• 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
    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

• <del>Opsonization</del>

  • <del>process in which microbes are coated by serum components in preparation for recognition/ingestion by phagocytic cells</del>

    • <del>molecules that carry out above are called opsonins</del>

    • <del>make pathogen more visible</del>

  • <del>some complement proteins are opsonins</del>

    • <del>bind to microbial cells, coating them for phagocyte recognition</del>

• 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