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

  
  

• 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

  
  

• 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

  
  

• 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

  

  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

  
  

• 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

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