inhospitable environment for many microbes
      * attached organisms removed by shedding of outer skin cells = part of your soap scum, eww
      * pH 3-5 = acidic
      * high NaCl concentration = why?
        * skin bacteria have a high salt toleration and dryness (mannitol salt agar!)
      * subject to periodic drying
      * Lysozyme in saliva and tears – function
        * prevents infection
      * Fungistatic fatty acids in sebum
      * Transferrin** in blood (who’s the bad guy?)
        * *Antagonisms: competitive exclusion of normal microbiota (our bacteria)
        * **iron-binding blood glycoproteins
  • More about Skin
      * specialized cells called skin-associated lymphoid tissue (SALT)
        * Langerhans cell---NOT islet of Langerhans in pancreas!!!
          * dendritic cell that can phagocytose antigens
            * have lots of branches; can eat the pathogens (bring inside cell)
          * differentiates into interdigitating dendritic cell–presents antigen to and activates T cells
            * uses piece of pathogen to present to T cell
  • Antimicrobial Secretions
      * lysozyme
        * How?: tears, saliva
          * cut 1-4 galoscidic bond
      * lactoperoxidase
        * produces superoxide radicals: toxic
        * mammary and salivary gland (saliva)
  • The Eye
      * flushing action of tears
      * lysozyme, lactoferrin and secretory IgA in tears
        * lactoferrin - transferrin (good?)
      * Lactoferrin: multifunctional protein (antimicrobial)
      * IgA = antibody
        * cover antibodies later
  • Mucous Membranes
      * form protective covering that resists penetration and traps many microbes
      * are often bathed in antimicrobial secretions which contain a variety of antimicrobial substances
      * contain mucosal-associated lymphoid tissue (MALT)
        * mucous can trap bacteria
  • Mucosal-Associated Lymphoid Tissue (MALT)
      * specialized immune barrier
        * gut-associated lymphoid tissue (GALT)
        * bronchial-associated lymphoid tissue (BALT)
          * two types of MALT
  • Respiratory system
      * turbulent air flow deposits microbes onto mucosal surfaces
      * COVID 19 TARGET
      * Mucociliary blanket
        * mucous secretions that traps microbes
        * once trapped, microbes transported away from the lungs (mucociliary escalator)
          * can be expelled by coughing or sneezing
          * salivation washes microbes to stomach (pH 3-5)
      * alveolar macrophages
        * phagocytic cells in alveoli of lungs
          * capsule bacteria prevent digestion by phagotcytic cells
  • When you smoke…
      * Cilia paralized, smoker’s cough
        * being moved upwards
      * Smokers are sick more often because……
        * cilia is paralized therefore cilia isn’t moving upwards
      * Morning cough
      * 80% lung cancer – due to smoking, 13% survive 5+ years
        * includes 2nd hand smoking
      * P53 gene – nose, liver, colon, myloid leukemia
        * cancer suppressing gene
      * Tobacco smoke contains a deadly mix of more than 7,000chemicals. Hundreds are toxic. About 70 can cause cancer. Here are some of the chemicals. (said wouldn’t ask about chemicals, just information)
        * Cancer-Causing Chemicals
          * Formaldehyde: Used to embalm dead bodies
          * Benzene: Found in gasoline
          * Polonium 210: Radioactive and very toxic
          * Vinyl chloride: Used to make pipes
        * Toxic Metals
          * Chromium: Used to make steel
          * Arsenic: Used in pesticides
          * Lead: Once used in paint
          * Cadmium: Used to make batteries
        * Poison Gases
          * Carbon monoxide: Found in car exhausts
          * Hydrogen cyanide: Used in chemical weapons
          * Ammonia: Used in household cleaners
          * Butane: Used in lighter fluid
          * Toluene: Found in paint thinners
  • Helicobacter pylori –in the disease packet
      * Gram -, Curved rod, Microaerophilic
        * microaerophilic - likes less oxygen (strept throat test)
      * 80% of infected people = asymptomatic
      * Gastritis, linked to duodenal and stomach cancer – stress was to blame before the discovery
        * burrow into stomach
        * high salt diet dissolves membrane in stomach (high salt diet = higher chance of stomach cancer)
      * Stomach acid gradient chemotaxis
        * urea in stomach acid
      * Urease –Ammonia production, ph?
        * metabolize protein, pH increases
      * 1st infection – antibody test
      * 2nd and after – Urea or stool test
        * because possible antibodies from last infection

  Picture: blood has plasma and cells (red blood cells, platelets, and white blood cells); centrifuge separates layers

  • Blood Plasma – approx. 55%
      * Glucose, fat
      * Protein – (antibodies 1/3)
      * Clotting factor
      * Electrolytes, vitamins
      * Hormones
      * BP, pH
        * less fluid increase BP; neutral pH
      * CO2

 Will not ask # or %; know majority is red blood cells; Acronym for remembering white blood cells - know the relative # in comparison to others (i.e basophils have the least amount of cells)

  • Donations
      * Blood donation ---- NO NO
        * Have tested positive for hepatitis B or hepatitis C, lived with or had sexual contact in the past 12 months with anyone who has hepatitis B or symptomatic hepatitis C.
        * After donation, test for ….HIV, hepatitis, syphilis, Human T-lymphotropic virus
      * Platelets donation – not from mama. Why????
        * pregnant - may have antibody from baby
      * Plasma donation – no tuberculosis, malaria, sickle cell anemia, cancer etc..
        * screening
  • White Blood Cells and the Nonspecific and Specific Responses
      * white blood cells (WBCs) - major role in the innate and specific responses
      * Hematopoesis – hematopoetic stem cell differentiation process (all blood components)
        * stem cells that differenate
        * umblitical cord has stem cells
          * development of white blood cells in bone marrow of mammals
            * WBCs that mature prior to leaving bone marrow, e.g. macrophages and dendritic cells, become part of innate immune system and will respond to all antigens
            * WBCs that are not fully functional after leaving bone marrow become part of the adaptive immune response, e.g.B and T cells and could differentiate in response to specific antigens
              * know the differences

 

  • Monocytes and macrophages
      * highly phagocytic cells, 6% of WBC
        * engulf pathogen, lysosome digests pathogen
      * make up monocyte-macrophage system
      * monocytes
        * are mononuclear phagocytic leukocytes
        * after circulating for ~8 hours, mature into macrophages
      * macrophages
        * reside in specific tissues
        * have a variety of surface receptors
          * senses the pathogens
        * named according to tissue in which they reside

 Bring inside and combine with lysosome to digest and do exocyotis; capsule bacteria may not die here and may continue to live inside the cell

  • Dendritic Cells: Antigen-presenting cells (APC)
      * present in small numbers in blood, skin, and mucous membranes of nose, lungs, and intestines
        * contact, phagocytose and process antigens → display foreign antigens on their surfaces (antigen presentation)
          * bring antigen/pathogen to surface to show other cells (i.e macrophages)
  • Basophils
      * stain bluish-black with basic dyes, 1% of WBC
      * Non-phagocytic
      * release histamine, heparin, prostaglandins, serotonin, and leukotrienes from granules
        * histamine most important
      * play important role in development of allergies and hypersensitivities (inflammation)
        * antihistamines
  • Eosinophils
      * stain red with acidic dyes, 3% of WBC
      * defend against parasites (protozoan and helminthes)
      * play a role in asthma/allergic reactions along with mast cells
  • Neutrophils
      * stain at neutral pH
      * 60% of WBC - majority
      * highly phagocytic - 1st to go to site
      * circulate in blood then migrate to sites of tissue damage
        * sequeeze through capillary walls
      * kill ingested microbes with lytic enzymes and reactive oxygen metabolites
        * high neutrophil count = bacterial infection
      * pus is normally dead neutrophils
  • Mast Cells
      * differentiate in blood and connective tissue
      * contain granules containing histamine, heparin, and other pharmacologically active chemicals, over 200+ chemicals
      * play important role in development of allergies and hypersensitivities
      * Mast cell activation syndrome
        * idopathic - don’t know what it is, may be genetic
  • Lymphocytes
      * major cells of the immune system, 30% of WBC
      * major populations include T cells, B cells, and natural killer (NK) cells
      * B and T lymphocytes differentiate in bone marrow from stem cells
  • B Lymphocytes
      * B cells (B lymphocytes)
        * mature mostly in lymph nodes and other lymph tissues
        * circulate in blood
        * can settle in lymphoid organs
        * after maturation and activation are called plasma cells and produce antibodies
          * memory and antibodies (after ~10 days)
          * outside of pathogens
  • T Lymphocytes
      * T cells (T lymphocytes)
        * Mature primarily in the thymus gland
        * can remain in thymus, circulate in blood, or reside in lymphoid tissue
        * like B cells, require antigen binding to surface receptors for activation and continuation of replication
          * need a signal (i.e antigen presenting cell - dendritic cell)
          * they have no memory or antibodies
        * cytokines, chemicals that have effects on other cells, are produced and secreted by activated T cells
  • Natural Killer (NK) Cells
      * small population of large non-phagocytic granular lymphocytes
        * kill malignant cells and cells infected with pathogens
      * two ways of recognizing target cells
        * bind to antibodies which coat infected or malignant cells (antibody-dependent cell-mediated cytotoxicity (ADCC))
        * recognizes cells that have lost their class I major histocompatibility (MHC) antigen due to presence of virus or cancer
          * organ transplant

 ADCC process

  • Cytotoxic T Cells and Natural Killer Cells
      * Cytotoxic T-cells : the specific antigens presented by their MHC class I molecule
        * recognize receptor and present it
      * NK cells : the absence of MHC class I molecules, specific types of antibodies, and \n some type of cellular stress
      * Know the difference!

 is an open system

  • Primary Lymphoid Organs and Tissues
      * immature undifferentiated lymphocytes (generated in the bone marrow) → mature
      * obtain a specific antigenic specificity within the primary lymphoid organs and tissues, bone marrow and thymus gland
        * unique to pathogens
  • Secondary Lymphoid Organ/Tissue
      * Secondary lymphoid tissue includes: lymph nodes, tonsils, adenoids, Peyer’s patches (intestine), spleen
        * throughout the body
        * interface between innate and acquired host immunity (overlap)
        * act as areas of antigen sampling and processing
          * determine if the threat needs to be neutralized
        * some lymphoid cells are found closely associated with specific tissues
          * e.g., skin-associated lymphoid tissue (SALT)
          * e.g., mucous-associated lymphoid tissue (MALT)
          * e.g. bronchial associated lymphoid tissue (BALT)
  • Secondary Lymphoid Organ/Tissue
      * spleen
        * highly organized lymphoid organ
        * filters blood - scanning
        * trap microbes and antigens
          * present antigens to B and T cells
            * most common way that lymphocytes become activated to carry out their immune functions
      * lymph nodes
        * highly organized lymphoid tissue
        * filter lymph
        * microbes and antigens trapped and phagocytosed by macrophages and dendritic cells
        * B cells differentiate into memory and plasma cells within lymph nodes
  • Phagocytosis
      * process by which phagocytic cells (monocytes, tissue macrophages, dendritic cells and neutrophils) recognize, ingest and kill extracellular microbes
      * How bacteria resist?
        * capsule

  yeast is eukaryotic cell

  • Phagocytosis
      * two mechanisms for recognition of microbe by phagocyte
        * opsonin-independent (nonopsonic) recognition
        * opsonin-dependent (opsonic) recognition
      * phagocytosis can be greatly increased by opsonization
  • Opsonization (stopped here w/ anki)
      * opsonin – Greek: prepare for eating
      * opson – Greek: delicious side dish
      * process in which microbes are coated by serum components in preparation for recognition/ingestion by phagocytic cells
        * molecules that carry out above are called opsonins = antibodies, complement molecules
      * some complement proteins are opsonins
        * bind to microbial cells, coating them for phagocyte recognition
  • Opsonin-Independent Mechanism
      * involves nonspecific and specific receptors on phagocytic cells
      * four main forms:
        * recognition by lectin-carbohydrate interactions
        * recognition by protein-protein interactions (PPI)
        * recognition by hydrophobic interactions
        * detection of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs, e.g., toll-like receptors)
          * *lectin: carbohydrate binding proteins
          * *PPI: Alzheimer’s, CJD, Cancer
  • Pathogen-Associated Molecular Patterns (PAMPs)
      * PAMPs are unique to microbes, not present in host
        * Examples of unqiue features
          * e.g., lipopolysaccharide (LPS) of gram negative bacteria
          * e.g., peptidoglycan of gram positive bacteria
      * PAMPs recognized by pattern recognition receptors (PRRs) on phagocytic cells
  • Toll-Like Receptors (TLRs)
      * recognize and bind unique PAMPs of viruses, bacteria or fungi
      * Innate
      * Macrophages, Dendritic cells
        * on these cells
  • Intracellular Digestion
      * phagolysosome
      * vacuole which results from fusion of phagosome with lysosome
        * presence of toxic chemicals
          * e.g., degradative enzymes
          * e.g., toxic reactive oxygen intermediates (ROIs) (kills microorganisms)
          * e.g., reactive nitrogen intermediates (RNIs)

 cytokines are the message that recruit for help from other immune cells; cytokines produce inflammation; cytokines killed a lot of people at the beginning of COVID; bacteria's weapon is leukocidins - kills WBCs; pus is dead WBCs; lysosome is chemical that helps kill the bacteria inside macrophage

  • Neutrophils – after digesting microbial fragments
      * also phagocytic - 1st to be at site of injury
        * Exocytosis
          * process used by neutrophils to expel microbial fragments after they have been digested
          * phagolysosome unites with cell membrane
            * results in extracellular release of microbial fragments
  • Inflammation (innate side)
      * nonspecific response to tissue injury
        * can be caused by pathogen or physical trauma
        * acute inflammation is the immediate response of body to injury or cell death
      * cardinal signs---PRISH (reactions from inflammation)
        * Pain – release of chemicals such as histamine
        * Redness – increased blood flow
        * Immobility - altered or loss of function
        * Swelling – edema (accumulation of fluid)
          * application of ice pack (no more than 20 min because it slows the process of blood flow which gets rid of the waste)
        * Heat – increased blood flow
  • Acute Inflammatory Response
      * Vascular phase first, then cellular phase
        * vascular is the fluid
      * the release of inflammatory mediators from injured tissue cells initiates a cascade of events which result in the signs of inflammation
      * involves chemical mediators
        * chemokines - signaling proteins/cytokines
          * released by injured cells
        * selectins
          * cell adhesion molecules on activated capillary endothelial cells
        * integrins
          * adhesion receptors on neutrophils
            * blood vessel will get loose because of histamine and neutrophils can squeeze through
  • Inflammatory Response Vascular Permeability
      * Vasodilation
      * Chemicals released by the inflammatory response stimulate mast cells next to capillaries
      * Mast cells release histamines to increase permeability of capillaries
        * histamines make you “leaky”
      * Plasma seeps into tissue (interstitial) spaces causing local edema (swelling), which contributes to the sensation of pain
        * *pain – Na+channel
          * lidocaine blocks Na+ channel
  • Inflammatory Response Phagocytic Mobilization
      * Margination – neutrophils cling to the walls of capillaries in the injured area
      * Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis
        * know margination and diapedesis
      * Chemotaxis – inflammatory chemicals attract neutrophils to the injury site

 gram + bacteria on skin; histamine relase -> loose capilaries -> neutrophils squeeze through; siderophores "bad guys" - take Fe and transferrins "good guys" - hold on Fe; platelets help clot bleeding; acute inflammation

  • Chronic Inflammation
      * slow process
        * may not notice
          * rhuematoid arthrisis
          * excema
      * involves formation of new connective tissue
      * usually causes permanent tissue damage
      * dense infiltration of lymphocytes and macrophages at site of inflammation
        * granuloma
          * walled off area formed when phagocytic cells can’t destroy pathogen

 Don't need to know this Flowchart of Events in Inflammation; summary chart; vasodilation - local loose capillary

  • ~~Opsonization~~
      * ~~process in which microbes are coated by serum components in preparation for recognition/ingestion by phagocytic cells~~
        * ~~molecules that carry out above are called opsonins~~
        * ~~make pathogen more visible~~
      * ~~some complement proteins are opsonins~~
        * ~~bind to microbial cells, coating them for phagocyte recognition~~
  • Pus
      * Dead leukocytes (mostly neutrophils)
      * Color varies
      * Abscess=enclosed in tissue
      * Pimple=visible collection within/beneath the epidermis
      * Pus causing bacteria = pyogenic
        * Example from your lab: Staphylococcus aureus (pink eye), S. epidermidis, S. pyogenes (strept throat) (Gram+, β-hemolysis, catalase-), Escherichia coli, Pseudomonas aeruginosa
  • The Complement System (or cascade)
      * composed of >30 serum proteins – mainly produced in liver (pro-proteins)
      * augments (or “complements”) the antibacterial activity of antibody
      * part of innate immunity, will NOT change over ones lifetime, does not adaptable
        * genetic, pre-determined
        * aide in getting rid of pathogen

 C3b is complement protein; combination of both opsonin increases visibility and recogniation of bacteria, increases binding

  • Other Functions of Complement Proteins
      * function as chemotactic signals that recruit phagocytes to their activation site
      * puncture cell membranes causing cell lysis
        * important function
      * many complement activities unite the nonspecific and specific arms of the immune system to destroy and remove invading pathogens
  • Complement Activation Pathways (innate)
      * specific proteins are unique to the first part of each of the three complement activation pathways, but all complement pathways have the same outcome
        * Opsonization - phagocytosis
        * stimulation of inflammatory mediators
        * lysis of microbes by membrane attack
      * all pathways are activated as a cascade; the activation of one protein results in the activation of the next
      * all complement proteins are in the inactive state until activation when the host is challenged by an invading microbe

 don't need to memorize; classic involves antibodies (adaptive); processes make different results like membrane attack complex (one that punctures cell wall) don't need to memorize details; showing the puncture of cell wall; all proteins in the complex need to be working in order to function correctly - reason for bacterial infections increase

  • Cytokines
      * soluble proteins or glycoproteins that are released by one cell population that act as intercellular mediators or signaling molecules
      * monokines
        * released from mononuclear phagocytes
        * i.e macrophages
      * lymphokines
        * released from T lymphocytes
      * interleukins
        * released from one leukocyte and act on another leukocyte
      * colony stimulating factors (CSFs)
        * act on hemopoietic stem cell, stimulate growth and differentiation of immature leukocytes in bone marrow
  • Interferons (IFNs) =type of cytokines
      * regulatory cytokines produced by some eukaryotic cells in response to viral infection
        * viral infection is important (acute)
          * do not prevent virus entry into host cells, but defend against viruses by preventing viral replication and assembly
      * also help to regulate the immune response
      * responsible for “flu-like” symptoms
      * clinical use for viral infection, MS and cancer treatment
        * cancer treatment: elicit T cells (side effects: thinning hair, flu-like symptoms); T cells attack cancer

 lytic cycle, interferons; process to treat cancer

  • Fever
      * 37.5-38.3 °C (99.5-100.9°F) or above
        * dr starts to get worried at 105
      * most common cause of fever is viral or bacterial infection or bacterial toxins
      * Viral --- DO NOT ask for antibiotics!!!!
      * Thermostat set point located in hypothalamus
  • More About Fever
      * in most cases, the endogenous pyrogen, a cytokine produced in response to pathogen, directly triggers fever production
      * after release, pyrogens → hypothalamus and induce production of prostaglandins which reset hypothalamus to a higher temperature
        * increase temp
      * When the hypothalamus is reset, what has to happen to increase body temperature?
        * *Pyrogen = a fever inducing substance
        * **Prostaglandins = found in every tissue, hormone-like effect, lipid derived
        * ***Physical activity is needed to increase metabolic rate, heat production = This accomplished by shivering thermogenesis.
        * know where body’s thermostat is
  • Should fever be reduced with medicines?
      * Yes! Because……
        * Febrile seizure (epileptic seizure) – can be dangerous
          * some people can get seizures from fever (temperature increases too quickly)
        * Feeling awful/miserable – treating the symptom, not the cause
          * fever caused by infection
          * bacterial infection treated by antibiotics, no treatment for viral infection
      * No! because……….
        * Not high enough fever
          * may hinder immune system
      * Research (2014) has shown that using fever-suppressing drugs may allow patients to mistakenly feel better quicker than normal resulting in their premature return to the population
      * Concerning influenza, it is estimated that this will result in a 1% increase in the number of cases and about 700 more deaths each year in the U.S.
        * contributes to spread