MA 4 Chapter Notes

Ch 17 Innate Immunity

17.1 Physical Defenses

Physical Defenses

• physical barriers

  • prevent microbes from reaching tissues that are susceptible to infection

  • barriers are composed of cells that are tightly joined to prevent invaders from crossing through to deeper tissue

    • ex. endothelial cells

  • cell junctions are composed of cell membrane proteins that may connect with the extracellular matrix or with complementary proteins from neighbouring cells

    • ex. tight junctions, desmosomes (intracellular junctions/ spot welds/bind adjacent animal cells), gap junctions

• skin barrier

  • composed of 3 layers of closely packed cells

    • epidermis: thin upper layer

      • cells w/ hella keratin

        • keratin makes surface tough and resistant to degradation by bacterial enzymes

      • dead cells remain tightly connected and create dense layers of protein filled cell husks on surface of skin    

        • frequently shed, along with microbes that may be clinging to them

        • shed skin cells are continually replaced with new cells from below

      • fatty acids on surface inhibits growth of some microbes and highly resistant to breakdown by bacterial enzymes

    • dermis: thicker, with hair follicles, sweat glands, nerves, and blood vessels

    • hypodermis: fatty tissue layer with blood and lymph vessels

• mucous membrane

  • line the nose, mouth, lungs, and urinary and digestive tracts

  • consist of a layer of epithelial cells bound by tight junctions

    • secrete a moist, sticky substance called mucus

      • covers and protects more fragile cell layers and traps debris and particulate matter, including microbes

      • secretions contain antimicrobial peptides

  • mechanical actions flush mucus out of body

    • removal system = mucociliary escalator

  • mucociliary blanket = debris caught in mucus lining RT

  • ciliated epithelial cells = EC lining the upper RT

    • has cilia

• Endothelia

  • epithelial cells that line the urogenital tract, blood vessels, lymphatic vessels, and other tissues

  • endothelia of blood-brain barrier protect from the central nervous system (brain/spinal cord)

    • microbial infections of CNS lead to serious/fatal inflammation

    • cell junctions in blood vessels of CNS are tightest/toughest in body

Mechanical Defenses

• shedding of skin cells, expulsion of mucus (mucociliary escalator), excretion of feces through intestinal peristalsis

• flushing of urine and tears—> carry microbes away from body

  • urinary tract: flushing of urine —> clearing of kidneys, ureters, urinary bladder

  • urine passing out of body washes out transient MOs

• eyes: physical and mechanical defense mechanisms for preventing infections

  • blinking

  • eyelashes and eyelids

Physical Defenses of Nonspecific Innate Immunity

17.2 Chemical Defenses

• Chemical and Enzymatic Mediators Found in Body Fluids

• fluids produced by skin can be both endogenous and exogenous mediators

• sebaceous glands secrete sebum —> released in the skin surface through hair follicles

  • endogenous mediator

  • seal off the pore via hair follicle

• Cutibacterium acnes/malassezia use lipasre enzymes to degrade sebum

  • produces oleic acid—> creates mildly acidic env inhospitable for pathogenic microbes

• oleic acid: exogenously produced mediator—> because produced by resident microbes and not directly by body cells

• environmental factors that affect microbiota have a direct impact on the production of chemical mediators

  • low humidity/decreased sebum production could make the skin less habitable for microbes that produce oleic acid

    • making skin more susceptible to pathogens normally inhibited by skin’s pH

  • digestive tract produces hella chemical mediators that inhibit or kill microbes

• Antimicrobial Peptides (AMPs)

• special class of nonspecific cell-derived mediators with broad spectrum antimicrobial properties

• most AMPs are produced in response to invading pathogen

  • may induce cell damage in MOs

    • inflicting damage to membranes

    • destroying DNA/RNA

    • interfering with cell-wall synthesis

  • depending on AM mechanism, AMPs may only inhibit certain groups of microbes (gram-positive/negative) or may be more effective against bacteria, fungi, protozoa, and viruses

• mostly found on skin but can be found in other regions of the body

• family “defensins” —> prod. by epithelial cells as macrophages/neutrophils

  • may be secreted/act inside host cells

    • combat MOs by damaging plasma membranes

    • AMPs called bacteriocins—> prod. exogenously by certain members of resident microbiota within gastrointestinal tract

    • bacteriocins—> genes carried on plasmids and can be passed between different species via lateral/horizontal gene transfer

Characteristics of Selected AMPs

Plasma Protein Mediators

• nonspecific innate immune factors are found in plasma (fluid portion of blood)

  • plasma contains electrolytes, sugars, lipids, proteins; also proteins involved in clotting blood; also acute-phase proteins, complement protein, and cytokines

• acute phase proteins

  • produced in liver and secreted into blood in response to inflammatory molecules from the immune system

  • ex. C-reactive protein, serum amyloid A, ferritin, transferrin, fibrinogen, and mannose-binding lectin

Functions of Some Acute-Phase Proteins

• all pathways produce the same protective outcomes:

  • opsonization: coating of a pathogen by a chemical substance (opsonin)

    • opsonins from CC (C1q, C3b, C4b)

      • *also imp. mannose-binding proteins and antibodies

  • complement fragments C3a/C5a are anaphylatoxins (inflammatory functions!)

    • anaphylatoxins: activate mast cells—>causing degranulation and release of inflammatory chemical signals

      • including mediators that cause vasodilation and increased vascular permeability

    • C5a =potent chemoattractants for neutrophils and other white blood cells

  • membrane attack complex: C6, C7, C8 and C9

    • enables C9 polymerize into pores in the membranes of gram-negative bacteria

      • pores facilitate water, ions,and other molecules to move in and out of targeted cells

      • *MAC cannot penetrate peptidoglycan in gram-positive bacteria

        • because of this lack of threat to g+ bacterial pathogens, complement-mediated opsonization is more important for clearance.

• cytokines:

  • soluble proteins that acts as communication signals between cells

  • in nonspecific innate immune response; cytokines may be released to stimulate production of chemical mediators or other cell fns

    • proliferation, cell differentiation, inhibition of cell division, apoptosis, and chemotaxis

  • when bound to target receptor: effect can vary widely depending on type of cytokine/type of cell or receptor to which it has bound

Autocrine	same cell secretes and receives cytokine signal
Paracrine	cytokine signal secreted to a nearby cell
Endocrine	cytokine signal secreted to circulatory system; travels to different cells

Important Classes of Cytokines

Inflammation-Eliciting Mediators

• chemical mediators previously mentioned contribute in some way to inflammation and fever—>nonspecific immune responses

  • cytokines stimulate prod. of acute-phase proteins (C-reactive/mannose-binding lectin) in liver

    • these proteins act as opsonins—> activate CC through lectin pathway

  • some cytokines also bind mast cells and basophils—>release histamine

    • histamine: proinflammatory compound

    • receptors found on variety of cells and mediate proinflammatory events

  • mast cells may also release leukotrienes

    • leukotrienes: lipid-based proinflammatory mediator prod. from metabolism of AA in cell membrane of leukocytes and tissue cells

    • effects are more potent and long lasting than histamines

  • leukotrienes + histamines = coughing, vomiting, diarrhea —> expel pathogens from body

  • cytokines can stim. prod. of prostaglandins

    • prostaglandins: chem. mediator that promote inflammatory effects of kinins and histamines

      • also set body temp. higher—>fever

        • promotes active white blood cells and inhibits the growth of pathogenic microbes

    • bradykinin: contributes to edema; when fluids and leukocytes leak out of bloodstream into tissues

17.3 Cellular Defenses

Hematopoiesis

• formed elements of blood come from HEMATOPOIETIC STEM CELLS (HSCs)

  • from bone marrow

  • as HSC makes copies of themselves in bone marrow, individual cells receive different cues from body on how to develop and mature

  • HSCs diferentiate into blood types that will circulate in peripheral blood

    • process of differentiation: hematopoiesis

• nonfluid portion of blood; formed elements: all formed from same stem cells found in bone marrow

• 3 major categories:

• GRANULOCYTES:

  • can be distinguished by appearance of nuclei and contents of granules (confer traits, functions, staining properties)

• neutrophils (polymorphonuclear neutrophils/PMNs):

  • nucleus with 3-5 lobes and small, numerous, lilac coloured granules

    • each lobe is connected

• eosinophils: fewer lobes in nucleus (2-3) and larger granules that stain reddish/orange

• basophils

  • 2 red lobed nucleus and large granules that stain dark blue/purple

Natural Killer Cells

• mononuclear lymphocytes—> nonspecific mechanisms to recognize and destroy cells that are abnormal in some way

  • abnormal cells: cancer cells/infected cells