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Non-Specific Resistance

Non-Specific Resistance. First Line of Defense * External physical barriers * Chemical Defenses Second Line of Defense: * Leukocytes & Lymphatic System * Fever & Inflammatory Responses * Complement Cascade Response * Interferon Responses.

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Non-Specific Resistance

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  1. Non-Specific Resistance First Line of Defense * External physical barriers * Chemical Defenses Second Line of Defense: * Leukocytes & Lymphatic System * Fever & Inflammatory Responses * Complement Cascade Response * Interferon Responses

  2. 1st - Line (external physical barriers and chemical defenses): • Intact Skin – low moisture; low pH; oily (sebum) residues inhibit microbes; desquamation (shed dead skin layers) • Conjunctiva (Eyes)(lacrimal apparatus) tear dilution and lysozyme • Outer Ear – antibacterial activity of waxes • Mucous membranes(gastrointestinal, genitourinary, respiratory) • Gastrointestinal: Saliva (swallowing, lysozyme, antibodies); stomach acids; intestinal mucus with antibacterial substances and antibodies) • Genitourinary: Low pH and high salt of urine flush urinary tract; acidic vagina; lysozyme in seminal fluids) • Respiratory: nasal hairs; nasal passages; ciliated epithelium (escalator); clearing/coughing; alveoli macrophage. • Normal flora (bacterial antagonism) - harmless bacteria compete with pathogens and may produce bacteriocins.

  3. (Mucus producers)

  4. 2nd –Line (generalized internal cellular and chemical defense): • White Blood Cells = Leukocytes • Granulocytes are polymorphonuclear (PMN) with intracellular granules that can be stained and seen by microscopy. All involved in non-specific resistance. • Neutrophils: highly phagocytic and microbicidal; 60-70% all leukocytes; will travel from blood to infected tissues via chemotaxis; live only days. • Basophils: release histamine, prostaglandins, serotinin, and leukotreins via degranularization; these stimulate vasodilation (permeability and dilation of capillaries) initiating the inflammation response; binding by IgE and/or complement protein C3b further stimulates release of these inflammatory mediators. • Eosinophils: mobile phagocyte; very antagonistic to multicellular parasite (worms).

  5. Origin of Cell Types in Blood and Lymph: Can release histimine.

  6. White Blood Cells = Leukocytes • Agranulocytes (monomorphonuclear; monocytes and lymphocytes) • Monocytes (mostly non-specific resistance) • Macrophage: highly phagocytic; high surface area of pseudopods; may be “wandering” in blood or “fixxed” in association with mucosal membranes of healthy tissues. • Dendritic cells: molecular pattern-associated receptors for detecting microorganisms; present antigens to T-cells. Located throughout lymph system, skin, and other tissues. • Lymphocytes: (involved in specific resistance) • B-cells: lymph system associated; specific clones recognize antigen and stimulate multiplication; some mature to antibody releasing plasma cells; others become a long living dormant population of “memory cells”. • T-cells: lymph system associated; involved in chemical communication and stimulation of B cell antibody production, and may become cytotoxic to kill infected cells. • {Natural Killer Cells: granular!; kill viral infected and tumor cells.}

  7. Lymphatic System Bone marrow is also the origin of undifferentiated lymphocytes. Some mature to B-cells in the bone marrow in adult humans. Others enter blood to thymus where they mature to T-cells and may become stored. Other T-cells and the B-cells travel to lymph nodes and spleen and become stored for months. Mast cells also mature in bone marrow and reside in connective tissues; release large stores of histamine upon injury and IgE or C5a binding; stimulates inflammation.

  8. Phagocytosis: It’s enhanced in neutrophils and macrophage by opsonization (phagocyte adhesion to antibodies and/or complement protein C3bbound to microbe).

  9. Fever as a Defense (Pyrogenic Response) • Phagocytic cells release IL-1 when exposed to endotoxins. • Hypothalmus resets temperature; resulting in blood vessel contraction, increased metabolic rate and shivering (raising body temperature). Skin stays cold; “the chills”. • When IL-1 levels drop off, hypothalmus resets to normal, heat-loss mechanism engage such as vasodilation and excessive sweating (“crisis”). • Higher temperatures increase rate of luekocyte production and maturation to T-cells and nuetrophils. Similarly, the rate of tissue repair is increased. Other fortuitous biochemical reactions are enhanced as well.

  10. Inflammation as a defense (Pyogenic Response) Any direct damage to host cells results in release of inflammatory mediators (IMs) and acidification that activates kallikrein protease to liberate bradykinin, which further stimulates release of IMs. Further damage by bacterial toxins enhances this effect. Histimine and bradykinin dilate & increase permeability of vessels increasing blood supply (redness), plasma release causing edema (swelling), clotting factor release (abscess isolates infection and toxin), and prostoglandin fires nerves creating a pain response.

  11. Capillary endothelial cells stimulated by IMs express selectins. Phagocytes slow and stick to endothelium, migrate via chemotaxis to sites adjacent to wound (high levels of IMs), attach by their integrins, and then emigrate from capillary. Phagocytosis of bacteria and damaged host cells results in reducing IMs commensurate with healing. Scabbing/healing

  12. Complement System A class of antimicrobial blood (serum) proteins that participate in foreign cell lysis, enhance inflammation and increase the effectiveness of phagocytosis. The system is activated by two mechanisms, each of which initiates a cascading sequence of interactions among complement proteins. Central is the C3 protein. Classic Pathway: Specific Resistance generates antibodies that bind to microbes; C1 protein is activated when bound to multiple antibodies; activation cleaves C2 & C4 whose “b” subunits bind to create a chimeric protein (C2b/C4b) that cleaves C3. Alternate Pathway: Low blood levels of C3b and protein factors B, D & P respond to foreign polysaccharides and endotoxins; results in cleaving more C3 protein.

  13. Complement System Summary Complement & Opsonization: C3b protein readily binds to Gram- outer membrane and “flags” these for phagocytosis.

  14. Complement and Inflammation Stimulation of Vasodilation: Both C3a and C5a bind to mast cells, basophils and platelets which induces degranularization and release of histamine and other IMs. Chemotaxis: C5a also functions as a chemotaxis attractant to bring more phagocytes to the infection site.

  15. Complement Cytolysis: “MAC attack” C3b protein cleaves C5, which initiates further cascading interaction among C5 – C9 proteins. The result is directed assembly of C9 proteins into a circular array that creates a transmembrane channel (pores) through which cytoplasmic contents of the bacterium leaks out, causing bacterial cell death.

  16. Interferons A class of antiviral proteins produced by viral infected cells. Their action is to prevent viral replication in adjacent uninfected host cells. Interferon (IFN) binding to host membrane stimulates intracellular antiviral proteins (AVPs) that defend against future infection.

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