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

  

• 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)

  

• 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

  

• 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

  

• 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

  

• 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!

  

• 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

  

• 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)

  

• 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

  

• 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

  

• ~~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

  

• 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

  

• 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

  

• 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

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